|
1
|
Li J, Sun M, Tang M, Song X, Zheng K, Meng T, Li C, Du L. Mechanism of PI3K/Akt‑mediated mitochondrial pathway in obesity‑induced apoptosis (Review). Biomed Rep 2025; 22:40. [PMID: 39781039 PMCID: PMC11707581 DOI: 10.3892/br.2024.1918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Obesity is a pervasive global health challenge that substantially reduces the quality of life of millions of individuals and impedes social and economic advancement. Obesity is an independent risk factor that contributes to a range of chronic non-communicable metabolic diseases, significantly affecting energy metabolism, mental health, cancer susceptibility, sleep quality, and other physiological processes. The PI3K/AKT signaling pathway, a significant glucose, lipid, and protein metabolism regulator, is integral to cellular growth, survival, and apoptosis. Apoptosis is a highly regulated form of programmed cell death that is critical for immune cell maturation and tissue repair. The present review examines the association between obesity, the PI3K/AKT pathway, and mitochondrial apoptosis to elucidate the potential mechanisms by which obesity may activate apoptotic pathways. These findings provide a theoretical foundation for mitigating obesity-related complications by targeting these critical pathways.
Collapse
Affiliation(s)
- Jiarui Li
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Mingxiu Sun
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Ming Tang
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Xin Song
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Kaize Zheng
- Liaoning University of Traditional Chinese Medicine Xinglin College, Shenyang, Liaoning 110167, P.R. China
| | - Tianwei Meng
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Chengjia Li
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Likun Du
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| |
Collapse
|
|
2
|
Ray SS, Mahapatra A, Gupta P, Suman A, Singh RK. An insight into the molecular mechanisms of persistent organic pollutants (POPs) mediated dysregulation of glucose and lipid homeostasis in Heteropneustes fossilis. Gen Comp Endocrinol 2025; 362:114670. [PMID: 39884368 DOI: 10.1016/j.ygcen.2025.114670] [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: 08/07/2024] [Revised: 01/07/2025] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
The study emphasises how ubiquitous persistent organic pollutants (POPs) are and how terrible they are for the environment, specifically because of their tendency to build up in living things and cause a variety of health problems, including diabetes, obesity, and cardiovascular disorders. Due to POPs affinity for lipid-rich tissues, they accumulate in a variety of organs, where they cause metabolic disruption and initiate various anabolic pathways. Studies that use fish as a model organism clarify the metabolic effects of POPs, demonstrating non-adipose lipid accumulation and abnormal glucose homeostasis. Further research on molecular mechanisms shows that POPs interact with gluconeogenic enzymes, causing blood glucose levels to rise. These results are supported by histological and biochemical examinations of fish exposed to POPs, which show changes in lipid composition and cause cellular damage. Molecular docking computational studies demonstrate POPs propensity for binding to gluconeogenic enzymes, providing insight into their potential to promote hyperglycaemia. This study provides a thorough summary of POPs harmful effects on organisms, highlighting their molecular and toxicological, impacts while arguing for better knowledge of their toxicity to vertebrates' developing embryos.
Collapse
Affiliation(s)
- Shubhendu Shekhar Ray
- Molecular Endocrinology and Toxicology Laboratory (METLab), Department of Zoology, Banaras Hindu University, Varanasi, India.
| | - Archisman Mahapatra
- Molecular Endocrinology and Toxicology Laboratory (METLab), Department of Zoology, Banaras Hindu University, Varanasi, India
| | - Priya Gupta
- Molecular Endocrinology and Toxicology Laboratory (METLab), Department of Zoology, Banaras Hindu University, Varanasi, India
| | - Anjali Suman
- Molecular Endocrinology and Toxicology Laboratory (METLab), Department of Zoology, Banaras Hindu University, Varanasi, India
| | - Rahul Kumar Singh
- Molecular Endocrinology and Toxicology Laboratory (METLab), Department of Zoology, Banaras Hindu University, Varanasi, India.
| |
Collapse
|
|
3
|
Jiménez-Sánchez C, Oberhauser L, Maechler P. Role of fatty acids in the pathogenesis of ß-cell failure and Type-2 diabetes. Atherosclerosis 2024; 398:118623. [PMID: 39389828 DOI: 10.1016/j.atherosclerosis.2024.118623] [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: 07/31/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/12/2024]
Abstract
Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.
Collapse
Affiliation(s)
- Cecilia Jiménez-Sánchez
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Lucie Oberhauser
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.
| |
Collapse
|
|
4
|
Zhang C, Wang H, Li Y, Wang X, Han Y, Gao X, Lai Y, Wang C, Teng W, Shan Z. Association between the triglyceride-glucose index and thyroid disorders: a cross-sectional survey and Mendelian randomization analysis. Endocrine 2024; 86:173-185. [PMID: 38782862 DOI: 10.1007/s12020-024-03858-5] [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: 12/04/2023] [Accepted: 04/30/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Metabolic diseases are associated with thyroid disorders. Insulin resistance is the common pathological basis of metabolic diseases. We explored the relationship between the triglyceride-glucose (TyG) index, a simple insulin-resistance marker, and thyroid disorders. METHODS Eligible TIDE (Thyroid Diseases, Iodine Status and Diabetes Epidemiology) subjects (n = 47,710) were screened with inclusion/exclusion criteria. Thyroid disorder prevalence among different TyG index groups was stratified by sex. Logistic regression evaluated the correlation between the TyG index and thyroid disorders. Multiple linear regression evaluated the association between the TyG index and TSH. Additionally, two-sample Mendelian randomization (MR) using published genome-wide association study data evaluated causality in the association between the TyG index and TSH. RESULTS Men and women with greater TyG indices had a significantly greater prevalence of thyroid disorders than individuals with the lowest quartile (Q1) of TyG index (p < 0.05). Following adjustment for confounding factors, we observed that a greater TyG index significantly increased the risk of subclinical hypothyroidism in men and women (men: Q2: odds ratio (OR) [95% confidence interval (CI)] = 1.22 [1.07-1.38], p = 0.002; Q3: OR [95% CI] = 1.28 [1.12-1.45], p < 0.001; Q4: OR [95% CI] = 1.29 [1.12-1.50], p = 0.001; women: Q2: OR [95% CI] = 1.25 [1.12-1.39], p < 0.001; Q3: OR [95% CI] = 1.47 [1.31-1.64], p < 0.001; Q4: OR [95% CI] = 1.61 [1.43-1.82], p < 0.001). Only among women was the highest TyG index quartile associated with hypothyroidism (OR [95% CI] = 1.70 [1.15-2.50], p = 0.007). Additionally, in men, the association exists only in the more than adequate iodine intake population. In women, the relationship between the TyG index and thyroid disorders disappears after menopause. Furthermore, the TyG index exhibited a linear positive correlation with TSH levels. The MR analysis results revealed a causal relationship between a genetically determined greater TyG index and increased TSH (inverse-variance weighting (IVW): OR [95% CI] = 1.14 [1.02-1.28], p = 0.020); however, this causal relationship disappeared after adjusting for BMI in multivariable MR (MVMR) analysis (MVMR-IVW: OR 1.03, 95% CI 0.87-1.22, p = 0.739). CONCLUSIONS A greater TyG index is associated with hypothyroidism and subclinical hypothyroidism and varies by sex and menopausal status. MR analysis demonstrated that the causal relationship between a genetically determined greater TyG index and elevated TSH levels is confounded or mediated by BMI.
Collapse
Affiliation(s)
- Chenyu Zhang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Haoyu Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Yongze Li
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Xichang Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Yutong Han
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Xiaotong Gao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Yaxin Lai
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Chuyuan Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Weiping Teng
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China
| | - Zhongyan Shan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China.
| |
Collapse
|
|
5
|
Huang P, Zhu Y, Qin J. Research advances in understanding crosstalk between organs and pancreatic β-cell dysfunction. Diabetes Obes Metab 2024; 26:4147-4164. [PMID: 39044309 DOI: 10.1111/dom.15787] [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: 06/18/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.
Collapse
Affiliation(s)
- Peng Huang
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yunling Zhu
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian Qin
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| |
Collapse
|
|
6
|
Yan M, Lin K, Huang D, Li J, Qu X, Chen K. Semaglutide attenuates pathological electrophysiological remodeling in diabetic cardiomyopathy via restoring Cx43 expression. Endocrine 2024; 84:969-979. [PMID: 38647981 DOI: 10.1007/s12020-024-03823-2] [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: 01/24/2024] [Accepted: 04/04/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Semaglutide is a relatively new anti-hyperglycemic agent that was shown to carry cardioprotective potentials. However, the exact effects of semaglutide on diabetic cardiomyopathy (DCM) and their underlining mechanism remain unclear. This study aimed to evaluate the effects of semaglutide on myocardium injury and cardiac function in DCM mice and its potential mechanisms, with emphasis on its effects on Cx43 and electrophysiological remodeling. METHODS C57BL/6 mice were randomly divided into four groups: control group, semaglutide group, diabetes group, and diabetes + semaglutide treatment group. Type 1 diabetes were induced by intraperitoneal injection of streptozotocin. Mice in the semaglutide intervention group were injected subcutaneously with semaglutide (0.15 mg/kg) every week for 8 weeks. The blood glucose, cardiac function, oxidative stress markers, apoptosis, expression of Sirt1, AMPK, Cx43, and electrocardiogram of mice in each group were evaluated. RESULTS Treatment with semaglutide alleviated glucose metabolism disorders and improved cardiac dysfunction in diabetic mice. In addition, semaglutide ameliorated the increase in oxidative stress and apoptosis in diabetic heart. Sirt1/AMPK pathway was activated after semaglutide treatment. Furthermore, diabetic mice showed reduced expression of Cx43 in the myocardium, accompanied by changes in electrocardiogram, including significantly prolonged RR, QRS, QT and QTc interval. Semaglutide treatment restored Cx43 expression and reversed the above-mentioned ECG abnormalities. CONCLUSIONS Our research results showed that semaglutide protected against oxidative stress and apoptosis in diabetic heart, thereby improving cardiac function and electrophysiological remodelling in DCM mice, which may attribute to activation of Sirt1/AMPK pathway and restore of Cx43 expression.
