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Dali R, Langlet F. Tanycytes in the nexus of hypothalamic inflammation, appetite control, and obesity. Physiol Behav 2025; 296:114917. [PMID: 40222438 DOI: 10.1016/j.physbeh.2025.114917] [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: 12/30/2024] [Revised: 03/16/2025] [Accepted: 04/10/2025] [Indexed: 04/15/2025]
Abstract
Hypothalamic inflammation has been identified as a critical factor driving the development of obesity and associated metabolic disorders. This inflammation-related disruption of energy balance relies on alterations in metabolic cues sensing and hypothalamic cellular functions, together leading to overeating and weight gain. Within the hypothalamic cellular networks controlling energy balance, recent studies have highlighted the significance of glial dysfunction in these processes, suggesting that these cells could provide new avenues for weight loss therapies. Glia rapidly activates following the consumption of a high-fat diet, even after a very short exposure, and contributes to the disruption of the entire system through inflammatory crosstalk. This review explores recent progress in understanding the molecular interactions between glial cells and neurons in hypothalamic inflammation related to obesity, diabetes, and associated complications. Notably, it highlights specialized ependymal cells called tanycytes, whose role is still underestimated in hypothalamic inflammation, and examines the potential for targeting this cell type as a treatment strategy for metabolic disorders.
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Affiliation(s)
- Rafik Dali
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Fanny Langlet
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
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2
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Sun YX, Guo JB, Chen BL. Effects of Physical Exercise on High-Fat Diet-Induced Hypothalamic Inflammation: Systematic Review. Mol Neurobiol 2025:10.1007/s12035-025-04927-0. [PMID: 40220246 DOI: 10.1007/s12035-025-04927-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/05/2025] [Indexed: 04/14/2025]
Abstract
The high-fat diet (HFD)-induced hypothalamic inflammatory response is considered a common pathogenic basis for various metabolic diseases. Exercise can improve overall metabolic health, and it exerts a positive impact on local inflammation. The purpose of this systematic review was to evaluate existing evidence and analyze the effects of exercise intervention on the behavior, inflammatory factors, glial cells, and feeding neurons of animals with HFD-induced hypothalamic inflammation. We systematically searched PubMed, Scopus, Ebsco, EMBASE, and Web of Science databases from database establishment to July 2024 to identify all animal studies on exercise intervention in HFD-induced hypothalamic inflammation. Two researchers independently conducted literature screening to determine inclusion in the study. Finally, SYRCLE's risk of bias tool for animal studies was used to assess the risk of bias in the included studies. A total of 11 studies were included. Among them, 10 studies used mice and 1 study used rabbits. Overall, the inclusion of research supported the improvement of behavior, inflammatory factors, glial cells, and feeding neurons in animals with HFD-induced hypothalamic inflammation through exercise. However, 2 studies did not find significant changes in food intake and body weight, and 4 studies found that exercise intervention reduced the expression of anti-inflammatory factors (IL- 10 and SOCS3). Different exercise programs, such as forced and voluntary exercise, may be potential reasons for the differences in outcomes. On the basis of existing evidence, exercise appeared to be a potential protective and preventive factor against HFD-induced hypothalamic inflammation. However, the inconsistent results suggest that further research is needed in the future to thoroughly elucidate the mechanisms by which exercise improves and prevents hypothalamic inflammation.
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Affiliation(s)
- Yu Xue Sun
- The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Jia Bao Guo
- The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Bing Lin Chen
- The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
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3
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Sirajee R, El Khatib S, Dieleman LA, Salla M, Baksh S. ImmunoMet Oncogenesis: A New Concept to Understand the Molecular Drivers of Cancer. J Clin Med 2025; 14:1620. [PMID: 40095546 PMCID: PMC11900543 DOI: 10.3390/jcm14051620] [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: 10/31/2024] [Revised: 02/10/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025] Open
Abstract
The appearance of cancer progresses through a multistep process that includes genetic, epigenetic, mutational, inflammatory and metabolic disturbances to signaling pathways within an organ. The combined influence of these changes will dictate the growth properties of the cells; the direction of further malignancy depends on the severity of these "disturbances". The molecular mechanisms driving abnormal inflammation and metabolism are beginning to be identified and, in some cases, are quite prominent in pre-condition states of cancer and are significant drivers of the malignant phenotype. As such, utilizing signaling pathways linked to inflammation and metabolism as biomarkers of cancer is an emerging method and includes pathways beyond those well characterized to drive metabolism or inflammation. In this review, we will discuss several emerging elements influencing proliferation, inflammation and metabolism that may play a part as drivers of the cancer phenotype. These include AMPK and leptin (linked to metabolism), NOD2/RIPK2, TAK1 (linked to inflammation), lactate and pyruvate transporters (monocarboxylate transporter [MCT], linked to mitochondrial biogenesis and metabolism) and RASSF1A (linked to proliferation, cell death, cell cycle control, inflammation and epigenetics). We speculate that the aforementioned elements are important drivers of carcinogenesis that should be collectively referenced as being involved in "ImmunoMET Oncogenesis", a new tripartite description of the role of elements in driving cancer. This term would suggest that for a better understanding of cancer, we need to understand how proliferation, inflammation and metabolic pathways are impacted and how they influence classical drivers of malignant transformation in order to drive ImmunoMET oncogenesis and the malignant state.
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Affiliation(s)
- Reshma Sirajee
- Faculty of Science, 1-001 CCIS, University of Alberta, Edmonton, AB T6G 2E1, Canada;
| | - Sami El Khatib
- Department of Biological & Chemical Sciences, Bekaa Campus, Lebanese International University, West Bekaa, Khiyara 1106, Lebanon; (S.E.K.); (M.S.)
- Center for Applied Mathematics and Bioinformatics (CAMB), Gulf University for Science and Technology, Kuwait City 32093, Kuwait
| | - Levinus A. Dieleman
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, 113 Street 87 Avenue, Edmonton, AB T6G 2E1, Canada;
| | - Mohamed Salla
- Department of Biological & Chemical Sciences, Bekaa Campus, Lebanese International University, West Bekaa, Khiyara 1106, Lebanon; (S.E.K.); (M.S.)
| | - Shairaz Baksh
- Department of Pediatrics, Biochemistry and Division of Experimental Oncology, Faculty of Medicine and Dentistry, University of Alberta, 113 Street 87 Avenue, Edmonton, AB T6G 2E1, Canada
- Women and Children’s Health Research Institute, Edmonton Clinic Health Academy (ECHA), University of Alberta, 4-081 11405 87 Avenue, Edmonton, AB T6G 1C9, Canada
- BioImmuno Designs, 4747 154 Avenue, Edmonton, AB T5Y 0C2, Canada
- Bio-Stream Diagnostics, 2011 94 Street, Edmonton, AB T6H 1N1, Canada
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Song M, Bai Y, Song F. High-fat diet and neuroinflammation: The role of mitochondria. Pharmacol Res 2025; 212:107615. [PMID: 39842474 DOI: 10.1016/j.phrs.2025.107615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/28/2024] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.
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Affiliation(s)
- Mingxue Song
- Department of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, China.
| | - Yao Bai
- NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100021, China.
| | - Fuyong Song
- Department of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, China.
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Yang S, Li Y, Tian M, Deng W, Liu D, Chen C, Zhu Z, Zheng H, Yang G, Li L, Yang M. Hypothalamic P62 (SQSTM1) regulates energy balance by modulating leptin signaling. Theranostics 2024; 14:6605-6624. [PMID: 39479445 PMCID: PMC11519807 DOI: 10.7150/thno.96480] [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: 03/21/2024] [Accepted: 09/22/2024] [Indexed: 10/30/2024] Open
Abstract
RATIONALE The multifaceted functions of p62 (SQSTM1) are increasingly recognized, but its role in hypothalamic metabolism-associated neurons for energy balance has yet to be elucidated. METHODS Single-nucleus RNA sequencing (snRNA-Seq) was performed on hypothalamic tissues from db/db and db/m mice to explore p62 expression. Overexpression and knockout of p62 in hypothalamic POMC neurons were performed via AAV-mediated gene delivery and Cre-loxP systems. Metabolic outcomes were assessed under normal chow (NCD) and high-fat diet (HFD) conditions. The co-immunoprecipitation and luciferase reporter assays were used to investigate the interaction between p62 and STAT3. RESULTS The snRNA-Seq analysis found that p62 was ubiquitously expressed in hypothalamic neurons, with significantly higher levels in POMC neurons of db/db mice compared to db/m controls. Under NCD or HFD conditions, the absence of p62 in POMC neurons led to increased body weight, decreased energy expenditure and leptin sensitivity, while its overexpression in POMC neurons produced the opposite phenotype. Mechanistically, p62 interacts with STAT3, facilitating its phosphorylation to initiate POMC transcription and amplify leptin sensitivity. CONCLUSION This study demonstrated the capacity of p62 to monogenically regulate the obesity phenotype and emphasized its dual role in managing energy homeostasis through direct modulation of STAT3/POMC signaling and amplification of leptin sensitivity.
