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Oh CM, Bang JI, Lee SY, Lee JK, Chai JW, Oh SW. An Analysis of Age-Related Body Composition Changes and Metabolic Patterns in Korean Adults Using FDG-PET/CT Health Screening Data. Diabetes Metab J 2025; 49:92-104. [PMID: 39219438 PMCID: PMC11788554 DOI: 10.4093/dmj.2024.0057] [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: 02/15/2024] [Accepted: 04/24/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGRUOUND F-18-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) can be used to measure bone mineral density (BMD), cross-sectional muscle area (CSMA), Hounsfield units (HU) of liver and muscle, subcutaneous adipose tissue (SAT), abdominal visceral adipose tissue (VAT), and glucose metabolism. The present study aimed to identify age-related changes in body composition and glucose metabolism in Korean using opportunistic FDG-PET/CT imaging. METHODS We analyzed FDG-PET/CT, clinical history, and laboratory data abstracted from the medical records of patients who underwent health screening at a single institute between 2017 and 2022. RESULTS In total, 278 patients were included in the analysis (male:female=140:138). Age and body mass index were positively correlated in female, but negatively correlated in male. BMD decreased with age more in female, and CSMA decreased with age more in male. Muscle HU decreased with age for both sexes. In female, SAT and VAT increased with age; and in male, SAT decreased slightly while VAT remained stable. Muscle glucose metabolism showed no association with age in male but increased with age in female. CSMA correlated positively with BMD overall; and positively correlated with VAT and SAT in male only. In female only, both SAT and VAT showed negative correlations with glucose metabolism and correlated positively with muscle glucose metabolism. Liver HU values were inversely correlated with VAT, especially in female; and positively correlated with muscle glucose metabolism in female only. CONCLUSION FDG-PET/CT demonstrated distinct patterns of age-related changes in body composition and glucose metabolism, with significant differences between sexes.
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Affiliation(s)
- Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Ji-In Bang
- Department of Nuclear Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Sang Yoon Lee
- Department of Rehabilitation Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Jae Kyung Lee
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Jee Won Chai
- Department of Radiology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - So Won Oh
- Department of Nuclear Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
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Yang Y, Wang TT, Xie HA, Hu PP, Li P. Experimental cell models of insulin resistance: overview and appraisal. Front Endocrinol (Lausanne) 2024; 15:1469565. [PMID: 39749015 PMCID: PMC11693592 DOI: 10.3389/fendo.2024.1469565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
Insulin resistance, a key factor in the development of type 2 diabetes mellitus (T2DM), is defined as a defect in insulin-mediated control of glucose metabolism in tissues such as liver, fat and muscle. Insulin resistance is a driving force behind various metabolic diseases, such as T2DM, hyperlipidemia, hypertension, coronary heart disease and fatty liver. Therefore, improving insulin sensitivity can be considered as an effective strategy for the prevention and treatment of these complex metabolic diseases. Cell-based models are extensively employed for the study of pathological mechanisms and drug screening, particularly in relation to insulin resistance in T2DM. Currently, numerous methods are available for the establishment of in vitro insulin resistance models, a comprehensive review of these models is required and can serve as an excellent introduction or understanding for researchers undertaking studies in this filed. This review examines and discusses the primary methods for establishing and evaluating insulin resistance cell models. Furthermore, it highlights key issues and suggestions on cell selection, establishment, evaluation and drug screening of insulin resistance, thereby providing valuable references for the future research efforts.
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Affiliation(s)
- Ying Yang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Ting-ting Wang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Hu-ai Xie
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Ping Ping Hu
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Pan Li
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
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3
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Friedman MI, Sørensen TIA, Taubes G, Lund J, Ludwig DS. Trapped fat: Obesity pathogenesis as an intrinsic disorder in metabolic fuel partitioning. Obes Rev 2024; 25:e13795. [PMID: 38961319 DOI: 10.1111/obr.13795] [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: 12/27/2023] [Revised: 05/24/2024] [Accepted: 06/13/2024] [Indexed: 07/05/2024]
Abstract
Our understanding of the pathophysiology of obesity remains at best incomplete despite a century of research. During this time, two alternative perspectives have helped shape thinking about the etiology of the disorder. The currently prevailing view holds that excessive fat accumulation results because energy intake exceeds energy expenditure, with excessive food consumption being the primary cause of the imbalance. The other perspective attributes the initiating cause of obesity to intrinsic metabolic defects that shift fuel partitioning from pathways for mobilization and oxidation to those for synthesis and storage. The resulting reduction in fuel oxidation and trapping of energy in adipose tissue drives a compensatory increase in energy intake and, under some conditions, a decrease in expenditure. This theory of obesity pathogenesis has historically garnered relatively less attention despite its pedigree. Here, we present an updated comprehensive formulation of the fuel partitioning theory, focused on evidence gathered over the last 80 years from major animal models of obesity showing a redirection of fuel fluxes from oxidation to storage and accumulation of excess body fat with energy intake equal to or even less than that of lean animals. The aim is to inform current discussions about the etiology of obesity and by so doing, help lay new foundations for the design of more efficacious approaches to obesity research, treatment and prevention.
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Affiliation(s)
| | - Thorkild I A Sørensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
- Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
- Center for Childhood Health, Copenhagen, Denmark
| | | | - Jens Lund
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - David S Ludwig
- New Balance Foundation Obesity Prevention Center, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
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4
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Tan J, Virtue S, Norris DM, Conway OJ, Yang M, Bidault G, Gribben C, Lugtu F, Kamzolas I, Krycer JR, Mills RJ, Liang L, Pereira C, Dale M, Shun-Shion AS, Baird HJ, Horscroft JA, Sowton AP, Ma M, Carobbio S, Petsalaki E, Murray AJ, Gershlick DC, Nathan JA, Hudson JE, Vallier L, Fisher-Wellman KH, Frezza C, Vidal-Puig A, Fazakerley DJ. Limited oxygen in standard cell culture alters metabolism and function of differentiated cells. EMBO J 2024; 43:2127-2165. [PMID: 38580776 PMCID: PMC11148168 DOI: 10.1038/s44318-024-00084-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/20/2024] [Accepted: 03/03/2024] [Indexed: 04/07/2024] Open
Abstract
The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1α activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, recapitulating a healthier adipocyte model. The functional benefits of increasing pericellular oxygen were also observed in macrophages, hPSC-derived hepatocytes and cardiac organoids. Our findings demonstrate that oxygen is limiting in many terminally-differentiated cell types, and that considering pericellular oxygen improves the quality, reproducibility and translatability of culture models.
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Affiliation(s)
- Joycelyn Tan
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Sam Virtue
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
| | - Dougall M Norris
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Olivia J Conway
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Ming Yang
- MRC Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
- CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, 50931, Germany
| | - Guillaume Bidault
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Christopher Gribben
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, UK
| | - Fatima Lugtu
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, UK
| | - Ioannis Kamzolas
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, UK
| | - James R Krycer
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, 4000, Australia
| | - Richard J Mills
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, 4000, Australia
| | - Lu Liang
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Conceição Pereira
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Martin Dale
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Amber S Shun-Shion
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Harry Jm Baird
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - James A Horscroft
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EL, UK
| | - Alice P Sowton
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EL, UK
| | - Marcella Ma
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Stefania Carobbio
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
- Centro de Investigacion Principe Felipe, Valencia, 46012, Spain
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, UK
| | - Andrew J Murray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EL, UK
| | - David C Gershlick
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - James A Nathan
- Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK
| | - James E Hudson
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, 4000, Australia
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Ludovic Vallier
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, UK
| | - Kelsey H Fisher-Wellman
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, 27834, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA
| | - Christian Frezza
- MRC Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
- CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, 50931, Germany
| | - Antonio Vidal-Puig
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
- Centro de Investigacion Principe Felipe, Valencia, 46012, Spain.
| | - Daniel J Fazakerley
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
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Johnson RJ, Sánchez-Lozada LG, Lanaspa MA. The fructose survival hypothesis as a mechanism for unifying the various obesity hypotheses. Obesity (Silver Spring) 2024; 32:12-22. [PMID: 37846155 DOI: 10.1002/oby.23920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 10/18/2023]
Abstract
The pathogenesis of obesity remains contested. Although genetics is important, the rapid rise in obesity with Western culture and diet suggests an environmental component. Today, some of the major hypotheses for obesity include the energy balance hypothesis, the carbohydrate-insulin model, the protein-leverage hypothesis, and the seed oil hypothesis. Each hypothesis has its own support, creating controversy over their respective roles in driving obesity. Here we propose that all hypotheses are largely correct and can be unified by another dietary hypothesis, the fructose survival hypothesis. Fructose is unique in resetting ATP levels to a lower level in the cell as a consequence of suppressing mitochondrial function, while blocking the replacement of ATP from fat. The low intracellular ATP levels result in carbohydrate-dependent hunger, impaired satiety (leptin resistance), and metabolic effects that result in the increased intake of energy-dense fats. This hypothesis emphasizes the unique role of carbohydrates in stimulating intake while fat provides the main source of energy. Thus, obesity is a disorder of energy metabolism, in which there is low usable energy (ATP) in the setting of elevated total energy. This leads to metabolic effects independent of excess energy while the excess energy drives weight gain.
