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Chen H, Yu Y, Zhu S, Zhao J, Ma Y, Huang Z, Jiang H, Wei Q. Impact of metabolic and nutritional disorders on the synergy between radiotherapy and immunotherapy in non-small-cell lung cancer. BMC Cancer 2025; 25:948. [PMID: 40426072 PMCID: PMC12107745 DOI: 10.1186/s12885-025-14278-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Patient conditions including metabolic and nutritional status were reported to be prognostic or predictive biomarkers of anti-cancer treatment, while little attention has been paid to its association with the synergistic effect of radiotherapy (RT) and immune checkpoint inhibitors (ICIs). METHODS Metastatic non-small-cell lung cancer (mNSCLC) patients who received concurrent RT and ICIs between 2018 and 2023 were included in this study. In addition, mNSCLC patients treated with ICIs alone were enrolled to confirm the synergetic effect of RT and ICIs. Clinicopathological, metabolic and nutritional factors were collected to analyze their influence on progression-free survival (PFS), overall survival and abscopal control time. Abdominal CT was used to obtain body composition data including abdominal obesity and muscle mass. RESULTS A total of 96 mNSCLC patients who received RT concurrent with ICIs were included, and a synergistic effect of significantly improved PFS was observed when compared with patients treated with ICIs alone. Among patients undergoing concurrent RT and ICIs, both total adipose area(HR = 2.81,P = 0.029) and prognosis nutritional index (HR = 0.24, P<0.001) were confirmed as independent positive prognostic markers for PFS. Later-line of immunotherapy (HR = 3.67, P = 0.006), low visceral-to-subcutaneous ratio (VSR, HR = 5.53, P = 0.002), high total adipose area (HR = 5.21, P = 0.0016) and high prognostic nutritional index (HR = 0.24, P = 0.002) were independent risk factors for abscopal progression. Then, we established a scoring system consisting of metabolic and nutritional factors to stratify patients into three groups. Patients with non-visceral obesity and good nutrition status have the longest PFS and abscopal control survival, while patients with poor nutritional status regardless of body composition represent the worst prognosis. CONCLUSION Metabolic and nutritional status, particularly the combined assessment of body composition and nutritional index, serves as a valuable predictor for the synergistic efficacy of concurrent RT and ICIs.
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Affiliation(s)
- Haiyan Chen
- Department of Radiation Oncology Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
- Cancer Institute Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China
- Zhejiang Provincial Clinical Research Center for CANCER Cancer Center of Zhejiang University, Hangzhou, China
- Anhui Campus of the Second Affiliated Hospital, Zhejiang University School of Medicine, Bengbu, 233000, China
| | - Yaner Yu
- Department of Radiation Oncology Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China.
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China.
- Cancer Institute Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China.
- Zhejiang Provincial Clinical Research Center for CANCER Cancer Center of Zhejiang University, Hangzhou, China.
| | - Shuangqiu Zhu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China
| | - Jian Zhao
- Department of Radiation Oncology Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China
| | - Yan Ma
- Department of Radiation Oncology Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Zhifei Huang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China
| | - Hao Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China.
| | - Qichun Wei
- Department of Radiation Oncology Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China.
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China.
- Cancer Institute Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang Province, China.
- Zhejiang Provincial Clinical Research Center for CANCER Cancer Center of Zhejiang University, Hangzhou, China.
- Anhui Campus of the Second Affiliated Hospital, Zhejiang University School of Medicine, Bengbu, 233000, China.
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Liu Y, Yu Z, Wang X, Yuan MQ, Lu MJ, Gong MR, Li Q, Xia YB, Yang GH, Xu B, Litscher G, Xu TC. Neurophysiological mechanisms of electroacupuncture in regulating pancreatic function and adipose tissue expansion. World J Diabetes 2025; 16. [DOI: doi：10.4239/wjd.v16.i5.101354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND
Electroacupuncture (EA) has been recognized for its beneficial effects on glucolipid metabolism, potentially through the regulation of sensory nerve coordination. The expandability of peripancreatic adipose tissue (PAT) is implicated in the transition from obesity to type 2 diabetes mellitus (T2DM). However, the specific pancreatic responses to EA require further elucidation.
AIM
To investigate the influence of EA on pancreatic glucolipid reduction level in a high-fat diet (HFD) rat model.
METHODS
To delineate the precise pathway through which EA mediates interactions between PAT and islets, we assessed the expression levels of NGF, TRPV1, insulin, as well as other proteins in the pancreas and PAT. This approach enabled us to identify the acupoints that are most conducive to optimizing glycolipid metabolism.
RESULTS
The ST25, LI11 and ST37 groups attenuated HFD-induced obesity and insulin resistance (IR) to distinct degrees, with ST25 group having the greatest effect. EA at ST25 was found to modify the local regulatory influence of PAT on the pancreatic intrinsic nervous system. Specifically, EA at ST25 obviously activated the TRPV1-CGRP-islet beta cell pathway, contributing to the relief of glucolipid metabolic stress. The beneficial effects were abrogated following the chemical silencing of TRPV1 sensory afferents, confirming their indispensable role in EA-mediated regulation of islet and PAT function. Furthermore, in TRPV1 knockout mice, a reduction in PAT inflammation was observed, along with the recovery of islet beta cell function. EA at LI11 and ST37 demonstrated anti-inflammatory properties and helped ameliorate IR.
CONCLUSION
The PAT ecological niche influenced the progression from obesity to T2DM through various immunometabolic pathways. EA at ST25 could regulate glucolipid metabolism via the TRPV1-CGRP-islet beta cell pathway.
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Liu Y, Yu Z, Wang X, Yuan MQ, Lu MJ, Gong MR, Li Q, Xia YB, Yang GH, Xu B, Litscher G, Xu TC. Neurophysiological mechanisms of electroacupuncture in regulating pancreatic function and adipose tissue expansion. World J Diabetes 2025; 16:101354. [DOI: 10.4239/wjd.v16.i5.101354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 02/12/2025] [Accepted: 03/14/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Electroacupuncture (EA) has been recognized for its beneficial effects on glucolipid metabolism, potentially through the regulation of sensory nerve coordination. The expandability of peripancreatic adipose tissue (PAT) is implicated in the transition from obesity to type 2 diabetes mellitus (T2DM). However, the specific pancreatic responses to EA require further elucidation.
AIM To investigate the influence of EA on pancreatic glucolipid reduction level in a high-fat diet (HFD) rat model.
METHODS To delineate the precise pathway through which EA mediates interactions between PAT and islets, we assessed the expression levels of NGF, TRPV1, insulin, as well as other proteins in the pancreas and PAT. This approach enabled us to identify the acupoints that are most conducive to optimizing glycolipid metabolism.
RESULTS The ST25, LI11 and ST37 groups attenuated HFD-induced obesity and insulin resistance (IR) to distinct degrees, with ST25 group having the greatest effect. EA at ST25 was found to modify the local regulatory influence of PAT on the pancreatic intrinsic nervous system. Specifically, EA at ST25 obviously activated the TRPV1-CGRP-islet beta cell pathway, contributing to the relief of glucolipid metabolic stress. The beneficial effects were abrogated following the chemical silencing of TRPV1 sensory afferents, confirming their indispensable role in EA-mediated regulation of islet and PAT function. Furthermore, in TRPV1 knockout mice, a reduction in PAT inflammation was observed, along with the recovery of islet beta cell function. EA at LI11 and ST37 demonstrated anti-inflammatory properties and helped ameliorate IR.
CONCLUSION The PAT ecological niche influenced the progression from obesity to T2DM through various immunometabolic pathways. EA at ST25 could regulate glucolipid metabolism via the TRPV1-CGRP-islet beta cell pathway.
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Affiliation(s)
- Yun Liu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zhi Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Xuan Wang
- College of Traditional Chinese Medicine, Jiangsu Vocational College of Medicine, Yancheng 224000, Jiangsu Province, China
| | - Ming-Qian Yuan
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Meng-Jiang Lu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Mei-Rong Gong
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Qian Li
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - You-Bing Xia
- Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Guan-Hu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH 45701, United States
| | - Bin Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Gerhard Litscher
- High-Tech Acupuncture and Digital Chinese Medicine, Swiss University of Traditional Chinese Medicine, Bad Zurzach 5530, Switzerland
| | - Tian-Cheng Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Shen LL, Zheng HL, Zheng ZW, Xu BB, Xue Z, Jia-Lin, Chen QY, Xie JW, Li P, Huang CM, Lin JX, Zheng CH. Paradoxical effects of adiposity and inflammation on immunotherapy efficacy in gastric cancer: novel insights from real-world data. Gastric Cancer 2025:10.1007/s10120-025-01622-w. [PMID: 40350511 DOI: 10.1007/s10120-025-01622-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Emerging studies suggest obesity may improve PD-1/PD-L1 inhibitor efficacy, correlating with prolonged survival, known as the 'obesity paradox'. However, the impact of this paradox and obesity-related chronic inflammation on immunotherapy for advanced gastric cancer (AGC) has not received sufficient research. METHODS Between January 2018 and December 2021, patients receiving neoadjuvant therapy were categorized into two groups: combined immunotherapy (ICIs, n = 173) and neoadjuvant chemotherapy (NAC, n = 126). Visceral (VATI) and subcutaneous adipose tissue index (SATI) were obtained from pre-treatment CT images. The systemic immune-inflammation index (SII) was calculated as platelet count multiplied by the neutrophil-to-lymphocyte ratio. RESULTS The median age of patients was 64 years (IQR 56-69), with 219 (73.2%) males and 80 (26.8%) females. In the ICIs group, the VATI-High group showed significantly higher 3-year overall survival (OS) (p = 0.010) and disease-free survival (DFS) (p = 0.029). Similar results were observed in the SATI analysis (p < 0.05). Conversely, OS (p = 0.040) and DFS (p = 0.039) were significantly lower in the SII-High group. Both VATI and SATI were independent protective factors for OS and DFS, but the effect disappeared after adjustment for SII. SII was associated with poorer OS and DFS, even after adjustment for VATI and SATI. No significant differences were observed in the analysis of the NAC group. CONCLUSIONS Elevated adiposity indices (VATI/SATI) and low SII correlate with survival benefit in ICI-treated AGC patients, and importantly, this paradoxical survival benefit is dependent on SII status. In contrast, no such benefit is observed in chemotherapy-alone cohorts.
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Affiliation(s)
- Li-Li Shen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Hua-Long Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Zhi-Wei Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Bin-Bin Xu
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
- Department of Digestive Endoscopy, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
| | - Zhen Xue
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jia-Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xin Quan Road, 59, Fuzhou, 350001, Fujian, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
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de Medeiros Pires LV, de Barros Martins A, Trindade CMDO, Dos Santos Baleeiro R, Peixoto TG, Teixeira E Silva VL, de Castro Pinto KM, Guimarães Drummond E Silva F, Coelho DB, de Oliveira EC, Becker LK. Effects of combined gamma aminobutyric acid supplementation and exercise training on the body composition of women: A randomized double-blind trial. Clin Nutr ESPEN 2025; 68:81-87. [PMID: 40345658 DOI: 10.1016/j.clnesp.2025.04.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 04/21/2025] [Accepted: 04/30/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Preclinical and clinical investigations have revealed the metabolic health benefits of gamma-aminobutyric acid (GABA) supplementation. Exercise training is widely acknowledged for its positive effects on the health of individuals with obesity. OBJECTIVE To investigate the effects of combined GABA supplementation and exercise training on the body composition, nutritional intake, physical performance, and serum biomarkers of women with obesity. METHODS Twenty-six women with obesity were investigated in this randomized, double-blind, placebo-controlled trial. They received daily GABA (200 mg) supplementation for 90 days alongside exercise training (3 days/week). RESULTS For intragroup comparisons hand grip improved in both groups (placebo, p = 0.00276; GABA, p = 0.00012), while sit-up performance increased only in the GABA group (p = 0.00664). Body mass index (p = 0.01273) and waist circumference (p = 0.01393) decreased in the GABA group. In the placebo group, body mass (p = 0.02956), fat-free mass (p = 0.00344), and basal metabolic rate (BMR) (p = 0.00386) decreased, while body fat increased (p = 0.02666). There were no differences in daily macronutrient intake, BMR, body mass, body fat, fat mass, fat-free mass, hip circumference, waist-hip ratio, blood pressure, heart rate, or serum levels of glucose, triglycerides, leptin, resistin, chemokine (C-C motif) ligand 2, chemokine ligand 16, and growth hormone between groups. CONCLUSION GABA supplementation combined with exercise training enhanced physical performance, accompanied by modest improvements in body composition, with no adverse effects on nutritional, physiological, or blood serum parameters. STUDY REGISTRATION https://ensaiosclinicos.gov.br/rg/RBR-8t7h259.