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Affiliation(s)
- Shan Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yang Li
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Mingyuan Tian
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Biochemistry and the Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Wuquan Deng
- Department of Endocrinology and Metabolism, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Jiankang Road, Yuzhong District, Chongqing, China
| | - Dongfang Liu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Chen Chen
- Endocrinology, SBMS, Faculty of Medicine, University of Queensland, Brisbane, 4072, Australia
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China
| | - Hongting Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Gangyi Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ling Li
- Department of Clinical Biochemistry and the Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Mengliu Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Schaefer M, Kühnel A, Enge S. Open-label placebos reduce weight in obesity: a randomized controlled trial. Sci Rep 2024; 14:21311. [PMID: 39266589 PMCID: PMC11392943 DOI: 10.1038/s41598-024-69866-7] [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: 04/17/2024] [Accepted: 08/09/2024] [Indexed: 09/14/2024] Open
Abstract
Obesity is a major public health problem worldwide. Different approaches are known to face this problem, for example, dieting, surgery, or drug interventions. It has also been shown that placebos may help to reduce weight and hunger feelings, but the use of placebos is linked to problems with respect to the patient-healthcare-provider relationship. However, recent studies demonstrated that even placebos without deception (open-label placebos) affect symptoms such as pain, anxiety, or emotional distress. Here we aimed to examine whether an open-label placebo may help to lose weight in obesity. Our study included fifty-seven overweight and obese patients who aimed to lose weight using a combination of diet and sports. Patients were randomly divided into two groups. Participants in the open-label placebo group received two placebos each day. A treatment-as-usual group received no pills. Primary outcome included changes of body weight. Secondary outcomes were change of eating behavior and self-management abilities. After 4 weeks we found that participants in the open-label placebo condition lost more weight than the treatment-as-usual group. Furthermore, OLP treatment affected eating behavior. No effects for self-management abilities were found. Although further research is necessary, open-label placebos might help individuals to lose weight.
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Affiliation(s)
- Michael Schaefer
- MSB Medical School Berlin, Rüdesheimer Str. 50, 14197, Berlin, Germany.
| | - Anja Kühnel
- MSB Medical School Berlin, Rüdesheimer Str. 50, 14197, Berlin, Germany
| | - Sören Enge
- MSB Medical School Berlin, Rüdesheimer Str. 50, 14197, Berlin, Germany
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Della Guardia L, Shin AC. Obesity-induced tissue alterations resist weight loss: A mechanistic review. Diabetes Obes Metab 2024; 26:3045-3057. [PMID: 38720199 DOI: 10.1111/dom.15637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 07/10/2024]
Abstract
Interventions aimed at weight control often have limited effectiveness in combating obesity. This review explores how obesity-induced dysfunction in white (WAT) and brown adipose tissue (BAT), skeletal muscle, and the brain blunt weight loss, leading to retention of stored fat. In obesity, increased adrenergic stimulation and inflammation downregulate β-adrenoreceptors and impair catecholaminergic signalling in adipocytes. This disrupts adrenergic-mediated lipolysis, diminishing lipid oxidation in both white and brown adipocytes, lowering thermogenesis and blunting fat loss. Emerging evidence suggests that WAT fibrosis is associated with worse weight loss outcomes; indeed, limiting collagen and laminin-α4 deposition mitigates WAT accumulation, enhances browning, and protects against high-fat-diet-induced obesity. Obesity compromises mitochondrial oxidative capacity and lipid oxidation in skeletal muscle, impairing its ability to switch between glucose and lipid metabolism in response to varying nutrient levels and exercise. This dysfunctional phenotype in muscle is exacerbated in the presence of obesity-associated sarcopenia. Additionally, obesity suppresses sarcolipin-induced sarcoplasmic reticulum calcium ATPase (SERCA) activation, resulting in reduced oxidative capacity, diminished energy expenditure, and increased adiposity. In the hypothalamus, obesity and overnutrition impair insulin and leptin signalling. This blunts central satiety signals, favouring a shift in energy balance toward energy conservation and body fat retention. Moreover, both obese animals and humans demonstrate impaired dopaminergic signalling and diminished responses to nutrient intake in the striatum, which tend to persist after weight loss. This may result in enduring inclinations toward overeating and a sedentary lifestyle. Collectively, the tissue adaptations described pose significant challenges to effectively achieving and sustaining weight loss in obesity.
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Affiliation(s)
- Lucio Della Guardia
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milano, Italy
| | - Andrew C Shin
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
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Malik S, Xavier S, Soch A, Younesi S, Yip J, Slayo M, Barrientos RM, Sominsky L, Spencer SJ. High-fat diet and aging-associated memory impairments persist in the absence of microglia in female rats. Neurobiol Aging 2024; 140:22-32. [PMID: 38703636 DOI: 10.1016/j.neurobiolaging.2024.04.010] [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: 01/06/2024] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 05/06/2024]
Abstract
Aging is associated with a priming of microglia such that they are hypersensitive to further immune challenges. As such high-fat diet during aging can have detrimental effects on cognition that is not seen in the young. However, conflicting findings also suggest that obesity may protect against cognitive decline during aging. Given this uncertainty we aimed here to examine the role of microglia in high-fat, high-sucrose diet (HFSD)-induced changes in cognitive performance in the aging brain. We hypothesised that 8 weeks of HFSD-feeding would alter microglia and the inflammatory milieu in aging and worsen aging-related cognitive deficits in a microglia-dependent manner. We found that both aging and HFSD reduced hippocampal neuron numbers and open field exploration; they also impaired recognition memory. However, the aging-related deficits occurred in the absence of a pro-inflammatory response and the deficits in memory performance persisted after depletion of microglia in the Cx3cr1-Dtr knock-in rat. Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction.
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Affiliation(s)
- Sajida Malik
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia; IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Soniya Xavier
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia
| | - Alita Soch
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
| | - Simin Younesi
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Jackson Yip
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia
| | - Mary Slayo
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia; Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Germany; Center for Mind, Brain and Behavior-CMBB, Giessen, Marburg, Germany
| | - Ruth M Barrientos
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA; Chronic Brain Injury Program, The Ohio State University, Columbus, OH, USA
| | - Luba Sominsky
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia; Barwon Health, Geelong, Victoria, Australia; IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Sarah J Spencer
- School of Health and Biomedical Sciences RMIT University, Melbourne, VIC, Australia.
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Le Thuc O, García-Cáceres C. Obesity-induced inflammation: connecting the periphery to the brain. Nat Metab 2024; 6:1237-1252. [PMID: 38997442 DOI: 10.1038/s42255-024-01079-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 06/11/2024] [Indexed: 07/14/2024]
Abstract
Obesity is often associated with a chronic, low-grade inflammatory state affecting the entire body. This sustained inflammatory state disrupts the coordinated communication between the periphery and the brain, which has a crucial role in maintaining homeostasis through humoural, nutrient-mediated, immune and nervous signalling pathways. The inflammatory changes induced by obesity specifically affect communication interfaces, including the blood-brain barrier, glymphatic system and meninges. Consequently, brain areas near the third ventricle, including the hypothalamus and other cognition-relevant regions, become susceptible to impairments, resulting in energy homeostasis dysregulation and an elevated risk of cognitive impairments such as Alzheimer's disease and dementia. This Review explores the intricate communication between the brain and the periphery, highlighting the effect of obesity-induced inflammation on brain function.
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Affiliation(s)
- Ophélia Le Thuc
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Cristina García-Cáceres
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.
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Tan W, Zhang J, Dai F, Yang D, Gu R, Tang L, Liu H, Cheng YX. Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets. Mol Cell Biochem 2024; 479:467-486. [PMID: 37097332 DOI: 10.1007/s11010-023-04736-w] [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: 02/03/2023] [Accepted: 04/07/2023] [Indexed: 04/26/2023]
Abstract
The nuclear factor κappa B (NF-κB) signaling plays a well-known function in inflammation and regulates a wide variety of biological processes. Low-grade chronic inflammation is gradually considered to be closely related to the pathogenesis of Polycystic ovary syndrome (PCOS). In this review, we provide an overview on the involvement of NF-κB in the progression of PCOS particularly, such as hyperandrogenemia, insulin resistance, cardiovascular diseases, and endometrial dysfunction. From a clinical perspective, progressive recognition of NF-κB pathway provides opportunities for therapeutic interventions aimed at inhibiting pathway-specific mechanisms. With the accumulation of basic experimental and clinical data, NF-κB signaling pathway was recognized as a therapeutic target. Although there have been no specific small molecule NF-κB inhibitors in PCOS, a plethora of natural and synthetic compound have emerged for the pharmacologic intervention of the pathway. The traditional herbs developed for NF-κB pathway have become increasingly popular in recent years. Abundant evidence elucidated that NF-κB inhibitors can significantly improve the symptoms of PCOS. Herein, we summarized evidence relating to how NF-κB pathway is involved in the development and progression of PCOS. Furthermore, we present an in-depth overview of NF-κB inhibitors for therapy interventions of PCOS. Taken together, the NF-κB signaling may be a futuristic treatment strategy for PCOS.
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Affiliation(s)
- Wei Tan
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Jie Zhang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Fangfang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Dongyong Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Ran Gu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Lujia Tang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Hua Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
| | - Yan-Xiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
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11
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Shi S, Wang J, Gong H, Huang X, Mu B, Cheng X, Feng B, Jia L, Luo Q, Liu W, Chen Z, Huang C. PGC-1α-Coordinated Hypothalamic Antioxidant Defense Is Linked to SP1-LanCL1 Axis during High-Fat-Diet-Induced Obesity in Male Mice. Antioxidants (Basel) 2024; 13:252. [PMID: 38397850 PMCID: PMC10885970 DOI: 10.3390/antiox13020252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
High-fat-diet (HFD)-induced obesity parallels hypothalamic inflammation and oxidative stress, but the correlations between them are not well-defined. Here, with mouse models targeting the antioxidant gene LanCL1 in the hypothalamus, we demonstrate that impaired hypothalamic antioxidant defense aggravates HFD-induced hypothalamic inflammation and obesity progress, and these could be improved in mice with elevated hypothalamic antioxidant defense. We also show that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical transcriptional coactivator, is implicated in regulating hypothalamic LanCL1 transcription, in collaboration with SP1 through a direct interaction, in response to HFD-induced palmitic acid (PA) accumulation. According to our results, when exposed to HFD, mice undergo a process of overwhelming hypothalamic antioxidant defense; short-time HFD exposure induces ROS production to activate PGC-1α and elevate LanCL1-mediated antioxidant defense, while long-time exposure promotes ubiquitin-mediated PGC-1α degradation and suppresses LanCL1 expression. Our findings show the critical importance of the hypothalamic PGC-1α-SP1-LanCL1 axis in regulating HFD-induced obesity, and provide new insights describing the correlations of hypothalamic inflammation and oxidative stress during this process.