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Affiliation(s)
- Richard J Johnson
- Division of Nephrology, Rocky Mountain VA Medical Center, Aurora, Colorado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Laura G Sánchez-Lozada
- Laboratory of Renal Physiopathology, Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico
| | - Miguel A Lanaspa
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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6
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Tokarz VL, Mylvaganam S, Klip A. Palmitate-induced insulin resistance causes actin filament stiffness and GLUT4 mis-sorting without altered Akt signalling. J Cell Sci 2023; 136:jcs261300. [PMID: 37815440 DOI: 10.1242/jcs.261300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 09/25/2023] [Indexed: 10/11/2023] Open
Abstract
Skeletal muscle insulin resistance, a major contributor to type 2 diabetes, is linked to the consumption of saturated fats. This insulin resistance arises from failure of insulin-induced translocation of glucose transporter type 4 (GLUT4; also known as SLC2A4) to the plasma membrane to facilitate glucose uptake into muscle. The mechanisms of defective GLUT4 translocation are poorly understood, limiting development of insulin-sensitizing therapies targeting muscle glucose uptake. Although many studies have identified early insulin signalling defects and suggest that they are responsible for insulin resistance, their cause-effect has been debated. Here, we find that the saturated fat palmitate (PA) causes insulin resistance owing to failure of GLUT4 translocation in skeletal muscle myoblasts and myotubes without impairing signalling to Akt2 or AS160 (also known as TBC1D4). Instead, PA altered two basal-state events: (1) the intracellular localization of GLUT4 and its sorting towards a perinuclear storage compartment, and (2) actin filament stiffness, which prevents Rac1-dependent actin remodelling. These defects were triggered by distinct mechanisms, respectively protein palmitoylation and endoplasmic reticulum (ER) stress. Our findings highlight that saturated fats elicit muscle cell-autonomous dysregulation of the basal-state machinery required for GLUT4 translocation, which 'primes' cells for insulin resistance.
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Affiliation(s)
- Victoria L Tokarz
- Department of Physiology, University of Toronto, Ontario, M5S 1A8, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
| | - Sivakami Mylvaganam
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
- Department of Biochemistry, University of Toronto, Ontario, M5S 1A8, Canada
| | - Amira Klip
- Department of Physiology, University of Toronto, Ontario, M5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Ontario, M5S 1A8, Canada
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7
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Johnson RJ, Lanaspa MA, Sanchez-Lozada LG, Tolan D, Nakagawa T, Ishimoto T, Andres-Hernando A, Rodriguez-Iturbe B, Stenvinkel P. The fructose survival hypothesis for obesity. Philos Trans R Soc Lond B Biol Sci 2023; 378:20220230. [PMID: 37482773 PMCID: PMC10363705 DOI: 10.1098/rstb.2022.0230] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 05/04/2023] [Indexed: 07/25/2023] Open
Abstract
The fructose survival hypothesis proposes that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response (survival switch) that aims to protect animals in advance of crisis. The response is characterized by hunger, thirst, foraging, weight gain, fat accumulation, insulin resistance, systemic inflammation and increased blood pressure. The process is initiated by the ingestion of fructose or by stimulating endogenous fructose production via the polyol pathway. Unlike other nutrients, fructose reduces the active energy (adenosine triphosphate) in the cell, while blocking its regeneration from fat stores. This is mediated by intracellular uric acid, mitochondrial oxidative stress, the inhibition of AMP kinase and stimulation of vasopressin. Mitochondrial oxidative phosphorylation is suppressed, and glycolysis stimulated. While this response is aimed to be modest and short-lived, the response in humans is exaggerated due to gain of 'thrifty genes' coupled with a western diet rich in foods that contain or generate fructose. We propose excessive fructose metabolism not only explains obesity but the epidemics of diabetes, hypertension, non-alcoholic fatty liver disease, obesity-associated cancers, vascular and Alzheimer's dementia, and even ageing. Moreover, the hypothesis unites current hypotheses on obesity. Reducing activation and/or blocking this pathway and stimulating mitochondrial regeneration may benefit health-span. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.
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Affiliation(s)
- Richard J. Johnson
- Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO 80016, USA
| | - Miguel A. Lanaspa
- Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO 80016, USA
| | - L. Gabriela Sanchez-Lozada
- Department of Cardio-Renal Physiopathology, Instituto Nacional de Cardiología ‘Ignacio Chavez’, Mexico City 14080, Mexico
| | - Dean Tolan
- Biology Department, Boston University, Boston, MA 02215, USA
| | - Takahiko Nakagawa
- Department of Nephrology, Rakuwakai-Otowa Hospital, Kyoto 607-8062, Japan
| | - Takuji Ishimoto
- Department of Nephrology and Rheumatology, Aichi Medical University, Aichi 480-1103, Japan
| | - Ana Andres-Hernando
- Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, CO 80016, USA
| | - Bernardo Rodriguez-Iturbe
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición ‘Salvador Zubirán’, Mexico City 14080, Mexico
| | - Peter Stenvinkel
- Department of Renal Medicine, Karolinska Institutet, Stockholm 171 77, Sweden
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Shimobayashi M, Thomas A, Shetty S, Frei IC, Wölnerhanssen BK, Weissenberger D, Vandekeere A, Planque M, Dietz N, Ritz D, Meyer-Gerspach AC, Maier T, Hay N, Peterli R, Fendt SM, Rohner N, Hall MN. Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia. eLife 2023; 12:85103. [PMID: 36920797 PMCID: PMC10017106 DOI: 10.7554/elife.85103] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/19/2023] [Indexed: 03/16/2023] Open
Abstract
Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.
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Affiliation(s)
- Mitsugu Shimobayashi
- Biozentrum, University of BaselBaselSwitzerland
- Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU LeuvenLeuvenBelgium
| | | | | | | | | | | | - Anke Vandekeere
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer BiologyLeuvenBelgium
- Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer InstituteLeuvenBelgium
| | - Mélanie Planque
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer BiologyLeuvenBelgium
- Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer InstituteLeuvenBelgium
| | | | - Danilo Ritz
- Biozentrum, University of BaselBaselSwitzerland
| | | | - Timm Maier
- Biozentrum, University of BaselBaselSwitzerland
| | - Nissim Hay
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at ChicagoChicagoUnited States
| | - Ralph Peterli
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver DiseasesBaselSwitzerland
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer BiologyLeuvenBelgium
- Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer InstituteLeuvenBelgium
| | - Nicolas Rohner
- Stowers Institute for Medical ResearchKansas CityUnited States
- Department of Cell Biology and Physiology at the University of Kansas School of MedicineKansas CityUnited States
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9
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Fazakerley DJ, van Gerwen J, Cooke KC, Duan X, Needham EJ, Díaz-Vegas A, Madsen S, Norris DM, Shun-Shion AS, Krycer JR, Burchfield JG, Yang P, Wade MR, Brozinick JT, James DE, Humphrey SJ. Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance. Nat Commun 2023; 14:923. [PMID: 36808134 PMCID: PMC9938909 DOI: 10.1038/s41467-023-36549-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 02/07/2023] [Indexed: 02/19/2023] Open
Abstract
The failure of metabolic tissues to appropriately respond to insulin ("insulin resistance") is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employ phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults causing insulin resistance, we observe a marked rewiring of the insulin signaling network. This includes both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults reveals subnetworks containing non-canonical regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several bona fide GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates, revealing widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reverses insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that includes dysregulated MARK2/3 and GSK3 activity.
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Affiliation(s)
- Daniel J Fazakerley
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia.
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
| | - Julian van Gerwen
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Kristen C Cooke
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Xiaowen Duan
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Elise J Needham
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Alexis Díaz-Vegas
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Søren Madsen
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Dougall M Norris
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Amber S Shun-Shion
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - James R Krycer
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
- QIMR Berghofer Medical Research Institute, Brisbane, QL, Australia
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QL, Australia
| | - James G Burchfield
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Pengyi Yang
- Charles Perkins Centre, School of Mathematics and Statistics, University of Sydney, Sydney, NSW, 2006, Australia
- Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, 2145, Australia
| | - Mark R Wade
- Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN, USA
| | - Joseph T Brozinick
- Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN, USA
| | - David E James
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia.
- Sydney Medical School, University of Sydney, Sydney, 2006, Australia.
| | - Sean J Humphrey
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia.
- Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, 3052, Australia.
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10
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Diaz-Vegas A, Norris DM, Jall-Rogg S, Cooke KC, Conway OJ, Shun-Shion AS, Duan X, Potter M, van Gerwen J, Baird HJ, Humphrey SJ, James DE, Fazakerley DJ, Burchfield JG. A high-content endogenous GLUT4 trafficking assay reveals new aspects of adipocyte biology. Life Sci Alliance 2023; 6:e202201585. [PMID: 36283703 PMCID: PMC9595207 DOI: 10.26508/lsa.202201585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Insulin-induced GLUT4 translocation to the plasma membrane in muscle and adipocytes is crucial for whole-body glucose homeostasis. Currently, GLUT4 trafficking assays rely on overexpression of tagged GLUT4. Here we describe a high-content imaging platform for studying endogenous GLUT4 translocation in intact adipocytes. This method enables high fidelity analysis of GLUT4 responses to specific perturbations, multiplexing of other trafficking proteins and other features including lipid droplet morphology. Using this multiplexed approach we showed that Vps45 and Rab14 are selective regulators of GLUT4, but Trarg1, Stx6, Stx16, Tbc1d4 and Rab10 knockdown affected both GLUT4 and TfR translocation. Thus, GLUT4 and TfR translocation machinery likely have some overlap upon insulin-stimulation. In addition, we identified Kif13A, a Rab10 binding molecular motor, as a novel regulator of GLUT4 traffic. Finally, comparison of endogenous to overexpressed GLUT4 highlights that the endogenous GLUT4 methodology has an enhanced sensitivity to genetic perturbations and emphasises the advantage of studying endogenous protein trafficking for drug discovery and genetic analysis of insulin action in relevant cell types.