Collapse
Affiliation(s)
- Meiling Yan
- Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China
| | - Kaibin Lin
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Dong Huang
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Jingbo Li
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xinkai Qu
- Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China.
| | - Kankai Chen
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| |
Collapse
|
|
7
|
Hua W, Peng L, Chen XM, Jiang X, Hu J, Jiang XH, Xiang X, Wan J, Long Y, Xiong J, Ma X, Du X. CD36-mediated podocyte lipotoxicity promotes foot process effacement. Open Med (Wars) 2024; 19:20240918. [PMID: 38584832 PMCID: PMC10996993 DOI: 10.1515/med-2024-0918] [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: 01/30/2023] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 04/09/2024] Open
Abstract
Background Lipid metabolism disorders lead to lipotoxicity. The hyperlipidemia-induced early stage of renal injury mainly manifests as podocyte damage. CD36 mediates fatty acid uptake and the subsequent accumulation of toxic lipid metabolites, resulting in podocyte lipotoxicity. Methods Male Sprague-Dawley rats were divided into two groups: the normal control group and the high-fat diet group (HFD). Podocytes were cultured and treated with palmitic acid (PA) and sulfo-N-succinimidyl oleate (SSO). Protein expression was measured by immunofluorescence and western blot analysis. Boron-dipyrromethene staining and Oil Red O staining was used to analyze fatty acid accumulation. Results Podocyte foot process (FP) effacement and marked proteinuria occurred in the HFD group. CD36 protein expression was upregulated in the HFD group and in PA-treated podocytes. PA-treated podocytes showed increased fatty acid accumulation, reactive oxygen species (ROS) production, and actin cytoskeleton rearrangement. However, pretreatment with the CD36 inhibitor SSO decreased lipid accumulation and ROS production and alleviated actin cytoskeleton rearrangement in podocytes. The antioxidant N-acetylcysteine suppressed PA-induced podocyte FP effacement and ROS generation. Conclusions CD36 participated in fatty acid-induced FP effacement in podocytes via oxidative stress, and CD36 inhibitors may be helpful for early treatment of kidney injury.
Collapse
Affiliation(s)
- Wei Hua
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing400000, China
| | - Lan Peng
- Basic Department, Chongqing Medical and Pharmaceutical College, Chongqing401331, China
| | - Xue-mei Chen
- Emergency Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing400042, China
| | - XuShun Jiang
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing400042, China
| | - JianGuo Hu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xian-Hong Jiang
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing400000, China
| | - Xu Xiang
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing400000, China
| | - Jiangmin Wan
- Department of Nephrology, People’s Hospital of Qijiang District, Chongqing401420, China
| | - Yingfei Long
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | | | - Xueyi Ma
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing400000, China
| | - Xiaogang Du
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1, Chongqing 400042, China
| |
Collapse
|
|
8
|
Engin AB. Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:131-166. [PMID: 39287851 DOI: 10.1007/978-3-031-63657-8_5] [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
The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.
Collapse
Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| |
Collapse
|
|
9
|
Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
10
|
Márquez Álvarez CDM, Gómez-Crisóstomo NP, De la Cruz-Hernández EN, El-Hafidi M, Pedraza-Chaverri J, Medina-Campos ON, Martínez-Abundis E. Chronic consumption of imbalance diets high in sucrose or fat induces abdominal obesity with different pattern of metabolic disturbances and lost in Langerhans cells population. Life Sci 2024; 336:122305. [PMID: 38030061 DOI: 10.1016/j.lfs.2023.122305] [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: 08/29/2023] [Revised: 11/15/2023] [Accepted: 11/23/2023] [Indexed: 12/01/2023]
Abstract
AIM Obesity is a worldwide health issue, associated with development of type 2 Diabetes Mellitus. The aim of this study is to analyze the effect of consumption of two hypercaloric diets on metabolic disturbance and beta cells damage. MAIN METHODS Male Wistar rats were subjected to twelve months consumption of three diets: a Control balanced diet (CTD, carbohydrates 58 %, proteins 29 %, lipids 13 %) and two hypercaloric diets, high in sucrose (HSD, carbohydrates 68 %, proteins 22 %, lipids 10 %) or high in fat (HFD, carbohydrates 31 %, proteins 14 %, lipids 55 %). Serum levels of glucose, triglycerides and free fatty acids were measured after zoometric parameters determination. Antioxidant enzymes activity and oxidative stress-marker were measured in pancreas tissue among histological analysis of Langerhans islets. KEY FINDINGS Although diets were hypercaloric, the amount of food consumed by rats decreased, resulting in an equal caloric consumption. The HSD induced hypertriglyceridemia and hyperglycemia with higher levels in free fatty acids (FFA, lipotoxicity); whereas HFD did not increased neither the triglycerides nor FFA, nevertheless the loss of islets' cell was larger. Both diets induced obesity with hyperglycemia and significant reduction in Langerhans islets size. SIGNIFICANCE Our results demonstrate that consumption of HSD induces more significant metabolic disturbances that HFD, although both generated pancreas damage; as well hypercaloric diet consumption is not indispensable to becoming obese; the chronic consumption of unbalanced diets (rich in carbohydrates or lipids) may lead to abdominal obesity with metabolic and functional disturbances, although the total amount of calories are similar.
Collapse
Affiliation(s)
- Corazón de María Márquez Álvarez
- Laboratorio de Investigación en Enfermedades Metabólicas e Infecciosas, División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Ranchería Sur, Cuarta Sección, C.P. 86650 Comalcalco, Tabasco, Mexico
| | - Nancy P Gómez-Crisóstomo
- Laboratorio de Investigación en Enfermedades Metabólicas e Infecciosas, División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Ranchería Sur, Cuarta Sección, C.P. 86650 Comalcalco, Tabasco, Mexico
| | - Erick N De la Cruz-Hernández
- Laboratorio de Investigación en Enfermedades Metabólicas e Infecciosas, División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Ranchería Sur, Cuarta Sección, C.P. 86650 Comalcalco, Tabasco, Mexico
| | - Mohammed El-Hafidi
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, 14080 CDMX, Mexico
| | - José Pedraza-Chaverri
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Omar Noel Medina-Campos
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Eduardo Martínez-Abundis
- Laboratorio de Investigación en Enfermedades Metabólicas e Infecciosas, División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Ranchería Sur, Cuarta Sección, C.P. 86650 Comalcalco, Tabasco, Mexico.
| |
Collapse
|
|
11
|
Engin AB, Engin A. The Checkpoints of Intestinal Fat Absorption in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:73-95. [PMID: 39287849 DOI: 10.1007/978-3-031-63657-8_3] [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
In this chapter, intestinal lipid transport, which plays a central role in fat homeostasis and the development of obesity in addition to the mechanisms of fatty acids and monoacylglycerol absorption in the intestinal lumen and reassembly of these within the enterocyte was described. A part of the resynthesized triglycerides (triacylglycerols; TAG) is repackaged in the intestine to form the hydrophobic core of chylomicrons (CMs). These are delivered as metabolic fuels, essential fatty acids, and other lipid-soluble nutrients, from enterocytes to the peripheral tissues following detachment from the endoplasmic reticulum membrane. Moreover, the attitudes of multiple receptor functions in dietary lipid uptake, synthesis, and transport are highlighted. Additionally, intestinal fatty acid binding proteins (FABPs), which increase the cytosolic flux of fatty acids via intermembrane transfer in enterocytes, and the functions of checkpoints for receptor-mediated fatty acid signaling are debated. The importance of the balance between storage and secretion of dietary fat by enterocytes in determining the physiological fate of dietary fat, including regulation of blood lipid concentrations and energy balance, is mentioned. Consequently, promising checkpoints regarding how intestinal fat processing affects lipid homeostatic mechanisms and lipid stores in the body and the prevention of obesity-lipotoxicity due to excessive intestinal lipid absorption are evaluated. In this context, dietary TAG digestion, pharmacological inhibition of TAG hydrolysis, the regulation of long-chain fatty acid uptake traffic into adipocytes, intracellular TAG resynthesis, the enlargement of cytoplasmic lipid droplets in enterocytes and constitutional alteration of their proteome, CD36-mediated conversion of diet-derived fatty acid into cellular lipid messengers and their functions are discussed.
Collapse
Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - 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
| |
Collapse
|
|
12
|
Engin AB, Engin ED, Engin A. Targeted Nano-Based Systems for the Anti-Obesity Agent's Delivery. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:657-676. [PMID: 39287868 DOI: 10.1007/978-3-031-63657-8_22] [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
Obesity is a global health concern and a chronic disease that is accompanied by excessive fat storage in adipose and nonadipose tissues. An increase in the body-mass index (BMI) is directly proportional to the 2- to 3.9-fold increase in all-cause mortality in obesity. If left untreated for a longer period, obesity-related metabolic, cardiovascular, inflammatory, and malignant diseases reduce life expectancy. Currently, most of the anti-obesity drugs have failed and fallen into disrepute, either due to their ineffectiveness or adverse effects. In this review, depending on their enhanced pharmacokinetic and biodistribution profiles, whether nanocarriers alter the basic properties and bioactivity of anti-obesity drugs used in clinical practice are debated. First, nanocarriers can improve the safety of still-used anti-obesity drugs by lowering their systemic toxicity through increasing targeting efficacy and preventing drug carrier toxicity. Second, when the micro-ribonucleic acids (miRNAs), which are aberrantly expressed in obesity and obesity-related diseases, are encapsulated into nanoparticles, they are effective in multiple obesity-related metabolic pathways and gene networks. Finally, a synergistic anti-obesity effect with low dose and low toxicity can be obtained with the combinatory therapy applied by encapsulating the anti-obesity drug and gene in the same nanocarrier delivery vehicle.
Collapse
Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Evren Doruk Engin
- Biotechnology Institute, Ankara University, Gumusdere, Ankara, Turkey
| | - 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
| |
Collapse
|
|
13
|
Priscila Busch Furlan C, Berilli Batista P, Akemi Kido L, Garbellini Duft R, Regina Cavaglieri C, de Oliveira Carvalho P, Roberto Maróstica Junior M. Synergistic effect rescue animal model from NASH caused by diet-inflammation inducer. Food Res Int 2023; 174:113562. [PMID: 37986439 DOI: 10.1016/j.foodres.2023.113562] [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: 03/21/2023] [Revised: 10/03/2023] [Accepted: 10/09/2023] [Indexed: 11/22/2023]
Abstract
Excessive intake of pro-inflammatory fatty acids is related to the development of insulin resistance, impaired oxidative stress enzymes, and lipid disorders, leading to inflammation and development of non-alcoholic steatohepatitis (NASH). Diet and physical exercise are considered to prevent and treat metabolic disorders caused by chronic inflammatory states (responsible for insulin resistance and diabetes type 2) in individuals with obesity and nonalcoholic fatty liver diseases (NAFLD). Our investigation tested the hypothesis that Hass avocado oil, a monounsaturated fatty acid and a source of phytosterol, may improve liver and metabolic parameters without adverse effects when combined with physical exercise. Rats ingested a high-fat diet for seven weeks and were then subjected to more six weeks with a standard diet, Hass avocado-oil ingestion, and swimming. The intervention showed significantly improvements by synergistic effect between Hass avocado-oil and swimming exercise (P < 0.05), including improving adiponectin, leptin, and fasting blood glucose levels, alleviating insulin resistance, reducing serum TNF-α, improving glutathione enzyme levels, and decreasing lipotoxicity in the liver and blood and serum triacylglycerides in blood (P < 0.05). Liver tissue markers of apoptosis and necrosis such as CK-18 filaments and dimethylamine (DMA) were significantly higher in the intervention group (P < 0.05). We were unable to fully confirm our hypothesis. Although the synergistic effects between Hass avocado-oil and the swimming regimen offer a promising chance of recovering liver health by improving 10 health biological markers, we must not ignore the cellular damage due to apoptosis and necrosis in liver cells and DMA. The data on metabolomic profile and avocado-oil-treated livers highlight the need for further investigation.