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Affiliation(s)
- Shuai Shi
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Jichen Wang
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Huan Gong
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiaohua Huang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.H.); (B.F.)
| | - Bin Mu
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiangyu Cheng
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Bin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.H.); (B.F.)
| | - Lanlan Jia
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Qihui Luo
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Wentao Liu
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Zhengli Chen
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Chao Huang
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (S.S.); (J.W.); (H.G.); (B.M.); (X.C.); (L.J.); (Q.L.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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Liu J, Zaidi A, Pike CJ. Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.13.580189. [PMID: 38405877 PMCID: PMC10888944 DOI: 10.1101/2024.02.13.580189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer's disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity. In the brain, obesity drives chronic neuroinflammation that involves microglial activation, however the contributions of microglia-derived TLR4 signaling to the consequences of obesity are poorly understood. To investigate this issue, we first generated mice that carry an inducible, microglia/macrophage-specific deletion of TLR4 that yields long-term TLR4 knockout only in brain indicating microglial specificity. Next, we analyzed the effects of microglial TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets. In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance. In female mice maintained on obesogenic diet, TLR4 deletion partially protected against weight gain, adiposity, and metabolic impairments. Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective. Collectively, these findings demonstrate a central role of microglial TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.
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13
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Lee J, Xue X, Au E, McIntyre WB, Asgariroozbehani R, Panganiban K, Tseng GC, Papoulias M, Smith E, Monteiro J, Shah D, Maksyutynska K, Cavalier S, Radoncic E, Prasad F, Agarwal SM, Mccullumsmith R, Freyberg Z, Logan RW, Hahn MK. Glucose dysregulation in antipsychotic-naive first-episode psychosis: in silico exploration of gene expression signatures. Transl Psychiatry 2024; 14:19. [PMID: 38199991 PMCID: PMC10781725 DOI: 10.1038/s41398-023-02716-8] [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: 11/23/2022] [Revised: 12/10/2023] [Accepted: 12/14/2023] [Indexed: 01/12/2024] Open
Abstract
Antipsychotic (AP)-naive first-episode psychosis (FEP) patients display early dysglycemia, including insulin resistance and prediabetes. Metabolic dysregulation may therefore be intrinsic to psychosis spectrum disorders (PSDs), independent of the metabolic effects of APs. However, the potential biological pathways that overlap between PSDs and dysglycemic states remain to be identified. Using meta-analytic approaches of transcriptomic datasets, we investigated whether AP-naive FEP patients share overlapping gene expression signatures with non-psychiatrically ill early dysglycemia individuals. We meta-analyzed peripheral transcriptomic datasets of AP-naive FEP patients and non-psychiatrically ill early dysglycemia subjects to identify common gene expression signatures. Common signatures underwent pathway enrichment analysis and were then used to identify potential new pharmacological compounds via Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our search results yielded 5 AP-naive FEP studies and 4 early dysglycemia studies which met inclusion criteria. We discovered that AP-naive FEP and non-psychiatrically ill subjects exhibiting early dysglycemia shared 221 common signatures, which were enriched for pathways related to endoplasmic reticulum stress and abnormal brain energetics. Nine FDA-approved drugs were identified as potential drug treatments, of which the antidiabetic metformin, the first-line treatment for type 2 diabetes, has evidence to attenuate metabolic dysfunction in PSDs. Taken together, our findings support shared gene expression changes and biological pathways associating PSDs with dysglycemic disorders. These data suggest that the pathobiology of PSDs overlaps and potentially contributes to dysglycemia. Finally, we find that metformin may be a potential treatment for early metabolic dysfunction intrinsic to PSDs.
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Grants
- R01 DK124219 NIDDK NIH HHS
- R01 HL150432 NHLBI NIH HHS
- R01 MH107487 NIMH NIH HHS
- R01 MH121102 NIMH NIH HHS
- Holds the Meighen Family Chair in Psychosis Prevention, the Cardy Schizophrenia Research Chair, a Danish Diabetes Academy Professorship, a Steno Diabetes Center Fellowship, and a U of T Academic Scholar Award, and is funded by operating grants from the Canadian Institutes of Health Research (CIHR), the Banting and Best Diabetes Center, the Miners Lamp U of T award, CIHR and Canadian Psychiatric Association Glenda MacQueen Memorial Award, and the PSI Foundation.
- Hilda and William Courtney Clayton Paediatric Research Fund and Dr. LG Rao/Industrial Partners Graduate Student Award from the University of Toronto, and Meighen Family Chair in Psychosis Prevention
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- UofT | Banting and Best Diabetes Centre, University of Toronto (BBDC)
- Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship-Master’s program
- Cleghorn Award
- University of Toronto (UofT)
- Centre for Addiction and Mental Health (Centre de Toxicomanie et de Santé Mentale)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
- U.S. Department of Defense (United States Department of Defense)
- Commonwealth of Pennsylvania Formula Fund, The Pittsburgh Foundation
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Affiliation(s)
- Jiwon Lee
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Xiangning Xue
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Emily Au
- Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - William B McIntyre
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Roshanak Asgariroozbehani
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Kristoffer Panganiban
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - George C Tseng
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Emily Smith
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | | | - Divia Shah
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kateryna Maksyutynska
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Samantha Cavalier
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Emril Radoncic
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Femin Prasad
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Sri Mahavir Agarwal
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Robert Mccullumsmith
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
- ProMedica, Toledo, OH, USA
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ryan W Logan
- Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Pharmacology, Physiology & Biophysics, Boston University School of Medicine, Boston, MA, USA
| | - Margaret K Hahn
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
- Centre for Addiction and Mental Health, Toronto, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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14
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Liu S, Song S, Wang S, Cai T, Qin L, Wang X, Zhu G, Wang H, Yang W, Fang C, Wei Y, Zhou F, Yu Y, Lin S, Peng S, Li L. Hypothalamic FTO promotes high-fat diet-induced leptin resistance in mice through increasing CX3CL1 expression. J Nutr Biochem 2024; 123:109512. [PMID: 37907171 DOI: 10.1016/j.jnutbio.2023.109512] [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: 06/26/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/02/2023]
Abstract
Long-term consumption of a high-fat diet (HFD) disrupts energy homeostasis and leads to weight gain. The fat mass and obesity-associated (FTO) gene has been consistently identified to be associated with HFD-induced obesity. The hypothalamus is crucial for regulating energy balance, and HFD-induced hypothalamic leptin resistance contributes to obesity. FTO, an N6-methyladenosine (m6A) RNA methylation regulator, may be a key mediator of leptin resistance. However, the exact mechanisms remain unclear. Therefore, the present study aims to investigate the association between FTO and leptin resistance. After HFD or standard diet (SD) feeding in male mice for 22 weeks, m6A-sequencing and western blotting assays were used to identify target genes and assess protein level, and molecular interaction changes. CRISPR/Cas9 gene knockout system was employed to investigate the potential function of FTO in leptin resistance and obesity. Our data showed that chemokine (C-X3-C motif) ligand 1 (CX3CL1) was a direct downstream target of FTO-mediated m6A modification. Furthermore, upregulation of FTO/CX3CL1 and suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus impaired leptin-signal transducer and activator of transcription 3 signaling, resulting in leptin resistance and obesity. Compared to wild-type (WT) mice, FTO deficiency in leptin receptor-expressing neurons of the hypothalamus significantly inhibited the upregulation of CX3CL1 and SOCS3, and partially ameliorating leptin resistance under HFD conditions. Our findings reveal that FTO involved in the hypothalamic leptin resistance and provides novel insight into the function of FTO in the contribution to hypothalamic leptin resistance and obesity.
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Affiliation(s)
- Shujing Liu
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Shiyu Song
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Shuan Wang
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Tonghui Cai
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, P.R. China
| | - Lian Qin
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Xinzhuang Wang
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Guangming Zhu
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Haibo Wang
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Wenqi Yang
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Chunlu Fang
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Yuan Wei
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Fu Zhou
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China
| | - Yang Yu
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China
| | - Shaozhang Lin
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, P.R. China.
| | - Shuang Peng
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China.
| | - Liangming Li
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China.
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15
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Takahashi K, Yamada T, Katagiri H. Inter-Organ Communication Involved in Brown Adipose Tissue Thermogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1461:161-175. [PMID: 39289280 DOI: 10.1007/978-981-97-4584-5_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Brown and beige adipocytes produce heat from substrates such as fatty acids and glucose. Such heat productions occur in response to various stimuli and are called adaptive non-shivering thermogenesis. This review introduces mechanisms known to regulate brown and beige adipocyte thermogenesis. Leptin and fibroblast growth factor 21 (FGF21) are examples of periphery-derived humoral factors that act on the central nervous system (CNS) and increase brown adipose tissue (BAT) thermogenesis. Additionally, neuronal signals such as those induced by intestinal cholecystokinin and hepatic peroxisome proliferator-activated receptor γ travel through vagal afferent-CNS-sympathetic efferent-BAT pathways and increase BAT thermogenesis. By contrast, some periphery-derived humoral factors (ghrelin, adiponectin, plasminogen activator inhibitor-1, and soluble leptin receptor) act also on CNS but inhibit BAT thermogenesis. Neuronal signals also reduce BAT sympathetic activities and BAT thermogenesis, one such example being signals derived by hepatic glucokinase activation. Beige adipocytes can be induced by myokines (interleukin 6, irisin, and β-aminoisobutyric acid), hepatokines (FGF21), and cardiac-secreted factors (brain natriuretic peptide). Cold temperature and leptin also stimulate beige adipocytes via sympathetic activation. Further investigation on inter-organ communication involving adipocyte thermogenesis may lead to the elucidation of how body temperature is regulated and, moreover, to the development of novel strategies to treat metabolic disorders.