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Affiliation(s)
| | - Adilson de Barros Martins
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil
| | | | | | - Thainá Gomes Peixoto
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil
| | | | | | | | - Daniel Barbosa Coelho
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil; Postgraduate Program in Biological Sciences/NUPEB, Federal University of Ouro Preto, Ouro Preto, Brazil; Physical Education Department, Physical Education School, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Emerson Cruz de Oliveira
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil; Postgraduate Program in Biological Sciences/NUPEB, Federal University of Ouro Preto, Ouro Preto, Brazil; Physical Education Department, Physical Education School, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Lenice Kappes Becker
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil; Postgraduate Program in Biological Sciences/NUPEB, Federal University of Ouro Preto, Ouro Preto, Brazil; Physical Education Department, Physical Education School, Federal University of Ouro Preto, Ouro Preto, Brazil.
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Jeon YG, Kim JB. The cellular basis for middle-age spread. Science 2025; 388:360. [PMID: 40273264 DOI: 10.1126/science.adx1198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
Age-specific adipocyte progenitors drive visceral adipose tissue expansion in middle age.
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Affiliation(s)
- Yong Geun Jeon
- National Leader Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Jae Bum Kim
- National Leader Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
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Song A, Huang Z, Chen J, Gong H, Yang C, Zhang Y, Jiang X, Zhu Z. Baseline and early changes in CT body composition can predict recurrence-free survival after radical gastrectomy: A sex-specific study. Eur J Radiol 2025; 183:111935. [PMID: 39848123 DOI: 10.1016/j.ejrad.2025.111935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/08/2025] [Accepted: 01/14/2025] [Indexed: 01/25/2025]
Abstract
OBJECTIVE This study aimed to explore the predictive value of baseline CT body composition and its early changes on recurrence-free survival (RFS) following radical gastrectomy, while also assessing potential sex-related differences. METHODS We conducted a retrospective analysis of gastric cancer (GC) patients with confirmed pathology from October 2019 to May 2023. All patients underwent preoperative and postoperative CT scans to assess visceral fat area (VFA), subcutaneous fat area (SFA), skeletal muscle area (SMA), and skeletal muscle density (SMD), along with calculating their respective rates of change. Multivariate Cox regression analyses were used to identify independent predictors of RFS in male and female patients separately, and nomogram models were subsequently developed. The models' predictive performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). RESULTS The study included 287 patients, consisting of 185 males and 102 females. At baseline, males had a lower subcutaneous adipose tissue index (SATI) but higher skeletal muscle index (SMI) and SMD compared to females (p＜0.001). Postoperatively, both SATI and visceral adipose tissue index (VATI) were significantly lower in both males and females than their corresponding preoperative values (p＜0.005). In males, SMI (HR = 0.442, p = 0.002), VATI (HR = 1.843, p = 0.018), lymphocyte (LYM) (HR = 0.486, p = 0.040), pathological T stage (HR = 3.004, p = 0.003), and postoperative complication (POC) (HR = 1.893, p = 0.014) were found to be independent predictors of RFS. In females, independent predictors of RFS included SMI (HR = 0.361, p = 0.013), SATI change rate (δSATI) (HR = 0.428, p = 0.024), albumin (ALB) (HR = 0.242, p = 0.003), CEA (HR = 5.418, p < 0.001), and POC (HR = 3.425, p < 0.001). The male-specific nomogram model demonstrated predictive accuracy for recurrence-free survival (RFS), with areas under the ROC curve (AUC) of 0.621, 0.783, and 0.796 at 1, 2, and 3 years, respectively. Similarly, the female-specific nomogram model achieved AUCs of 0.796, 0.836, and 0.783 at the corresponding time points. Calibration curves indicated a strong concordance between predicted and observed outcomes, while DCA validated the clinical utility of both models. Additionally, the models effectively stratified patients into low-risk and high-risk groups. CONCLUSION Sex differences were observed in the predictive value of CT body composition for RFS after gastrectomy. By incorporating CT body composition parameters and clinical indicators, sex-specific nomogram models were developed, demonstrating effective prediction of RFS in gastric cancer patients post-surgery.
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Affiliation(s)
- Anyi Song
- Department of Medical Imaging, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Zhaoheng Huang
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Jinghao Chen
- Department of Medical Imaging, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Haipeng Gong
- Jiangsu Province Nantong City Cancer Hospital, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Chunyan Yang
- Jiangsu Province Nantong City Cancer Hospital, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Yuan Zhang
- Jiangsu Province Nantong City Cancer Hospital, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Xuan Jiang
- Jiangsu Province Nantong City Cancer Hospital, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Zhengqi Zhu
- Jiangsu Province Nantong City Cancer Hospital, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
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Huang Z, Niu R, Xu Q, Zhang R, Hu W, Qin Y, Wang X, Xu Q, Xia Y, Fan Y, Lu C. Impact of Maternal BPA Exposure during Pregnancy on Obesity in Male Offspring: A Mechanistic Mouse Study of Adipose-Derived Exosomal miRNA. ENVIRONMENTAL HEALTH PERSPECTIVES 2025; 133:17011. [PMID: 39886984 PMCID: PMC11783688 DOI: 10.1289/ehp14888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 12/18/2024] [Accepted: 12/26/2024] [Indexed: 02/01/2025]
Abstract
BACKGROUND The widespread use of bisphenol A (BPA) has led to universal exposure among the population, raising concerns about its health effects. Epidemiological studies have linked environmentally relevant levels of BPA exposure to obesity. OBJECTIVES We aimed to uncover the complex mechanisms by which oral exposure during pregnancy with BPA affects the offspring. METHODS We conducted a two-stage mouse study. In stage 1, we gavaged dams with BPA at 0.05, 0.5, and 5 mg / kg per day during pregnancy, and we tracked the offspring's weight and diet to 12 wk of age. In stage 2, exosomes from BPA-exposed dams and offspring were injected into pregnant mice and 3-wk-old males, respectively, and the mice were observed up to 12 wk. We then sequenced exosomal microRNAs (miRNAs) in male offspring whose dams had been exposed to BPA during pregnancy and checked their expression in adipose, liver, and serum samples at weeks 3, 6, 9, and 12. Finally, we explored the functions of exosomes and exosomal miRNAs secreted by adipose-derived mesenchymal stem cells, and we investigated whether the exosomes and miRNAs they secreted could affect glucose uptake, triglyceride synthesis, and the expression of genes related to glucose and lipid metabolism in alpha mouse liver 12 cells. RESULTS Gavage of 0.05 mg / kg per day of BPA during pregnancy in dams led to obesity in male offspring mice, and injection of exosomes from male offspring with BPA exposure during pregnancy also induced similar outcomes in the next generation of male pups. Exosomal miRNA sequencing identified differentially expressed miRNAs associated with BPA-induced obesity in male offspring, revealing sustained high expression of miRNAs in adipose tissue and a gradual increase in the liver and serum over time. Further mechanistic studies showed that exosomes derived from BPA-treated adipose-derived stem cells reduced the expression of peroxisome proliferator-activated receptor-gamma and fibroblast growth factor 21, leading to impaired insulin signaling and lipid metabolism in hepatocytes. Overexpression of miR-124-3p in hepatocytes mimicked these effects; in contrast, knockdown of miR-124-3p or inhibition of exosome secretion reversed them. DISCUSSION The present study corroborates the regulatory function of adipose-derived exosomal miRNAs in obesity in male offspring mice resulting from BPA exposure during pregnancy. Exosomal miRNA may be a key and novel molecular biomarker in the adverse effects of chemical exposure during pregnancy. https://doi.org/10.1289/EHP14888.
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Affiliation(s)
- Zhenyao Huang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
| | - Rui Niu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qiaoqiao Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Rui Zhang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weiyue Hu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yufeng Qin
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinru Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qiujin Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Chinese Research Academy of Environmental Sciences, Beijing, China
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yun Fan
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chuncheng Lu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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9
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Maloum-Rami F, Cheung P, Antoni G, Jin Z, Eriksson O, Espes D. PET imaging of GABA A receptors in pancreatic islets by [ 11C]flumazenil. EJNMMI Res 2024; 14:122. [PMID: 39623212 PMCID: PMC11612099 DOI: 10.1186/s13550-024-01176-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 11/05/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by a progressive β-cell destruction. There are no clinically established methods for quantifying endocrine cells of the pancreas and current knowledge is almost exclusively based on autopsy material and functional measurements. Based on the expression of the γ-aminobutyric acid A receptors (GABAARs) in pancreatic islets and the fact that GABAAR agonists are being explored as treatment for T1D, we hypothesized that the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ) could serve as a marker of the endocrine mass of the pancreas. The in vivo uptake of [11C]FMZ in pig pancreas was evaluated by PET/CT, either tracer alone or after blockade of GABAAR by unlabeled flumazenil. The pancreatic binding of [11C]FMZ was investigated in vitro with frozen sections of pig pancreas as well as human organ donors, in addition to isolated mouse and human islets and exocrine preparations. The expression of GABAAR subunits in pig, human and mouse pancreas was explored by immunohistochemistry. RESULTS Strong specific in vivo uptake of [11C]FMZ was observed in the pig brain as expected, but in the pancreas the signal was moderate and only partially reduced by blockade. In vitro experiments revealed a positive but weak and variable binding of [11C]FMZ in islets compared to exocrine tissue in the mouse, pig and human pancreas. In pig and mouse pancreatic islets we identified the GABAAR subunits β2 and γ2 but not α2. In the human pancreas from non-diabetic donors, we have identified the α2, β2 (although weak) and γ2 subunits, whereas from a T2D donor the α2 subunit was missing. CONCLUSIONS Our findings suggest that [11C]FMZ bind to GABAARs in the islets, but not with a sufficient contrast or magnitude to be implemented as an in vivo PET marker for the endocrine mass of the pancreas. However, GABAARs with different subunits are widely expressed in the endocrine cells within the pancreas in pig, human and mouse. Hence, the GABAAR could still be a potential imaging target for the endocrine cells of the pancreas but would require tracers with higher affinity and selectivity for individual GABAAR subunits.
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Affiliation(s)
- Faïza Maloum-Rami
- Department of Medical Cell Biology, Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Box 571, 75123, Uppsala, Sweden
| | - Pierre Cheung
- Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds Väg 14C, 3Tr, 75183, Uppsala, Sweden
| | - Gunnar Antoni
- Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds Väg 14C, 3Tr, 75183, Uppsala, Sweden
- PET Center, Center for Medical Imaging, Uppsala University Hospital, Uppsala, Sweden
| | - Zhe Jin
- Department of Medical Cell Biology, Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Box 571, 75123, Uppsala, Sweden
| | - Olof Eriksson
- Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds Väg 14C, 3Tr, 75183, Uppsala, Sweden.
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
| | - Daniel Espes
- Department of Medical Cell Biology, Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Box 571, 75123, Uppsala, Sweden.
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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10
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Pak K, Santavirta S, Shin S, Nam HY, De Maeyer S, Nummenmaa L. Glucose metabolism and radiodensity of abdominal adipose tissue: A 5-year longitudinal study in a large PET cohort. Clin Endocrinol (Oxf) 2024; 101:623-630. [PMID: 39038172 DOI: 10.1111/cen.15121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/27/2024] [Accepted: 07/14/2024] [Indexed: 07/24/2024]
Abstract
OBJECTIVE 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) allows noninvasive assessment of glucose metabolism and radiodensity in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). We aimed to address the effects of ageing and metabolic factors on abdominal adipose tissue. DESIGN, PATIENTS AND MEASUREMENTS We retrospectively analyzed data from 435 healthy men (mean 42.8 years) who underwent a health check-up programme twice, at baseline and the 5-year follow-up. The mean standardized uptake value (SUV) was measured using SAT and VAT and divided by the liver SUV. The mean Hounsfield units (HU) of the SAT and VAT were measured from the CT scans. The effects of clinical variable clusters on SUVR were investigated using Bayesian hierarchical modelling; metabolic cluster (BMI, waist-to-hip ratio, fat percentage, muscle percentage*-1, HOMA-IR), blood pressure (systolic, diastolic), glucose (fasting plasma glucose level, HbA1c) and C-reactive protein. RESULTS All the clinical variables changed during the 5-year follow-up period. The SUVR and HU of the VAT increased during follow-up; however, those of the SAT did not change. SUVR and HU were positively correlated with both VAT and SAT. SAT and VAT SUVR were negatively associated with metabolic clusters. CONCLUSIONS Ageing led to increased glucose metabolism and radiodensity in VAT, but not in SAT. VAT may reflect the ageing process more directly than SAT. Glucose metabolism was higher and radiodensity was lower in VAT than in SAT, probably owing to differences in gene expression and lipid density. Both glucose metabolism and radiodensity of VAT and SAT reflect metabolic status.