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Affiliation(s)
- Alexis Diaz-Vegas
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Dougall M Norris
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Sigrid Jall-Rogg
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Kristen C Cooke
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Olivia J Conway
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Amber S Shun-Shion
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Xiaowen Duan
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Meg Potter
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Julian van Gerwen
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Harry Jm Baird
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Sean J Humphrey
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - David E James
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
- School of Medical Sciences, University of Sydney, Sydney, Australia
| | - Daniel J Fazakerley
- Metabolic Research Laboratories, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - James G Burchfield
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
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11
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Li Q, Spalding KL. The regulation of adipocyte growth in white adipose tissue. Front Cell Dev Biol 2022; 10:1003219. [PMID: 36483678 PMCID: PMC9723158 DOI: 10.3389/fcell.2022.1003219] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/03/2022] [Indexed: 10/25/2023] Open
Abstract
Adipocytes can increase in volume up to a thousand-fold, storing excess calories as triacylglycerol in large lipid droplets. The dramatic morphological changes required of adipocytes demands extensive cytoskeletal remodeling, including lipid droplet and plasma membrane expansion. Cell growth-related signalling pathways are activated, stimulating the production of sufficient amino acids, functional lipids and nucleotides to meet the increasing cellular needs of lipid storage, metabolic activity and adipokine secretion. Continued expansion gives rise to enlarged (hypertrophic) adipocytes. This can result in a failure to maintain growth-related homeostasis and an inability to cope with excess nutrition or respond to stimuli efficiently, ultimately leading to metabolic dysfunction. We summarize recent studies which investigate the functional and cellular structure remodeling of hypertrophic adipocytes. How adipocytes adapt to an enlarged cell size and how this relates to cellular dysfunction are discussed. Understanding the healthy and pathological processes involved in adipocyte hypertrophy may shed light on new strategies for promoting healthy adipose tissue expansion.
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Affiliation(s)
- Qian Li
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Kirsty L. Spalding
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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12
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Wu Y, Zhao R, Li M, Li H, Chen Z, Zhao Y. Novel soybean peptide iglycin ameliorates insulin resistance of high-fat diet fed C57BL/6J mice and differentiated 3T3L1 adipocytes with improvement of insulin signaling and mitochondrial function. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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13
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A Thai Traditional Triple-Fruit Formulation "Phikud Tri-Phon" May Provide Fat Loss and Nutritional Benefits. Foods 2022; 11:foods11193067. [PMID: 36230143 PMCID: PMC9563312 DOI: 10.3390/foods11193067] [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: 08/19/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
Abstract
Obesity and overweight have serious health outcomes. “Phikud Tri-Phon” (PTP) is a traditional Thai medicine comprising three dried fruits from Aegle marmelos L., Morinda citrifolia L., and Coriandrum sativum L. Whether this medicine impacts on metabolic disease is unclear. This study aimed to investigate the phenolic and flavonoid contents of PTP and each of its herbal components, and further assess their antioxidant and anti-adipogenetic activities. Oil-red O staining was measured for lipid accumulation in 3T3-L1 adipocytes. The chemical profiles of PTP and each herbal extract were determined by LC-ESI-QTOF-MS/MS. Our results show that the total phenolic and flavonoid contents of PTP water extract were 22.35–108.42 mg of gallic acid equivalents and PTP ethanolic extract was 1.19–0.93 mg of quercetin equivalents and the DPPH scavenging capacity assay of PTP ethanolic extract (1 mg/mL) was 92.45 ± 6.58 (Trolox equivalent)/g. The PTP extracts and individual herbs had inhibitory adipogenesis activity, which reduced lipid accumulation by approximately 31% in PTP water extract and 22% in PTP ethanolic extract compared with control cells. These results provided insights into the traditional preparation method of using boiling water as a vehicle for PTP. In conclusion, PTP has antioxidant and anti-adipogenesis potential, indicating it is a promising ingredient in functional food and herbal health products.
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14
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Insulin sensitivity is associated with the observed variation of de novo lipid synthesis and body composition in finishing pigs. Sci Rep 2022; 12:14586. [PMID: 36028540 PMCID: PMC9418310 DOI: 10.1038/s41598-022-18799-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 08/19/2022] [Indexed: 11/08/2022] Open
Abstract
Variations in body composition among pigs can be associated with insulin sensitivity given the insulin anabolic effect. The study objectives were to characterize this association and to compare de novo lipogenesis and the gene expression in the adipose tissue of pigs of the same genetic background. Thirty 30-95 kg of body weight (BW) pigs, catheterized in the jugular vein participated into an oral glucose tolerance test (OGTT; 1.75 g glucose/kg of BW) to calculate insulin-related indexes. The 8 fattest and the 8 leanest pigs were used to determine the relative mRNA abundance of studied genes. The rate of lipogenesis was assessed by incorporation of [U-13C]glucose into lipids. The QUICKI and Matsuda indexes negatively correlated with total body lipids (r = - 0.67 and r = - 0.59; P < 0.01) and de novo lipogenesis (r = - 0.58; P < 0.01). Fat pigs had a higher expression level of lipogenic enzymes (ACACA, ACLY; P < 0.05) than lean pigs. The reduced insulin sensitivity in fat pigs was associated with a higher expression level of glucose-6-phosphate dehydrogenase (G6PD) and a lower expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ). In conclusion, pigs with increased body lipids have lower insulin sensitivity which is associated with increased de novo lipogenesis.
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15
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A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ. Commun Biol 2022; 5:807. [PMID: 35962183 PMCID: PMC9374667 DOI: 10.1038/s42003-022-03776-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 07/27/2022] [Indexed: 11/09/2022] Open
Abstract
Berberine (BBR) exerts specific therapeutic effects on various diseases such as diabetes, obesity, and other inflammation-associated diseases. However, the low oral bioavailability (below 1%) of berberine due to its poor solubility and membrane permeability limits its clinical use. In this paper, we have prepared a 1:1 co-crystal berberine-ibuprofen (BJ) using drug salt metathesis and co-crystal technology. Pharmacokinetic studies demonstrate a 3-fold increase in vivo bioavailability of BJ compared to that of BBR, and BJ is more effective in treating obesity and its related metabolism in vitro and in vivo. We also find that BJ promotes mitochondrial biogenesis by inhibiting TBK1 and inducing AMP-activated protein kinase (AMPK) phosphorylation, and BJ increases adipocyte sensitivity to catecholamine by inhibiting IKKε. Together, our findings support that co-crystal BJ is likely to be an effective agent for treating obesity and its related metabolic diseases targeting TBK1 and IKKε.
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16
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Sinha K, Kumar S, Rawat B, Singh R, Purohit R, Kumar D, Padwad Y. Kutkin, iridoid glycosides enriched fraction of Picrorrhiza kurroa promotes insulin sensitivity and enhances glucose uptake by activating PI3K/Akt signaling in 3T3-L1 adipocytes. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 103:154204. [PMID: 35671635 DOI: 10.1016/j.phymed.2022.154204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 03/21/2022] [Accepted: 05/24/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Therapeutic failure and drug resistance are common sequelae to insulin resistance associated with type 2 diabetes mellitus (T2DM). Consequently, there is an unmet need of alternative strategies to overcome insulin resistance associated complications. PURPOSE To demonstrate whether Kutkin (KT), iridoid glycoside enriched fraction of Picrorhiza kurroa extract (PKE) has potential to increase the insulin sensitivity vis à vis glucose uptake in differentiated adipocytes. METHODS Molecular interaction of KT phytoconstituents, picroside-I (P-I) & picroside- II (P-II) with peroxisome proliferator-activated receptor gamma (PPARγ), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were analyzed in silico. Cellular viability and adipogenesis were determined by following 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium bromide (MTT) assay and Oil Red-O staining. Further, ELISA kit based triglycerides and diacylglycerol-O-Acyltransferase-1 (DGAT1) were assessed in differentiated adipocytes. ELISA based determination were performed to check the levels of adiponectin and tumor necrosis factor alpha (TNF-α). However, Flow cytometry and immunofluorescence based assays were employed to measure the glucose uptake and glucose transporter 4 (glut4) expression in differentiated adipocytes, respectively. Further to explore the targeted signaling axis, mRNA expression levels of PPARγ, CCAAT/enhancer binding protein α (CEBPα), and glut4 were determined using qRT-PCR and insulin receptor substrate-1 (IRS-1), Insulin receptor substrate-2 (IRS-2), PI3K/Akt, AS160, glut4 followed by protein validation using immunoblotting in differentiated adipocytes. RESULTS In silico analysis revealed the binding affinities of major constituents of KT (P-I& P-II) with PPARγ/PI3K/Akt. The enhanced intracellular accumulation of triglycerides with concomitant activation of PPARγ and C/EBPα in KT treated differentiated adipocytes indicates augmentation of adipogenesis in a concentration-dependent manner. Additionally, at cellular level, KT upregulated the expression of DAGT1, and decreases fatty acid synthase (FAS), and lipoprotein lipase (LPL), further affirmed improvement in lipid milieu. It was also observed that KT upregulated the levels of adiponectin and reduced TNFα expression, thus improving the secretory functions of adipocytes along with enhanced insulin sensitivity. Furthermore, KT significantly promoted insulin mediated glucose uptake by increasing glut4 translocation to the membrane via PI3/Akt signaling cascade. The results were further validated using PI3K specific inhibitor, wortmannin and findings revealed that KT treatment significantly enhanced the expression and activation of p-PI3K/PI3K and p-Akt/Akt even in case of treatment with PI3K inhibitor wortmannin alone and co-treatment with KT in differentiated adipocytes and affirmed that KT as activator of PI3K/Akt axis in the presence of inhibitor as well. CONCLUSION Collectively, KT fraction of PKE showed anti-diabetic effects by enhancing glucose uptake in differentiated adipocytes via activation of PI3K/Akt signaling cascade. Therefore, KT may be used as a promising novel natural therapeutic agent for managing T2DMand to the best of our knowledge, this is the first report, showing the efficacy and potential molecular mechanism of KT in enhancing insulin sensitivity and glucose uptake in differentiated adipocytes.