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Affiliation(s)
- Kei Takahashi
- Department of Diabetes, Metabolism and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Hideki Katagiri
- Department of Diabetes, Metabolism and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan
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16
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Kim JD, Copperi F, Diano S. Microglia in Central Control of Metabolism. Physiology (Bethesda) 2024; 39:0. [PMID: 37962895 PMCID: PMC11283896 DOI: 10.1152/physiol.00021.2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/12/2023] [Accepted: 11/12/2023] [Indexed: 11/15/2023] Open
Abstract
Beyond their role as brain immune cells, microglia act as metabolic sensors in response to changes in nutrient availability, thus playing a role in energy homeostasis. This review highlights the evidence and challenges of studying the role of microglia in metabolism regulation.
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Affiliation(s)
- Jung Dae Kim
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, New York, United States
| | - Francesca Copperi
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, New York, United States
| | - Sabrina Diano
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, New York, United States
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York, United States
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, New York, United States
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17
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Engin A. The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:463-487. [PMID: 39287862 DOI: 10.1007/978-3-031-63657-8_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Leptin resistance is induced via leptin signaling blockade by chronic overstimulation of the leptin receptor and intracellular signaling defect or increased hypothalamic inflammation and suppressor of cytokine signaling (SOCS)-3 expression. High-fat diet triggers leptin resistance induced by at least two independent causes: first, the limited ability of peripheral leptin to activate hypothalamic signaling transducers and activators of transcription (STAT) signaling and secondly a signaling defect in leptin-responsive hypothalamic neurons. Central leptin resistance is dependent on decreased leptin transport efficiency across the blood brain barrier (BBB) rather than hypothalamic leptin insensitivity. Since the hypothalamic phosphorylated STAT3 (pSTAT3) represents a sensitive and specific readout of leptin receptor-B signaling, the assessment of pSTAT3 levels is the gold standard. Hypertriglyceridemia is one of important factors to inhibit the transport of leptin across BBB in obesity. Mismatch between high leptin and the amount of leptin receptor expression in obesity triggers brain leptin resistance via increasing hypothalamic inflammation and SOCS-3 expression. Therapeutic strategies that regulate the passage of leptin to the brain include the development of modifications in the structure of leptin analogues as well as the synthesis of new leptin receptor agonists with increased BBB permeability. In the hyperleptinemic state, polyethylene glycol (PEG)-modified leptin is unable to pass through the BBB. Peripheral histone deacetylase (HDAC) 6 inhibitor, tubastatin, and metformin increase central leptin sensitization. While add-on therapy with anagliptin, metformin and miglitol reduce leptin concentrations, the use of long-acting leptin analogs, and exendin-4 lead to the recovery of leptin sensitivity. Contouring surgery with fat removal, and bariatric surgery independently of the type of surgery performed provide significant improvement in leptin concentrations. Although approaches to correcting leptin resistance have shown some success, no clinically effective application has been developed to date. Due to the impairment of central and peripheral leptin signaling, as well as the extensive integration of leptin-sensitive metabolic pathways with other neurons, the effectiveness of methods used to eliminate leptin resistance is extremely limited.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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18
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Guo Q, Chen N, Patel K, Wan M, Zheng J, Cao X. Unloading-Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2305042. [PMID: 37880864 PMCID: PMC10724445 DOI: 10.1002/advs.202305042] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/02/2023] [Indexed: 10/27/2023]
Abstract
Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)-mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH+ sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2-mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated.
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Affiliation(s)
- Qiaoyue Guo
- Department of Orthopedic SurgeryJohns Hopkins University School of MedicineBaltimoreMD21205USA
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Ningrong Chen
- Department of Orthopedic SurgeryJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Kalp Patel
- Department of Orthopedic SurgeryJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Mei Wan
- Department of Orthopedic SurgeryJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Junying Zheng
- Department of Orthopedic SurgeryJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Xu Cao
- Department of Orthopedic SurgeryJohns Hopkins University School of MedicineBaltimoreMD21205USA
- Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreMD21205USA
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Zhao Q, Wu J, Ding Y, Pang Y, Jiang C. Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions. LIFE METABOLISM 2023; 2:load032. [PMID: 39872860 PMCID: PMC11749371 DOI: 10.1093/lifemeta/load032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 01/03/2025]
Abstract
In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.
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Affiliation(s)
- Qixiang Zhao
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Jiayu Wu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yong Ding
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yanli Pang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Changtao Jiang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
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20
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Liu Z, Sun H, Xu S, Wang H, Zhang Z, Wei Y, Kou Y, Wang Y. Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity. Nutr Neurosci 2023; 26:1183-1193. [PMID: 36342063 DOI: 10.1080/1028415x.2022.2142129] [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] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. METHODS Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. RESULTS A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. CONCLUSIONS Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.
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Affiliation(s)
- Zhuanzhuan Liu
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Hongxiang Sun
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Shihong Xu
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Hanying Wang
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Zhiwei Zhang
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Yanxia Wei
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Yanbo Kou
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Yugang Wang
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, People's Republic of China
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21
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Hammerschmidt P, Steculorum SM, Bandet CL, Del Río-Martín A, Steuernagel L, Kohlhaas V, Feldmann M, Varela L, Majcher A, Quatorze Correia M, Klar RFU, Bauder CA, Kaya E, Porniece M, Biglari N, Sieben A, Horvath TL, Hornemann T, Brodesser S, Brüning JC. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nat Commun 2023; 14:7824. [PMID: 38016943 PMCID: PMC10684560 DOI: 10.1038/s41467-023-42595-7] [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: 08/06/2021] [Accepted: 10/17/2023] [Indexed: 11/30/2023] Open
Abstract
Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.
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Affiliation(s)
- Philipp Hammerschmidt
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Sophie M Steculorum
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Max Planck Institute for Metabolism Research, Research Group Neurocircuit Wiring and Function, Cologne, Germany
- National Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany
| | - Cécile L Bandet
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Almudena Del Río-Martín
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Lukas Steuernagel
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Vivien Kohlhaas
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Marvin Feldmann
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany
| | - Luis Varela
- Yale Center for Molecular and Systems Metabolism, Department of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., BML 330, New Haven, CT, 06520, USA
- Laboratory of Glia-Neuron Interactions in the Control of Hunger. Achucarro Basque Center for Neuroscience, Leioa, 48940, Spain
- Ikerbasque-Basque Foundation for Science, Bilbao, 48013, Spain
| | - Adam Majcher
- Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland
- Institute of Clinical Chemistry, University Hospital, Zürich, Switzerland
| | - Marta Quatorze Correia
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
| | - Rhena F U Klar
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
| | - Corinna A Bauder
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Ecem Kaya
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Marta Porniece
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Nasim Biglari
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Anna Sieben
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Tamas L Horvath
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Yale Center for Molecular and Systems Metabolism, Department of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., BML 330, New Haven, CT, 06520, USA
- Laboratory of Glia-Neuron Interactions in the Control of Hunger. Achucarro Basque Center for Neuroscience, Leioa, 48940, Spain
- Ikerbasque-Basque Foundation for Science, Bilbao, 48013, Spain
| | - Thorsten Hornemann
- Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland
- Institute of Clinical Chemistry, University Hospital, Zürich, Switzerland
| | - Susanne Brodesser
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Jens C Brüning
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany.
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
- National Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
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22
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Ullah R, Shen Y, Zhou YD, Fu J. Perinatal metabolic inflammation in the hypothalamus impairs the development of homeostatic feeding circuitry. Metabolism 2023; 147:155677. [PMID: 37543245 DOI: 10.1016/j.metabol.2023.155677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/14/2023] [Accepted: 08/01/2023] [Indexed: 08/07/2023]
Abstract
Over the past few decades, there has been a global increase in childhood obesity. This rise in childhood obesity contributes to the susceptibility of impaired metabolism during both childhood and adulthood. The hypothalamus, specifically the arcuate nucleus (ARC), houses crucial neurons involved in regulating homeostatic feeding. These neurons include proopiomelanocortin (POMC) and agouti-related peptide (AGRP) secreting neurons. They play a vital role in sensing nutrients and metabolic hormones like insulin, leptin, and ghrelin. The neurogenesis of AGRP and POMC neurons completes at birth; however, axon development and synapse formation occur during the postnatal stages in rodents. Insulin, leptin, and ghrelin are the essential regulators of POMC and AGRP neurons. Maternal obesity and postnatal overfeeding or a high-fat diet (HFD) feeding cause metabolic inflammation, disrupted signaling of metabolic hormones, netrin-1, and neurogenic factors, neonatal obesity, and defective neuronal development in animal models; however, the mechanism is unclear. Within the hypothalamus and other brain areas, there exists a wide range of interconnected neuronal populations that regulate various aspects of feeding. However, this review aims to discuss how perinatal metabolic inflammation influences the development of POMC and AGRP neurons within the hypothalamus.
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Affiliation(s)
- Rahim Ullah
- Department of Endocrinology, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, China; Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China
| | - Yi Shen
- Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China.
| | - Yu-Dong Zhou
- Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, China.