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Affiliation(s)
- Kyoungjune Pak
- Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
- School of Medicine, Pusan National University, Busan, Republic of Korea
| | - Severi Santavirta
- Turku PET Centre, University of Turku, Turku, Finland
- Turku University Hospital, Turku, Finland
| | - Seunghyeon Shin
- Department of Nuclear Medicine, Samsung Changwon Hospital, School of Medicine, Sungkyunkwan University, Changwon, Republic of Korea
| | - Hyun-Yeol Nam
- Department of Nuclear Medicine, Samsung Changwon Hospital, School of Medicine, Sungkyunkwan University, Changwon, Republic of Korea
| | - Sven De Maeyer
- Department of Training and Education Sciences, Faculty of Social Sciences, University of Antwerp, Antwerp, Belgium
| | - Lauri Nummenmaa
- Turku PET Centre, University of Turku, Turku, Finland
- Turku University Hospital, Turku, Finland
- Department of Psychology, University of Turku, Turku, Finland
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11
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Mick GJ, McCormick KL. The role of GABA in type 1 diabetes. Front Endocrinol (Lausanne) 2024; 15:1453396. [PMID: 39619323 PMCID: PMC11604429 DOI: 10.3389/fendo.2024.1453396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 10/22/2024] [Indexed: 12/13/2024] Open
Abstract
Gamma aminobutyric acid (GABA) is synthesized from glutamate by glutamic decarboxylase (GAD). The entero-pancreatic biology of GABA, which is produced by pancreatic islets, GAD-expressing microbiota, enteric immune cells, or ingested through diet, supports an essential physiologic role of GABA in the health and disease. Outside the central nervous system (CNS), GABA is uniquely concentrated in pancreatic β-cells. They express GAD65, which is a type 1 diabetes (T1D) autoantigen. Glutamate constitutes 10% of the amino acids in dietary protein and is preeminently concentrated in human milk. GABA is enriched in many foods, such as tomato and fermented cheese, and is an over-the-counter supplement. Selected microbiota in the midgut have the enzymatic capacity to produce GABA. Intestinal microbiota interact with gut-associated lymphoid tissue to maintain host defenses and immune tolerance, which are implicated in autoimmune disease. Although GABA is a widely known inhibitory neurotransmitter, oral GABA does not cross the blood brain barrier. Three diabetes-related therapeutic actions are ascribed to GABA, namely, increasing pancreatic β-cell content, attenuating excess glucagon and tamping down T-cell immune destruction. These salutary actions have been observed in numerous rodent diabetes models that usually employed high or near-continuous GABA doses. Clinical studies, to date, have identified positive effects of oral GABA on peripheral blood mononuclear cell cytokine release and plasma glucagon. Going forward, it is reassuring that oral GABA therapy has been well-tolerated and devoid of serious adverse effects.
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Affiliation(s)
- Gail J. Mick
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
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12
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Wang FD, Ding Y, Zhou JH, Zhou E, Zhang TT, Fan YQ, He Q, Zhang ZQ, Mao CY, Zhang JF, Zhou J. Gamma-aminobutyric acid enhances miR-21-5p loading into adipose-derived stem cell extracellular vesicles to alleviate myocardial ischemia-reperfusion injury via TXNIP regulation. World J Stem Cells 2024; 16:873-895. [PMID: 39493825 PMCID: PMC11525649 DOI: 10.4252/wjsc.v16.i10.873] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/21/2024] [Accepted: 09/27/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Myocardial ischemia-reperfusion injury (MIRI) poses a prevalent challenge in current reperfusion therapies, with an absence of efficacious interventions to address the underlying causes. AIM To investigate whether the extracellular vesicles (EVs) secreted by adipose mesenchymal stem cells (ADSCs) derived from subcutaneous inguinal adipose tissue (IAT) under γ-aminobutyric acid (GABA) induction (GABA-EVsIAT) demonstrate a more pronounced inhibitory effect on mitochondrial oxidative stress and elucidate the underlying mechanisms. METHODS We investigated the potential protective effects of EVs derived from mouse ADSCs pretreated with GABA. We assessed cardiomyocyte injury using terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/propidium iodide assays. The integrity of cardiomyocyte mitochondria morphology was assessed using electron microscopy across various intervention backgrounds. To explore the functional RNA diversity between EVsIAT and GABA-EVsIAT, we employed microRNA (miR) sequencing. Through a dual-luciferase reporter assay, we confirmed the molecular mechanism by which EVs mediate thioredoxin-interacting protein (TXNIP). Western blotting and immunofluorescence were conducted to determine how TXNIP is involved in mediation of oxidative stress and mitochondrial dysfunction. RESULTS Our study demonstrates that, under the influence of GABA, ADSCs exhibit an increased capacity to encapsulate a higher abundance of miR-21-5p within EVs. Consequently, this leads to a more pronounced inhibitory effect on mitochondrial oxidative stress compared to EVs from ADSCs without GABA intervention, ultimately resulting in myocardial protection. On a molecular mechanism level, EVs regulate the expression of TXNIP and mitigating excessive oxidative stress in mitochondria during MIRI process to rescue cardiomyocytes. CONCLUSION Administration of GABA leads to the specific loading of miR-21-5p into EVs by ADSCs, thereby regulating the expression of TXNIP. The EVs derived from ADSCs treated with GABA effectively ameliorates mitochondrial oxidative stress and mitigates cardiomyocytes damage in the pathological process of MIRI.
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Affiliation(s)
- Feng-Dan Wang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yi Ding
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jian-Hong Zhou
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - En Zhou
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Tian-Tian Zhang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yu-Qi Fan
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Qing He
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Zong-Qi Zhang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Cheng-Yu Mao
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jun-Feng Zhang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jing Zhou
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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Nagao T, Braga JD, Chen S, Thongngam M, Chartkul M, Yanaka N, Kumrungsee T. Synergistic effects of peripheral GABA and GABA-transaminase inhibitory drugs on food intake control and weight loss in high-fat diet-induced obese mice. Front Pharmacol 2024; 15:1487585. [PMID: 39415835 PMCID: PMC11480068 DOI: 10.3389/fphar.2024.1487585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Background Developing anti-obesity interventions targeting appetite or food intake, the primary driver of obesity, remains challenging. Here, we demonstrated that dietary γ-aminobutyric acid (GABA) with GABA-degradation inhibitory drugs could be an anti-obesity intervention possessing strong food intake-suppressive and weight-loss effects. Methods High-fat (HF)-diet-induced obese mice were divided into six groups receiving either the HF diet or the 2% GABA-HF diet with daily administration of PBS or the GABA-degradation inhibitory drugs, vigabatrin and ethanolamine-O-sulfate (EOS). In 24-h fast-induced refeeding, lean mice with a basal diet were used, and food intake was measured from 0.5 to 24 h after refeeding. Results Coadministration of the 2% GABA-HF diet with vigabatrin or EOS significantly decreased food intake (-53%, -35%) and body weight (-22%, -16%) within 11 days in obese mice, along with a marked increase in plasma GABA levels. Mice receiving dietary GABA alone or the drugs alone exhibited no such effects. Hypothalamic GABA levels increased in drug-treated mice, regardless of diet. At 0.5 h after refeeding, food intake was similar in all groups. However, at 0.5 h, plasma GABA levels were markedly increased only in mice receiving coadministration of dietary GABA and the drugs, and their food intake was completely inhibited for over 6 h, while mice in other groups gradually increased their food intake. Conclusion Combining dietary GABA with GABA-degradation inhibitory drugs effectively suppresses food intake and promotes weight loss in obese mice, primarily through increased plasma GABA availability. These findings may advance the development of food intake-controlling strategies for obesity management.
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Affiliation(s)
- Tomoka Nagao
- Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Jason D. Braga
- Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Institute of Food Science and Technology, College of Agriculture, Food, Environment and Natural Resources, Cavite State University, Indang, Philippines
| | - Siyi Chen
- Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Masubon Thongngam
- Department of Food Science and Technology, Faculty of Agro-Industry, Kasetsart University, Bangkok, Thailand
| | - Maesaya Chartkul
- Weight Care Clinic, Health Promotion Center, Bangkok Chanthaburi Hospital, Chanthaburi, Thailand
| | - Noriyuki Yanaka
- Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Thanutchaporn Kumrungsee
- Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Smart Agriculture, Graduate School of Innovation and Practice for Smart Society, Hiroshima University, Hiroshima, Japan
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14
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Kumrungsee T. Is hepatic GABA transaminase a promising target for obesity and epilepsy treatments? Biosci Biotechnol Biochem 2024; 88:839-849. [PMID: 38749549 DOI: 10.1093/bbb/zbae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 05/05/2024] [Indexed: 07/23/2024]
Abstract
γ-Aminobutyric acid (GABA) transaminase (GABA-T) is a GABA-degrading enzyme that plays an essential role in regulating GABA levels and maintaining supplies of GABA. Although GABA in the mammalian brain was discovered 70 years ago, research on GABA and GABA-T has predominantly focused on the brain. Notwithstanding the high activity and expression of GABA-T in the liver, the exact functions of GABA-T in the liver remain unknown. This article reviews the up-to-date information on GABA-T in the liver. It presents recent findings on the role of liver GABA-T in food intake suppression and appetite regulation. Finally, the potential functions of liver GABA-T in other neurological diseases, natural GABA-T inhibitors, and future perspectives in this research area are discussed.
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Affiliation(s)
- Thanutchaporn Kumrungsee
- Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Smart Agriculture, Graduate School of Innovation and Practice for Smart Society, Hiroshima University, Hiroshima, Japan
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15
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Ren L, Xuan L, Li A, Yang Y, Zhang W, Zhang J, Zhang Y, An Z. Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue. Diabetes Obes Metab 2024; 26:2695-2705. [PMID: 38660748 DOI: 10.1111/dom.15585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/08/2024] [Accepted: 03/19/2024] [Indexed: 04/26/2024]
Abstract
AIMS To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. RESULTS We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. CONCLUSIONS These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.
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Affiliation(s)
- Lulu Ren
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lingling Xuan
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Anning Li
- Beijing Anding Hospital, Capital Medical University, Beijing, China
- National Medical Center for Mental Disorders, Beijing, China
| | - Yaqi Yang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Wen Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jie Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yi Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhuoling An
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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16
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Zheng T, Li S, Zhang T, Fu W, Liu S, He Y, Wang X, Ma T. Exosome-shuttled miR-150-5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis. Front Immunol 2024; 15:1397722. [PMID: 38957471 PMCID: PMC11217356 DOI: 10.3389/fimmu.2024.1397722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/04/2024] [Indexed: 07/04/2024] Open
Abstract
Rationale Sepsis is a life-threatening organ dysfunction and lack of effective measures in the current. Exosomes from mesenchymal stem cells (MSCs) reported to alleviate inflammation during sepsis, and the preconditioning of MSCs could enhance their paracrine potential. Therefore, this study investigated whether exosomes secreted by lipopolysaccharide (LPS)-pretreated MSCs exert superior antiseptic effects, and explored the underlying molecular mechanisms. Methods Exosomes were isolated and characterized from the supernatants of MSCs. The therapeutic efficacy of normal exosomes (Exo) and LPS-pretreated exosomes (LPS-Exo) were evaluated in terms of survival rates, inflammatory response, and organ damage in an LPS-induced sepsis model. Macrophages were stimulated with LPS and treated with Exo or LPS-Exo to confirm the results of the in vivo studies, and to explain the potential mechanisms. Results LPS-Exo were shown to inhibit aberrant pro-inflammatory cytokines, prevent organ damages, and improve survival rates of the septic mice to a greater extent than Exo. In vitro, LPS-Exo significantly promoted the M2 polarization of macrophages exposed to inflammation. miRNA sequencing and qRT-PCR analysis identified the remarkable expression of miR-150-5p in LPS-Exo compared to that in Exo, and exosomal miR-150-5p was transferred into recipient macrophages and mediated macrophage polarization. Further investigation demonstrated that miR-150-5p targets Irs1 in recipient macrophages and subsequently modulates macrophage plasticity by down-regulating the PI3K/Akt/mTOR pathway. Conclusion The current findings highly suggest that exosomes derived from LPS pre-conditioned MSCs represent a promising cell-free therapeutic method and highlight miR-150-5p as a novel molecular target for regulating immune hyperactivation during sepsis.
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Affiliation(s)
- Ting Zheng
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Sipeng Li
- Department of Orthopedics, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Teng Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Shuchang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuxin He
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Tao Ma
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
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Wang J, Zhang H, Yuan H, Chen S, Yu Y, Zhang X, Gao Z, Du H, Li W, Wang Y, Xia P, Wang J, Song M. Prophylactic Supplementation with Lactobacillus Reuteri or Its Metabolite GABA Protects Against Acute Ischemic Cardiac Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2307233. [PMID: 38487926 PMCID: PMC11095141 DOI: 10.1002/advs.202307233] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/06/2023] [Indexed: 05/16/2024]
Abstract
The gut microbiome has emerged as a potential target for the treatment of cardiovascular disease. Ischemia/reperfusion (I/R) after myocardial infarction is a serious complication and whether certain gut bacteria can serve as a treatment option remains unclear. Lactobacillus reuteri (L. reuteri) is a well-studied probiotic that can colonize mammals including humans with known cholesterol-lowering properties and anti-inflammatory effects. Here, the prophylactic cardioprotective effects of L. reuteri or its metabolite γ-aminobutyric acid (GABA) against acute ischemic cardiac injury caused by I/R surgery are demonstrated. The prophylactic gavage of L. reuteri or GABA confers cardioprotection mainly by suppressing cardiac inflammation upon I/R. Mechanistically, GABA gavage results in a decreased number of proinflammatory macrophages in I/R hearts and GABA gavage no longer confers any cardioprotection in I/R hearts upon the clearance of macrophages. In vitro studies with LPS-stimulated bone marrow-derived macrophages (BMDM) further reveal that GABA inhibits the polarization of macrophages toward the proinflammatory M1 phenotype by inhibiting lysosomal leakage and NLRP3 inflammasome activation. Together, this study demonstrates that the prophylactic oral administration of L. reuteri or its metabolite GABA attenuates macrophage-mediated cardiac inflammation and therefore alleviates cardiac dysfunction after I/R, thus providing a new prophylactic strategy to mitigate acute ischemic cardiac injury.