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Affiliation(s)
- Kajal Sinha
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Shiv Kumar
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Bindu Rawat
- Chemical Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 HP., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Rahul Singh
- Structural Bioinformatics Lab, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Rituraj Purohit
- Structural Bioinformatics Lab, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Dinesh Kumar
- Chemical Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 HP., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Yogendra Padwad
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061 H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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17
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Mei Y, Hu H, Deng L, Sun X, Tan W. Isosteviol sodium attenuates high fat/high cholesterol-induced myocardial dysfunction by regulating the Sirt1/AMPK pathway. Biochem Biophys Res Commun 2022; 621:80-87. [PMID: 35810595 DOI: 10.1016/j.bbrc.2022.06.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/14/2022] [Indexed: 11/02/2022]
Abstract
A fat-rich diet triggers obesity, and promotes cardiomyocyte injury. Till now, no prior investigations suggested a beneficial role of Isosteviol Sodium (STVNa) in cardiac activity in high fat diet (HFD)-exposed obese rats. However, there is evidence that STVNa accelerates healing of multiple tissue injuries. Herein, we explored the underlying mechanism behind the STVNa-based protection against HFD-induced myocardial dysfunction (MCD) in a rat model of myocardial injury. We employed dosages of 1, 10, and 20 mg/kg STVNa to treat MCD in rats fed with a HFD. Based on our results, STVNa repressed MCD (as indicated by ecocardiographic analysis), myocardium function, pathological structure, and myocardial enzymes. Mechanistically, the STVNa-mediated protection against HFD-induced MCD involved inhibition of inflammation and oxidative stress. Furthermore, using Western blot analysis, we revealed that the critical members of the Sirt1/AMPK network were markedly activated in the STVNa-treated group, relative to HFD-fed controls. Collectively, these evidences suggested that the STVNa offered strong protection against HFD-induced MCD. Moreover, this effect was mediated by the activation of the Sirt1/AMPK network, which, in turn, promoted lipid metabolism.
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Affiliation(s)
- Ying Mei
- School of Pharmacy, Jinan University, Guangzhou, 510632, China; YZ Health-tech Inc, Hengqin District, Zhuhai, 519000, China
| | - Hui Hu
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Liangjun Deng
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Xiaoou Sun
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China.
| | - Wen Tan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, 47500, Malaysia.
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18
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Rodriguez-Iturbe B, Johnson RJ, Lanaspa MA, Nakagawa T, Garcia-Arroyo FE, Sánchez-Lozada LG. Sirtuin deficiency and the adverse effects of fructose and uric acid synthesis. Am J Physiol Regul Integr Comp Physiol 2022; 322:R347-R359. [PMID: 35271385 PMCID: PMC8993531 DOI: 10.1152/ajpregu.00238.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/21/2022] [Accepted: 03/03/2022] [Indexed: 12/17/2022]
Abstract
Fructose metabolism and hyperuricemia have been shown to drive insulin resistance, metabolic syndrome, hepatic steatosis, hypertension, inflammation, and innate immune reactivity in experimental studies. We suggest that these adverse effects are at least in part the result of suppressed activity of sirtuins, particularly Sirtuin1. Deficiency of sirtuin deacetylations is a consequence of reduced bioavailability of its cofactor nicotinamide adenine dinucleotide (NAD+). Uric acid-induced inflammation and oxidative stress consume NAD+ and activation of the polyol pathway of fructose and uric acid synthesis also reduces the NAD+-to-NADH ratio. Variability in the compensatory regeneration of NAD+ could result in variable recovery of sirtuin activity that may explain the inconsistent benefits of treatments directed to reduce uric acid in clinical trials. Here, we review the pathogenesis of the metabolic dysregulation driven by hyperuricemia and their potential relationship with sirtuin deficiency. In addition, we discuss therapeutic options directed to increase NAD+ and sirtuins activity that may improve the adverse effects resulting from fructose and uric acid synthesis.
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Affiliation(s)
- Bernardo Rodriguez-Iturbe
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán," Mexico City, Mexico
- Departments of Cardio-Renal Physiopathology Instituto Nacional de Cardiología "Ignacio Chavez," Mexico City, Mexico
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Denver, Colorado
- Kidney Disease Division, Rocky Mountain Regional Veterans Affairs Medical Center, Denver, Colorado
| | - Miguel A Lanaspa
- Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon
| | | | - Fernando E Garcia-Arroyo
- Departments of Cardio-Renal Physiopathology Instituto Nacional de Cardiología "Ignacio Chavez," Mexico City, Mexico
| | - Laura G Sánchez-Lozada
- Departments of Cardio-Renal Physiopathology Instituto Nacional de Cardiología "Ignacio Chavez," Mexico City, Mexico
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19
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Miao R, Fang X, Wei J, Wu H, Wang X, Tian J. Akt: A Potential Drug Target for Metabolic Syndrome. Front Physiol 2022; 13:822333. [PMID: 35330934 PMCID: PMC8940245 DOI: 10.3389/fphys.2022.822333] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/07/2022] [Indexed: 12/21/2022] Open
Abstract
The serine/threonine kinase Akt, also known as protein kinase B (PKB), is one of the key factors regulating glucose and lipid energy metabolism, and is the core focus of current research on diabetes and metabolic diseases. Akt is mostly expressed in key metabolism-related organs and it is activated in response to various stimuli, including cell stress, cell movement, and various hormones and drugs that affect cell metabolism. Genetic and pharmacological studies have shown that Akt is necessary to maintain the steady state of glucose and lipid metabolism and a variety of cellular responses. Existing evidence shows that metabolic syndrome is related to insulin resistance and lipid metabolism disorders. Based on a large number of studies on Akt-related pathways and reactions, we believe that Akt can be used as a potential drug target to effectively treat metabolic syndrome.
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Affiliation(s)
- Runyu Miao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Xinyi Fang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Jiahua Wei
- Graduate College, Changchun University of Chinese Medicine, Changchun, China
| | - Haoran Wu
- Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Xinmiao Wang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaxing Tian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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20
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Integrating adipocyte insulin signaling and metabolism in the multi-omics era. Trends Biochem Sci 2022; 47:531-546. [PMID: 35304047 DOI: 10.1016/j.tibs.2022.02.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/08/2022] [Accepted: 02/21/2022] [Indexed: 12/16/2022]
Abstract
Insulin stimulates glucose uptake into adipocytes via mTORC2/AKT signaling and GLUT4 translocation and directs glucose carbons into glycolysis, glycerol for TAG synthesis, and de novo lipogenesis. Adipocyte insulin resistance is an early indicator of type 2 diabetes in obesity, a worldwide health crisis. Thus, understanding the interplay between insulin signaling and central carbon metabolism pathways that maintains adipocyte function, blood glucose levels, and metabolic homeostasis is critical. While classically viewed through the lens of individual enzyme-substrate interactions, advances in mass spectrometry are beginning to illuminate adipocyte signaling and metabolic networks on an unprecedented scale, yet this is just the tip of the iceberg. Here, we review how 'omics approaches help to elucidate adipocyte insulin action in cellular time and space.
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21
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Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes. Int J Obes (Lond) 2022; 46:535-543. [PMID: 34799672 DOI: 10.1038/s41366-021-01021-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/22/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND In obesity, adipose tissue dysfunction resulting from excessive fat accumulation leads to systemic insulin resistance (IR), the underlying alteration of Type 2 Diabetes. The specific pathways dysregulated in dysfunctional adipocytes and the extent to which it affects adipose metabolic functions remain incompletely characterized. METHODS We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceral white adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulin sensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming and glucose utilization using 13C-isotopic glucose tracing. RESULTS We found that gene expression associated with impaired glucose and lipid metabolism and inflammation represented the strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in mature human white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functions such as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucose metabolism, with higher incorporation of glucose into citrate, but not into downstream metabolites within the TCA cycle. CONCLUSIONS Collectively, our data highlight the importance of obesity-derived insulin resistance in impacting the expression of key metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation in adipose dysfunction in humans.
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22
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Raun SH, Knudsen JR, Han X, Jensen TE, Sylow L. Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner. FASEB J 2022; 36:e22211. [PMID: 35195922 DOI: 10.1096/fj.202101759r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/21/2022] [Accepted: 02/03/2022] [Indexed: 12/14/2022]
Abstract
Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3 H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.
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Affiliation(s)
- Steffen H Raun
- Section of Molecular Physiology, Department of nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Jonas Roland Knudsen
- Section of Molecular Physiology, Department of nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Xiuqing Han
- Section of Molecular Physiology, Department of nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Thomas E Jensen
- Section of Molecular Physiology, Department of nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Lykke Sylow
- Section of Molecular Physiology, Department of nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.,Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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23
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Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance. Cell Metab 2022; 34:227-239.e6. [PMID: 35021042 DOI: 10.1016/j.cmet.2021.12.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/13/2021] [Accepted: 12/10/2021] [Indexed: 02/08/2023]
Abstract
Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.