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23
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Patra D, Banerjee D, Ramprasad P, Roy S, Pal D, Dasgupta S. Recent insights of obesity-induced gut and adipose tissue dysbiosis in type 2 diabetes. Front Mol Biosci 2023; 10:1224982. [PMID: 37842639 PMCID: PMC10575740 DOI: 10.3389/fmolb.2023.1224982] [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: 05/18/2023] [Accepted: 09/14/2023] [Indexed: 10/17/2023] Open
Abstract
An imbalance in microbial homeostasis, referred to as dysbiosis, is critically associated with the progression of obesity-induced metabolic disorders including type 2 diabetes (T2D). Alteration in gut microbial diversity and the abundance of pathogenic bacteria disrupt metabolic homeostasis and potentiate chronic inflammation, due to intestinal leakage or release of a diverse range of microbial metabolites. The obesity-associated shifts in gut microbial diversity worsen the triglyceride and cholesterol level that regulates adipogenesis, lipolysis, and fatty acid oxidation. Moreover, an intricate interaction of the gut-brain axis coupled with the altered microbiome profile and microbiome-derived metabolites disrupt bidirectional communication for instigating insulin resistance. Furthermore, a distinct microbial community within visceral adipose tissue is associated with its dysfunction in obese T2D individuals. The specific bacterial signature was found in the mesenteric adipose tissue of T2D patients. Recently, it has been shown that in Crohn's disease, the gut-derived bacterium Clostridium innocuum translocated to the mesenteric adipose tissue and modulates its function by inducing M2 macrophage polarization, increasing adipogenesis, and promoting microbial surveillance. Considering these facts, modulation of microbiota in the gut and adipose tissue could serve as one of the contemporary approaches to manage T2D by using prebiotics, probiotics, or faecal microbial transplantation. Altogether, this review consolidates the current knowledge on gut and adipose tissue dysbiosis and its role in the development and progression of obesity-induced T2D. It emphasizes the significance of the gut microbiota and its metabolites as well as the alteration of adipose tissue microbiome profile for promoting adipose tissue dysfunction, and identifying novel therapeutic strategies, providing valuable insights and directions for future research and potential clinical interventions.
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Affiliation(s)
- Debarun Patra
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, Punjab, India
| | - Dipanjan Banerjee
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Assam, India
| | - Palla Ramprasad
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, Punjab, India
| | - Soumyajit Roy
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, Punjab, India
| | - Durba Pal
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Punjab, Punjab, India
| | - Suman Dasgupta
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Assam, India
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24
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Douglass JD, Ness KM, Valdearcos M, Wyse-Jackson A, Dorfman MD, Frey JM, Fasnacht RD, Santiago OD, Niraula A, Banerjee J, Robblee M, Koliwad SK, Thaler JP. Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance. Cell Metab 2023; 35:1613-1629.e8. [PMID: 37572666 PMCID: PMC10528677 DOI: 10.1016/j.cmet.2023.07.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/09/2023] [Accepted: 07/19/2023] [Indexed: 08/14/2023]
Abstract
Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.
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Affiliation(s)
- John D Douglass
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Kelly M Ness
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Martin Valdearcos
- The Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alice Wyse-Jackson
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Mauricio D Dorfman
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Jeremy M Frey
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Rachael D Fasnacht
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Olivia D Santiago
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Anzela Niraula
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Jineta Banerjee
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Megan Robblee
- The Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Suneil K Koliwad
- The Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
| | - Joshua P Thaler
- UW Medicine Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA.
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25
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Isola JVV, Ko S, Ocañas SR, Stout MB. Role of Estrogen Receptor α in Aging and Chronic Disease. ADVANCES IN GERIATRIC MEDICINE AND RESEARCH 2023; 5:e230005. [PMID: 37425648 PMCID: PMC10327608 DOI: 10.20900/agmr20230005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Estrogen receptor alpha (ERα) plays a crucial role in reproductive function in both sexes. It also mediates cellular responses to estrogens in multiple nonreproductive organ systems, many of which regulate systemic metabolic homeostasis and inflammatory processes in mammals. The loss of estrogens and/or ERα agonism during aging is associated with the emergence of several comorbid conditions, particularly in females undergoing the menopausal transition. Emerging data also suggests that male mammals likely benefit from ERα agonism if done in a way that circumvents feminizing characteristics. This has led us, and others, to speculate that tissue-specific ERα agonism may hold therapeutic potential for curtailing aging and chronic disease burden in males and females that are at high-risk of cancer and/or cardiovascular events with traditional estrogen replacement therapies. In this mini-review, we emphasize the role of ERα in the brain and liver, summarizing recent evidence that indicates these two organs systems mediate the beneficial effects of estrogens on metabolism and inflammation during aging. We also discuss how 17α-estradiol administration elicits health benefits in an ERα-dependent manner, which provides proof-of-concept that ERα may be a druggable target for attenuating aging and age-related disease burden.
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Affiliation(s)
- José V. V. Isola
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Sunghwan Ko
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Sarah R. Ocañas
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Michael B. Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
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26
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Dali R, Estrada-Meza J, Langlet F. Tanycyte, the neuron whisperer. Physiol Behav 2023; 263:114108. [PMID: 36740135 DOI: 10.1016/j.physbeh.2023.114108] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/23/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023]
Abstract
Reciprocal communication between neurons and glia is essential for normal brain functioning and adequate physiological functions, including energy balance. In vertebrates, the homeostatic process that adjusts food intake and energy expenditure in line with physiological requirements is tightly controlled by numerous neural cell types located within the hypothalamus and the brainstem and organized in complex networks. Within these neural networks, peculiar ependymoglial cells called tanycytes are nowadays recognized as multifunctional players in the physiological mechanisms of appetite control, partly by modulating orexigenic and anorexigenic neurons. Here, we review recent advances in tanycytes' impact on hypothalamic neuronal activity, emphasizing on arcuate neurons.
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Affiliation(s)
- Rafik Dali
- Department of biomedical sciences, University of Lausanne, 1005 Lausanne, Switzerland
| | - Judith Estrada-Meza
- Department of biomedical sciences, University of Lausanne, 1005 Lausanne, Switzerland
| | - Fanny Langlet
- Department of biomedical sciences, University of Lausanne, 1005 Lausanne, Switzerland.
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27
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Li Y, Zhu S, Du D, Li Q, Xie K, Chen L, Feng X, Wu X, Sun Z, Zhou J, Yang J, Shu G, Wang S, Gao P, Zhu C, Jiang Q, Wang L. TLR4 in POMC neurons regulates thermogenesis in a sex-dependent manner. J Lipid Res 2023; 64:100368. [PMID: 37028769 PMCID: PMC10205441 DOI: 10.1016/j.jlr.2023.100368] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/10/2023] [Accepted: 03/17/2023] [Indexed: 04/08/2023] Open
Abstract
The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.
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Affiliation(s)
- Yongxiang Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Shuqing Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Dan Du
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Qiyong Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Kailai Xie
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Lvshuang Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Xiajie Feng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Xin Wu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Zhonghua Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Jingjing Zhou
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Jinping Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Canjun Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, South China Agricultural University, Guangzhou, Guangdong, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.
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Hong H, Su J, Zhang Y, Xu G, Huang C, Bao G, Cui Z. A novel role of lactate: Promotion of Akt-dependent elongation of microglial process. Int Immunopharmacol 2023; 119:110136. [PMID: 37075668 DOI: 10.1016/j.intimp.2023.110136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/21/2023] [Accepted: 03/31/2023] [Indexed: 04/21/2023]
Abstract
As a key component of the innate immune system, over-activation of microglia that occurs in nervous system diseases is usually accompanied by retraction of their branched processes. Reversal of microglial process retraction is a potential strategy to prevent neuroinflammation. In our previous studies, we reported some molecules that can promote the elongation of microglial processes under in vitro and in vivo conditions, such as butyrate, β-hydroxybutyrate, sulforaphane, diallyl disulfide, compound C, and KRIBB11. Here, we found that lactate, a molecule that mimics endogenous lactic acid and has been shown to suppress neuroinflammation, reversibly triggered significant elongations of processes in microglia under cultured and in vivo conditions. Pretreatment with lactate also prevented lipopolysaccharide (LPS)-induced shortening of microglial processes under cultured and in vivo conditions, pro-inflammatory responses in primary cultured microglia and prefrontal cortex, and depression-like behaviors in mice. Mechanistic studies revealed that incubation with lactate increased phospho-Akt levels in primary cultured microglia and inhibition of Akt blocked the pro-elongation effect of lactate on the microglial process under cultured and in vivo conditions, suggesting that the regulatory effect of lactate on the microglial process is dependent on activation of Akt. Inhibition of Akt also abolished the preventive effect of lactate on LPS-induced inflammatory responses in primary cultured microglia and prefrontal cortex and on LPS-induced depression-like behaviors in mice. Overall, these results demonstrate that lactate can induce Akt-mediated elongation of the microglial process, which appropriately contributes to the inhibition of microglia-mediated neuroinflammation.
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Affiliation(s)
- Hongxiang Hong
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China
| | - Jianbin Su
- Department of Endocrinology, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China
| | - Yi Zhang
- Department of Pharmacy, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated of Nanjing University Medical School, #66 Renmin South Road, Yancheng 224006, Jiangsu Province, China; Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China
| | - Guanhua Xu
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China
| | - Guofeng Bao
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China
| | - Zhiming Cui
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong 226001, Jiangsu Province, China.
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Della Guardia L, Wang L. Fine particulate matter induces adipose tissue expansion and weight gain: Pathophysiology. Obes Rev 2023; 24:e13552. [PMID: 36700515 DOI: 10.1111/obr.13552] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 11/25/2022] [Accepted: 01/08/2023] [Indexed: 01/27/2023]
Abstract
Dysregulations in energy balance represent a major driver of obesity. Recent evidence suggests that environmental factors also play a pivotal role in inducing weight gain. Chronic exposure to fine particulate matter (PM2.5 ) is associated with white adipose tissue (WAT) expansion in animals and higher rates of obesity in humans. This review discusses metabolic adaptions in central and peripheral tissues that promote energy storage and WAT accumulation in PM2.5 -exposed animals and humans. Chronic PM2.5 exposure produces inflammation and leptin resistance in the hypothalamus, decreasing energy expenditure and increasing food intake. PM2.5 promotes the conversion of brown adipocytes toward the white phenotype, resulting in decreased energy expenditure. The development of inflammation in WAT can stimulate adipogenesis and hampers catecholamine-induced lipolysis. PM2.5 exposure affects the thyroid, reducing the release of thyroxine and tetraiodothyronine. In addition, PM2.5 exposure compromises skeletal muscle fitness by inhibiting Nitric oxide (NO)-dependent microvessel dilation and impairing mitochondrial oxidative capacity, with negative effects on energy expenditure. This evidence suggests that pathological alterations in the hypothalamus, brown adipose tissue, WAT, thyroid, and skeletal muscle can alter energy homeostasis, increasing lipid storage and weight gain in PM2.5 -exposed animals and humans. Further studies will enrich this pathophysiological model.