Collapse
Affiliation(s)
- Cibele Priscila Busch Furlan
- Department of Food and Nutrition, Faculty of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Patricia Berilli Batista
- Department of Food and Nutrition, Faculty of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Larissa Akemi Kido
- Department of Food and Nutrition, Faculty of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Renata Garbellini Duft
- Laboratory of Exercise Physiology, Faculty of Physical Education, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Claudia Regina Cavaglieri
- Laboratory of Exercise Physiology, Faculty of Physical Education, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | | | | |
Collapse
|
|
14
|
Wan S, Xie J, Liang Y, Yu X. Pathological roles of bone marrow adipocyte-derived monocyte chemotactic protein-1 in type 2 diabetic mice. Cell Death Discov 2023; 9:412. [PMID: 37957155 PMCID: PMC10643445 DOI: 10.1038/s41420-023-01708-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/23/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has become a prevalent public health concern, with beta-cell dysfunction involved in its pathogenesis. Bone marrow adipose tissue (BMAT) increases in both the quantity and area in individuals with T2DM along with heightened monocyte chemotactic protein-1 (MCP-1) secretion. This study aims to investigate the influence and underlying mechanisms of MCP-1 originating from bone marrow adipocytes (BMAs) on systemic glucose homeostasis in T2DM. Initially, a substantial decrease in the proliferation and glucose-stimulated insulin secretion (GSIS) of islet cells was observed. Moreover, a comparative analysis between the control (Ctrl) group and db/db mice revealed significant alterations in the gene expression profiles of whole bone marrow cells, with a noteworthy upregulation of Mcp-1. And the primary enriched pathways included chemokine signaling pathway and AGE-RAGE signaling pathway in diabetic complications. In addition, the level of MCP-1 was distinctly elevated in BMA-derived conditional media (CM), leading to a substantial inhibition of proliferation, GSIS and the protein level of phosphorylated Akt (p-Akt) in Min6 cells. After blocking MCP-1 pathway, we observed a restoration of p-Akt and the proliferation of islet cells, resulting in a marked improvement in disordered glucose homeostasis. In summary, there is an accumulation of BMAs in T2DM, which secrete excessive MCP-1, exacerbating the abnormal accumulation of BMAs in the bone marrow cavity through paracrine signaling. The upregulated MCP-1, in turn, worsens glucose metabolism disorder by inhibiting the proliferation and insulin secretion of islet cells through an endocrine pathway. Inhibiting MCP-1 signaling can partially restore the proliferation and insulin secretion of islet cells, ultimately ameliorating glucose metabolism disorder. It's worth noting that to delve deeper into the impact of MCP-1 derived from BMAs on islet cells and its potential mechanisms, it is imperative to develop genetically engineered mice with conditional Mcp-1 knockout from BMAs.
Collapse
Affiliation(s)
- Shan Wan
- Laboratory of Endocrinology and Metabolism/Department of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jinwei Xie
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Liang
- Core Facilities of West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism/Department of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China.
| |
Collapse
|
|
15
|
Macon EL, Harris P, Bailey S, Caldwell Barker A, Adams A. Identifying possible thresholds for nonstructural carbohydrates in the insulin dysregulated horse. Equine Vet J 2023; 55:1069-1077. [PMID: 36537847 DOI: 10.1111/evj.13910] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 11/10/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND Identifying intake levels of nonstructural carbohydrates (NSCs) that limit the postprandial insulinaemic response in the insulin dysregulated (ID) horse may help reduce hyperinsulinaemia-associated laminitis (HAL) risk. OBJECTIVE To determine if ID horses have thresholds for pure sources of starch and sugar, above which there is an augmented insulin response. STUDY DESIGN Randomised crossover experiment. METHODS Fourteen adult horses (6 ID and 8 noninsulin dysregulated, NID; matched for bodyweight) were randomly fed eight dietary treatments. Dietary treatments were formulated using a base of low-nonstructural carbohydrate pellet (LNSC; 0.04 g of water-soluble carbohydrates (WSCs)/kg bwt and 0.01 g of starch/kg bwt), to which pure sugar (dextrose) or starch (50:50 mix of waxy-maize and oat starch powder) sources were titrated to create diets with increasing amounts of either WSC (0.06-0.17 g WSC/kg bwt), or starch (0.03-0.1 g starch/kg bwt). Horses were fed each dietary treatment at a rate of 1 g/kg bwt once over 12 weeks. Serial blood samples were collected pre- and up to 240 min postprandially. Insulin was determined via RIA and diet analytes were determined via wet chemistry. Statistical analysis was performed with a mixed effect model. Positive incremental area under the curve for insulin (IAUCi) was calculated for all horses and dietary treatments. RESULTS There was no significant effect of diet in NID horses but diets with NSC >0.1 g/kg bwt produced an augmented response in ID horses compared with the LNSC (p < 0.05). ID horses IAUCi were also significantly different to all NID IAUCi for diets with NSC >0.1 g/kg (p < 0.04). Apparent thresholds for sugar and starch addition varied. CONCLUSIONS Based on this study, using supplemental pure starch and sugar sources, ID horses seem to have an apparent threshold for NSC of around 0.1 g/kg bwt/meal, above which significantly increased insulin responses are seen compared with NID horses.
Collapse
Affiliation(s)
- Erica Lyn Macon
- 108 M.H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, Kentucky, USA
| | - Patricia Harris
- Equine Studies Group, Waltham Petcare Science Institute, Leicestershire, UK
| | - Simon Bailey
- Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Amanda Adams
- Mars Equestrian™ Fellow, Department of Veterinary Science, M.H. Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, USA
| |
Collapse
|
|
16
|
Nagy N, Kaber G, Sunkari VG, Marshall PL, Hargil A, Kuipers HF, Ishak HD, Bogdani M, Hull RL, Grandoch M, Fischer JW, McLaughlin TL, Wight TN, Bollyky PL. Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes. Matrix Biol 2023; 123:34-47. [PMID: 37783236 PMCID: PMC10841470 DOI: 10.1016/j.matbio.2023.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low concentrations of HA were present in healthy pancreatic islets. However, HA substantially accumulated in cadaveric islets of T2D patients and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the main HA receptor CD44, preserved glycemic control and insulin concentrations in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserved glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we found that 4-MU increased the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation did not result in β-cell apoptosis. These data indicated a role for HA accumulation in diabetes pathogenesis and suggested that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.
Collapse
Affiliation(s)
- Nadine Nagy
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | - Gernot Kaber
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | - Vivekananda G Sunkari
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | - Payton L Marshall
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | - Aviv Hargil
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | - Hedwich F Kuipers
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | - Heather D Ishak
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA
| | | | - Rebecca L Hull
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA
| | - Maria Grandoch
- Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Jens W Fischer
- Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Tracey L McLaughlin
- Department of Medicine, Medicine - Endocrinology, Endocrine Clinic, Stanford School of Medicine, Stanford, CA, USA
| | | | - Paul L Bollyky
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA.
| |
Collapse
|
|
17
|
Liu W, Zhu M, Gong M, Zheng W, Zeng X, Zheng Q, Li X, Fu F, Chen Y, Cheng J, Rao Z, Lu Y, Chen Y. Comparison of the Effects of Monounsaturated Fatty Acids and Polyunsaturated Fatty Acids on Liver Lipid Disorders in Obese Mice. Nutrients 2023; 15:3200. [PMID: 37513618 PMCID: PMC10386220 DOI: 10.3390/nu15143200] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Obesity is a recognized epidemic worldwide, and the accumulation of excess free saturated fatty acids (SFAs) in cells induces cellular lipotoxic damage and increases the risk of a wide spectrum of metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat SFA-induced cellular damage. However, the comparative studies of the two types of unsaturated fatty acids (UFAs) are still limited. We investigated the effects of different MUFAs and PUFAs in the human hepatocyte line L-02 cells in vitro, and in high-fat-diet (HFD)-induced obese C57BL/6 mice in vivo. The results of the in vitro study showed that SFAs induced significant cellular lipotoxic damage, but the combination of MUFAs/PUFAs with SFAs significantly improved the impaired cell viability. Particularly, oleic acid (OA) was superior to eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and arachidonic acid (AA) in terms of its anti-apoptotic effect and inhibition of endoplasmic reticulum (ER) stress. In vivo, both olive-oil-enriched (HFD + OO) and fish-oil-enriched high-fat diets (HFD + FO) reduced hepatic steatosis and improved insulin sensitivity in obese mice. However, FO induced an abnormal increase in serum aspartate aminotransferase (AST) and an increase in the oxidative stress indicator Malondialdehyde (MDA). Liver-targeted lipidomic analysis showed that liver lipid metabolites under the two types of UFA dietary interventions differed from the HFD group, modulating the abundance of some lipid metabolites such as triglycerides (TGs) and glycerophospholipids. Furthermore, the FO diet significantly increased the abundance of the associated FA 20:5 long-chain lipid metabolites, whereas the OO diet regulated the unsaturation of all fatty acids in general and increased the abundance of FA 18:1 in the overall lipid metabolites, especially TGs, which may primarily contribute to the FO, and OO drove protection in NAFLD.
Collapse
Affiliation(s)
- Wen Liu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Min Zhu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meng Gong
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China
- Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wen Zheng
- Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xin Zeng
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qing Zheng
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoyu Li
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Fudong Fu
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Yingyi Chen
- Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jingqiu Cheng
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Zhiyong Rao
- Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanrong Lu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Younan Chen
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China
| |
Collapse
|
|
18
|
Li T, Jin Y, Wu J, Ren Z. Beyond energy provider: multifunction of lipid droplets in embryonic development. Biol Res 2023; 56:38. [PMID: 37438836 DOI: 10.1186/s40659-023-00449-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 06/23/2023] [Indexed: 07/14/2023] Open
Abstract
Since the discovery, lipid droplets (LDs) have been recognized to be sites of cellular energy reserves, providing energy when necessary to sustain cellular life activities. Many studies have reported large numbers of LDs in eggs and early embryos from insects to mammals. The questions of how LDs are formed, what role they play, and what their significance is for embryonic development have been attracting the attention of researchers. Studies in recent years have revealed that in addition to providing energy for embryonic development, LDs in eggs and embryos also function to resist lipotoxicity, resist oxidative stress, inhibit bacterial infection, and provide lipid and membrane components for embryonic development. Removal of LDs from fertilized eggs or early embryos artificially leads to embryonic developmental arrest and defects. This paper reviews recent studies to explain the role and effect mechanisms of LDs in the embryonic development of several species and the genes involved in the regulation. The review contributes to understanding the embryonic development mechanism and provides new insight for the diagnosis and treatment of diseases related to embryonic developmental abnormalities.
Collapse
Affiliation(s)
- Tai Li
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China
| | - Yi Jin
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China
| | - Jian Wu
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China
- Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, China
| | - Zhuqing Ren
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China.
- Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, 430070, China.