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24
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Krycer JR, Lor M, Fitzsimmons RL, Hudson JE. A cell culture platform for quantifying metabolic substrate oxidation in bicarbonate-buffered medium. J Biol Chem 2021; 298:101547. [PMID: 34971704 PMCID: PMC8819040 DOI: 10.1016/j.jbc.2021.101547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 12/21/2022] Open
Abstract
Complex diseases such as cancer and diabetes are underpinned by changes in metabolism, specifically by which and how nutrients are catabolized. Substrate utilization can be directly examined by measuring a metabolic endpoint rather than an intermediate (such as tricarboxylic cycle metabolite). For instance, oxidation of specific substrates can be measured in vitro by incubation of live cultures with substrates containing radiolabeled carbon and measuring radiolabeled carbon dioxide. To increase throughput, we previously developed a miniaturized platform to measure substrate oxidation of both adherent and suspension cells using multiwell plates rather than flasks. This enabled multiple conditions to be examined simultaneously, ideal for drug screens and mechanistic studies. However, like many metabolic assays, this was not compatible with bicarbonate-buffered media, which is susceptible to alkalinization upon exposure to gas containing little carbon dioxide such as air. While other buffers such as HEPES can overcome this problem, bicarbonate has additional biological roles as a metabolic substrate and in modulating hormone signaling. Here, we create a bicarbonate-buffered well-plate platform to measure substrate oxidation. This was achieved by introducing a sealed environment within each well that was equilibrated with carbon dioxide, enabling bicarbonate buffering. As proof of principle, we assessed metabolic flux in cultured adipocytes, demonstrating that bicarbonate-buffered medium increased lipogenesis, glucose oxidation, and sensitivity to insulin in comparison to HEPES-buffered medium. This convenient and high-throughput method facilitates the study and screening of metabolic activity under more physiological conditions to aid biomedical research.
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Affiliation(s)
- James R Krycer
- QIMR Berghofer Medical Research Institute; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
| | - Mary Lor
- QIMR Berghofer Medical Research Institute
| | | | - James E Hudson
- QIMR Berghofer Medical Research Institute; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland.
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25
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The aetiology and molecular landscape of insulin resistance. Nat Rev Mol Cell Biol 2021; 22:751-771. [PMID: 34285405 DOI: 10.1038/s41580-021-00390-6] [Citation(s) in RCA: 311] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2021] [Indexed: 02/07/2023]
Abstract
Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues - prominently in muscle, fat and liver - is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance.
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26
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Mileti E, Kwok KHM, Andersson DP, Mathelier A, Raman A, Bäckdahl J, Jalkanen J, Massier L, Thorell A, Gao H, Arner P, Mejhert N, Daub CO, Rydén M. Human White Adipose Tissue Displays Selective Insulin Resistance in the Obese State. Diabetes 2021; 70:1486-1497. [PMID: 33863803 DOI: 10.2337/db21-0001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 04/14/2021] [Indexed: 11/13/2022]
Abstract
Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of those with obesity and to what extent these are normalized by weight loss are unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and insulin response in subcutaneous WAT by RNA sequencing in 23 women with obesity before and 2 years after bariatric surgery. To control for effects of surgery, women postsurgery were matched to never-obese women. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodeling and protein translation was selectively regulated in the two nonobese states; and several postobesity-enriched genes encoding proteins involved in, for example, one-carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state, where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.
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Affiliation(s)
- Enrichetta Mileti
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Kelvin H M Kwok
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Daniel P Andersson
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Anthony Mathelier
- Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo, Oslo, Norway
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | | | - Jesper Bäckdahl
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jutta Jalkanen
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Lucas Massier
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Thorell
- Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
- Department of Surgery, Ersta Hospital, Stockholm, Sweden
| | - Hui Gao
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Peter Arner
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas Mejhert
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Carsten O Daub
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Science for Life Laboratory, Stockholm, Sweden
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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27
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Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue. Nat Commun 2021; 12:2999. [PMID: 34016966 PMCID: PMC8137956 DOI: 10.1038/s41467-021-22579-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/12/2021] [Indexed: 12/22/2022] Open
Abstract
The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes. The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.
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28
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Stöhr O, Tao R, Miao J, Copps KD, White MF. FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance. Cell Rep 2021; 34:108893. [PMID: 33761350 PMCID: PMC8529953 DOI: 10.1016/j.celrep.2021.108893] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/22/2020] [Accepted: 03/02/2021] [Indexed: 12/28/2022] Open
Abstract
Fgf21 (fibroblast growth factor 21) is a regulatory hepatokine that, in pharmacologic form, powerfully promotes weight loss and glucose homeostasis. Although "Fgf21 resistance" is inferred from higher plasma Fgf21 levels in insulin-resistant mice and humans, diminished Fgf21 function is understood primarily via Fgf21 knockout mice. By contrast, we show that modestly reduced Fgf21-owing to cell-autonomous suppression by hepatic FoxO1-contributes to dysregulated metabolism in LDKO mice (Irs1L/L⋅Irs2L/L⋅CreAlb), a model of severe hepatic insulin resistance caused by deletion of hepatic Irs1 (insulin receptor substrate 1) and Irs2. Knockout of hepatic Foxo1 in LDKO mice or direct restoration of Fgf21 by adenoviral infection restored glucose utilization by BAT (brown adipose tissue) and skeletal muscle, normalized thermogenic gene expression in LDKO BAT, and corrected acute cold intolerance of LDKO mice. These studies highlight the Fgf21-dependent plasticity and importance of BAT function to metabolic health during hepatic insulin resistance.
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Affiliation(s)
- Oliver Stöhr
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Rongya Tao
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Ji Miao
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Kyle D Copps
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Morris F White
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
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29
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Lima TDR, Voltarelli FA, Freire LS, da Silva FA, de Almeida PC, Ávila ETP, de França SA, Pereira MP, Damazo AS, Navalta JW, Fett CA, Kawashita NH. High-fat diet and fructose drink introduced after weaning rats, induces a better human obesity model than very high-fat diet. J Food Biochem 2021; 45:e13671. [PMID: 33694197 DOI: 10.1111/jfbc.13671] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 12/28/2022]
Abstract
In the present study, we associated a high-fat diet (HF group: 45% kcal from lipids) or very high-fat (VHF group: 60% kcal from lipids) diet with a fructose drink (10% fructose) for hydration. Normal rat chow that received the control diet (content 16.3% kcal from lipid-AIN93G) and water. The treatments were introduced soon after weaning and were administered for 70 days. We aimed to compare HF and VHF groups and find which acts as a better model mimicking human obesity. Body mass gain, final body weight, adipocyte area in inguinal depots, visceral and subcutaneous adipose depots, serum triacylglycerol, and VLDL-c were all higher in the HF group, followed by the VHF group, compared to the C group. Only the HF group showed hyperinsulinemia and hyperleptinemia and higher total caloric intake, Lee index, HOMA2-IR, and total cholesterol. Serum TNF-α and IL-6 levels were lower in the HF and VHF groups than in the C group at the end for 70 days. In Summary, the HF (45%) diet administered with fructose induced a higher similarity of metabolic and hormonal alterations associated with human obesity. PRACTICAL APPLICATIONS: High intake of lipids with sugary drinks has been associated with obesity and its comorbidities. Although a diet with 45% or 60% of lipids is considered hyperlipidic, they are different in their effects on eating behavior and also probably from a metabolic point of view. Common sense is that the reduction in intake of lipids is favorable to health. Our study shows that this is not wholly true, and this information contributes to the guidelines for the treatment of obesity. In addition, the scientific literature on the subject has shown the most diverse results and also the use of experimental models with few similarities with human obesity. Our findings can contribute as a good model of obesity initiated during childhood to investigate possible using nutritional strategies, or the adoption of ergogenic nutritional resources in future studies, for example.
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Affiliation(s)
- Thiago da Rosa Lima
- Department of Chemistry, Federal University of Mato Grosso, Cuiabá, Brazil.,Department of Health Sciences and Nutrition, Academic Center of Varzea Grande, Várzea Grande, Brazil
| | | | | | | | - Paula Caroline de Almeida
- Department of Basic Health Sciences, Faculty of Medicine, Federal University of Mato Grosso, Cuiabá, Brazil
| | - Eudes Thiago Pereira Ávila
- Department of Basic Health Sciences, Faculty of Medicine, Federal University of Mato Grosso, Cuiabá, Brazil
| | | | | | - Amílcar Sabino Damazo
- Department of Basic Health Sciences, Faculty of Medicine, Federal University of Mato Grosso, Cuiabá, Brazil
| | - James Wilfred Navalta
- Department of Kinesiology and Nutrition Sciences, University of Nevada, Las Vegas, Nevada
| | - Carlos Alexandre Fett
- Department of Basic Health Sciences, Faculty of Medicine, Federal University of Mato Grosso, Cuiabá, Brazil
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30
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Norris D, Yang P, Shin SY, Kearney AL, Kim HJ, Geddes T, Senior AM, Fazakerley DJ, Nguyen LK, James DE, Burchfield JG. Signaling Heterogeneity is Defined by Pathway Architecture and Intercellular Variability in Protein Expression. iScience 2021; 24:102118. [PMID: 33659881 PMCID: PMC7892930 DOI: 10.1016/j.isci.2021.102118] [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: 11/16/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin's activation of PI3K/Akt signaling, stimulates glucose uptake by enhancing delivery of GLUT4 to the cell surface. Here we examined the origins of intercellular heterogeneity in insulin signaling. Akt activation alone accounted for ~25% of the variance in GLUT4, indicating that additional sources of variance exist. The Akt and GLUT4 responses were highly reproducible within the same cell, suggesting the variance is between cells (extrinsic) and not within cells (intrinsic). Generalized mechanistic models (supported by experimental observations) demonstrated that the correlation between the steady-state levels of two measured signaling processes decreases with increasing distance from each other and that intercellular variation in protein expression (as an example of extrinsic variance) is sufficient to account for the variance in and between Akt and GLUT4. Thus, the response of a population to insulin signaling is underpinned by considerable single-cell heterogeneity that is largely driven by variance in gene/protein expression between cells.