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Affiliation(s)
- Jiawan Wang
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
- Beijing Chao‐Yang HospitalDepartment of AnesthesiologyBeijing100020China
| | - Hao Zhang
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Hailong Yuan
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
- Joint National Laboratory for Antibody Drug EngineeringHenan UniversityKaifeng475004China
| | - Siqi Chen
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Ying Yu
- University of Chinese Academy of SciencesBeijing100049China
- CAS Key Laboratory of Pathogenic Microbiology and ImmunologyChinese Academy of SciencesBeijing100101China
| | - Xuan Zhang
- CAS Key Laboratory of Pathogenic Microbiology and ImmunologyChinese Academy of SciencesBeijing100101China
| | - Zeyu Gao
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
| | - Heng Du
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Weitao Li
- Department of ImmunologySchool of Basic Medical SciencesPeking UniversityBeijing100191China
| | - Yaohui Wang
- Joint National Laboratory for Antibody Drug EngineeringHenan UniversityKaifeng475004China
| | - Pengyan Xia
- Department of ImmunologySchool of Basic Medical SciencesPeking UniversityBeijing100191China
| | - Jun Wang
- University of Chinese Academy of SciencesBeijing100049China
- CAS Key Laboratory of Pathogenic Microbiology and ImmunologyChinese Academy of SciencesBeijing100101China
| | - Moshi Song
- State Key Laboratory of Membrane BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
- Beijing Institute for Stem Cell and Regenerative MedicineBeijing100101China
- Key Laboratory of Organ Regeneration and ReconstructionChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
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18
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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19
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Yong GJM, Porsche CE, Sitarik AR, Fujimura KE, McCauley K, Nguyen DT, Levin AM, Woodcroft KJ, Ownby DR, Rundle AG, Johnson CC, Cassidy-Bushrow A, Lynch SV. Precocious infant fecal microbiome promotes enterocyte barrier dysfuction, altered neuroendocrine signaling and associates with increased childhood obesity risk. Gut Microbes 2024; 16:2290661. [PMID: 38117587 PMCID: PMC10761186 DOI: 10.1080/19490976.2023.2290661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/29/2023] [Indexed: 12/22/2023] Open
Abstract
Early life gut microbiome composition has been correlated with childhood obesity, though microbial functional contributions to disease origins remain unclear. Here, using an infant birth cohort (n = 349) we identify a distinct fecal microbiota composition in 1-month-old infants with the lowest rate of exclusive breastfeeding, that relates with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant fecal microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to fecal extracts from higher-risk infants led to upregulation of genes associated with obesity and with expansion of nutrient sensing enteroendocrine progenitor cells. Fecal extracts from higher-risk infants also promoted enterocyte barrier dysfunction. These data implicate dysregulation of infant microbiome functional development, and more specifically promotion of enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.
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Affiliation(s)
- Germaine J. M. Yong
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
- Asian Microbiome Library Pte Ltd, Singapore and Singapore Institute of Food and Biotechnology Innovation, Singapore, Singapore
| | - Cara E. Porsche
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Alexandra R. Sitarik
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA
| | - Kei E. Fujimura
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
- Genetic Disease Laboratory, California Department of Public Health, San Francisco, CA, USA
| | - Kathryn McCauley
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Dat T. Nguyen
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Albert M. Levin
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA
| | | | - Dennis R. Ownby
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Augusta University, Augusta, GA, USA
| | - Andrew G. Rundle
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Christine C. Johnson
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA
| | | | - Susan V. Lynch
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
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20
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Wang D, Deng Y, Zhao L, Wang K, Wu D, Hu Z, Liu X. GABA and fermented litchi juice enriched with GABA promote the beneficial effects in ameliorating obesity by regulating the gut microbiota in HFD-induced mice. Food Funct 2023; 14:8170-8185. [PMID: 37466048 DOI: 10.1039/d2fo04038g] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Gamma-aminobutyric acid (GABA) dietary intervention is considered to have therapeutic potential against obesity. Microbial enrichment is an effective strategy to naturally and safely enhance GABA production in food. As litchi is "the king of GABA" in fruits, the retention or enrichment of its content during processing has been a key issue in the litchi industry. This study aimed to investigate the potential of GABA and fermented litchi juice enriched with GABA (FLJ) to protect against obesity in a high-fat diet (HFD) mouse model. Supplementation of GABA and FLJ displayed an anti-obesogenic effect by attenuating body weight gain, fat accumulation, and oxidative damage, and improving the serum lipid profile and hepatic function. Sequencing (16S rRNA) of fecal samples indicated that GABA and FLJ intervention displayed different regulatory effects on HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as the F/B ratio of GABA and FLJ groups were reversed compared to those of the HFD-induced mice. Our finding broadens the potential mechanisms by which GABA regulates gut flora in the amelioration of obesity and provides guidance for developing FLJ as a functional food to prevent obesity.
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Affiliation(s)
- Dongwei Wang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China.
| | - Yani Deng
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China.
| | - Lei Zhao
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China.
| | - Kai Wang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China.
| | - Dongmei Wu
- College of Biosystem Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
| | - Zhuoyan Hu
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China.
| | - Xuwei Liu
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China.
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21
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He M, Chen ZF, Zhang L, Gao X, Chong X, Li HS, Shen L, Ji J, Zhang X, Dong B, Li ZY, Lei T. Associations of subcutaneous fat area and Systemic Immune-inflammation Index with survival in patients with advanced gastric cancer receiving dual PD-1 and HER2 blockade. J Immunother Cancer 2023; 11:e007054. [PMID: 37349127 PMCID: PMC10314655 DOI: 10.1136/jitc-2023-007054] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Systemic Immune-inflammation Index (SII) and body composition parameters are easily assessed, and can predict overall survival (OS) in various cancers, allowing early intervention. This study aimed to assess the correlation between CT-derived body composition parameters and SII and OS in patients with advanced gastric cancer receiving dual programmed death-1 (PD-1) and human epidermal growth factor receptor 2 (HER2) blockade. MATERIALS AND METHODS This retrospective study enrolled patients with advanced gastric cancer treated with dual PD-1 and HER2 blockade from March 2019 to June 2022. We developed a deep learning model based on nnU-Net to automatically segment skeletal muscle, subcutaneous fat and visceral fat at the third lumbar level, and calculated the corresponding Skeletal Muscle Index, skeletal muscle density, subcutaneous fat area (SFA) and visceral fat area. SII was computed using the formula that total peripheral platelet count×neutrophil/lymphocyte ratio. Univariate and multivariate Cox regression analysis were used to determine the associations between SII, body composition parameters and OS. RESULTS The automatic segmentation deep learning model was developed to efficiently segment body composition in 158 patients (0.23 s/image). Multivariate Cox analysis revealed that high SII (HR=2.49 (95% CI 1.54 to 4.01), p<0.001) and high SFA (HR=0.42 (95% CI 0.24 to 0.73), p=0.002) were independently associated with OS, whereas sarcopenia was not an independent prognostic factor for OS (HR=1.41 (95% CI 0.86 to 2.31), p=0.173). In further analysis, patients with high SII and low SFA had worse long-term prognosis compared with those with low SII and high SFA (HR=8.19 (95% CI 3.91 to 17.16), p<0.001). CONCLUSION Pretreatment SFA and SII were significantly associated with OS in patients with advanced gastric cancer. A comprehensive analysis of SII and SFA may improve the prognostic stratification of patients with gastric cancer receiving dual PD-1 and HER2 blockade.
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Affiliation(s)
- Meng He
- Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China
| | - Zi-Fan Chen
- Center for Data Science, Peking University, Beijing, China
| | - Li Zhang
- Center for Data Science, Peking University, Beijing, China
| | - Xiangyu Gao
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China
| | - Xiaoyi Chong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Hao-Shen Li
- Center for Data Science, Peking University, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Bin Dong
- Beijing International Center for Mathematical Research, Peking University; Center for Machine Learning Research, Peking University; National Biomedical Imaging Center, Peking University, Beijing, China
| | - Zi-Yu Li
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China
| | - Tang Lei
- Department of Radiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China
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22
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Kim K, Yoon H. Gamma-Aminobutyric Acid Signaling in Damage Response, Metabolism, and Disease. Int J Mol Sci 2023; 24:ijms24054584. [PMID: 36902014 PMCID: PMC10003236 DOI: 10.3390/ijms24054584] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/03/2023] Open
Abstract
Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we will discuss recent advances in understanding GABA metabolism with a focus on its biosynthesis and cellular functions in other organs. The mechanisms of GABA in liver biology and disease have revealed new ways to link the biosynthesis of GABA to its cellular function. By reviewing what is known about the distinct effects of GABA and GABA-mediated metabolites in physiological pathways, we provide a framework for understanding newly identified targets regulating the damage response, with implications for ameliorating metabolic diseases. With this review, we suggest that further research is necessary to develop GABA's beneficial and toxic effects on metabolic disease progression.
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23
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Behan-Bush R, Liszewski JN, Schrodt MV, Vats B, Li X, Lehmler HJ, Klingelhutz AJ, Ankrum JA. Toxicity Impacts on Human Adipose Mesenchymal Stem/Stromal Cells Acutely Exposed to Aroclor and Non-Aroclor Mixtures of Polychlorinated Biphenyl. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:1731-1742. [PMID: 36651682 PMCID: PMC9893815 DOI: 10.1021/acs.est.2c07281] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/06/2023] [Accepted: 01/06/2023] [Indexed: 06/17/2023]
Abstract
Polychlorinated biphenyl (PCB) accumulates in adipose where it may impact the growth and function of cells within the tissue. This is particularly concerning during adolescence when adipocytes expand rapidly. Herein, we sought to understand how exposure to PCB mixtures found in U.S. schools affects human adipose mesenchymal stem/stromal cell (MSC) health and function. We investigated how exposure to Aroclor 1016 and Aroclor 1254, as well as a newly characterized non-Aroclor mixture that resembles the PCB profile found in cabinets, Cabinet Mixture, affects adipose MSC growth, viability, and function in vitro. We found that exposure to all three mixtures resulted in two distinct types of toxicity. At PCB concentrations >20 μM, the majority of MSCs die, while at 1-10 μM, MSCs remained viable but display numerous alterations to their phenotype. At these sublethal concentrations, the MSC rate of expansion slowed and morphology changed. Further assessment revealed that PCB-exposed MSCs had impaired adipogenesis and a modest decrease in immunosuppressive capabilities. Thus, exposure to PCB mixtures found in schools negatively impacts the health and function of adipose MSCs. This work has implications for human health due to MSCs' role in supporting the growth and maintenance of adipose tissue.
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Affiliation(s)
- Riley
M. Behan-Bush
- Roy
J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242, United States
- Fraternal
Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, United States
| | - Jesse N. Liszewski
- Roy
J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242, United States
- Fraternal
Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, United States
| | - Michael V. Schrodt
- Roy
J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242, United States
- Fraternal
Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, United States
| | - Bhavya Vats
- Roy
J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242, United States
| | - Xueshu Li
- Department
of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242, United States
| | - Hans-Joachim Lehmler
- Department
of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242, United States
| | - Aloysius J. Klingelhutz
- Fraternal
Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, United States
- Department
of Microbiology and Immunology, University
of Iowa, Iowa City, Iowa 52242, United States
| | - James A. Ankrum
- Roy
J. Carver Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242, United States
- Fraternal
Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, United States
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24
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Secreted immune metabolites that mediate immune cell communication and function. Trends Immunol 2022; 43:990-1005. [PMID: 36347788 DOI: 10.1016/j.it.2022.10.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
Metabolites are emerging as essential factors for the immune system that are involved in both metabolic circuits and signaling cascades. Accumulated evidence suggests that altered metabolic programs initiated by the activation and maturation of immune cell types are accompanied by the delivery of various metabolites into the local environment. We propose that, in addition to protein/peptide ligands, secreted immune metabolites (SIMets) are essential components of immune communication networks that fine-tune immune responses under homeostatic and pathological conditions. We summarize recent advances in our understanding of SIMets and discuss the potential mechanisms by which some metabolites engage in immunological responses through receptor-, transporter-, and post-translational-mediated regulation. These insights may contribute to understanding physiology and developing effective therapeutics for inflammatory and immune-mediated diseases.