- Hubei Hongshan Laboratory, Wuhan, China.
| |
Collapse
|
|
19
|
Solovieva AO, Sitnikova NA, Nimaev VV, Koroleva EA, Manakhov AM. PRP of T2DM Patient Immobilized on PCL Nanofibers Stimulate Endothelial Cells Proliferation. Int J Mol Sci 2023; 24:ijms24098262. [PMID: 37175994 PMCID: PMC10179416 DOI: 10.3390/ijms24098262] [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: 03/21/2023] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Diabetic foot ulcers (DFU) are a common complication of Type 2 Diabetes Mellitus (T2DM). Development of bioactive wound healing covers is an important task in medicine. The use of autologous platelet-rich plasma (PRP) consisting of growth factors, cytokines and components of extracellular matrix is a perspective approach for DFU treatment, but we previously found that some T2DM PRP samples have a toxic effect on mesenchymal stem cells (MSCs) in vitro. Here, we covalently immobilized T2DM PRP proteins on polycaprolactone (PCL) nanofibers, and the growth of endothelial cells on the PCL-COOH-PRP was investigated. Additionally, the level of NO reflecting the cytotoxic effects of PRP, angiogenin, and VEGF levels were measured in T2DM PRP samples. The results showed that the application of PCL-COOH-PRP nanofibers allows to remove the cytotoxicity of T2DM PRP and to improve endothelial cell adhesion and proliferative activity. We showed that the origin of T2DM PRP (the level of PRP toxicity or presence/absence of DFU) does not influence the efficiency of cell growth on PCL-COOH-PRP, and on the level of angiogenin, vascular epidermal growth factor (VEGF) in PRP itself.
Collapse
Affiliation(s)
- Anastasiya O Solovieva
- Research Institute of Clinical and Experimental Lymphology-Branch of the ICG SB RAS, 2 Timakova Str., 630060 Novosibirsk, Russia
| | - Natalia A Sitnikova
- Research Institute of Clinical and Experimental Lymphology-Branch of the ICG SB RAS, 2 Timakova Str., 630060 Novosibirsk, Russia
| | - Vadim V Nimaev
- Research Institute of Clinical and Experimental Lymphology-Branch of the ICG SB RAS, 2 Timakova Str., 630060 Novosibirsk, Russia
| | - Elena A Koroleva
- Research Institute of Clinical and Experimental Lymphology-Branch of the ICG SB RAS, 2 Timakova Str., 630060 Novosibirsk, Russia
| | - Anton M Manakhov
- Research Institute of Clinical and Experimental Lymphology-Branch of the ICG SB RAS, 2 Timakova Str., 630060 Novosibirsk, Russia
| |
Collapse
|
|
20
|
Nagy N, Kaber G, Sunkari VG, Marshall PL, Hargil A, Kuipers HF, Ishak HD, Bogdani M, Hull RL, Grandoch M, Fischer JW, McLaughlin TL, Wight TN, Bollyky PL. Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.28.530522. [PMID: 36909502 PMCID: PMC10002695 DOI: 10.1101/2023.02.28.530522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We have identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low levels of HA are present in healthy pancreatic islets. However, HA substantially accumulates in cadaveric islets of human T2D and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the major HA receptor CD44, preserve glycemic control and insulin levels in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserve glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we find that 4-MU increases the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation does not result in β-cell apoptosis. These data indicate a role for HA accumulation in diabetes pathogenesis and suggest that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.
Collapse
|
|
21
|
Yu S, Wang B, Guo X, Li G, Yang H, Sun Y. Weight-Adjusted-Waist Index Predicts Newly Diagnosed Diabetes in Chinese Rural Adults. J Clin Med 2023; 12:jcm12041620. [PMID: 36836156 PMCID: PMC9961347 DOI: 10.3390/jcm12041620] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 02/22/2023] Open
Abstract
The relationship between the weight-adjusted waist index (WWI) and newly diagnosed type 2 diabetes (T2D) remains uncertain. This study intended to explore the association between the WWI and the incidence of newly diagnosed T2D among participants in rural areas of China. In the Northeast China Rural Cardiovascular Health Study, 9205 non-diabetic individuals (mean age 53 ± 10, 53.1% women) without T2D were included at baseline during 2012-2013. They were followed up from 2015 to 2017. WWI was calculated as waist circumference (cm) divided by the square root of weight (kg). We used multivariate logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the probability of new diagnoses across three WWI categories. A total of 358 participants had been diagnosed with T2D during a median follow-up of 4.6 years. After adjusting for potential confounders, compared with the lowest WWI category (<9.79 cm/√kg in men; <10.06 in women), men with WWI 10.06-10.72 and ≥10.37 cm/√kg showed OR (95%CI) for T2D 1.200 (0.816, 1.767) and 1.604 (1.088, 2.364), respectively, while women with WWI 10.06-10.72 and ≥10.37 cm/√kg showed ORs (95%CIs) for T2D 1.191 (0.703, 2.018) and 1.604 (1.088, 2.364), respectively. The ORs were generally consistent on subgroup analysis by gender, age, body mass index, and current smoking and drinking status. Increasing WWI was significantly associated with a higher incidence of newly diagnosed T2D among rural Chinese adults. Our findings help clarify the harmful effect of increasing WWI on newly diagnosed T2D and provide evidence for formulating healthcare policy in rural China.
Collapse
Affiliation(s)
- Shasha Yu
- Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China
| | - Bo Wang
- Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China
| | - Xiaofan Guo
- Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China
| | - Guangxiao Li
- Department of Clinical Epidemiology, Institute of Cardiovascular Diseases, First Hospital of China Medical University, Shenyang 110001, China
| | - Hongmei Yang
- Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China
| | - Yingxian Sun
- Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China
- Correspondence: ; Tel.: +86-02483282888; Fax: +86-24-8328-2346
| |
Collapse
|
|
22
|
Sun K, Li X, Scherer PE. Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives. Compr Physiol 2023; 13:4387-4407. [PMID: 36715281 PMCID: PMC9957663 DOI: 10.1002/cphy.c220020] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fibrosis in adipose tissue is a major driver of obesity-related metabolic dysregulation. It is characterized by an overaccumulation of extracellular matrix (ECM) during unhealthy expansion of adipose tissue in response to over nutrition. In obese adipose-depots, hypoxia stimulates multiple pro-fibrotic signaling pathways in different cell populations, thereby inducing the overproduction of the ECM components, including collagens, noncollagenous proteins, and additional enzymatic components of ECM synthesis. As a consequence, local fibrosis develops. The result of fibrosis-induced mechanical stress not only triggers cell necrosis and inflammation locally in adipose tissue but also leads to system-wide lipotoxicity and insulin resistance. A better understanding of the mechanisms underlying the obesity-induced fibrosis will help design therapeutic approaches to reduce or reverse the pathological changes associated with obese adipose tissue. Here, we aim to summarize the major advances in the field, which include newly identified fibrotic factors, cell populations that contribute to the fibrosis in adipose tissue, as well as novel mechanisms underlying the development of fibrosis. We further discuss the potential therapeutic strategies to target fibrosis in adipose tissue for the treatment of obesity-linked metabolic diseases and cancer. © 2023 American Physiological Society. Compr Physiol 13:4387-4407, 2023.
Collapse
Affiliation(s)
- Kai Sun
- Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Xin Li
- Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Philipp E. Scherer
- Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
- Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| |
Collapse
|
|
23
|
Mo H, Liu Y, Zhang M, Qiu Z, Li Y, Zhang Z, Li Y, Xu G. The Role of Pancreatic Fatty Acid Synthesis in Islet Morphology and Function after Caloric Restriction or Roux-En-Y Gastric Bypass Surgery in Mice. Genes (Basel) 2022; 14:genes14010005. [PMID: 36672747 PMCID: PMC9858859 DOI: 10.3390/genes14010005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/11/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Both caloric restriction (CR) and Roux-en-Y gastric bypass (RYGB) are practical interventions for type 2 diabetes mellitus (T2DM), while the molecular mechanisms of CR and RYGB regarding glycemic control are still poorly understood. Here, we explore the effects and underlying mechanisms of CR and RYGB on β-cell area and function. METHODS Average islet size was measured by histological analysis. The pancreatic lipid content was detected by using a commercial lipid assay kit. The expression levels of lipogenic transcription factors and enzymes in mouse pancreas were determined by quantitative PCR, Western blot, and immunofluorescence. RESULTS CR decreased the mean size of islets and pancreatic insulin production in both regular diet-fed and high-fat diet-fed mice. Increased β-cell apoptosis was detected in the calorie-restricted mice. Interestingly, the lipogenic transcription factors and enzymes such as SREBP1c, PPARγ, FASN and ACC were upregulated in the pancreas after CR. In contrast to CR, RYGB decreased the apoptosis of β-cells and the expression of fatty acid synthase. CONCLUSIONS Pancreatic fatty acid synthesis is critical to the β-cell function after CR and RYGB.
Collapse
Affiliation(s)
- Haocong Mo
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Yang Liu
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Mengyuan Zhang
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Zirui Qiu
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Yilin Li
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Zhejiao Zhang
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Yanting Li
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Geyang Xu
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
- Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou 510317, China
- Correspondence:
| |
Collapse
|
|
24
|
UPLC-ESI-QTOF-MS Profiling of Phenolic Compounds from Eriocephalus africanus: In Vitro Antioxidant, Antidiabetic, and Anti-Inflammatory Potentials. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248912. [PMID: 36558046 PMCID: PMC9782900 DOI: 10.3390/molecules27248912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/08/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
The present study investigated phenolic compounds, antioxidant, antidiabetic, and the anti-inflammatory potentials of methanolic and chloroform extracts of Eriocephalus africanus. The methanolic extract included, polyphenols (112 ± 2.81 mg gallic acid equivalent (GAE)/g), flavonols (76.12 ± 7.95 mg quercetin equivalents (QE)/g); antioxidant capacity (Ferric Reducing Antioxidant Power (FRAP) (752.64 ± 89.0 μmol of ascorbic acid equivalents (AAE) per g dry weight (µmol AAE/g), 2,2-dyphenyl-1-picrylhydrazyl (DPPH) (812.18 ± 51.12 Trolox equivalents per gram of dry mass of plant extracts (μmol TE/g), TEAC (631.63 ± 17.42 µmol TE/g)), while the chloroform extract included polyphenols (39.93 ± 1.36 mg GAE/g), flavonols (44.81 ± 3.74 mg QE/g); antioxidant capacity, DPPH (58.70 ± 5.18 µmol TE/g), TEAC (118.63 ± 3.74 µmol TE/g) and FRAP (107.10 ± 2.41 µmol AAE/g). The phytochemicals profiling performed by UPLC-ESI-QTOF-MS revealed some important polyphenols, predominantly flavonoids, that could be responsible for the antioxidant capacity and biological effects. Both extracts demonstrated a dose-dependent manner of the alpha-glucosidase inhibition with an IC50 between 125 and 250 μg/mL for methanolic extract, while the chloroform extract was at 250 μg/mL. In the L6 myoblasts and C3A hepatocytes, the methanolic extract slightly increased the utilization of glucose, and both extracts exhibited a dose-dependent increase in the glucose uptake in both cell types without significantly increasing the cytotoxicity. Furthermore, both extracts exhibited an anti-inflammatory potential and the findings from the present study could serve as a baseline for further research in the development of pharmaceutical agents.