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Affiliation(s)
- Lucio Della Guardia
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Ling Wang
- Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, School of Environment and Health, Jianghan University, Wuhan, China
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30
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Leng L, Yuan Z, Su X, Chen Z, Yang S, Chen M, Zhuang K, Lin H, Sun H, Li H, Xue M, Xu J, Yan J, Chen Z, Yuan T, Zhang J. Hypothalamic Menin regulates systemic aging and cognitive decline. PLoS Biol 2023; 21:e3002033. [PMID: 36928253 PMCID: PMC10019680 DOI: 10.1371/journal.pbio.3002033] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 02/09/2023] [Indexed: 03/18/2023] Open
Abstract
Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.
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Affiliation(s)
- Lige Leng
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
- * E-mail: (LL); (JZ)
| | - Ziqi Yuan
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Xiao Su
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Zhenlei Chen
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Shangchen Yang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Meiqin Chen
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Kai Zhuang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Hui Lin
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Hao Sun
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Huifang Li
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Maoqiang Xue
- Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Jun Xu
- Institute for AI in Medicine, School of Automation, Nanjing University of Information Science and Technology, Nanjing, China
| | - Jingqi Yan
- Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio, United States of America
| | - Zhenyi Chen
- Department of Anesthesiology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Tifei Yuan
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai China
| | - Jie Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Anesthesiology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- * E-mail: (LL); (JZ)
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Fernández-Felipe J, López LL, Cano V, Sánchez-Hita E, Belén Sanz A, Chowen JA, Del Olmo N, Ruiz-Gayo M, Merino B. Regional specific effect of saturated vs unsaturated fat on leptin receptor signalling in mice brain areas regulating feeding. Neurosci Lett 2023; 793:136996. [PMID: 36481371 DOI: 10.1016/j.neulet.2022.136996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022]
Abstract
Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake.
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Affiliation(s)
- Jesús Fernández-Felipe
- AdipoBrain, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain
| | - Lucía L López
- AdipoBrain, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain
| | - Victoria Cano
- AdipoBrain, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain
| | - Enrique Sánchez-Hita
- AdipoBrain, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain
| | - A Belén Sanz
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain
| | - Julie A Chowen
- Departamento de Endocrinología, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, 28009 Madrid, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (CIBEROBN, ISCIII), 28029, Madrid, Spain; IMDEA Alimentación, CEI UAM + CSIC, 28049 Madrid, Spain
| | - Nuria Del Olmo
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain
| | - Mariano Ruiz-Gayo
- AdipoBrain, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain
| | - Beatriz Merino
- AdipoBrain, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28660 Madrid, Spain.
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Obesity-Induced Brain Neuroinflammatory and Mitochondrial Changes. Metabolites 2023; 13:metabo13010086. [PMID: 36677011 PMCID: PMC9865135 DOI: 10.3390/metabo13010086] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/31/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023] Open
Abstract
Obesity is defined as abnormal and excessive fat accumulation, and it is a risk factor for developing metabolic and neurodegenerative diseases and cognitive deficits. Obesity is caused by an imbalance in energy homeostasis resulting from increased caloric intake associated with a sedentary lifestyle. However, the entire physiopathology linking obesity with neurodegeneration and cognitive decline has not yet been elucidated. During the progression of obesity, adipose tissue undergoes immune, metabolic, and functional changes that induce chronic low-grade inflammation. It has been proposed that inflammatory processes may participate in both the peripheral disorders and brain disorders associated with obesity, including the development of cognitive deficits. In addition, mitochondrial dysfunction is related to inflammation and oxidative stress, causing cellular oxidative damage. Preclinical and clinical studies of obesity and metabolic disorders have demonstrated mitochondrial brain dysfunction. Since neuronal cells have a high energy demand and mitochondria play an important role in maintaining a constant energy supply, impairments in mitochondrial activity lead to neuronal damage and dysfunction and, consequently, to neurotoxicity. In this review, we highlight the effect of obesity and high-fat diet consumption on brain neuroinflammation and mitochondrial changes as a link between metabolic dysfunction and cognitive decline.
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Camacho-Morales A, Montalvo-Martínez L, Cruz-Carrillo G, Maldonado-Ruiz R, Trujillo-Villarreal L, Garza-Villarreal E. Prenatal programing of motivated behaviors: can innate immunity prime behavior? Neural Regen Res 2023; 18:280-283. [PMID: 35900403 PMCID: PMC9396490 DOI: 10.4103/1673-5374.346475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli. Accordingly, pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu. Maternal exposure to high-energy dense diets can affect motivated behavior in the offspring leading to addiction and impaired sociability. A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring. While still under investigation, prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring. The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring. We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth. We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.
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Sánchez-Alegría K, Arias C. Functional consequences of brain exposure to saturated fatty acids: From energy metabolism and insulin resistance to neuronal damage. Endocrinol Diabetes Metab 2023; 6:e386. [PMID: 36321333 PMCID: PMC9836261 DOI: 10.1002/edm2.386] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/06/2022] [Accepted: 10/09/2022] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Saturated fatty acids (FAs) are the main component of high-fat diets (HFDs), and high consumption has been associated with the development of insulin resistance, endoplasmic reticulum stress and mitochondrial dysfunction in neuronal cells. In particular, the reduction in neuronal insulin signaling seems to underlie the development of cognitive impairments and has been considered a risk factor for Alzheimer's disease (AD). METHODS This review summarized and critically analyzed the research that has impacted the field of saturated FA metabolism in neurons. RESULTS We reviewed the mechanisms for free FA transport from the systemic circulation to the brain and how they impact neuronal metabolism. Finally, we focused on the molecular and the physiopathological consequences of brain exposure to the most abundant FA in the HFD, palmitic acid (PA). CONCLUSION Understanding the mechanisms that lead to metabolic alterations in neurons induced by saturated FAs could help to develop several strategies for the prevention and treatment of cognitive impairment associated with insulin resistance, metabolic syndrome, or type II diabetes.
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Affiliation(s)
- Karina Sánchez-Alegría
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Clorinda Arias
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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35
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Benbaibeche H, Hichami A, Oudjit B, Haffaf EM, Kacimi G, Koceïr EA, Khan NA. Circulating mir-21 and mir-146a are associated with increased cytokines and CD36 in Algerian obese male participants. Arch Physiol Biochem 2022; 128:1461-1466. [PMID: 32536220 DOI: 10.1080/13813455.2020.1775655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The microRNAs have come up as crucial mediators of energy balance and metabolic control. CD36 is potential biomarker of obesity and metabolic syndrome. This study investigates the concentration of miR-146a and miR-21 and CD 36 in blood samples of obese and healthy young participants. We assessed the association of mir-146a and mir-21 with inflammatory states in Algerian young participants. METHODS Our study included male obese, without co-morbidities (n = 29), and healthy participants (n = 13). miRNA and CD36 expression was measured by real-time RT-PCR, respectively, in serum and blood. RESULTS miR-146a and miR-21 concentrations were significantly decreased; however, CD36 expression was increased in obese subjects. Interestingly, miR-146a and miR-21 concentrations were negatively correlated to IL-6, TNF-α, and CD36 in obese participants. CONCLUSION We demonstrate that the downregulation of miR-146a and miR-21 was associated with upregulation of inflammatory state and increased CD36 expression in obese participants.
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Affiliation(s)
- Hassiba Benbaibeche
- Département des Sciences de la Nature Et de la Vie, Faculté des Sciences, Université d'Alger, Algérie
- Bioenergetics and Intermediary Metabolism Laboratory, Department of Biological Sciences and Physiology, Faculty of Biologic Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | - Aziz Hichami
- Physiologie de la Nutrition & Toxicologie, UMR 1231 INSERM/Université de Bourgogne/Agro-Sup, Dijon, France
| | | | | | | | - Elhadj Ahmed Koceïr
- Bioenergetics and Intermediary Metabolism Laboratory, Department of Biological Sciences and Physiology, Faculty of Biologic Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | - Naim Akhtar Khan
- Physiologie de la Nutrition & Toxicologie, UMR 1231 INSERM/Université de Bourgogne/Agro-Sup, Dijon, France
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Chen X, Huang L, Cui L, Xiao Z, Xiong X, Chen C. Sodium-glucose cotransporter 2 inhibitor ameliorates high fat diet-induced hypothalamic-pituitary-ovarian axis disorders. J Physiol 2022; 600:4549-4568. [PMID: 36048516 PMCID: PMC9826067 DOI: 10.1113/jp283259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/16/2022] [Indexed: 01/11/2023] Open
Abstract
High-fat diet (HFD) consumption is known to be associated with ovulatory disorders among women of reproductive age. Previous studies in animal models suggest that HFD-induced microglia activation contributes to hypothalamic inflammation. This causes the dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis, leading to subfertility. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of lipid-soluble antidiabetic drugs that target primarily the early proximal tubules in kidney. Recent evidence revealed an additional expression site of SGLT2 in the central nervous system (CNS), indicating a promising role of SGLT2 inhibitors in the CNS. In type 2 diabetes patients and rodent models, SGLT2 inhibitors exhibit neuroprotective properties through reduction of oxidative stress, alleviation of cerebral atherosclerosis and suppression of microglia-induced neuroinflammation. Furthermore, clinical observations in patients with polycystic ovary syndrome (PCOS) demonstrated that SGLT2 inhibitors ameliorated patient anthropometric parameters, body composition and insulin resistance. Therefore, it is of importance to explore the central mechanism of SGLT2 inhibitors in the recovery of reproductive function in patients with PCOS and obesity. Here, we review the hypothalamic inflammatory mechanisms of HFD-induced microglial activation, with a focus on the clinical utility and possible mechanism of SGLT2 inhibitors in promoting reproductive fitness.