Insulin signaling is heterogeneous between cells in the same population The temporal response of signaling components within a cell is highly reproducible Upstream responses (Akt) can only partially predict downstream response (GLUT4) Protein expression variance is a driver of intercellular signaling heterogeneity
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Affiliation(s)
- Dougall Norris
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
| | - Pengyi Yang
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia.,Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
| | - Sung-Young Shin
- Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.,Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Alison L Kearney
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
| | - Hani Jieun Kim
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia.,Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
| | - Thomas Geddes
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia.,Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
| | - Alistair M Senior
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
| | - Daniel J Fazakerley
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
| | - Lan K Nguyen
- Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.,Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - David E James
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.,Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
| | - James G Burchfield
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.,School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
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31
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Rossi A, Eid M, Dodgson J, Davies G, Musial B, Wabitsch M, Church C, Hornigold D. In vitro characterization of the effects of chronic insulin stimulation in mouse 3T3-L1 and human SGBS adipocytes. Adipocyte 2020; 9:415-426. [PMID: 32718202 PMCID: PMC7469436 DOI: 10.1080/21623945.2020.1798613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Hyperinsulinemia is the hallmark of the development of insulin resistance and precedes the diagnosis of type 2 diabetes. Here we evaluated the effects of prolonged exposure (≥4 days) to high insulin doses (150 nM) in vitro in two adipose cell types, mouse 3T3-L1 and human SGBS. Chronic insulin treatment significantly decreased lipid droplet size, insulin signalling and insulin-stimulated glucose uptake. 3T3-L1 displayed an increased basal glucose internalization following chronic insulin treatment, which was associated with increased GLUT1 expression. In addition, both cells showed increased basal lipolysis. In conclusion, we report the effects of prolonged hyperinsulinemia in 3T3-L1 and SGBS, highlighting similarities and discrepancies between the cell types, to be considered when using these cells to model insulin-induced insulin resistance.
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Affiliation(s)
- A. Rossi
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - M. Eid
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - J. Dodgson
- Biologics Therapeutics, Antibody and Protein Engineering, R&D, AstraZeneca, Cambridge, UK
| | - G. Davies
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - B. Musial
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - M. Wabitsch
- Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany
| | - C. Church
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - D.C. Hornigold
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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32
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Gatticchi L, Petricciuolo M, Scarpelli P, Macchioni L, Corazzi L, Roberti R. Tm7sf2 gene promotes adipocyte differentiation of mouse embryonic fibroblasts and improves insulin sensitivity. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1868:118897. [PMID: 33121932 DOI: 10.1016/j.bbamcr.2020.118897] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022]
Abstract
Adipogenesis is a finely orchestrated program involving a transcriptional cascade coordinated by CEBP and PPAR family members and by hormonally induced signaling pathways. Alterations in any of these factors result into impaired formation of fully differentiated adipocytes. Tm7sf2 gene encodes for a Δ(14)-sterol reductase primarily involved in cholesterol biosynthesis. Furthermore, TM7SF2 modulates the expression of the master gene of adipogenesis PPARγ, suggesting a role in the regulation of adipose tissue homeostasis. We investigated the differentiation of Tm7sf2-/- MEFs into adipocytes, compared to Tm7sf2+/+ MEFs. Tm7sf2 expression was increased at late stage of differentiation in wild type cells, while Tm7sf2-/- MEFs exhibited a reduced capacity to differentiate into mature adipocytes. Indeed, Tm7sf2-/- MEFs had lower neutral lipid accumulation and reduced expression of adipogenic regulators. At early stage, the reduction in C/EBPβ expression impaired mitotic clonal expansion, which is needed by preadipocytes for adipogenesis induction. At late stage, the expression and activity of C/EBPα and PPARγ were inhibited in Tm7sf2-/- cells, leading to the reduced expression of adipocyte genes like Srebp-1c, Fasn, Scd-1, Adipoq, Fabp4, and Glut4. Loss of the acquisition of adipocyte phenotype was accompanied by a reduction in the levels of Irs1, and phosphorylated Akt and ERK1/2, indicating a blunted insulin signaling in differentiating Tm7sf2-/- cells. Moreover, throughout the differentiation process, increased expression of the antiadipogenic Mmp3 was observed in MEFs lacking Tm7sf2. These findings indicate Tm7sf2 as a novel factor influencing adipocyte differentiation that could be relevant to adipose tissue development and maintenance of metabolic health.
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Affiliation(s)
- Leonardo Gatticchi
- Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, 06132 Perugia, Italy.
| | - Maya Petricciuolo
- Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, 06132 Perugia, Italy
| | - Paolo Scarpelli
- Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, 06132 Perugia, Italy
| | - Lara Macchioni
- Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, 06132 Perugia, Italy.
| | - Lanfranco Corazzi
- Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, 06132 Perugia, Italy.
| | - Rita Roberti
- Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, 06132 Perugia, Italy.
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33
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The NLRP3 inflammasome regulates adipose tissue metabolism. Biochem J 2020; 477:1089-1107. [PMID: 32202638 DOI: 10.1042/bcj20190472] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/27/2020] [Accepted: 02/28/2020] [Indexed: 12/27/2022]
Abstract
Adipose tissue regulates metabolic homeostasis by participating in endocrine and immune responses in addition to storing and releasing lipids from adipocytes. Obesity skews adipose tissue adipokine responses and degrades the coordination of adipocyte lipogenesis and lipolysis. These defects in adipose tissue metabolism can promote ectopic lipid deposition and inflammation in insulin-sensitive tissues such as skeletal muscle and liver. Sustained caloric excess can expand white adipose tissue to a point of maladaptation exacerbating both local and systemic inflammation. Multiple sources, instigators and propagators of adipose tissue inflammation occur during obesity. Cross-talk between professional immune cells (i.e. macrophages) and metabolic cells (i.e. adipocytes) promote adipose tissue inflammation during metabolic stress (i.e. metaflammation). Metabolic stress and endogenous danger signals can engage pathogen recognition receptors (PRRs) of the innate immune system thereby activating pro-inflammatory and stress pathways in adipose tissue. The Nod-like receptor protein 3 (NLRP3) inflammasome can act as a metabolic danger sensor to a wide range of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Activation of the NLRP3 inflammasome facilitates caspase-1 dependent production of the pro-inflammatory cytokines IL-1β and IL-18. Activation of the NLRP3 inflammasome can promote inflammation and pyroptotic cell death, but caspase-1 is also involved in adipogenesis. This review discusses the role of the NLRP3 inflammasome in adipose tissue immunometabolism responses relevant to metabolic disease. Understanding the potential sources of NLRP3 activation and consequences of NLRP3 effectors may reveal therapeutic opportunities to break or fine-tune the connection between metabolism and inflammation in adipose tissue during obesity.
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34
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Adipocyte lipolysis: from molecular mechanisms of regulation to disease and therapeutics. Biochem J 2020; 477:985-1008. [PMID: 32168372 DOI: 10.1042/bcj20190468] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/19/2020] [Accepted: 02/26/2020] [Indexed: 12/20/2022]
Abstract
Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids are mobilized during adipocyte lipolysis, the fundamental process of hydrolyzing TAG to FAs for internal or systemic energy use. Our understanding of adipocyte lipolysis has greatly increased over the past 50 years from a basic enzymatic process to a dynamic regulatory one, involving the assembly and disassembly of protein complexes on the surface of LDs. These dynamic interactions are regulated by hormonal signals such as catecholamines and insulin which have opposing effects on lipolysis. Upon stimulation, patatin-like phospholipase domain containing 2 (PNPLA2)/adipocyte triglyceride lipase (ATGL), the rate limiting enzyme for TAG hydrolysis, is activated by the interaction with its co-activator, alpha/beta hydrolase domain-containing protein 5 (ABHD5), which is normally bound to perilipin 1 (PLIN1). Recently identified negative regulators of lipolysis include G0/G1 switch gene 2 (G0S2) and PNPLA3 which interact with PNPLA2 and ABHD5, respectively. This review focuses on the dynamic protein-protein interactions involved in lipolysis and discusses some of the emerging concepts in the control of lipolysis that include allosteric regulation and protein turnover. Furthermore, recent research demonstrates that many of the proteins involved in adipocyte lipolysis are multifunctional enzymes and that lipolysis can mediate homeostatic metabolic signals at both the cellular and whole-body level to promote inter-organ communication. Finally, adipocyte lipolysis is involved in various diseases such as cancer, type 2 diabetes and fatty liver disease, and targeting adipocyte lipolysis is of therapeutic interest.