Collapse
|
|
25
|
Joffin N, Gliniak CM, Funcke JB, Paschoal VA, Crewe C, Chen S, Gordillo R, Kusminski CM, Oh DY, Geldenhuys WJ, Scherer PE. Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations. Nat Metab 2022; 4:1474-1494. [PMID: 36329217 PMCID: PMC11750126 DOI: 10.1038/s42255-022-00664-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 09/20/2022] [Indexed: 11/05/2022]
Abstract
Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
Collapse
Affiliation(s)
- Nolwenn Joffin
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Christy M Gliniak
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jan-Bernd Funcke
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Vivian A Paschoal
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Clair Crewe
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Cell Biology, Washington University, St. Louis, MO, USA
| | - Shiuhwei Chen
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ruth Gordillo
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Christine M Kusminski
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Da Young Oh
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Werner J Geldenhuys
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|
|
26
|
Lu Z, Sun GF, Pan XA, Qu XH, Yang P, Chen ZP, Han XJ, Wang T. BCATc inhibitor 2 ameliorated mitochondrial dysfunction and apoptosis in oleic acid-induced non-alcoholic fatty liver disease model. Front Pharmacol 2022; 13:1025551. [PMID: 36386234 PMCID: PMC9650408 DOI: 10.3389/fphar.2022.1025551] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/18/2022] [Indexed: 09/14/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent hepatic disease in the world. Disorders of branched chain amino acid (BCAA) metabolism is involved in various diseases. In this study, we aim to explore the role of BCAA metabolism in the development of NAFLD and the protective effect of BCATc Inhibitor 2, an inhibitor of cytosolic branched chain amino acid transaminase, against NAFLD as well as its underlying mechanism. It was found that oleic acid induced lipid accumulation and apoptosis in HepG2 and LO2 cells. Supplementation of BCAAs further aggravated oleic acid-induced lipid accumulation and apoptosis. In contrast, treatment of BCATc Inhibitor 2 ameliorated oleic acid-induced lipid accumulation and apoptosis. Molecularly, supplementation of BCAAs or treatment of BCATc Inhibitor 2 up-regulated or down-regulated the expression of SREBP1 and lipogenesis-related genes without affecting lipolysis-related genes. BCATc Inhibitor 2 maintained mitochondrial function by ameliorating oleic acid-induced mitochondrial ROS generation and mitochondrial membrane potential disruption. In addition, BCATc Inhibitor 2 treatment alleviated oleic acid-induced activation of JNK and AKT signaling pathway and Bcl2/Bax/Caspase axis. In conclusion, our results indicate BCAA metabolism is involved in NAFLD and BCATc Inhibitor 2 protects against oleic acid-induced lipid accumulation and apoptosis. These findings suggest that BCATc Inhibitor 2 is a promising candidate drug for the treatment of NAFLD.
Collapse
Affiliation(s)
- Zhuo Lu
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Gui-Feng Sun
- Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China
| | - Xiao-An Pan
- Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China
| | - Xin-Hui Qu
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Ping Yang
- Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Zhi-Ping Chen
- Department of Critical Care Medicine, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Xiao-Jian Han
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China
- Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Tao Wang
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| |
Collapse
|
|
27
|
Diamanti K, Cavalli M, Pereira MJ, Pan G, Castillejo-López C, Kumar C, Mundt F, Komorowski J, Deshmukh AS, Mann M, Korsgren O, Eriksson JW, Wadelius C. Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues. Cell Rep Med 2022; 3:100763. [PMID: 36198307 PMCID: PMC9589007 DOI: 10.1016/j.xcrm.2022.100763] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/02/2022] [Accepted: 09/13/2022] [Indexed: 11/28/2022]
Abstract
Environmental and genetic factors cause defects in pancreatic islets driving type 2 diabetes (T2D) together with the progression of multi-tissue insulin resistance. Mass spectrometry proteomics on samples from five key metabolic tissues of a cross-sectional cohort of 43 multi-organ donors provides deep coverage of their proteomes. Enrichment analysis of Gene Ontology terms provides a tissue-specific map of altered biological processes across healthy, prediabetes (PD), and T2D subjects. We find widespread alterations in several relevant biological pathways, including increase in hemostasis in pancreatic islets of PD, increase in the complement cascade in liver and pancreatic islets of PD, and elevation in cholesterol biosynthesis in liver of T2D. Our findings point to inflammatory, immune, and vascular alterations in pancreatic islets in PD that are hypotheses to be tested for potential contributions to hormonal perturbations such as impaired insulin and increased glucagon production. This multi-tissue proteomic map suggests tissue-specific metabolic dysregulations in T2D.
Collapse
Affiliation(s)
- Klev Diamanti
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Marco Cavalli
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Maria J Pereira
- Department of Medical Sciences, Clinical Diabetes and Metabolism, Uppsala University, Uppsala, Sweden
| | - Gang Pan
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Casimiro Castillejo-López
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Chanchal Kumar
- Translational Science & Experimental Medicine, Early Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Department of Medicine, Novum, Huddinge, Sweden
| | - Filip Mundt
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Jan Komorowski
- Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden; Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA; Swedish Collegium for Advanced Study, Uppsala, Sweden
| | - Atul S Deshmukh
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Jan W Eriksson
- Department of Medical Sciences, Clinical Diabetes and Metabolism, Uppsala University, Uppsala, Sweden
| | - Claes Wadelius
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
| |
Collapse
|
|
28
|
Zhang M, Tu W, Zhang Q, Wu X, Zou X, Jiang S. Osteocalcin reduces fat accumulation and inflammatory reaction by inhibiting ROS-JNK signal pathway in chicken embryonic hepatocytes. Poult Sci 2022; 101:102026. [PMID: 36174267 PMCID: PMC9519800 DOI: 10.1016/j.psj.2022.102026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/16/2022] [Accepted: 06/18/2022] [Indexed: 11/24/2022] Open
Abstract
Osteocalcin (OCN) has a function in preventing fatty liver hemorrhagic syndrome (FLHS) in poultry. The aim of this study was to investigate the effects of OCN on fat emulsion stimulated chicken embryonic hepatocytes and related signaling pathways. The primary chicken embryonic hepatocytes were isolated from the incubated 15-day (E15) pathogen free eggs and cultured with dulbecco's modified eagle medium (DMEM). After the hepatocyte density reached 80%, the cells were divided into 5 groups: control group (CONT), fat emulsion group (FE, 10% FE, v/v), FE with ucOCN at 1 ng/mL (FE-LOCN), 3 ng/mL (FE-MOCN), and 9 ng/mL (FE-HOCN). In addition, 2 mM N-Acetyl-L-cysteine (NAC) a reactive oxygen species (ROS) scavenger, and 5 μM SP600125, a Jun N-terminal kinase (JNK) inhibitor, were added separately in to the DMEM with 10% FE to test effects of FE on the function of ROS-JNK signal pathway. The number of hepatocytes, cell ultra-microstructure, viability, and apoptosis were detected after 48 h treatment, and the protein expressions and enzyme concentrations were detected after 72 h treatment. The results showed that, compared to the control group, FE increased the triglyceride (TG) concentration and lipid droplets (LDs) in chicken embryonic hepatocytes (P < 0.05), and induced hepatocytic edema with obviously mitochondrial swelling, membrane damage, and cristae rupture. FE also decreased ATP concentration, increased ROS concentrations and mitochondrial DNA (mtDNA) copy number, promoted inflammatory interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α) concentrations and hepatocytic apoptosis rate, and raised phospho-c-Jun N-terminal kinase (p-JNK) protein expressions. Compared to the FE group, ucOCN significantly increased hepatocyte viability, reduced hepatocytic TG concentrations and LDs numbers, and alleviated hepatocytic edema and mitochondrial swelling. Furthermore, ucOCN significantly decreased ROS concentrations, increased ATP concentrations, reduced IL-1, IL-6, TNF-α concentrations and hepatocytic apoptosis rate, and inhibited p-JNK protein expressions (P < 0.05). NAC had the similar functions of ucOCN reduced the ROS concentration and inhibited the TNF-α protein expression and p-JNK/JNK ration. Similarly, SP600125 reduced p-JNK/JNK protein expression, IL-1, IL-6, TNF-α, and TG concentrations without effects on ROS concentration and hepatocytic apoptosis. These results suggest that ucOCN alleviates FE-induced mitochondrial damage, cellular edema, and apoptosis of hepatocytes. These results reveal that the functions of ucOCN in reducing fat accumulation and inflammatory reaction in chicken embryonic hepatocytes are mostly via inhibiting the ROS-JNK signal pathway.
Collapse
|
|
29
|
Hu L, Zhang Q, Bai Y, Hu G, Li J. Triglyceride-Glucose Index Correlate With Telomere Length in Healthy Adults From the National Health and Nutrition Examination Survey. Front Endocrinol (Lausanne) 2022; 13:844073. [PMID: 35721750 PMCID: PMC9201959 DOI: 10.3389/fendo.2022.844073] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
AIM The present investigation was designed to test the association between leukocyte telomere length (LTL) and two simple markers of insulin resistance, that is, homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride-glucose (TyG) index in U.S. adults without metabolic diseases. METHODS A total of 6489 U.S. adults without diabetes from NHANES 1999-2002 were analyzed. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. HOMA-Index was calculated as fasting plasma glucose (mmol/L) × fasting serum insulin (mU/mL)/22.5. LTL was obtained using the quantitative polymerase chain reaction method. Multivariate linear regression analysis was assessed to evaluate the association of TyG index HOMA-IR with LTL. We further conducted a generalized additive model (GAM) and a fitted smoothing curve with penalized spline method. RESULTS It was found that the mean LTL was 5796.1 bp in the measured healthy adults. Overall, TyG index was significantly associated with LTL, while HOMA-IR was not. Compared with participants in tertile 1 of the TyG index, the β (95% CI) for those in the second (8.27 to 8.77) and third (≥ 8.77) were -4.31 (95% CI: -48.12~39.49) and -95.98 (95% CI: -145.08~-46.89), respectively. Subjects with TyG index ≥ 8.77 had statistically significant shorter LTL (β = -93.33, 95%CI: -134.33~-52.32), compared with TyG index < 8.77. We further explored a dose-response relation between TyG index by a decile approach [≤ 7.81 (reference), 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, 8.52-8.68, 8.68-8.83, 8.83-9.03, 9.03-9.33, and >9.33] and LTL. Five subgroups (TyG index 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, and 8.52-8.68) did not show significant effect on LTL; while there was a significantly shorter LTL for participants with the TyG index > 8.68, supporting a threshold effect of TyG index on LTL. CONCLUSIONS The results suggested that higher TyG index (> 8.68) was closely related to shorter LTL and the TyG index was better associated with LTL than HOMA-IR.