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Affiliation(s)
- Xiaolin Chen
- Department of EndocrinologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Lili Huang
- School of Biomedical ScienceUniversity of QueenslandBrisbaneQueenslandAustralia
| | - Ling Cui
- Department of Reproduction and InfertilityChengdu Women's and Children's Central HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Zhuoni Xiao
- Reproductive Medical CenterRenmin Hospital of Wuhan UniversityWuhanChina
| | - Xiaoxing Xiong
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Chen Chen
- School of Biomedical ScienceUniversity of QueenslandBrisbaneQueenslandAustralia
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Li Y, Huang X, Yang G, Xu K, Yin Y, Brecchia G, Yin J. CD36 favours fat sensing and transport to govern lipid metabolism. Prog Lipid Res 2022; 88:101193. [PMID: 36055468 DOI: 10.1016/j.plipres.2022.101193] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 06/26/2022] [Accepted: 08/26/2022] [Indexed: 11/24/2022]
Abstract
CD36, located on the cell membrane, transports fatty acids in response to dietary fat. It is a critical fatty acid sensor and regulator of lipid metabolism. The interaction between CD36 and lipid dysmetabolism and obesity has been identified in various models and human studies. Nevertheless, the mechanisms by which CD36 regulates lipid metabolism and the role of CD36 in metabolic diseases remain obscure. Here, we summarize the latest research on the role of membrane CD36 in fat metabolism, with emphasis on CD36-mediated fat sensing and transport. This review also critically discusses the factors affecting the regulation of CD36-mediated fat dysfunction. Finally, we review previous clinical evidence of CD36 in metabolic diseases and consider the path forward.
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Affiliation(s)
- Yunxia Li
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China
| | - Xingguo Huang
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China
| | - Guan Yang
- Department of Infectious Diseases and Public Health, City University of Hong Kong, Hong Kong SAR, China
| | - Kang Xu
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China.
| | - Yulong Yin
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China
| | - Gabriele Brecchia
- Department of Veterinary Medicine, University of Milano, Via dell'Università, 26900 Lodi, Italy
| | - Jie Yin
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China.
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Les approches thérapeutiques non invasives de l’obésité : hier, aujourd’hui et demain. NUTR CLIN METAB 2022. [DOI: 10.1016/j.nupar.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Diet-induced inflammation in the anterior paraventricular thalamus induces compulsive sucrose-seeking. Nat Neurosci 2022; 25:1009-1013. [PMID: 35915173 DOI: 10.1038/s41593-022-01129-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/22/2022] [Indexed: 11/08/2022]
Abstract
Overconsumption of palatable food may initiate neuroadaptive responses in brain reward circuitry that may contribute to eating disorders. Here we report that high-fat diet (HFD) consumption impedes threat-cue-induced suppression of sucrose-seeking in mice. This compulsive sucrose-seeking was due to enhanced cue-triggered neuronal activity in the anterior paraventricular thalamus (aPVT) resulting from HFD-induced microglia activation. Thus, metabolic inflammation in the aPVT produces an adaptive response to threat cues, leading to compulsive food-seeking.
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Liu J, Lai F, Hou Y, Zheng R. Leptin signaling and leptin resistance. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:363-384. [PMID: 37724323 PMCID: PMC10388810 DOI: 10.1515/mr-2022-0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/12/2022] [Indexed: 09/20/2023]
Abstract
With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)-signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.
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Affiliation(s)
- Jiarui Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Futing Lai
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Yujia Hou
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Ruimao Zheng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
- Neuroscience Research Institute, Peking University, Beijing, China
- Key Laboratory for Neuroscience of Ministry of Education, Peking University, Beijing, China
- Key Laboratory for Neuroscience of National Health Commission, Peking University, Beijing 100191, China
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Meng Y, Kautz A. An evidence review of the association of immune and inflammatory markers with obesity-related eating behaviors. Front Immunol 2022; 13:902114. [PMID: 35911732 PMCID: PMC9336186 DOI: 10.3389/fimmu.2022.902114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background Eating behaviors contribute to disproportionate energy intake and are linked to the development of obesity. Animal studies support the role of inflammatory cytokines and chemokines in the regulation of obesity-related eating behaviors and offer a potential target to combat obesity through the modulation of inflammation. However, more complex eating behaviors are present in humans, and their relationships with immune/inflammation markers are unclear. The present study reviewed current literature to synthesize the evidence on the association of immune/inflammation markers with obesity-related eating behaviors in humans. Methods A systematic search of three electronic databases yielded 811 articles, of which 11 met the inclusion criteria. Results The majority of the included studies (91%) were either case-control or cross-sectional studies. A variety of immune/inflammation markers and obesity-related eating behaviors have been assessed in the chosen studies. Three out of four studies identified a positive relationship between C-reactive protein (CRP)/high-sensitivity CRP and loss of control eating. Other inflammatory markers that potentially have a positive relationship with obesity-related eating behaviors include fractalkine and fibrinogen. Additionally, immune molecules, including interferon gamma (INF-γ), interleukin (IL)-7, IL-10, and α-melanocyte-stimulating hormone-reactive immunoglobulin G (α-MSH/IgG) immune complex, may have negative associations with obesity-related eating behaviors. However, most findings were identified by single studies. Conclusion Limited studies have been conducted in humans. Current evidence indicates a potential bi-directional relationship between inflammatory/immune markers and obesity-related eating behaviors. Additional studies with sophisticated research design and comprehensive theoretical models are warranted to further delineate the relationship between immune/inflammation markers and obesity-related eating behaviors.
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Affiliation(s)
- Ying Meng
- School of Nursing, University of Rochester, Rochester, NY, United States
| | - Amber Kautz
- Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, United States
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Song Q, Huang W, Ye W, Yan H, Wang L, Yang Y, Cheng X, Zhang W, Zheng J, He P, He Y, Fang D, Han X. Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression. Front Aging Neurosci 2022; 14:869274. [PMID: 35875795 PMCID: PMC9305198 DOI: 10.3389/fnagi.2022.869274] [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: 02/04/2022] [Accepted: 06/07/2022] [Indexed: 12/18/2022] Open
Abstract
Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.
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Contribution of specific ceramides to obesity-associated metabolic diseases. Cell Mol Life Sci 2022; 79:395. [PMID: 35789435 PMCID: PMC9252958 DOI: 10.1007/s00018-022-04401-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022]
Abstract
Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.
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Li Y, Wei M, Yuan Q, Liu Y, Tian T, Hou L, Zhang J. MyD88 in hepatic stellate cells promotes the development of alcoholic fatty liver via the AKT pathway. J Mol Med (Berl) 2022; 100:1071-1085. [PMID: 35708745 DOI: 10.1007/s00109-022-02196-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/22/2022] [Accepted: 03/28/2022] [Indexed: 10/18/2022]
Abstract
Myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in the Toll-like receptors (TLRs) signalling pathway, is expressed in various liver cells including hepatocytes, Kupffer cells and hepatic stellate cells (HSCs). And yet, the functional role of MyD88 in HSCs is poorly elucidated in alcoholic fatty liver (AFL). Here, to study the functional role of MyD88 in HSCs and the molecular mechanism related to the development of AFL, chronic-binge ethanol mouse models were established in mice with specific MyD88 knockout in quiescent (MyD88GFAP-KO) and activated HSCs (MyD88SMA-KO), respectively. Our results clearly showed an elevated expression of MyD88 in liver tissues of ethanol treated mouse model which harbours the wild type. Intriguingly, ethanol treatment profoundly inhibited inflammation in both MyD88GFAP-KO and MyD88SMA-KO mice, but the suppression of lipogenesis was only observed in MyD88GFAP-KO mice. Molecularly, our study indicated that MyD88 induced osteopontin (OPN) secretion in HSCs, which consequently resulted in activation of AKT signalling pathway and accumulation of fat in hepatocytes. Additionally, our data also suggested that OPN promoted inflammation by activating p-STAT1. Thus, targeting MyD88 may be a potentially represent a promising strategy for the prevention and treatment of AFL. KEY MESSAGES: The expression of MyD88 in HSCs was significantly increased in ethanol-induced liver tissues of wild-type mice. MyD88 deficiency in quiescent HSCs inhibited inflammation and lipogenesis under the ethanol feeding condition. MyD88 deficiency in activated HSCs only inhibited inflammation under the ethanol feeding condition. MyD88 promoted the OPN secretion of HSCs, which further activated the AKT signalling pathway of hepatocytes and upregulated lipogenic gene expression to promote fat accumulation. OPN also promotes inflammation by activating p-STAT1.
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Affiliation(s)
- Yukun Li
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China
| | - Miaomiao Wei
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China
| | - Qi Yuan
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China
| | - Yu Liu
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China
| | - Tian Tian
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China
| | - Lingling Hou
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China.
| | - Jinhua Zhang
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China.