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Velasco M, Ortiz-Huidobro RI, Larqué C, Sánchez-Zamora YI, Romo-Yáñez J, Hiriart M. Sexual dimorphism in insulin resistance in a metabolic syndrome rat model. Endocr Connect 2020; 9:890-902. [PMID: 33069157 PMCID: PMC7583132 DOI: 10.1530/ec-20-0288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE We assessed the sex-specific differences in the molecular mechanisms of insulin resistance in muscle and adipose tissue, in a MS rat model induced by a high sucrose diet. METHODS Male, female, and ovariectomized female Wistar rats were randomly distributed in control and high-sucrose diet (HSD) groups, supplemented for 24 weeks with 20% sucrose in the drinking water. At the end, we assessed parameters related to MS, analyzing the effects of the HSD on critical nodes of the insulin signaling pathway in muscle and adipose tissue. RESULTS At the end of the treatment, HSD groups of both sexes developed obesity, with a 15, 33 and 23% of body weight gain in male, female, and OVX groups respectively, compared with controls; mainly related to hypertrophy of peripancreatic and gonadal adipose tissue. They also developed hypertriglyceridemia, and liver steatosis, with the last being worse in the HSD females. Compared to the control groups, HSD rats had higher IL1B and TNFA levels and insulin resistance. HSD females were more intolerant to glucose than HSD males. Our observations suggest that insulin resistance mechanisms include an increase in phosphorylated AKT(S473) form in HSD male and female groups and a decrease in phosphorylated P70S6K1(T389) in the HSD male groups from peripancreatic adipose tissue. While in gonadal adipose tissue the phosphorylated form of AKT decreased in HSD females, but not in HSD males. Finally, HSD groups showed a reduction in p-AKT levels in gastrocnemius muscle. CONCLUSION A high-sucrose diet induces MS and insulin resistance with sex-associated differences and in a tissue-specific manner.
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Affiliation(s)
- Myrian Velasco
- Neuroscience Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Rosa Isela Ortiz-Huidobro
- Neuroscience Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Carlos Larqué
- Department of Embryology and Genetics, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Yuriko Itzel Sánchez-Zamora
- Neuroscience Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - José Romo-Yáñez
- Department of Gynecological and Perinatal Endocrinology, Instituto Nacional de Perinatología ‘Isidro Espinosa de los Reyes’, Mexico City, Mexico
| | - Marcia Hiriart
- Neuroscience Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Krycer JR, Quek LE, Francis D, Zadoorian A, Weiss FC, Cooke KC, Nelson ME, Diaz-Vegas A, Humphrey SJ, Scalzo R, Hirayama A, Ikeda S, Shoji F, Suzuki K, Huynh K, Giles C, Varney B, Nagarajan SR, Hoy AJ, Soga T, Meikle PJ, Cooney GJ, Fazakerley DJ, James DE. Insulin signaling requires glucose to promote lipid anabolism in adipocytes. J Biol Chem 2020; 295:13250-13266. [PMID: 32723868 DOI: 10.1074/jbc.ra120.014907] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride-glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.
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Affiliation(s)
- James R Krycer
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Lake-Ee Quek
- Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia
| | - Deanne Francis
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Armella Zadoorian
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Fiona C Weiss
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Kristen C Cooke
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Marin E Nelson
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Alexis Diaz-Vegas
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Sean J Humphrey
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Richard Scalzo
- Faculty of Engineering and Information Technologies, University of Sydney, Sydney, New South Wales, Australia
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Otemachi, Chiyoda-Ku, Tokyo, Japan
| | - Satsuki Ikeda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Futaba Shoji
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Kumi Suzuki
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Kevin Huynh
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Corey Giles
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Bianca Varney
- Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Shilpa R Nagarajan
- Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Andrew J Hoy
- Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Otemachi, Chiyoda-Ku, Tokyo, Japan
| | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Gregory J Cooney
- Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Daniel J Fazakerley
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - David E James
- School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
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Tanataweethum N, Zhong F, Trang A, Lee C, Cohen RN, Bhushan A. Towards an Insulin Resistant Adipose Model on a Chip. Cell Mol Bioeng 2020; 14:89-99. [PMID: 33643468 DOI: 10.1007/s12195-020-00636-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 07/07/2020] [Indexed: 12/25/2022] Open
Abstract
Introduction Adipose tissue and adipocytes are primary regulators of insulin sensitivity and energy homeostasis. Defects in insulin sensitivity of the adipocytes predispose the body to insulin resistance (IR) that could lead to diabetes. However, the mechanisms mediating adipocyte IR remain elusive, which emphasizes the need to develop experimental models that can validate the insulin signaling pathways and discover new mechanisms in the search for novel therapeutics. Currently in vitro adipose organ-chip devices show superior cell function over conventional cell culture. However, none of these models represent disease states. Only when these in vitro models can represent both healthy and disease states, they can be useful for developing therapeutics. Here, we establish an organ-on-chip model of insulin-resistant adipocytes, as well as characterization in terms of insulin signaling pathway and lipid metabolism. Methods We differentiated, maintained, and induced insulin resistance into primary adipocytes in a microfluidic organ-on-chip. We then characterized IR by looking at the insulin signaling pathway and lipid metabolism, and validated by studying a diabetic drug, rosiglitazone. Results We confirmed the presence of insulin resistance through reduction of Akt phosphorylation, Glut4 expression, Glut4 translocation and glucose uptake. We also confirmed defects of disrupted insulin signaling through reduction of lipid accumulation from fatty acid uptake and elevation of glycerol secretion. Testing with rosiglitazone showed a significant improvement in insulin sensitivity and fatty acid metabolism as suggested by previous reports. Conclusions The adipose-chip exhibited key characteristics of IR and can serve as model to study diabetes and facilitate discovery of novel therapeutics.
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Affiliation(s)
- Nida Tanataweethum
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA
| | - Franklin Zhong
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA
| | - Allyson Trang
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA
| | - Chaeeun Lee
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA
| | - Ronald N Cohen
- Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, IL 60637 USA
| | - Abhinav Bhushan
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA
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Insulin and β-adrenergic receptors mediate lipolytic and anti-lipolytic signalling that is not altered by type 2 diabetes in human adipocytes. Biochem J 2020; 476:2883-2908. [PMID: 31519735 PMCID: PMC6792037 DOI: 10.1042/bcj20190594] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/11/2019] [Accepted: 09/12/2019] [Indexed: 12/21/2022]
Abstract
Control of fatty acid storage and release in adipose tissue is fundamental in energy homeostasis and the development of obesity and type 2 diabetes. We here take the whole signalling network into account to identify how insulin and β-adrenergic stimulation in concert controls lipolysis in mature subcutaneous adipocytes obtained from non-diabetic and, in parallel, type 2 diabetic women. We report that, and show how, the anti-lipolytic effect of insulin can be fully explained by protein kinase B (PKB/Akt)-dependent activation of the phosphodiesterase PDE3B. Through the same PKB-dependent pathway β-adrenergic receptor signalling, via cAMP and PI3Kα, is anti-lipolytic and inhibits its own stimulation of lipolysis by 50%. Through this pathway both insulin and β-adrenergic signalling control phosphorylation of FOXO1. The dose–response of lipolysis is bell-shaped, such that insulin is anti-lipolytic at low concentrations, but at higher concentrations of insulin lipolysis was increasingly restored due to inhibition of PDE3B. The control of lipolysis was not altered in adipocytes from diabetic individuals. However, the release of fatty acids was increased by 50% in diabetes due to reduced reesterification of lipolytically liberated fatty acids. In conclusion, our results reveal mechanisms of control by insulin and β-adrenergic stimulation — in human adipocytes — that define a network of checks and balances ensuring robust control to secure uninterrupted supply of fatty acids without reaching concentrations that put cellular integrity at risk. Moreover, our results define how selective insulin resistance leave lipolytic control by insulin unaltered in diabetes, while the fatty acid release is substantially increased.
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Czech MP. Mechanisms of insulin resistance related to white, beige, and brown adipocytes. Mol Metab 2020; 34:27-42. [PMID: 32180558 PMCID: PMC6997501 DOI: 10.1016/j.molmet.2019.12.014] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The diminished glucose lowering effect of insulin in obesity, called "insulin resistance," is associated with glucose intolerance, type 2 diabetes, and other serious maladies. Many publications on this topic have suggested numerous hypotheses on the molecular and cellular disruptions that contribute to the syndrome. However, significant uncertainty remains on the mechanisms of its initiation and long-term maintenance. SCOPE OF REVIEW To simplify insulin resistance analysis, this review focuses on the unifying concept that adipose tissue is a central regulator of systemic glucose homeostasis by controlling liver and skeletal muscle metabolism. Key aspects of adipose function related to insulin resistance reviewed are: 1) the modes by which specific adipose tissues control hepatic glucose output and systemic glucose disposal, 2) recently acquired understanding of the underlying mechanisms of these modes of regulation, and 3) the steps in these pathways adversely affected by obesity that cause insulin resistance. MAJOR CONCLUSIONS Adipocyte heterogeneity is required to mediate the multiple pathways that control systemic glucose tolerance. White adipocytes specialize in sequestering triglycerides away from the liver, muscle, and other tissues to limit toxicity. In contrast, brown/beige adipocytes are very active in directly taking up glucose in response to β adrenergic signaling and insulin and enhancing energy expenditure. Nonetheless, white, beige, and brown adipocytes all share the common feature of secreting factors and possibly exosomes that act on distant tissues to control glucose homeostasis. Obesity exerts deleterious effects on each of these adipocyte functions to cause insulin resistance.
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Affiliation(s)
- Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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40
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Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 2020; 9:cells9030706. [PMID: 32183037 PMCID: PMC7140703 DOI: 10.3390/cells9030706] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
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Martinez Calejman C, Trefely S, Entwisle SW, Luciano A, Jung SM, Hsiao W, Torres A, Hung CM, Li H, Snyder NW, Villén J, Wellen KE, Guertin DA. mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat Commun 2020; 11:575. [PMID: 31996678 PMCID: PMC6989638 DOI: 10.1038/s41467-020-14430-w] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 12/10/2019] [Indexed: 01/09/2023] Open
Abstract
mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis. mTORC2 activates Akt, a regulator of cell growth and metabolism, however, the role of mTORC2 in adipocytes is incompletely understood. Here the authors report that a mTORC2-Akt axis specifically activates ACLY to promote lipid synthesis and histone acetylation during brown adipocyte differentiation.