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25
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Chen Q, Gao Y, Yang F, Deng H, Wang Y, Yuan L. Angiotensin-converting enzyme 2 improves hepatic insulin resistance by regulating GABAergic signaling in the liver. J Biol Chem 2022; 298:102603. [PMID: 36265585 PMCID: PMC9668738 DOI: 10.1016/j.jbc.2022.102603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 10/07/2022] [Accepted: 10/10/2022] [Indexed: 11/07/2022] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7/MAS axis and the gamma-aminobutyric acid (GABA)ergic signaling system have both been shown to have the dual potential to improve insulin resistance (IR) and hepatic steatosis associated with obesity in the liver. Recent studies have demonstrated that ACE2 can regulate the GABA signal in various tissues. Notwithstanding this evidence, the functional relationship between ACE2 and GABA signal in the liver under IR remains elusive. Here, we used high-fat diet-induced models of IR in C57BL/6 mice as well as ACE2KO and adeno-associated virus-mediated ACE2 overexpression mouse models to address this knowledge gap. Our analysis showed that glutamate decarboxylase (GAD)67/GABA signaling was weakened in the liver during IR, whereas the expression of GAD67 and GABA decreased significantly in ACE2KO mice. Furthermore, exogenous administration of angiotensin 1-7 and adeno-associated virus- or lentivirus-mediated overexpression of ACE2 significantly increased hepatic GABA signaling in models of IR both in vivo and in vitro. We found that this treatment prevented lipid accumulation and promoted fatty acid β oxidation in hepatocytes as well as inhibited the expression of gluconeogenesis- and inflammation-related genes, which could be reversed by allylglycine, a specific GAD67 inhibitor. Collectively, our findings show that signaling via the ACE2/A1-7/MAS axis can improve hepatic IR by regulating hepatic GABA signaling. We propose that this research might indicate a potential strategy for the management of diabetes.
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26
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Lactic Acid Bacteria in Raw-Milk Cheeses: From Starter Cultures to Probiotic Functions. Foods 2022; 11:foods11152276. [PMID: 35954043 PMCID: PMC9368153 DOI: 10.3390/foods11152276] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/15/2022] [Accepted: 07/25/2022] [Indexed: 12/04/2022] Open
Abstract
Traditional cheeses produced from raw milk exhibit a complex microbiota, characterized by a sequence of different microorganisms from milk coagulation and throughout maturation. Lactic acid bacteria (LAB) play an essential role in traditional cheese making, either as starter cultures that cause the rapid acidification of milk or as secondary microbiota that play an important role during cheese ripening. The enzymes produced by such dynamic LAB communities in raw milk are crucial, since they support proteolysis and lipolysis as chief drivers of flavor and texture of cheese. Recently, several LAB species have been characterized and used as probiotics that successfully promote human health. This review highlights the latest trends encompassing LAB acting in traditional raw milk cheeses (from cow, sheep, and goat milk), and their potential as probiotics and producers of bioactive compounds with health-promoting effects.
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27
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Choi M, Mukherjee S, Yun JW. Colchicine stimulates browning via antagonism of GABA receptor B and agonism of β3-adrenergic receptor in 3T3-L1 white adipocytes. Mol Cell Endocrinol 2022; 552:111677. [PMID: 35598717 DOI: 10.1016/j.mce.2022.111677] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 11/20/2022]
Abstract
Colchicine has been used for therapeutic purposes and has attracted considerable attention because of its association with tubulin and the inhibition of small tubular polymerization. Although several studies have examined the possible preventive role of colchicine in metabolic diseases, its role in adipocytes is largely unknown. This study examined the novel functional role of colchicine in adipocytes demonstrating that colchicine stimulates browning in cultured white adipocytes. Colchicine stimulates browning by increasing the brown- and beige fat-specific markers in 3T3-L1 white adipocytes. Interestingly, colchicine decreased the expression of the main lipolytic proteins (ATGL, p-HSL) while it activated Ces3, suggesting a possibility for supplying essential fatty acids for inducing thermogenesis. Molecular docking analysis showed that colchicine has a strong affinity against GABA-BR and β3-AR, and its binding activity with GABA-BR (-26.52 kJ/mol) was stronger than β3-AR (-20.71 kJ/mol). Mechanistic studies were conducted by treating the cells separately with agonists and antagonists of GABA-BR and β3-AR to understand the molecular mechanism underlying the browning effect of colchicine. The results showed that colchicine stimulates browning via the antagonism of GABA-BR and the agonism of β3-AR in 3T3-L1 white adipocytes. The colchicine-mediated activation of β3-AR stimulated the PKA/p38 MAPK signaling pathway, where consequently ATF2 acted as a positive regulator, but AFT4 was a negative regulator for the induction of browning.
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Affiliation(s)
- MinJi Choi
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea
| | - Sulagna Mukherjee
- Laboratory of Metabolic Signaling,Institute of Bioengineering, School of Life Sciences, EPFL, CH-1015 Lausanne, Switzerland.
| | - Jong Won Yun
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
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28
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Red Rice Bran Extract Attenuates Adipogenesis and Inflammation on White Adipose Tissues in High-Fat Diet-Induced Obese Mice. Foods 2022; 11:foods11131865. [PMID: 35804681 PMCID: PMC9266166 DOI: 10.3390/foods11131865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/13/2022] [Accepted: 06/23/2022] [Indexed: 11/17/2022] Open
Abstract
Red rice bran extract (RRBE) has been reported to have the potential for in vitro metabolic modulation and anti-inflammatory properties. However, little is known about the molecular mechanisms of these potentials in adipose tissue. This study aimed to evaluate the in vivo anti-adipogenic, anti-hypertrophic, and anti-inflammatory activities of RRBE and its major bioactive compounds in mice. After six weeks of consuming either a low-fat diet or a high-fat diet (HFD), 32 mice with initial body weights of 20.76 ± 0.24 g were randomly divided into four groups; the four groups were fed a low-fat diet, a HFD, a HFD plus 0.5 g/kg of RRBE, or a HFD plus 1 g/kg of RRBE, respectively. The 6-week treatment using RRBE reduced HFD-induced adipocyte hypertrophy, lipid accumulation, and inflammation in intra-abdominal epididymal white adipose tissue (p < 0.05) without causing significant changes in body and adipose tissue weight, which reductions were accompanied by the down-regulated expression of adipogenic and lipid metabolism genes, including CCAAT/enhancer-binding protein-alpha, sterol regulatory element-binding protein-1c, and hormone-sensitive lipase (p < 0.05), as well as inflammatory genes, including macrophage marker F4/80, nuclear factor-kappa B p65, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and inducible nitric oxide synthase (p < 0.05), in adipose tissue. Furthermore, RRBE significantly decreased serum tumor necrosis factor-alpha levels (p < 0.05). Bioactive compound analyses revealed the presence of phenolics, flavonoids, anthocyanins, and proanthocyanidins in these extracts. Collectively, this study demonstrates that RRBE effectively attenuates HFD-induced pathological adipose tissue remodeling by suppressing adipogenesis, lipid dysmetabolism, and inflammation. Therefore, RRBE may emerge as one of the alternative food products to be used against obesity-associated adipose tissue dysfunction.
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Zhang L, Ma J, Pan X, Zhang M, Huang W, Liu Y, Yang H, Cheng Z, Zhang G, Qie M, Tong N. LncRNA MIR99AHG enhances adipocyte differentiation by targeting miR-29b-3p to upregulate PPARγ. Mol Cell Endocrinol 2022; 550:111648. [PMID: 35430304 DOI: 10.1016/j.mce.2022.111648] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/16/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022]
Abstract
AIM The aim is to identify new long noncoding RNAs (lncRNAs) involved in adipocyte differentiation. METHODS High-throughput RNA sequencing of 3T3-L1 preadipocytes was carried out before and after differentiation to identify the target lncRNAs and miRNAs. The effects of lncRNA, miRNA and the network mechanism on adipocyte differentiation were evaluated in vitro and in vivo. Visceral adipose tissue (VAT) was collected from Chinese subjects with obesity or a normal body mass index (BMI), and the levels of lncRNAs, adipogenic genes and miRNAs were measured. RESULTS MIR99AHG, miR-29b-3p were selected as the target lncRNA and miRNA. Short hairpin RNA against MIR99AHG inhibited the differentiation of 3T3-L1 preadipocytes, reduced the expression of the peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer-binding protein alpha (C/EBPα) and fatty acid binding protein 4 (FABP4) genes, upregulated the expression of miR-29b-3p. Overexpression of MIR99AHG showed the opposite effects. Overexpression of miR-29b-3p inhibited the differentiation of 3T3-L1 preadipocytes and decreased the PPARγ level, while inhibition of miR-29b-3p showed the opposite effects. MIR99AHG and PPARγ competed for binding to miR-29b-3p. In mice with high-fat diet-induced obesity, MIR99AHG and miR-29b-3p mRNA level were increased and decreased, respectively. Tail vein injection of adeno-associated virus 9-MIR99AHG-RNA interference (AAV9-MIR99AHG-RNAi) reduced the body weight, epididymal fat mass, MIR99AHG level and increased the expression of miR-29b-3p. The expression levels of MIR99AHG, PPARγ, C/EBPα and FABP4 in human visceral adipose tissue were higher in the obese group than in the normal weight group. CONCLUSIONS MIR99AHG enhances adipogenesis by regulating miR-29b-3p and PPARγ, providing a new target for therapeutic intervention in obesity.
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Affiliation(s)
- Lin Zhang
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Jinfang Ma
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaohui Pan
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Mei Zhang
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Huang
- Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yanjun Liu
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China
| | - Huawu Yang
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China
| | - Zhong Cheng
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Guixiang Zhang
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Mingrong Qie
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China; Laboratory of Diabetes and Islet Transplantation Research, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China.
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Yuan A, Wu P, Zhong Z, He Z, Li W. Long non-coding RNA Gm37494 alleviates osteoarthritis chondrocyte injury via the microRNA-181a-5p/GABRA1 axis. J Orthop Surg Res 2022; 17:304. [PMID: 35689264 PMCID: PMC9185876 DOI: 10.1186/s13018-022-03202-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/25/2022] [Indexed: 11/10/2022] Open
Abstract
Objective This study was conducted to investigate the effect of long non-coding RNA (lncRNA) Gm37494 on osteoarthritis (OA) and its related molecular mechanism. Methods The cartilage tissues were obtained from OA patients, and an OA mouse model was induced by the destabilization of the medial meniscus, followed by measurement of Gm37494, microRNA (miR)-181a-5p, GABRA1 mRNA, and the encoded GABAARα1 protein expression. Thereafter, a cellular model was induced by interleukin-1β (IL-1β) treatment in chondrocytes, followed by ectopic and silencing experiments. Chondrocyte proliferation was detected by CCK-8 and EdU assays, chondrocyte apoptosis by flow cytometry and western blot, and the levels of inflammatory factors by ELISA. The binding of Gm37494 to miR-181a-5p was evaluated by dual-luciferase reporter gene and RIP assays, and that of GABRA1 to miR-181a-5p by dual-luciferase reporter gene and RNA pull-down assays. Results OA patients and mice had decreased GABRA1 mRNA and GABAARα1 protein levels and elevated miR-181a-5p expression in cartilage tissues. Additionally, Gm37494 was poorly expressed in OA mice. Mechanistically, Gm37494 directly bound to and inversely modulated miR-181a-5p that negatively targeted GABRA1. In IL-1β-induced chondrocytes, Gm37494 overexpression enhanced cell proliferation and suppressed cell apoptosis and inflammation, whereas further miR-181a-5p up-regulation or GABRA1 silencing abolished these trends. Conclusions Conclusively, Gm37494 elevated GABRA1 expression by binding to miR-181a-5p, thus ameliorating OA-induced chondrocyte damage. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-022-03202-5.