Collapse
Affiliation(s)
- Lihua Hu
- Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Qiaojian Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, China
| | - Yi Bai
- Department of Epidemiology and Health Statistics, Peking University, Beijing, China
| | - Guiping Hu
- School of Engineering Medicine, Beihang University, Beijing, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, and Advanced Innovation Centre for Biomedical Engineering, Beihang University, Beijing, China
- *Correspondence: Guiping Hu, ; Jianping Li,
| | - Jianping Li
- Department of Cardiology, Peking University First Hospital, Beijing, China
- *Correspondence: Guiping Hu, ; Jianping Li,
| |
Collapse
|
|
30
|
Park J, Heo YJ, Kwon S. Interaction Between Hepatocytes and Proximal Tubular Epithelial Cells in Hypoxia-induced Lipotoxicity. BIOTECHNOL BIOPROC E 2021. [DOI: 10.1007/s12257-021-0137-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
|
|
31
|
Oberhauser L, Maechler P. Lipid-Induced Adaptations of the Pancreatic Beta-Cell to Glucotoxic Conditions Sustain Insulin Secretion. Int J Mol Sci 2021; 23:324. [PMID: 35008750 PMCID: PMC8745448 DOI: 10.3390/ijms23010324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 12/16/2022] Open
Abstract
Over the last decades, lipotoxicity and glucotoxicity emerged as established mechanisms participating in the pathophysiology of obesity-related type 2 diabetes in general, and in the loss of β-cell function in particular. However, these terms hold various potential biological processes, and it is not clear what precisely they refer to and to what extent they might be clinically relevant. In this review, we discuss the basis and the last advances of research regarding the role of free fatty acids, their metabolic intracellular pathways, and receptor-mediated signaling related to glucose-stimulated insulin secretion, as well as lipid-induced β-cell dysfunction. We also describe the role of chronically elevated glucose, namely, glucotoxicity, which promotes failure and dedifferentiation of the β cell. Glucolipotoxicity combines deleterious effects of exposures to both high glucose and free fatty acids, supposedly provoking synergistic defects on the β cell. Nevertheless, recent studies have highlighted the glycerolipid/free fatty acid cycle as a protective pathway mediating active storage and recruitment of lipids. Finally, we discuss the putative correspondence of the loss of functional β cells in type 2 diabetes with a natural, although accelerated, aging process.
Collapse
Affiliation(s)
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism, Faculty Diabetes Center, University of Geneva Medical Center, 1206 Geneva, Switzerland;
| |
Collapse
|
|
32
|
Sex differences in white adipose tissue expansion: emerging molecular mechanisms. Clin Sci (Lond) 2021; 135:2691-2708. [PMID: 34908104 DOI: 10.1042/cs20210086] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/15/2021] [Accepted: 11/29/2021] [Indexed: 12/15/2022]
Abstract
The escalating prevalence of individuals becoming overweight and obese is a rapidly rising global health problem, placing an enormous burden on health and economic systems worldwide. Whilst obesity has well described lifestyle drivers, there is also a significant and poorly understood component that is regulated by genetics. Furthermore, there is clear evidence for sexual dimorphism in obesity, where overall risk, degree, subtype and potential complications arising from obesity all differ between males and females. The molecular mechanisms that dictate these sex differences remain mostly uncharacterised. Many studies have demonstrated that this dimorphism is unable to be solely explained by changes in hormones and their nuclear receptors alone, and instead manifests from coordinated and highly regulated gene networks, both during development and throughout life. As we acquire more knowledge in this area from approaches such as large-scale genomic association studies, the more we appreciate the true complexity and heterogeneity of obesity. Nevertheless, over the past two decades, researchers have made enormous progress in this field, and some consistent and robust mechanisms continue to be established. In this review, we will discuss some of the proposed mechanisms underlying sexual dimorphism in obesity, and discuss some of the key regulators that influence this phenomenon.
Collapse
|
|
33
|
Gonzalez MB, Robker RL, Rose RD. Obesity and oocyte quality: Significant implications for ART and Emerging mechanistic insights. Biol Reprod 2021; 106:338-350. [PMID: 34918035 DOI: 10.1093/biolre/ioab228] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/22/2021] [Accepted: 12/07/2021] [Indexed: 11/14/2022] Open
Abstract
The prevalence of obesity in adults worldwide, and specifically in women of reproductive age, is concerning given the risks to fertility posed by the increased risk of type 2 diabetes, metabolic syndrome and other non-communicable diseases. Obesity has a multi-systemic impact in female physiology that is characterized by the presence of oxidative stress, lipotoxicity, and the activation of pro-inflammatory pathways, inducing tissue-specific insulin resistance and ultimately conducive to abnormal ovarian function. A higher body mass is linked to Polycystic Ovary Syndrome, dysregulated menstrual cycles, anovulation, and longer time to pregnancy, even in ovulatory women. In the context of ART, compared to women of normal BMI, obese women have worse outcomes in every step of their journey, resulting in reduced success measured as live birth rate. Even after pregnancy is achieved, obese women have a higher chance of miscarriage, gestational diabetes, pregnancy complications, birth defects, and most worryingly, a higher risk of stillbirth and neonatal death. The potential for compounding effects of ART on pregnancy complications and infant morbidities in obese women has not been studied. There is still much debate in the field on whether these poorer outcomes are mainly driven by defects in oocyte quality, abnormal embryo development or an unaccommodating uterine environment, however the clinical evidence to date suggests a combination of all three are responsible. Animal models of maternal obesity shed light on the mechanisms underlaying the effects of obesity on the peri-conception environment, with recent findings pointing to lipotoxicity in the ovarian environment as a key driver of defects in oocytes that have not only reduced developmental competence but long-lasting effects in offspring health.
Collapse
Affiliation(s)
- Macarena B Gonzalez
- Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Rebecca L Robker
- Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Ryan D Rose
- Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia.,Fertility SA, St. Andrews Hospital, Adelaide, South Australia, Australia
| |
Collapse
|
|
34
|
Sasaki H, Saisho Y, Inaishi J, Itoh H. Revisiting Regulators of Human β-cell Mass to Achieve β-cell-centric Approach Toward Type 2 Diabetes. J Endocr Soc 2021; 5:bvab128. [PMID: 34405128 PMCID: PMC8361804 DOI: 10.1210/jendso/bvab128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell–centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.
Collapse
Affiliation(s)
- Hironobu Sasaki
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Inaishi
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
35
|
Sun X, Ji G, Li P, Li W, Li J, Zhu L. miR-344-5p Modulates Cholesterol-Induced β-Cell Apoptosis and Dysfunction Through Regulating Caveolin-1 Expression. Front Endocrinol (Lausanne) 2021; 12:695164. [PMID: 34394002 PMCID: PMC8355992 DOI: 10.3389/fendo.2021.695164] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a metabolic disorder induced by the modulation of insulin on glucose metabolism, and the dysfunction and decreased number of islets β-cells are the main causes of T2DM (type 2 diabetes mellitus). Among multiple factors that might participate in T2DM pathogenesis, the critical roles of miRNAs in T2DM and β-cell dysfunction have been reported. Through bioinformatics analyses and literature review, we found that miR-344 might play a role in the occurrence and progression of diabetes in rats. The expression levels of miR-344-5p were dramatically decreased within cholesterol-stimulated and palmitic acid (PA)-induced rats' islet β-cells. In cholesterol-stimulated and PA-induced diabetic β-cell model, cholesterol-caused and PA-caused suppression on cell viability, increase in intracellular cholesterol level, decrease in GSIS, and increase in lip droplet deposition were dramatically attenuated via the overexpression of miR-344-5p, whereas aggravated via the inhibition of miR-344-5p. miR-344-5p also inhibited cholesterol-induced β-cell death via affecting the apoptotic caspase 3/Bax signaling. Insulin receptor downstream MPAK/ERK signaling was involved in the protection of miR-344-5p against cholesterol-induced pancreatic β-cell dysfunction. Moreover, miR-344-5p directly targeted Cav1; Cav1 silencing could partially reverse the functions of miR-344-5p inhibition upon cholesterol-induced β-cell dysfunction, β-cell apoptosis, the apoptotic caspase 3/Bax signaling, and insulin receptor downstream MPAK/ERK signaling. In conclusion, the miR-344-5p/Cav1 axis modulates cholesterol-induced β-cell apoptosis and dysfunction. The apoptotic caspase 3/Bax signaling and MAPK/ERK signaling might be involved.
Collapse
Affiliation(s)
| | | | | | | | | | - Liyong Zhu
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
36
|
Zhao Y, Albrecht E, Li Z, Schregel J, Sciascia QL, Metges CC, Maak S. Distinct Roles of Perilipins in the Intramuscular Deposition of Lipids in Glutamine-Supplemented, Low-, and Normal-Birth-Weight Piglets. Front Vet Sci 2021; 8:633898. [PMID: 34235195 PMCID: PMC8257002 DOI: 10.3389/fvets.2021.633898] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
Piglets with low birth weight (LBW) usually have reduced muscle mass and increased lipid deposition compared with their normal-birth-weight (NBW) littermates. Supplementation of piglets with amino acids during the first days of life may improve muscle growth and simultaneously alter the intramuscular lipid deposition. The aim of the current study was to investigate the influence of glutamine (Gln) supplementation during the early suckling period on lipid deposition in the longissimus muscle (MLD) and the role of different perilipin (PLIN) family members in this process. Four groups were generated consisting of 72 male LBW piglets and 72 NBW littermates. Piglets were supplemented with either 1 g Gln/kg body weight or an isonitrogenous amount of alanine (Ala) between days post natum (dpn) 1 and 12. Twelve piglets per group were slaughtered at 5, 12, and 26 dpn, and muscle tissue was collected. Perilipins were localized by immunohistochemistry in muscle sections. The mRNA and protein abundances of PLIN family members and related lipases were quantified by quantitative RT-PCR (qPCR) and western blots, respectively. While PLIN1 was localized around lipid droplets in mature and developing adipocytes, PLIN2 was localized at intramyocellular lipid droplets, PLIN3 and 4 at cell membranes of muscle fibers and adipocytes, and PLIN5 in the cytoplasm of undefined cells. The western blot results indicated higher protein abundances of PLIN2, 3, 4, and 5 in LBW piglets (p < 0.05) at 5 dpn compared with their NBW littermates independent of supplementation, while not directly reflecting the mRNA expression levels. The mRNA abundance of PLIN2 was lower while PLIN4 was higher in piglets at 26 dpn in comparison with piglets at 5 dpn (p < 0.01). Relative mRNA expression of LPL and CGI-58 was lowest in piglets at 5 dpn (p < 0.001). However, ATGL mRNA was not influenced by birth weight or supplementation, but the Spearman correlation coefficient analysis revealed close correlations with PLIN2, 4, and 5 mRNA at 5 and 26 dpn (r > 0.5, p < 0.001). The results indicated the importance of birth weight and age for intramuscular lipid deposition and different roles of PLIN family members in this process, but no clear modulating effect of Gln supplementation.