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Nampoothiri S, Nogueiras R, Schwaninger M, Prevot V. Glial cells as integrators of peripheral and central signals in the regulation of energy homeostasis. Nat Metab 2022; 4:813-825. [PMID: 35879459 PMCID: PMC7613794 DOI: 10.1038/s42255-022-00610-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 06/15/2022] [Indexed: 01/03/2023]
Abstract
Communication between the periphery and the brain is key for maintaining energy homeostasis. To do so, peripheral signals from the circulation reach the brain via the circumventricular organs (CVOs), which are characterized by fenestrated vessels lacking the protective blood-brain barrier (BBB). Glial cells, by virtue of their plasticity and their ideal location at the interface of blood vessels and neurons, participate in the integration and transmission of peripheral information to neuronal networks in the brain for the neuroendocrine control of whole-body metabolism. Metabolic diseases, such as obesity and type 2 diabetes, can disrupt the brain-to-periphery communication mediated by glial cells, highlighting the relevance of these cell types in the pathophysiology of such complications. An improved understanding of how glial cells integrate and respond to metabolic and humoral signals has become a priority for the discovery of promising therapeutic strategies to treat metabolic disorders. This Review highlights the role of glial cells in the exchange of metabolic signals between the periphery and the brain that are relevant for the regulation of whole-body energy homeostasis.
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Affiliation(s)
- Sreekala Nampoothiri
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Ruben Nogueiras
- Universidade de Santiago de Compostela-Instituto de Investigation Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatologia de la Obesidad y Nutrition, Santiago de Compostela, Spain
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Vincent Prevot
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France.
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Kaneko K, Takekuma Y, Goto T, Ohinata K. An orally active plant Rubisco-derived peptide increases neuronal leptin responsiveness. Sci Rep 2022; 12:8599. [PMID: 35597815 PMCID: PMC9124197 DOI: 10.1038/s41598-022-12595-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/13/2022] [Indexed: 11/25/2022] Open
Abstract
Nutrient excess, such as the intake of a high-fat diet, reduces hypothalamic responses to exogenously administered leptin and induces dietary obesity; however, orally active components that attenuate neural leptin dysregulation have yet to be identified. We herein demonstrated that YHIEPV, derived from the pepsin-pancreatin digestion of the green leaf protein Rubisco, increased the leptin-induced phosphorylation of STAT3 in ex vivo hypothalamic slice cultures. We also showed that YHIEPV mitigated palmitic acid-induced decreases in leptin responsiveness. Furthermore, orally administered YHIEPV promoted leptin-induced reductions in body weight and food intake in obese mice. In addition, dietary-induced body weight gain was significantly less in mice orally or centrally administered YHIEPV daily than in saline-control mice. Cellular leptin sensitivity and the levels of proinflammatory-related factors, such as IL1β and Socs-3, in the hypothalamus of obese mice were also restored by YHIEPV. YHIEPV blocked cellular leptin resistance induced by forskolin, which activates Epac-Rap1 signaling, and reduced the level of the GTP-bound active form of Rap1 in the brains of obese mice. Collectively, the present results demonstrated that the orally active peptide YHIEPV derived from a major green leaf protein increased neural leptin responsiveness and reduced body weight gain in mice with dietary obesity.
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Affiliation(s)
- Kentaro Kaneko
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan. .,Department of Agricultural Chemistry, School of Agriculture, Meiji University, 1-1-1, Higashimita, Tama-ku, Kawasaki-shi, Kanagawa, 214-8571, Japan.
| | - Yukihiro Takekuma
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan
| | - Kousaku Ohinata
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan.
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Prolonged Activation of Brain CB2 Signaling Modulates Hypothalamic Microgliosis and Astrogliosis in High Fat Diet-Fed Mice. Int J Mol Sci 2022; 23:ijms23105527. [PMID: 35628338 PMCID: PMC9141740 DOI: 10.3390/ijms23105527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 12/19/2022] Open
Abstract
Low-grade inflammation of the hypothalamus is associated with the disturbance of energy balance. The endocannabinoid system has been implicated in the development and maintenance of obesity as well as in the control of immune responses. The type 2 cannabinoid receptor (CB2) signaling has been associated with anti-inflammatory effects. Therefore, in high fat diet (HFD)-induced obese mice, we modulated CB2 signaling and investigated its effects on energy homeostasis and hypothalamic microgliosis/astrogliosis. We observed no effect on caloric intake and body weight gain in control diet-fed animals that received prolonged icv infusion of the CB2 receptor agonist HU308. Interestingly, we observed a decrease in glucose tolerance in HFD-fed animals treated with HU308. Prolonged icv infusion of HU308 increases astrogliosis in the ventromedial nucleus (VMH) of obese animals and reduced HFD-induced microgliosis in the hypothalamic arcuate (ARC) but not in the paraventricular (PVN) or VMH nuclei. These data indicate that central CB2 signaling modulates glucose homeostasis and glial reactivity in obesogenic conditions, irrespective of changes in body weight.
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The central nervous system control of energy homeostasis: high fat diet induced hypothalamic microinflammation and obesity. Brain Res Bull 2022; 185:99-106. [PMID: 35525336 DOI: 10.1016/j.brainresbull.2022.04.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 04/27/2022] [Accepted: 04/30/2022] [Indexed: 11/22/2022]
Abstract
Obesity is believed to arise through the imbalance of energy homeostasis controlled by the central nervous system, where the hypothalamus plays the fundamental role in energy metabolism. In this review, we will provide an overview regarding the functions of POMC neurons and AgRP neurons in acute nucleus of the hypothalamus which mediated the energy metabolism, highlighting their interactions with peripheral organs derived hormones in control of energy homeostasis. Furthermore, the role of high fat diet induced hypothalamic microinflammation in the pathogenesis of obesity will be discussed. We hope this review could help researchers to understand the mechanism of hypothalamus in control of energy metabolism, and design related drugs to block the pathways involving in the impaired metabolism in obese patients.
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Gao D, Jiao J, Wang Z, Huang X, Ni X, Fang S, Zhou Q, Zhu X, Sun L, Yang Z, Yuan H. The roles of cell-cell and organ-organ crosstalk in the type 2 diabetes mellitus associated inflammatory microenvironment. Cytokine Growth Factor Rev 2022; 66:15-25. [PMID: 35459618 DOI: 10.1016/j.cytogfr.2022.04.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 11/30/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a classic metaflammatory disease, and the inflammatory states of the pancreatic islet and insulin target organs have been well confirmed. However, abundant evidence demonstrates that there are countless connections between these organs in the presence of a low degree of inflammation. In this review, we focus on cell-cell crosstalk among local cells in the islet and organ-organ crosstalk among insulin-related organs. In contrast to that in acute inflammation, macrophages are the dominant immune cells causing inflammation in the islets and insulin target organs in T2DM. In the inflammatory microenvironment (IME) of the islet, cell-cell crosstalk involving local macrophage polarization and proinflammatory cytokine production impair insulin secretion by β-cells. Furthermore, organ-organ crosstalk, including the gut-brain-pancreas axis and interactions among insulin-related organs during inflammation, reduces insulin sensitivity and induces endocrine dysfunction. Therefore, this crosstalk ultimately results in a cascade leading to β-cell dysfunction. These findings could have broad implications for therapies aimed at treating T2DM.
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Affiliation(s)
- Danni Gao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China; Peking University Fifth School of Clinical Medicine, Beijing 100730, PR China
| | - Juan Jiao
- Department of Clinical Laboratory, the Seventh Medical Centre of Chinese PLA General Hospital, Beijing 100700, PR China
| | - Zhaoping Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Xiuqing Huang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Xiaolin Ni
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Sihang Fang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Qi Zhou
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Xiaoquan Zhu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Liang Sun
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Ze Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Huiping Yuan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China; Peking University Fifth School of Clinical Medicine, Beijing 100730, PR China.
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50
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Su J, Dou Z, Hong H, Xu F, Lu X, Lu Q, Ye T, Huang C. KRIBB11: A Promising Drug that Promotes Microglial Process Elongation and Suppresses Neuroinflammation. Front Pharmacol 2022; 13:857081. [PMID: 35370703 PMCID: PMC8971675 DOI: 10.3389/fphar.2022.857081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
Microglia are key components of the central innate immune system. The over-activation of microglia, which occurs in nervous system disorders, is usually accompanied with retractions of their ramified processes. Reversing of microglial process retraction is a potential strategy for the prevention of neuroinflammation. Our previous studies have reported some endogenous molecules and drugs that can promote microglial process elongation at conditions in vitro and in vivo, such as butyrate and β-hydroxybutyrate, sulforaphane, and diallyl disulfide. Here, reported another compound that can promote microglial process elongation. We found that KRIBB11, a compound which has been reported to suppress nitric oxide production in microglia, induced significant elongations of the processes in microglia in cultured and in vivo conditions in a reversible manner. KRIBB11 pretreatment also prevented lipopolysaccharide (LPS)-induced shortenings of microglial process in cultured conditions and in vivo conditions, inflammatory responses in primary cultured microglia and the prefrontal cortex, and depression-like behaviors in mice. Mechanistic studies revealed that KRIBB11 incubation up-regulated phospho-Akt in cultured microglia and Akt inhibition blocked the pro-elongation effect of KRIBB11 on microglial process in cultured conditions and in vivo conditions, suggesting that the regulatory effect of KRIBB11 is Akt-dependent. Akt inhibition was also found to abrogate the preventive effect of KRIBB11 on LPS-induced inflammatory responses in primary cultured microglia and prefrontal cortexes as well as LPS-induced depression-like behaviors in mice. Collectively, our findings demonstrated that KRIBB11 is a novel compound that can prevent microglial activation and neuroinflammation-associated behavioral deficits possibly through inducing the Akt-mediated elongation of microglial process.
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Affiliation(s)
- Jianbin Su
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, Nantong, China
- *Correspondence: Jianbin Su, ; Chao Huang,
| | - Zhihua Dou
- Department of Pharmacy, Nantong Third Hospital Affiliated to Nantong University, Nantong, China
| | - Hongxiang Hong
- Department of Spine Surgery, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, Nantong, China
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, Nantong, China
| | - Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
| | - Qun Lu
- Department of Pharmacy, Nantong Third Hospital Affiliated to Nantong University, Nantong, China
| | - Ting Ye
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
- *Correspondence: Jianbin Su, ; Chao Huang,
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