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Affiliation(s)
- Aidong Yuan
- Department of Joint and Sports Medicine, The First People's Hospital of Shaoguan City, No.3 Dongdi South Road, Zhenjiang District, Shaoguan, 512000, Guangdong, People's Republic of China.
| | - Penghuan Wu
- Department of Joint and Sports Medicine, The First People's Hospital of Shaoguan City, No.3 Dongdi South Road, Zhenjiang District, Shaoguan, 512000, Guangdong, People's Republic of China
| | - Zhinian Zhong
- Department of Joint and Sports Medicine, The First People's Hospital of Shaoguan City, No.3 Dongdi South Road, Zhenjiang District, Shaoguan, 512000, Guangdong, People's Republic of China
| | - Zhengyan He
- Department of Joint and Sports Medicine, The First People's Hospital of Shaoguan City, No.3 Dongdi South Road, Zhenjiang District, Shaoguan, 512000, Guangdong, People's Republic of China
| | - Wenhu Li
- Department of Joint and Sports Medicine, The First People's Hospital of Shaoguan City, No.3 Dongdi South Road, Zhenjiang District, Shaoguan, 512000, Guangdong, People's Republic of China
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Zhang S, Zhao J, Hu J, He H, Wei Y, Ji L, Ma X. Gama-aminobutyric acid (GABA) alleviates hepatic inflammation via GABA receptors/TLR4/NF-κB pathways in growing-finishing pigs generated by super-multiparous sows. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2022; 9:280-290. [PMID: 35600552 PMCID: PMC9092368 DOI: 10.1016/j.aninu.2022.02.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/11/2021] [Accepted: 02/11/2022] [Indexed: 01/08/2023]
Abstract
The offspring of super-multiparous sows face problems such as decreased growth performance, poor meat quality and even diseases in animal husbandry. Gama-aminobutyric acid (GABA) has long been known to promote growth and suppress inflammation, but little is known about the mechanisms. A total of 72 growing-finishing pigs from the 8th generation were randomly allotted to 2 groups with 6 replicates per treatment to receive a corn–soybean basal diet or the basal diet supplemented 20 mg/kg GABA for 60 d. After the animal-trial period, samples of serum and liver were collected for further analysis. Additionally, a lipopolysaccharide (LPS)-induced inflammatory model using HepG2 cells was established to explore the role of GABA on regulating hepatic inflammation. The results indicated that inflammatory cell infiltration occurs in the liver of progeny of super-multiparous sows, and dietary supplementation with GABA influenced liver morphology, increased activities of antioxidant enzymes and decreased the expression abundance of pro-inflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, in the liver of growing-finishing pigs (P < 0.05). In addition, GABA supplementation increased mRNA expressions of peroxisome proliferator-activated receptor γ (PPARγ) and GABA receptors (GABARs), and reduced the expression of toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling (P < 0.05). Additionally, an in vitro experiment demonstrated that GABA decreased the expressions of hepatic TLR4/NF-κB signaling via activating GABARs under LPS-stress (P < 0.05). In summary, liver injury may affect the growth performance of growing-finishing pigs by changing hepatic mitochondrial metabolism, the expression of pro-inflammatory cytokines and TLR4/NF-κB pathway and that GABA supplementation has a restorative effect by acting on GABARs.
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Affiliation(s)
- Shumin Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Jinbiao Zhao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Jinhua Hu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Hengxun He
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yihan Wei
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Linbao Ji
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
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Lee G, Kim YY, Jang H, Han JS, Nahmgoong H, Park YJ, Han SM, Cho C, Lim S, Noh JR, Oh WK, Lee CH, Kim S, Kim JB. SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity. Cell Metab 2022; 34:702-718.e5. [PMID: 35417665 DOI: 10.1016/j.cmet.2022.03.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 12/28/2021] [Accepted: 03/23/2022] [Indexed: 01/10/2023]
Abstract
Emerging evidence indicates that the accretion of senescent cells is linked to metabolic disorders. However, the underlying mechanisms and metabolic consequences of cellular senescence in obesity remain obscure. In this study, we found that obese adipocytes are senescence-susceptible cells accompanied with genome instability. Additionally, we discovered that SREBP1c may play a key role in genome stability and senescence in adipocytes by modulating DNA-damage responses. Unexpectedly, SREBP1c interacted with PARP1 and potentiated PARP1 activity during DNA repair, independent of its canonical lipogenic function. The genetic depletion of SREBP1c accelerated adipocyte senescence, leading to immune cell recruitment into obese adipose tissue. These deleterious effects provoked unhealthy adipose tissue remodeling and insulin resistance in obesity. In contrast, the elimination of senescent adipocytes alleviated adipose tissue inflammation and improved insulin resistance. These findings revealed distinctive roles of SREBP1c-PARP1 axis in the regulation of adipocyte senescence and will help decipher the metabolic significance of senescence in obesity.
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Affiliation(s)
- Gung Lee
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Ye Young Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Hagoon Jang
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Ji Seul Han
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Hahn Nahmgoong
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Yoon Jeong Park
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Sang Mun Han
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Changyun Cho
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea
| | - Sangsoo Lim
- Bioinformatics Institute, Seoul National University, Seoul 08826, South Korea
| | - Jung-Ran Noh
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Yuseong-gu, Daejeon 34141, South Korea
| | - Won Keun Oh
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Yuseong-gu, Daejeon 34141, South Korea
| | - Sun Kim
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea; Bioinformatics Institute, Seoul National University, Seoul 08826, South Korea; Department of Computer Science and Engineering, Institute of Engineering Research, Seoul National University, Seoul 08826, South Korea
| | - Jae Bum Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
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GABA and Fermented Curcuma longa L. Extract Enriched with GABA Ameliorate Obesity through Nox4-IRE1α Sulfonation-RIDD-SIRT1 Decay Axis in High-Fat Diet-Induced Obese Mice. Nutrients 2022; 14:nu14081680. [PMID: 35458241 PMCID: PMC9031358 DOI: 10.3390/nu14081680] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 12/11/2022] Open
Abstract
Gamma-aminobutyric acid (GABA) is a natural amino acid with antioxidant activity and is often considered to have therapeutic potential against obesity. Obesity has long been linked to ROS and ER stress, but the effect of GABA on the ROS-associated ER stress axis has not been thoroughly explored. Thus, in this study, the effect of GABA and fermented Curcuma longa L. extract enriched with GABA (FCLL-GABA) on the ROS-related ER stress axis and inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) sulfonation were examined with the HFD model to determine the underlying anti-obesity mechanism. Here, GABA and FCLL-GABA supplementations significantly inhibited the weight gain in HFD fed mice. The GABA and FCLL-GABA supplementation lowered the expressions of adipogenic transcription factors such as PPAR-γ, C/EBPα, FAS, and SREBP-1c in white adipose tissue (WAT) and liver from HFD-fed mice. The enhanced hyper-nutrient dysmetabolism-based NADPH oxidase (Nox) 4 and the resultant IRE1α sulfonation-RIDD-SIRT1 decay under HFD conditions were controlled with GABA and FCLL-GABA. Notably, GABA and FCLL-GABA administration significantly increased AMPK and sirtuin 1 (SIRT1) levels in WAT of HFD-fed mice. These significant observations indicate that ER-localized Nox4-induced IRE1α sulfonation results in the decay of SIRT1 as a novel mechanism behind the positive implications of GABA on obesity. Moreover, the investigation lays a firm foundation for the development of FCLL-GABA as a functional ingredient.
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Xu J, Dong J, Ding H, Wang B, Wang Y, Qiu Z, Yao F. Ginsenoside compound K inhibits obesity-induced insulin resistance by regulation of macrophage recruitment and polarization via activating PPARγ. Food Funct 2022; 13:3561-3571. [PMID: 35260867 DOI: 10.1039/d1fo04273d] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Obesity disrupts the immune system of adipose tissue, and the activation of its macrophages constantly infiltrating adipose tissue is a crucial cause of insulin resistance induced by obesity. We previously reported for the first time in vitro that the antidiabetic effect of CK may be through the inhibition of macrophage activation and we further explored the specific mechanism in vivo. In order to clarify it, the C57BL/6J mice were fed with a high fat diet and then administered with CK orally. The related biochemical indices were detected, the inflammatory factors in serum and tissues were measured, and the related protein expression levels in insulin pathways and inflammatory signaling pathways were observed. The results showed that CK could dose-dependently reduce macrophage M1-type inflammatory factor expression in serum and adipose tissue, improve insulin resistance and glucose tolerance effectively, upregulate PPARγ expression and block TLR4/TRAF6/TAK1/NF-κB activation in obese mice. In addition, CK promoted the expression of IRS1/PI3K/AKT. Furthermore, our study showed that ginsenoside CK could improve insulin resistance by reducing inflammation through the PPARγ/NF-κB signaling pathway, which implies that ginsenoside CK may be an effective agent against obesity or early diabetes.
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Affiliation(s)
- Jie Xu
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Jinxiang Dong
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Hongyue Ding
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Bei Wang
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Yuqi Wang
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Zhidong Qiu
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Fan Yao
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
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Cai WX, Shen K, Cao T, Wang J, Zhao M, Wang KJ, Zhang Y, Han JT, Hu DH, Tao K. [Effects of exosomes from human adipose-derived mesenchymal stem cells on pulmonary vascular endothelial cells injury in septic mice and its mechanism]. ZHONGHUA SHAO SHANG YU CHUANG MIAN XIU FU ZA ZHI 2022; 38:266-275. [PMID: 35325972 DOI: 10.3760/cma.j.cn501120-20211020-00362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Objective: To investigate the effects of exosomes from human adipose-derived mesenchymal stem cells (ADSCs) on pulmonary vascular endothelial cells (PMVECs) injury in septic mice and its mechanism. Methods: The experimental research method was adopted. The primary ADSCs were isolated and cultured from the discarded fresh adipose tissue of 3 patients (female, 10-25 years old), who were admitted to the First Affiliated Hospital of Air Force Medical University undergoing abdominal surgery, and the cell morphology was observed by inverted phase contrast microscope on the 5th day. The expressions of CD29, CD34, CD44, CD45, CD73, and CD90 of ADSCs in the third passage were detected by flow cytometry. The third to the fifth passage of ADSCs were collected, and their exosomes from the cell supernatant were obtained by differential ultracentrifugation, and the shape, particle size, and the protein expressions of CD9, CD63, tumor susceptibility gene 101 (TSG101), and β-actin of exosomes were detected, respectively, by transmission electron microscopy, nano-particle tracking analysis and Western blotting. Twenty-four adult male BALB/c mice were adopted and were divided into normal control group, caecal ligation perforation (CLP) alone group, and CLP+ADSC-exosome group with each group of 8 according to random number table (the same grouping method below) and were treated accordingly. At 24 h after operation, tumor necrosis factor (TNF-α) and interleukin 1β (IL-1β) levels of mice serum were detected by enzyme-linked immunosorbent assay, and lung tissue morphology of mice was detected by hematoxylin-eosin and myeloperoxidase staining, and the expression of 8-hydroxy-deoxyguanosine (8-OHdG) of mouse lung cells was detected by immunofluorescence method. Primary PMVECs were obtained from 1-month-old C57 mice regardless gender by tissue block method. The expression of CD31 of PMVECs was detected by immunofluorescence and flow cytometry. The third passage of PMVECs was co-cultured with ADSCs derived exosomes for 12 h, and the phagocytosis of exosomes by PMVECs was detected by PKH26 kit. The third passage of PMVECs were adopted and were divided into blank control group, macrophage supernatant alone group, and macrophage supernatant+ADSC-exosome group, with 3 wells in each group, which were treated accordingly. After 24 h, the content of reactive oxygen species in cells was detected by flow cytometry, the expression of 8-OHdG in cells was detected by immunofluorescence, and Transwell assay was used to determine the permeability of cell monolayer. The number of samples in above were all 3. Data were statistically analyzed with one-way analysis of variance and least significant difference t test. Results: The primary ADSCs were isolated and cultured to day 5, growing densely in a spindle shape with a typical swirl-like. The percentages of CD29, CD44, CD73 and CD90 positive cells of ADSCs in the third passage were all >90%, and the percentages of CD34 and CD45 positive cells were <5%. Exosomes derived from ADSCs of the third to fifth passages showed a typical double-cavity disc-like structure with an average particle size of 103 nm, and the protein expressions of CD9, CD63 and TSG101 of exosomes were positive, while the protein expression of β-actin of exosomes was negative. At 24 h after operation, compared with those in normal control group, both the levels of TNF-α and IL-1β of mice serum in CLP alone group were significantly increased (with t values of 28.76 and 29.69, respectively, P<0.01); compared with those in CLP alone group, both the content of TNF-α and IL-1β of mice serum in CLP+ADSC-exosome group was significantly decreased (with t values of 9.90 and 4.76, respectively, P<0.05 or P<0.01). At 24 h after surgery, the pulmonary tissue structure of mice in normal control group was clear and complete without inflammatory cell infiltration; compared with those in normal control group, the pulmonary tissue edema and inflammatory cell infiltration of mice in CLP alone group were more obvious; compared with those in CLP alone group, the pulmonary tissue edema and inflammatory cell infiltration of mice in CLP+ADSC-exosome group were significantly reduced. At 24 h after operation, endothelial cells in lung tissues of mice in 3 groups showed positive expression of CD31; compared with that in normal control group, the fluorescence intensity of 8-OHdG positive cells of the lung tissues of mice in CLP alone group was significantly increased, and compared with that in CLP alone group, the fluorescence intensity of 8-OHdG positive cells in the lung tissues of mice in CLP+ADSC-exosome group was significantly decreased. The PMVECs in the 3rd passage showed CD31 positive expression by immunofluorescence, and the result of flow cytometry showed that CD31 positive cells accounted for 99.5%. At 12 h after co-culture, ADSC-derived exosomes were successfully phagocytose by PMVECs and entered its cytoplasm. At 12 h after culture of the third passage of PMVECs, compared with that in blank control group, the fluorescence intensity of reactive oxygen species of PMVECs in macrophage supernatant alone group was significantly increased (t=15.73, P<0.01); compared with that in macrophage supernatant alone group, the fluorescence intensity of reactive oxygen species of PMVECs in macrophage supernatant+ADSC-exosome group was significantly decreased (t=4.72, P<0.01). At 12 h after culture of the third passage of PMVECs, and the 8-OHdG positive fluorescence intensity of PMVECs in macrophage supernatant alone group was significantly increased; and compared with that in blank control group, the 8-OHdG positive fluorescence intensity of PMVECs in macrophage+ADSC-exosome supernatant group was between blank control group and macrophage supernatant alone group. At 12 h after culture of the third passage PMVECs, compared with that in blank control group, the permeability of PMVECs monolayer in macrophage supernatant alone group was significantly increased (t=6.34, P<0.01); compared with that in macrophage supernatant alone group, the permeability of PMVECs monolayer cells in macrophage supernatant+ADSC-exosome group was significantly decreased (t=2.93, P<0.05). Conclusions: Exosomes derived from ADSCs can ameliorate oxidative damage in mouse lung tissue, decrease the level of reactive oxygen species, 8-OHdG expression, and permeability of PMVECs induced by macrophage supernatant.