Collapse
Affiliation(s)
- Yaolu Zhao
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Elke Albrecht
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Zeyang Li
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Johannes Schregel
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Quentin L Sciascia
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Cornelia C Metges
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Steffen Maak
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| |
Collapse
|
|
37
|
Zhang B, Xu S, Liu J, Xie Y, Xiaobo S. Long Noncoding RNAs: Novel Important Players in Adipocyte Lipid Metabolism and Derivative Diseases. Front Physiol 2021; 12:691824. [PMID: 34168572 PMCID: PMC8217837 DOI: 10.3389/fphys.2021.691824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/14/2021] [Indexed: 01/08/2023] Open
Abstract
Obesity, a global public health issue, is characterized by excessive adiposity and is strongly related to some chronic diseases including cardiovascular diseases and diabetes. Extra energy intake-induced adipogenesis involves various transcription factors and long noncoding RNAs (lncRNAs) that control lipogenic mRNA expression. Currently, lncRNAs draw much attention for their contribution to adipogenesis and adipose tissue function. Increasing evidence also manifests the pivotal role of lncRNAs in modulating white, brown, and beige adipose tissue development and affecting the progression of the diseases induced by adipose dysfunction. The aim of this review is to summarize the roles of lncRNAs in adipose tissue development and obesity-caused diseases to provide novel drug targets for the treatment of obesity and metabolic diseases.
Collapse
Affiliation(s)
- Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Saijun Xu
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jinyan Liu
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yong Xie
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Sun Xiaobo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
38
|
Salgado M, García-Robles MÁ, Sáez JC. Purinergic signaling in tanycytes and its contribution to nutritional sensing. Purinergic Signal 2021; 17:607-618. [PMID: 34018139 DOI: 10.1007/s11302-021-09791-w] [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: 03/07/2021] [Accepted: 04/19/2021] [Indexed: 10/21/2022] Open
Abstract
Tanycytes are hypothalamic radial glial-like cells with an important role in the regulation of neuroendocrine axes and energy homeostasis. These cells have been implicated in glucose, amino acids, and fatty acid sensing in the hypothalamus of rodents, where they are strategically positioned. While their cell bodies contact the cerebrospinal fluid, their extensive processes contact neurons of the arcuate and ventromedial nuclei, protagonists in the regulation of food intake. A growing body of evidence has shown that purinergic signaling plays a relevant role in this homeostatic role of tanycytes, likely regulating the release of gliotransmitters that will modify the activity of satiety-controlling hypothalamic neurons. Connexin hemichannels have proven to be particularly relevant in these mechanisms since they are responsible for the release of ATP from tanycytes in response to nutritional signals. On the other hand, either ionotropic or metabotropic ATP receptors are involved in the generation of intracellular Ca2+ waves in response to hypothalamic nutrients, which can spread between glial cells and towards neighboring neurons. This review will summarize recent evidence that supports a nutrient sensor role for tanycytes, highlighting the participation of purinergic signaling in this process.
Collapse
Affiliation(s)
- Magdiel Salgado
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.,Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
| | - María Á García-Robles
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
| | - Juan C Sáez
- Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile.
| |
Collapse
|
|
39
|
Yang Y, Sun K, Liu W, Li X, Tian W, Shuai P, Zhu X. The phosphatidylserine flippase β-subunit Tmem30a is essential for normal insulin maturation and secretion. Mol Ther 2021; 29:2854-2872. [PMID: 33895325 PMCID: PMC8417432 DOI: 10.1016/j.ymthe.2021.04.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/17/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
The processing, maturation, and secretion of insulin are under precise regulation, and dysregulation causes profound defects in glucose handling, leading to diabetes. Tmem30a is the β subunit of the phosphatidylserine (PS) flippase, which maintains the membrane asymmetric distribution of PS. Tmem30a regulates cell survival and the localization of subcellular structures and is thus critical to the normal function of multiple physiological systems. Here, we show that conditional knockout of Tmem30a specifically in pancreatic islet β cells leads to obesity, hyperglycemia, glucose intolerance, hyperinsulinemia, and insulin resistance in mice, due to insufficient insulin release. Moreover, we reveal that Tmem30a plays an essential role in clathrin-mediated vesicle transport between the trans Golgi network (TGN) and the plasma membrane (PM), which comprises immature secretory granule (ISG) budding at the TGN. We also find that Tmem30a deficiency impairs clathrin-mediated vesicle budding and thus blocks both insulin maturation in ISGs and the transport of glucose-sensing Glut2 to the PM. Collectively, these disruptions compromise both insulin secretion and glucose sensitivity, thus contributing to impairments in glucose-stimulated insulin secretion. Taken together, our data demonstrate an important role of Tmem30a in insulin maturation and glucose metabolic homeostasis and suggest the importance of membrane phospholipid distribution in metabolic disorders.
Collapse
Affiliation(s)
- Yeming Yang
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Kuanxiang Sun
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Wenjing Liu
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Xiao Li
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Wanli Tian
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Ping Shuai
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072 China.
| | - Xianjun Zhu
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072 China; Natural Products Research Center, Institute of Chengdu Biology, Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, Sichuan 610072, China; Department of Ophthalmology, First People's Hospital of Shangqiu, Shangqiu, Hennan 476100, China.
| |
Collapse
|
|
40
|
Blair HR, Tomas C, Miwa S, Heath A, Russell A, Ginkel MV, Gunn D, Walker M. Peroxisomes and pancreatic beta-cell lipo-dysfunction. J Diabetes Complications 2021; 35:107843. [PMID: 33419633 DOI: 10.1016/j.jdiacomp.2020.107843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/20/2020] [Indexed: 10/22/2022]
Abstract
AIMS Pancreatic beta-cell lipo-dysfunction decreases insulin secretion and predisposes to the development of type 2 diabetes. Through targeted Pex11β knockdown and peroxisome depletion, our aim was to investigate the specific contribution of peroxisomes to palmitate mediated pancreatic beta-cell dysfunction. METHODS MIN6 cells were transfected with probes targeted against Pex11β, a regulator of peroxisome abundance, or with scrambled control probes. Peroxisome abundance was measured by PMP-70 protein expression. 48 h post transfection, cells were incubated with 250 μM palmitate or BSA control for a further 48 h before measurement of glucose stimulated insulin secretion and of reactive oxygen species. RESULTS Pex11β knockdown decreased target gene expression by >80% compared with the scrambled control (P<0.001). This led to decreased PMP-70 expression (p<0.01) and a 22% decrease in peroxisome number (p<0.05). At 25 mM glucose, palmitate treatment decreased insulin secretion by 64% in the scrambled control cells (2.54±0.25 vs 7.07±0.83 [mean±SEM] ng/h/μg protein; Palmitate vs BSA P<0.001), but by just 37% in the Pex11β knockdown cells. Comparing responses in the presence of palmitate, insulin secretion at 25 mM glucose was significantly greater in the Pex11β knockdown cells compared with the scrambled controls (4.04±0.46 vs 2.54±0.25 ng/h/μg protein; p<0.05). Reactive oxygen species generation with palmitate was lower in the Pex11β knockdown cells compared with the scrambled controls (P<0.001). CONCLUSION Pex11β knockdown decreased peroxisome abundance, decreased palmitate mediated reactive oxygen species generation, and reversed the inhibitory effect of palmitate on insulin secretion. These findings reveal a distinct role of peroxisomes in palmitate mediated beta-cell dysfunction.
Collapse
Affiliation(s)
- Helen R Blair
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Cara Tomas
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Satomi Miwa
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Alan Heath
- Unilever Discover, Colworth Science Park, Sharnbrook, Bedford, UK
| | - Alison Russell
- Unilever Discover, Colworth Science Park, Sharnbrook, Bedford, UK
| | | | - David Gunn
- Unilever Discover, Colworth Science Park, Sharnbrook, Bedford, UK
| | - Mark Walker
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| |
Collapse
|
|
41
|
Ma D, Suh DH, Zhang J, Chao Y, Duttlinger AW, Johnson JS, Lee CH, Kim YHB. Elucidating the involvement of apoptosis in postmortem proteolysis in porcine muscles from two production cycles using metabolomics approach. Sci Rep 2021; 11:3465. [PMID: 33568769 PMCID: PMC7876139 DOI: 10.1038/s41598-021-82929-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 01/27/2021] [Indexed: 11/13/2022] Open
Abstract
Apoptosis has been suggested as the first step in the process of conversion of muscle into meat. While a potential role of apoptosis in postmortem proteolysis has been proposed, the underlying mechanisms by which metabolome changes in muscles would influence apoptotic and proteolytic process, leading to meat quality variation, has not been determined. Here, apoptotic and proteolytic attributes and metabolomics profiling of longissimus dorsi (LD) and psoas major (PM) muscles in pigs from two different production cycles (July–Jan vs. Apr–Sep) were evaluated. PM showed higher mitochondrial membrane permeability (MMP), concurrent with less extent of calpain-1 autolysis and troponin T degradation and higher abundance of HSP27 and αβ-crystallin compared to LD (P < 0.05). Apr–Sep muscles showed concurrence of extended apoptosis (indicated by higher MMP), calpain-1 autolysis and troponin T degradation, regardless of muscle effects (P < 0.05). Metabolomics profiling showed Apr–Sep muscles to increase in oxidative stress-related macronutrients, including 6-carbon sugars, some branched-chain AA, and free fatty acids. Antioxidant AA (His and Asp) and ascorbic acid were higher in July–Jan (P < 0.05). The results of the present study suggest that early postmortem apoptosis might be positively associated with pro-oxidant macronutrients and negatively associated with antioxidant metabolites, consequently affecting meat quality attributes in a muscle-specific manner.
Collapse
Affiliation(s)
- Danyi Ma
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Dong Ho Suh
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, 05029, South Korea
| | - Jiaying Zhang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Yufan Chao
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Alan W Duttlinger
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.,USDA-ARS Livestock Behavior Research Unit, West Lafayette, IN, 47907, USA
| | - Jay S Johnson
- USDA-ARS Livestock Behavior Research Unit, West Lafayette, IN, 47907, USA
| | - Choong Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, 05029, South Korea. .,Research Institute for Bioactive-Metabolome Network, Konkuk University, Seoul, 05029, South Korea.
| | - Yuan H Brad Kim
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
| |
Collapse
|
|
42
|
Huang JS, Guo BB, Wang GH, Zeng LM, Hu YH, Wang T, Wang HY. DGAT1 inhibitors protect pancreatic β-cells from palmitic acid-induced apoptosis. Acta Pharmacol Sin 2021; 42:264-271. [PMID: 32737468 DOI: 10.1038/s41401-020-0482-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 07/14/2020] [Indexed: 12/24/2022]
Abstract
Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic β-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic β-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 μM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic β-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 μM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic β-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.