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Affiliation(s)
- W X Cai
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - K Shen
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - T Cao
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - J Wang
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - M Zhao
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - K J Wang
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - Y Zhang
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - J T Han
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - D H Hu
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - K Tao
- Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
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Nahmgoong H, Jeon YG, Park ES, Choi YH, Han SM, Park J, Ji Y, Sohn JH, Han JS, Kim YY, Hwang I, Lee YK, Huh JY, Choe SS, Oh TJ, Choi SH, Kim JK, Kim JB. Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics. Cell Metab 2022; 34:458-472.e6. [PMID: 35021043 DOI: 10.1016/j.cmet.2021.11.014] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 09/16/2021] [Accepted: 11/22/2021] [Indexed: 12/22/2022]
Abstract
In mammals, white adipose tissues are largely divided into visceral epididymal adipose tissue (EAT) and subcutaneous inguinal adipose tissue (IAT) with distinct metabolic properties. Although emerging evidence suggests that subpopulations of adipose stem cells (ASCs) would be important to explain fat depot differences, ASCs of two fat depots have not been comparatively investigated. Here, we characterized heterogeneous ASCs and examined the effects of intrinsic and tissue micro-environmental factors on distinct ASC features. We demonstrated that ASC subpopulations in EAT and IAT exhibited different molecular features with three adipogenic stages. ASC transplantation experiments revealed that intrinsic ASC features primarily determined their adipogenic potential. Upon obesogenic stimuli, EAT-specific SDC1+ ASCs promoted fibrotic remodeling, whereas IAT-specific CXCL14+ ASCs suppressed macrophage infiltration. Moreover, IAT-specific BST2high ASCs exhibited a high potential to become beige adipocytes. Collectively, our data broaden the understanding of ASCs with new insights into the origin of white fat depot differences.
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Affiliation(s)
- Hahn Nahmgoong
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yong Geun Jeon
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Eun Seo Park
- Department of New Biology, DGIST, Daegu 42988, Republic of Korea
| | - Yoon Ha Choi
- Department of New Biology, DGIST, Daegu 42988, Republic of Korea
| | - Sang Mun Han
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Jeu Park
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yul Ji
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Jee Hyung Sohn
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Ji Seul Han
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Ye Young Kim
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Injae Hwang
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yun Kyung Lee
- Internal Medicine, Seoul National University College of Medicine & Seoul National University Bundang Hospital, Seoul 03080, Republic of Korea
| | - Jin Young Huh
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Sung Sik Choe
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Tae Jung Oh
- Internal Medicine, Seoul National University College of Medicine & Seoul National University Bundang Hospital, Seoul 03080, Republic of Korea
| | - Sung Hee Choi
- Internal Medicine, Seoul National University College of Medicine & Seoul National University Bundang Hospital, Seoul 03080, Republic of Korea
| | - Jong Kyoung Kim
- Department of New Biology, DGIST, Daegu 42988, Republic of Korea.
| | - Jae Bum Kim
- National Creative Research Initiatives Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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Zhang A, Jiang X, Ge Y, Xu Q, Li Z, Tang H, Cao D, Zhang D. The Effects of GABA-Rich Adzuki Beans on Glycolipid Metabolism, as Well as Intestinal Flora, in Type 2 Diabetic Mice. Front Nutr 2022; 9:849529. [PMID: 35237647 PMCID: PMC8883037 DOI: 10.3389/fnut.2022.849529] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 01/19/2022] [Indexed: 12/16/2022] Open
Abstract
Objectives In this study, the effects of γ-aminobutyric acid (GABA)-rich sprouted adzuki beans on the glycolipid metabolism and gastrointestinal health were investigated in mice with type 2 diabetes mellitus (T2DM). Methods Mice with T2DM were subjected to dietary intervention with different doses of GABA-rich sprouted adzuki beans for 6 consecutive weeks, during which growth indicators, glycolipid metabolism, and the composition and diversity of the gut microbiota changes were observed. Results A high dietary intake of GABA-rich sprouted adzuki beans had a preventive effect against weight gain, significantly reduced serum levels of FBG, TG, and TC. Additionally, high dietary intake of GABA-rich sprouted adzuki beans increased the abundances of Firmicutes, Bacteroidetes, Verrucomicrobia, and Akkermansia, leading to a shift in the structure of the gut microbiota toward the dominance of probiotics with regulatory effects on glycolipid metabolism. Conclusions GABA-rich sprouted adzuki beans can effectively control the bodyweight of mice with T2DM, maintain a balanced blood glucose level, improve glycolipid metabolism and the changes in the microbiota may mediate the anti-diabetic effect of sprouted adzuki beans.
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Affiliation(s)
- Aiwu Zhang
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Xiujie Jiang
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
- National Coarse Cereals Engineering Research Center, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yunfei Ge
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangneung, South Korea
| | - Qingpeng Xu
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Zhijiang Li
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Huacheng Tang
- National Coarse Cereals Engineering Research Center, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Dongmei Cao
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Dongjie Zhang
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
- National Coarse Cereals Engineering Research Center, Heilongjiang Bayi Agricultural University, Daqing, China
- *Correspondence: Dongjie Zhang
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The Functional Interplay between Gut Microbiota, Protein Hydrolysates/Bioactive Peptides, and Obesity: A Critical Review on the Study Advances. Antioxidants (Basel) 2022; 11:antiox11020333. [PMID: 35204214 PMCID: PMC8868115 DOI: 10.3390/antiox11020333] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/04/2022] [Accepted: 02/06/2022] [Indexed: 02/05/2023] Open
Abstract
Diet is an essential factor determining the ratio of pathogenic and beneficial gut microbiota. Hydrolysates and bioactive peptides have been described as crucial ingredients from food protein that potentially impact human health beyond their roles as nutrients. These compounds can exert benefits in the body, including modulation of the gut microbiota, and thus, they can reduce metabolic disorders. This review summarized studies on the interaction between hydrolysates/peptides, gut microbes, and obesity, focusing on how hydrolysates/peptides influence gut microbiota composition and function that improve body weight. Findings revealed that gut microbes could exert anti-obesity effects by controlling the host’s energy balance and food intake. They also exhibit activity against obesity-induced inflammation by changing the expression of inflammatory-related transcription factors. Protein hydrolysates/peptides can suppress the growth of pro-obesity gut bacteria but facilitate the proliferation of those with anti-obesity effects. The compounds provide growth factors to the beneficial gut bacteria and also improve their resistance against extreme pH. Hydrolysates/peptides are good candidates to target obesity and obesity-related complications. Thus, they can allow the development of novel strategies to fight incidences of obesity. Future studies are needed to understand absorption fate, utilization by gut microbes, and stability of hydrolysates/peptides in the gut under obesity.
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Kim JK, Park EJ, Jo EK. Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection. Front Immunol 2022; 13:832015. [PMID: 35185924 PMCID: PMC8855927 DOI: 10.3389/fimmu.2022.832015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/13/2022] [Indexed: 12/29/2022] Open
Abstract
Immune metabolic regulation shapes the host-pathogen interaction during infection with Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB). Several immunometabolites generated by metabolic remodeling in macrophages are implicated in innate immune protection against Mtb infection by fine-tuning defensive pathways. Itaconate, produced by the mitochondrial enzyme immunoresponsive gene 1 (IRG1), has antimicrobial and anti-inflammatory effects, restricting intracellular mycobacterial growth. L-arginine, a component of the urea cycle, is critical for the synthesis of nitric oxide (NO) and is implicated in M1-mediated antimycobacterial responses in myeloid cells. L-citrulline, a by-product of NO production, contributes to host defense and generates L-arginine in myeloid cells. In arginase 1-expressing cells, L-arginine can be converted into ornithine, a polyamine precursor that enhances autophagy and antimicrobial protection against Mtb in Kupffer cells. Gamma-aminobutyric acid (GABA), a metabolite and neurotransmitter, activate autophagy to induce antimycobacterial host defenses. This review discusses the recent updates of the functions of the three metabolites in host protection against mycobacterial infection. Understanding the mechanisms by which these metabolites promote host defense will facilitate the development of novel host-directed therapeutics against Mtb and drug-resistant bacteria.
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Affiliation(s)
- Jin Kyung Kim
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Eun-Jin Park
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea
- *Correspondence: Eun-Kyeong Jo,
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Lu M, Yu Z, Li Q, Gong M, An L, Xu T, Yuan M, Liang C, Yu Z, Xu B. Electroacupuncture Stimulation Regulates Adipose Lipolysis via Catecholamine Signaling Mediated by NLRP3 Suppression in Obese Rats. Front Endocrinol (Lausanne) 2022; 12:773127. [PMID: 35046893 PMCID: PMC8762326 DOI: 10.3389/fendo.2021.773127] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic low-grade inflammation of visceral adipose tissue can cause obesity-associated insulin resistance, leading to metabolic syndrome. However, anti-inflammatory drugs and those for obesity management can lead to serious side effects such as abnormal heart rate and blood pressure. Consequently, this study aimed to explore the therapeutic potential of electroacupuncture stimulation (ES) for obesity and associated chronic inflammation. Sprague-Dawley male rats were fed a high-fat diet (HFD) for ten weeks to build an obesity model, and half of the diet-induced obesity (DIO) rats were received ES. The levels of inflammatory factors were detected by ELISA and qPCR analysis. The nerve-associated macrophages were marked with immunofluorescence staining. The molecular mechanism of NLRP3 inflammasome in ES was determined by the NLRP3 inflammasome activation model. Compared to HDF rats, ES showed decreased body weight and chronic inflammatory damage. Specifically, this occurred via a decrease in monoamine oxidase-A (MAOA) expression, which suppressed noradrenaline degradation. MAOA is expressed in nerve-associated macrophages (NAMs), and ES attenuated NAMs by suppressing the NLRP3 inflammasome. The NLRP3 agonist blocked the noradrenaline degradation-reducing effect of ES, and an increase in lipolysis via the inhibition of the NLRP3 inflammasome attenuated NAMs. Thus, our findings suggest that ES induced lipolysis via activation of the NLRP3 inflammasome in nerve-associated macrophages (NAMs), independently of sympathetic nervous system activity.
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Affiliation(s)
- Mengjiang Lu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziwei Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qian Li
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Meirong Gong
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li An
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Tiancheng Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengqian Yuan
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Chao Liang
- Medical College, Hebei University of Engineering, Hebei, China
| | - Zhi Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bin Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
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Choi WG, Choi W, Oh TJ, Cha HN, Hwang I, Lee YK, Lee SY, Shin H, Lim A, Ryu D, Suh JM, Park SY, Choi SH, Kim H. Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance. J Clin Invest 2021; 131:145331. [PMID: 34618686 DOI: 10.1172/jci145331] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 10/05/2021] [Indexed: 12/28/2022] Open
Abstract
Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.
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Affiliation(s)
- Won Gun Choi
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
| | - Wonsuk Choi
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea.,Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, South Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Hye-Na Cha
- Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea
| | - Inseon Hwang
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
| | - Yun Kyung Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung Yeon Lee
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
| | - Hyemi Shin
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
| | - Ajin Lim
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
| | - Dongryeol Ryu
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Jae Myoung Suh
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
| | - So-Young Park
- Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Hail Kim
- Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea
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Lu J, Xia H, Li W, Shen X, Guo H, Zhang J, Fan X. Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:1141-1150. [PMID: 34552348 PMCID: PMC8450188 DOI: 10.2147/pgpm.s329594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/02/2021] [Indexed: 12/25/2022]
Abstract
Background Valproic acid (VPA) is recommended as a first-line treatment for children with epilepsy. GABRG2 polymorphism is found to be associated with epilepsy susceptibility and therapeutic response of anti-seizure medications (ASM); however, the role of GABRG2 in VPA treatment still remains unknown. Objective The purpose of this study was to explore the association of GABRG2 gene polymorphism with the drug response and adverse drug reactions (ADRs) related to VPA. Methods A retrospective study including 96 Chinese children with epilepsy treated by VPA was carried out. The ADRs were collected during VPA therapy and GABRG2 rs211037 in enrolled patients was genotyped using Sequenom MassArray system. A network pharmacological analysis involved protein–protein interaction and enrichment analysis was constructed to investigate the potential targets and pathways of GABRG2 on VPA-related ADRs. Results Among 96 patients, 41 individuals were defined as seizure together with 49 patients with seizure-free and 6 patients unclassified. Carriers of homozygote GABRG2 rs211037 CC genotype exhibited seizure-free to VPA (P = 0.042), whereas those with CT genotype showed seizure. Furthermore, CC genotype had predisposition to digestive ADRs (P = 0.037) but was a protective factor for VPA-associated weight gain (P = 0.013). Ten key genes related to digestive ADRs and weight gain induced by VPA were identified by network pharmacological analysis and mainly involved in “GABAergic synaptic signaling”, “GABA receptor signaling”, and “taste transduction” pathways/processes through enrichment analysis. Conclusion This study revealed that GABRG2 variation exerted a predictable role in the efficacy and safety of VPA treatment for Chinese children with epilepsy.
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Affiliation(s)
- Jieluan Lu
- Department of Clinical Pharmacology, College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Hanbing Xia
- Department of Pharmacy, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, 518102, People's Republic of China
| | - Wenzhou Li
- Department of Pharmacy, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, 518102, People's Republic of China
| | - Xianhuan Shen
- Department of Clinical Pharmacology, College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Huijuan Guo
- Department of Pharmacy, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, 518102, People's Republic of China
| | - Jianping Zhang
- Department of Clinical Pharmacology, College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Xiaomei Fan
- Department of Pharmacy, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, 518102, People's Republic of China
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DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics. Proc Natl Acad Sci U S A 2021; 118:2021073118. [PMID: 33836591 DOI: 10.1073/pnas.2021073118] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1-like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.
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44
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Li H, Wu Y, Huang N, Zhao Q, Yuan Q, Shao B. γ-Aminobutyric Acid Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Inducing TNFAIP3. Curr Gene Ther 2021; 20:152-161. [PMID: 32951573 DOI: 10.2174/1566523220999200727122502] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Osteoporosis is the most common metabolic bone disease. There is still an unmet need for novel therapeutic agents that could be beneficial as osteoporosis treatments. It has been reported that the neurotransmitter γ-aminobutyric acid (GABA) might be associated with human bone formation. However, the precise mechanism remains unclear. OBJECTIVE To investigate the effect of GABA on bone metabolism and explore the possible role of TNFAIP3 in this process. METHODS GABA had little effect on the proliferation of human mesenchymal stem cells (hMSCs) and RAW 264.7 cells, as indicated by the cell counting kit-8 (CCK-8) assay. The results showed that GABA enhanced the intensity of ALP staining, ALP activity, and accumulation of Ca2+ mineralized nodules in hMSCs during osteogenic induction. RESULTS The qRT-PCR results indicated that GABA treatment significantly increased the mRNA expression of osteogenic genes in hMSCs. In RAW 264.7 cells, TRAP staining showed that GABA did not alter the number or size of osteoclasts or the expression of osteoclastic genes, which suggests that GABA does not affect osteoclastic differentiation. Mechanistically, GABA treatment significantly induced the sustained expression of TNFAIP3. Furthermore, by knocking down TNFAIP3, the osteogenic effect of GABA was antagonized, which suggests that TNFAIP3 mediates the effects of GABA in hMSCs. CONCLUSION Our results suggested that GABA treatment positively regulated osteogenic differentiation by upregulating TNFAIP3, while no obvious effect on osteoclastic differentiation was detected. Therefore, our results provide a potential gene therapy for the treatment of osteoporosis and low bone mineral density.
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Affiliation(s)
- Hanwen Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yongyao Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ning Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Qi Zhao
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Quan Yuan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Bin Shao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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45
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Zhu L, Feng Z, Shu X, Gao Q, Wu J, Du Z, Li R, Wang L, Chen N, Li Y, Luo M, Wu J. In situ transplantation of adipose-derived stem cells via photoactivation improves glucose metabolism in obese mice. Stem Cell Res Ther 2021; 12:408. [PMID: 34266493 PMCID: PMC8281693 DOI: 10.1186/s13287-021-02494-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 07/04/2021] [Indexed: 01/10/2023] Open
Abstract
Background Accumulating evidence suggests that enhanced adipose tissue macrophages (ATMs) are associated with metabolic disorders in obesity and type 2 diabetes. However, therapeutic persistence and reduced homing stem cell function following cell delivery remains a critical hurdle for the clinical translation of stem cells in current approaches. Methods We demonstrate that the effect of a combined application of photoactivation and adipose-derived stem cells (ASCs) using transplantation into visceral epididymal adipose tissue (EAT) in obesity. Cultured ASCs were derived from subcutaneous white adipose tissue isolated from mice fed a normal diet (ND). Results In diet-induced obesity, implantation of light-treated ASCs improved glucose tolerance and ameliorated systemic insulin resistance. Intriguingly, compared with non-light-treated ASCs, light-treated ASCs reduced monocyte infiltration and the levels of ATMs in EAT. Moreover, implantation of light-treated ASCs exerts more anti-inflammatory effects by suppressing M1 polarization and enhancing macrophage M2 polarization in EAT. Mass spectrometry revealed that light-treated human obese ASCs conditioned medium retained a more complete secretome with significant downregulation of pro-inflammatory cytokines and chemokines. Conclusions These data suggest that the combined application of photoactivation and ASCs using transplantation into dysfunctional adipose tissue contribute to selective suppression of inflammatory responses and protection from insulin resistance in obesity and type 2 diabetes. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02494-4.
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Affiliation(s)
- Luochen Zhu
- Nantong Tumor Hospital (Tumor Hospital Affiliated to Nantong University), Nantong, Jiangsu, People's Republic of China.,Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Ziqian Feng
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Xin Shu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Qian Gao
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Jiaqi Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Zuoqin Du
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Rong Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Liqun Wang
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Ni Chen
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Yi Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Mao Luo
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Jianbo Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People's Republic of China. .,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
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46
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Zhou Z, Tao Y, Zhao H, Wang Q. Adipose Extracellular Vesicles: Messengers From and to Macrophages in Regulating Immunometabolic Homeostasis or Disorders. Front Immunol 2021; 12:666344. [PMID: 34108967 PMCID: PMC8183682 DOI: 10.3389/fimmu.2021.666344] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is comprised of heterogenous cell populations that regulate both energy metabolism and immune reactions. Macrophages play critical roles in regulating immunometabolic homeostasis or disorders through cooperation with adipocytes, adipose tissue-derived stem cells (ADSCs) or other cells in adipose tissue. Extracellular vesicles (EVs) are recently recognized as efficient messengers for intercellular communication. Emerging evidences have demonstrated that adipose EVs are actively involved in the mutual interactions of macrophages, adipocytes and ADSCs, which produce considerable influences on immunometabolism under healthy or obese conditions. Here, we will elaborate the production and the characteristics of adipose EVs that are related to macrophages under different metabolic demands or stresses, whilst discuss the roles of these EVs in regulating local or systemic immunometabolic homeostasis or disorders in the context of adipocyte-macrophage dialogue and ADSC-macrophage interaction. Particularly, we provide a profile of dynamic adipose microenvironments based on macrophages. Adipose EVs act as the messengers between ADSCs and macrophages to maintain the balance of metabolism and immunity, while drive a vicious cycle between hypertrophic adipocytes and inflammatory macrophages to cause immunometabolic imbalance. This review may provide valuable information about the physio- or pathological roles of adipose EVs and the application of adipose EVs in the diagnosis and treatment of metabolic diseases.
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Affiliation(s)
- Zixin Zhou
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yan Tao
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hui Zhao
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qun Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
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Salehian-Dehkordi H, Xu YX, Xu SS, Li X, Luo LY, Liu YJ, Wang DF, Cao YH, Shen M, Gao L, Chen ZH, Glessner JT, Lenstra JA, Esmailizadeh A, Li MH, Lv FH. Genome-Wide Detection of Copy Number Variations and Their Association With Distinct Phenotypes in the World's Sheep. Front Genet 2021; 12:670582. [PMID: 34093663 PMCID: PMC8175073 DOI: 10.3389/fgene.2021.670582] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/31/2021] [Indexed: 11/19/2022] Open
Abstract
Copy number variations (CNVs) are a major source of structural variation in mammalian genomes. Here, we characterized the genome-wide CNV in 2059 sheep from 67 populations all over the world using the Ovine Infinium HD (600K) SNP BeadChip. We tested their associations with distinct phenotypic traits by conducting multiple independent genome-wide tests. In total, we detected 7547 unique CNVs and 18,152 CNV events in 1217 non-redundant CNV regions (CNVRs), covering 245 Mb (∼10%) of the whole sheep genome. We identified seven CNVRs with frequencies correlating to geographical origins and 107 CNVRs overlapping 53 known quantitative trait loci (QTLs). Gene ontology and pathway enrichment analyses of CNV-overlapping genes revealed their common involvement in energy metabolism, endocrine regulation, nervous system development, cell proliferation, immune, and reproduction. For the phenotypic traits, we detected significantly associated (adjusted P < 0.05) CNVRs harboring functional candidate genes, such as SBNO2 for polycerate; PPP1R11 and GABBR1 for tail weight; AKT1 for supernumerary nipple; CSRP1, WNT7B, HMX1, and FGFR3 for ear size; and NOS3 and FILIP1 in Wadi sheep; SNRPD3, KHDRBS2, and SDCCAG3 in Hu sheep; NOS3, BMP1, and SLC19A1 in Icelandic; CDK2 in Finnsheep; MICA in Romanov; and REEP4 in Texel sheep for litter size. These CNVs and associated genes are important markers for molecular breeding of sheep and other livestock species.
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Affiliation(s)
- Hosein Salehian-Dehkordi
- CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Ya-Xi Xu
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Song-Song Xu
- CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Xin Li
- CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Ling-Yun Luo
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Ya-Jing Liu
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Dong-Feng Wang
- CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Yin-Hong Cao
- CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Min Shen
- State Key Laboratory of Sheep Genetic Improvement and Healthy Breeding, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Lei Gao
- State Key Laboratory of Sheep Genetic Improvement and Healthy Breeding, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Ze-Hui Chen
- CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), Beijing, China.,College of Life Sciences, University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Joseph T Glessner
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Johannes A Lenstra
- Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Ali Esmailizadeh
- Department of Animal Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Meng-Hua Li
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Feng-Hua Lv
- College of Animal Science and Technology, China Agricultural University, Beijing, China
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Li X, Tian S, Wang Y, Liu J, Wang J, Lu Y. Broccoli microgreens juice reduces body weight by enhancing insulin sensitivity and modulating gut microbiota in high-fat diet-induced C57BL/6J obese mice. Eur J Nutr 2021; 60:3829-3839. [PMID: 33866422 DOI: 10.1007/s00394-021-02553-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE This study aimed to explore the protective effect of broccoli microgreens juice (BMJ) during C57BL/6J mice obesity development. METHODS The obese model mice, induced by feeding high-fat diet (HFD), were treated with BMJ by gavage for 10 weeks. Melbine was gavaged at 300 mg/(kg bw)/d, as a positive control group. RESULTS BMJ supplementation significantly reduced white adipose tissues (WAT) mass, the body weight and adipocyte size, and increased water intake in HFD-fed mice. Moreover, it improved glucose tolerance, reduced insulin level and HOMA-IR value, and alleviated insulin resistance. Compared with the HFD group, BMJ supplementation significantly increased the relative abundance of Bacteroidetes and decreased the ratio of Firmicutes to Bacteroidetes at the phylum level, and enriched Bacteroides_acidifaciens at the species level. These changes in the composition of gut microbiota are associated with the production of short-chain fatty acids (SCFAs), and reduced LPS levels, and had an obvious anti-inflammatory effect. CONCLUSIONS These findings suggested that the protective effects of BMJ on diet-induced obesity may be involved in gut microbiota-SCFAs-LPS-inflammatory axis. In addition, BMJ can enhance liver antioxidant capacity and reduce liver fat accumulation. Consequently, these results sustain BMJ as a novel functional food for obesity, on the basis of its opposing effects on HFD-induced obesity in mice.
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Affiliation(s)
- Xiangfei Li
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, People's Republic of China.,College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, People's Republic of China
| | - Shuhua Tian
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, People's Republic of China
| | - Yunfan Wang
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, People's Republic of China
| | - Jie Liu
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology and Business University, Beijing, 100048, China
| | - Jing Wang
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology and Business University, Beijing, 100048, China
| | - Yingjian Lu
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, People's Republic of China.
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49
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Xia Y, He F, Wu X, Tan B, Chen S, Liao Y, Qi M, Chen S, Peng Y, Yin Y, Ren W. GABA transporter sustains IL-1β production in macrophages. SCIENCE ADVANCES 2021; 7:7/15/eabe9274. [PMID: 33827820 PMCID: PMC8026138 DOI: 10.1126/sciadv.abe9274] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 02/18/2021] [Indexed: 05/03/2023]
Abstract
Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3-ASC-caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.
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Affiliation(s)
- Yaoyao Xia
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Fang He
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Xiaoyan Wu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Bie Tan
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Siyuan Chen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yuexia Liao
- College of Nursing, Yangzhou University, Yangzhou 225009, China
| | - Ming Qi
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Shuai Chen
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Yuanyi Peng
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Yulong Yin
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Wenkai Ren
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China.
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50
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Dietary GABA and its combination with vigabatrin mimic calorie restriction and induce antiobesity-like effects in lean mice. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104367] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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