Collapse
|
|
43
|
Therapeutic effect of curcumin and C60 fullerene against hyperglycemia-mediated tissue damage in diabetic rat lungs. J Bioenerg Biomembr 2021; 53:25-38. [PMID: 33411205 DOI: 10.1007/s10863-020-09861-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/16/2020] [Indexed: 01/02/2023]
Abstract
Increasing evidence suggests that diabetes also targets lung tissues resulting in structural and physiological abnormalities. The present study evaluated the impact of pristine C60 fullerene (C60) against diabetes-induced lung damage for the first time. The objective was to evaluate the impacts of Curcumin (Cur), C60 and C60 fullerene+Curcumin (C60 + Cur) combination on oxidative stress (MDA, GSH, CAT, GST, Retinol, α-tocopherol), apoptosis (Caspase-3, Bcl-2), cholesterol and fatty acid profile (16:0,18:0,18:1,18:2, 22:4, 22:6) against changes in the lung tissue of diabetic rats. Streptozotocin (STZ) was used for inducing diabetes with Cur, C60 and C60 + Cur combination administered for eight weeks to treat diabetic and control rats. Increased oxidative stress, apoptosis and significant changes in cell structure were observed in the lung tissues of diabetic rats. The combination of Cur, C60 and C60 + Cur reduced oxidative stress in the lung tissue of diabetic rats while increasing the antioxidant defense capacity of the tissue, exhibiting tissue protective properties against apoptosis. The diabetic rats displayed favorable properties against lipotoxicity-induced tissue damage due to the increase in the fatty acid and cholesterol levels in lung tissue. It was observed that Cur, C60 and C60 + Cur combination displays protective effects against hyperglycemia induced oxidative damage to lung tissue. Oxidative stress, prevention of lipid and cholesterol accumulation, and weakening of lung apoptosis may be associated with these effects.
Collapse
|
|
44
|
Deletion of Trim28 in committed adipocytes promotes obesity but preserves glucose tolerance. Nat Commun 2021; 12:74. [PMID: 33397965 PMCID: PMC7782476 DOI: 10.1038/s41467-020-20434-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 12/01/2020] [Indexed: 12/19/2022] Open
Abstract
The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. However, in the current study we demonstrate that mice with deletion of Trim28 specifically in committed adipocytes, also develop obesity similar to global Trim28 deletion models, highlighting a post-developmental role for Trim28. These effects were exacerbated in female mice, contributing to the growing notion that Trim28 is a sex-specific regulator of obesity. Mechanistically, this phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf14 expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. Thus, these findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and WAT function.
Collapse
|
|
45
|
Mondal A, Burchat N, Sampath H. Palmitate exacerbates bisphenol A toxicity via induction of ER stress and mitochondrial dysfunction. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158816. [PMID: 32976987 PMCID: PMC7686068 DOI: 10.1016/j.bbalip.2020.158816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/14/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022]
Abstract
Combined exposure to dietary nutrients and environmental chemicals may elicit significantly different physiological effects than single exposures. Exposure to dietary saturated fats and environmental toxins is a physiologically-significant dual exposure that is particularly associated with lower socioeconomic status, potentially placing these individuals at heightened risk of xenobiotic toxicities. However, no prior studies have examined interactions between specific lipids and environmental xenobiotics in modulating cellular health. Using primary mouse embryonic fibroblasts, we have discovered that prior exposure to the saturated fatty acid, palmitate, exacerbates cellular toxicity associated with the industrial plasticizer, bisphenol A (BPA). Cell death upon BPA exposure following palmitate pre-treatment was greater than that occurring with either exposure alone. Mechanistically, cell death was preceded by increased endoplasmic reticulum stress and loss of mitochondrial membrane potential in palmitate plus BPA exposed cells, leading to increased caspase-3 cleavage and subsequent apoptosis. Interestingly, inclusion of the unsaturated fatty acid, oleate, along with palmitate during the pre-treatment period completely abrogated the ER stress, mitochondrial toxicity, and cell death induced by subsequent exposure to BPA. Thus, our data identify for the first time an important interaction between a fatty acid and an environmental toxin and have implications for developing nutritional interventions to mitigate the deleterious effects of such xenobiotic exposures.
Collapse
Affiliation(s)
- Anupom Mondal
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Center for Nutrition, Microbiome, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USA; Invivotek, A Genesis Biotechnology Group, Hamilton, NJ, USA
| | - Natalie Burchat
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Center for Nutrition, Microbiome, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USA
| | - Harini Sampath
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Center for Nutrition, Microbiome, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USA; Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA.
| |
Collapse
|
|
46
|
Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review. Nutrients 2020; 12:nu12123846. [PMID: 33339276 PMCID: PMC7766247 DOI: 10.3390/nu12123846] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/14/2020] [Accepted: 12/14/2020] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.
Collapse
|
|
47
|
Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease. Proc Natl Acad Sci U S A 2020; 117:33282-33294. [PMID: 33310904 DOI: 10.1073/pnas.2011124117] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Fatty acids (FAs) are central cellular metabolites that contribute to lipid synthesis, and can be stored or harvested for metabolic energy. Dysregulation in FA processing and storage causes toxic FA accumulation or altered membrane compositions and contributes to metabolic and neurological disorders. Saturated lipids are particularly detrimental to cells, but how lipid saturation levels are maintained remains poorly understood. Here, we identify the cerebellar ataxia spinocerebellar ataxia, autosomal recessive 20 (SCAR20)-associated protein Snx14, an endoplasmic reticulum (ER)-lipid droplet (LD) tethering protein, as a factor required to maintain the lipid saturation balance of cell membranes. We show that following saturated FA (SFA) treatment, the ER integrity of SNX14 KO cells is compromised, and both SNX14 KO cells and SCAR20 disease patient-derived cells are hypersensitive to SFA-mediated lipotoxic cell death. Using APEX2-based proximity labeling, we reveal the protein composition of Snx14-associated ER-LD contacts and define a functional interaction between Snx14 and Δ-9 FA desaturase SCD1. Lipidomic profiling reveals that SNX14 KO cells increase membrane lipid saturation following exposure to palmitate, phenocopying cells with perturbed SCD1 activity. In line with this, SNX14 KO cells manifest delayed FA processing and lipotoxicity, which can be rescued by SCD1 overexpression. Altogether, these mechanistic insights reveal a role for Snx14 in FA and ER homeostasis, defects in which may underlie the neuropathology of SCAR20.
Collapse
|
|
48
|
Xia ZH, Zhang SY, Chen YS, Li K, Chen WB, Liu YQ. Curcumin anti-diabetic effect mainly correlates with its anti-apoptotic actions and PI3K/Akt signal pathway regulation in the liver. Food Chem Toxicol 2020; 146:111803. [PMID: 33035629 DOI: 10.1016/j.fct.2020.111803] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 01/30/2023]
Abstract
This study aimed to investigate the therapeutic effect of curcumin on type 2 diabetes and its underlying mechanisms. A type 2 diabetes mellitus rat model was established by providing high-fat diet and low doses of streptozotocin. Type 2 diabetes mellitus rats were treated with low dose and high dose of curcumin for 8 weeks. The results showed that high-dose curcumin significantly reduced fasting blood glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase, and aspartate transaminase, liver coefficient, and malondialdehyde levels, and BCL2-Associated X expression in the type 2 diabetes mellitus rats. High-dose curcumin increased the levels of liver superoxide dismutase, catalase, and glutathione; as well as the expression of liver B-cell lymphoma-2, phosphatidylinositol 3-kinase, phosphorylated phosphatidylinositol 3-kinase, protein kinase B, and phosphorylated protein kinase B in type 2 diabetes mellitus rats. Furthermore, it ameliorated the histological structure of the liver and pancreas in diabetes mellitus model rats. However, low-dose curcumin had no significant effect on diabetes mellitus model rats. The results suggest that adequate doses of curcumin controls type 2 diabetes mellitus development as well as the mechanism involved in its anti-apoptotic actions and phosphatidylinositol 3-hydroxy kinase/protein kinase B signal pathway regulation in the liver.
Collapse
Affiliation(s)
- Zhen-Hong Xia
- College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Sai-Ya Zhang
- College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yu-Si Chen
- College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Ke Li
- College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Wen-Bo Chen
- College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yan-Qiang Liu
- College of Life Sciences, Nankai University, Tianjin, 300071, China.
| |
Collapse
|
|
49
|
Liu N, Li Y, Nan W, Zhou W, Huang J, Li R, Zhou L, Hu R. Interaction of TPPP3 with VDAC1 Promotes Endothelial Injury through Activation of Reactive Oxygen Species. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5950195. [PMID: 33082910 PMCID: PMC7556057 DOI: 10.1155/2020/5950195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/27/2020] [Accepted: 09/07/2020] [Indexed: 11/22/2022]
Abstract
Endothelial injury plays a critical role in the pathogenesis of cardiovascular disorders and metabolic-associated vascular complications which are the leading cause of death worldwide. However, the mechanism underlying endothelial dysfunction is not completely understood. The study is aimed at investigating the role of tubulin polymerization-promoting protein family member 3 (TPPP3) in palmitic acid- (PA-) induced endothelial injury. The effect of TPPP3 on human umbilical vein endothelial cells (HUVECs) was determined by evaluating apoptosis, tube formation, and reactive oxygen species (ROS) production. TPPP3 silencing inhibited PA overload-induced apoptosis and production of ROS, along with the alteration of apoptosis-related key proteins such as BCL-2 and Bax. Mechanically, voltage-dependent anion channel 1 (VDAC1) was identified as a novel functional binding partner of TPPP3, and TPPP3 promoted VDAC1 protein stability and its activity. Further studies indicated that TPPP3 could promote apoptosis, ROS production, tube formation, and proapoptotic protein expression and reduce antiapoptotic protein expression through increasing VDAC1 expression under mildly elevated levels of PA. Collectively, these results demonstrated that TPPP3 could promote PA-induced oxidative damage in HUVECs via a VDAC1-dependent pathway, suggesting that TPPP3 might be considered as a potential therapeutic target in vascular disease.
Collapse
Affiliation(s)
- Naijia Liu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Yintao Li
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wu Nan
- Department of Geriatrics, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenbai Zhou
- Department of Medicine, Emanuel Medical Center, Turlock, California, USA
| | - Jinya Huang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Rumei Li
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Linuo Zhou
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Renming Hu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| |
Collapse
|
|
50
|
Michael NJ, Watt MJ. Long Chain Fatty Acids Differentially Regulate Sub-populations of Arcuate POMC and NPY Neurons. Neuroscience 2020; 451:164-173. [PMID: 33002557 DOI: 10.1016/j.neuroscience.2020.09.045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 09/09/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
Long chain fatty acids (LCFAs) have been suggested to influence the activity of hypothalamic neurons, however, limited studies have attempted to identify the neurochemical phenotype of these neurons. We aimed to determine if physiological levels of LCFAs alter the electrical excitability of pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) neurons in the arcuate nucleus of the hypothalamus. We utilised whole-cell patch-clamp electrophysiology on brain slice preparations from genetic mouse models where green fluorescent protein was expressed in either POMC or NPY expressing cells. All animals had undergone an overnight fast to replicate conditions in which fatty acids would usually increase. Bath application of LCFAs were found to predominantly inhibit POMC neurons and predominantly excite NPY neurons. Differences between oleic and palmitic acid were not observed. These results suggest that LCFAs in the cerebrospinal fluid exert an underlying orexigenic tone to key hypothalamic neurons known to regulate energy homeostasis.
Collapse
Affiliation(s)
- Natalie J Michael
- Metabolic Disease, Obesity and Diabetes Program, Biomedicine Discovery Institute and the Department of Physiology, Monash University, Clayton 3800, VIC, Australia; Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City G1V4G5, Québec, Canada.
| | - Matthew J Watt
- Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne 3010, VIC, Australia
| |
Collapse
|