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Affiliation(s)
- C Martinez Calejman
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - S Trefely
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.,Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.,AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, 19104, USA
| | - S W Entwisle
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.,Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, 98195, USA
| | - A Luciano
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - S M Jung
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - W Hsiao
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - A Torres
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.,Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - C M Hung
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - H Li
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - N W Snyder
- AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, 19104, USA
| | - J Villén
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.,Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, 98195, USA
| | - K E Wellen
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.,Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - D A Guertin
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA. .,Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
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Krycer JR, Elkington SD, Diaz-Vegas A, Cooke KC, Burchfield JG, Fisher-Wellman KH, Cooney GJ, Fazakerley DJ, James DE. Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes. J Biol Chem 2020; 295:99-110. [PMID: 31744882 PMCID: PMC6952605 DOI: 10.1074/jbc.ra119.011695] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Indexed: 11/06/2022] Open
Abstract
Insulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Because insulin stimulates glucose utilization, we hypothesized that glucose oxidation would fuel respiration, in turn generating mitochondrial oxidants. This would impair insulin action, limiting further glucose uptake in a negative feedback loop of "glucose-dependent" insulin resistance. Using primary rat adipocytes and cultured 3T3-L1 adipocytes, we observed that insulin increased respiration, but notably this occurred independently of glucose supply. In contrast, glucose was required for insulin to increase mitochondrial oxidants. Despite rising to similar levels as when treated with other agents that cause insulin resistance, glucose-dependent mitochondrial oxidants failed to cause insulin resistance. Subsequent studies revealed a temporal relationship whereby mitochondrial oxidants needed to increase before the insulin stimulus to induce insulin resistance. Together, these data reveal that (a) adipocyte respiration is principally fueled from nonglucose sources; (b) there is a disconnect between respiration and oxidative stress, whereby mitochondrial oxidant levels do not rise with increased respiration unless glucose is present; and (c) mitochondrial oxidative stress must precede the insulin stimulus to cause insulin resistance, explaining why short-term, insulin-dependent glucose utilization does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance.
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Affiliation(s)
- James R Krycer
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Sarah D Elkington
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Alexis Diaz-Vegas
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Kristen C Cooke
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - James G Burchfield
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Kelsey H Fisher-Wellman
- East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834
| | - Gregory J Cooney
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Daniel J Fazakerley
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
| | - David E James
- School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
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Wang Q, Mu H, Shen H, Gu Z, Liu D, Yang M, Zhang Y, Xu W, Zhang W, Mai K. Comparative analysis of glucose metabolism responses of large yellow croaker Larimichthys crocea fed diet with fish oil and palm oil. FISH PHYSIOLOGY AND BIOCHEMISTRY 2019; 45:1603-1614. [PMID: 31054044 DOI: 10.1007/s10695-019-00646-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 04/23/2019] [Indexed: 06/09/2023]
Abstract
In order to study the effects of dietary fatty acid compositions on glucose metabolism, large yellow croaker juveniles Larimichthys crocea (initial weight, 36.80 ± 0.39 g) were fed with two experiment diets for 12 weeks. The two diets contained 6.5% of fish oil (FO) and palm oil (PO), respectively. Results showed that the contents of saturated fatty acids in liver and muscle, levels of glucose, triglyceride (TG), non-esterified fatty acid (NEFA), and leptin in blood were significantly higher in PO group, while the hepatic glycogen and muscle glycogen significantly decreased (P < 0.05). There were no significant differences in blood insulin and adiponectin levels between the two groups (P > 0.05). Compared with the FO group, the expressions of glucokinase (GK), glucose-6-phosphate dehydrogenase, glycogen synthase (GYS), glucose transporter 2 (GLUT2), insulin receptor 1 (IR1), insulin receptor substrate 1 (IRS1), insulin receptor substrate (IRS2), and protein kinase B (AKT2) were significantly decreased, and the expressions of phosphoenolpyruvate carboxykinase (PEPCK) in liver were significantly increased in the PO group. Meanwhile, the expressions of GK, phosphofructokinase, GYS, GLUT4, and insulin receptor 2 (IR2) were significantly reduced, and the expressions PEPCK, fructose-1 and 6-diphosphatase in muscle were significantly increased in the PO group. In conclusion, palm oil in diet could inhibit the utilization of glucose and promote the endogenous glucose production in large yellow croaker by reducing the sensitivity of insulin, so as to increase the blood glucose level.
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Affiliation(s)
- Qi Wang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Hua Mu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Haohao Shen
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Zhixiang Gu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Dong Liu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Mengxi Yang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Yue Zhang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Weiqi Xu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
| | - Wenbing Zhang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China.
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Wen Hai Road, Qingdao, 266237, China.
| | - Kangsen Mai
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture), Fisheries College, Ocean University of China, Qingdao, 266003, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Wen Hai Road, Qingdao, 266237, China
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Kearney AL, Cooke KC, Norris DM, Zadoorian A, Krycer JR, Fazakerley DJ, Burchfield JG, James DE. Serine 474 phosphorylation is essential for maximal Akt2 kinase activity in adipocytes. J Biol Chem 2019; 294:16729-16739. [PMID: 31548312 DOI: 10.1074/jbc.ra119.010036] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/15/2019] [Indexed: 01/06/2023] Open
Abstract
The Ser/Thr protein kinase Akt regulates essential biological processes such as cell survival, growth, and metabolism. Upon growth factor stimulation, Akt is phosphorylated at Ser474; however, how this phosphorylation contributes to Akt activation remains controversial. Previous studies, which induced loss of Ser474 phosphorylation by ablating its upstream kinase mTORC2, have implicated Ser474 phosphorylation as a driver of Akt substrate specificity. Here we directly studied the role of Akt2 Ser474 phosphorylation in 3T3-L1 adipocytes by preventing Ser474 phosphorylation without perturbing mTORC2 activity. This was achieved by utilizing a chemical genetics approach, where ectopically expressed S474A Akt2 was engineered with a W80A mutation to confer resistance to the Akt inhibitor MK2206, and thus allow its activation independent of endogenous Akt. We found that insulin-stimulated phosphorylation of four bona fide Akt substrates (TSC2, PRAS40, FOXO1/3a, and AS160) was reduced by ∼50% in the absence of Ser474 phosphorylation. Accordingly, insulin-stimulated mTORC1 activation, protein synthesis, FOXO nuclear exclusion, GLUT4 translocation, and glucose uptake were attenuated upon loss of Ser474 phosphorylation. We propose a model where Ser474 phosphorylation is required for maximal Akt2 kinase activity in adipocytes.
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Affiliation(s)
- Alison L Kearney
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Kristen C Cooke
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Dougall M Norris
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Armella Zadoorian
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - James R Krycer
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Daniel J Fazakerley
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - James G Burchfield
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
| | - David E James
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia .,Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
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45
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Boland ML, Oró D, Tølbøl KS, Thrane ST, Nielsen JC, Cohen TS, Tabor DE, Fernandes F, Tovchigrechko A, Veidal SS, Warrener P, Sellman BR, Jelsing J, Feigh M, Vrang N, Trevaskis JL, Hansen HH. Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source. World J Gastroenterol 2019; 25:4904-4920. [PMID: 31543682 PMCID: PMC6737317 DOI: 10.3748/wjg.v25.i33.4904] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/28/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The trans-fat containing AMLN (amylin liver non-alcoholic steatohepatitis, NASH) diet has been extensively validated in C57BL/6J mice with or without the Lepob/Lepob (ob/ob) mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH. Due to a recent ban on trans-fats as food additive, there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.
AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.
METHODS Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat (Primex shortening) substituted by equivalent amounts of palm oil [Gubra amylin NASH, (GAN) diet] for 8, 12 and 16 wk. C57BL/6J mice were fed the same diets for 28 wk. AMLN and GAN diets had similar caloric content (40% fat kcal), fructose (22%) and cholesterol (2%) level.
RESULTS The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance. Biopsy-confirmed steatosis, lobular inflammation, hepatocyte ballooning, fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet. C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.
CONCLUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsy-confirmed NASH in ob/ob and C57BL/6J mice, making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments.
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Affiliation(s)
- Michelle L Boland
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
- Pharmacology, Gubra, Hørsholm DK-2970, Denmark
| | - Denise Oró
- Pharmacology, Gubra, Hørsholm DK-2970, Denmark
| | | | | | | | - Taylor S Cohen
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - David E Tabor
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - Fiona Fernandes
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - Andrey Tovchigrechko
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | | | - Paul Warrener
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | - Bret R Sellman
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
| | | | | | - Niels Vrang
- Pharmacology, Gubra, Hørsholm DK-2970, Denmark
| | - James L Trevaskis
- Cardiovascular, Renal and Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, United States
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46
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Ely BR, Clayton ZS, McCurdy CE, Pfeiffer J, Needham KW, Comrada LN, Minson CT. Heat therapy improves glucose tolerance and adipose tissue insulin signaling in polycystic ovary syndrome. Am J Physiol Endocrinol Metab 2019; 317:E172-E182. [PMID: 31136202 PMCID: PMC7199222 DOI: 10.1152/ajpendo.00549.2018] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Polycystic ovary syndrome (PCOS) is associated with high rates of obesity and metabolic dysfunction. Repeated passive heat exposure (termed heat therapy) is a novel lifestyle intervention for improving health in obese women with PCOS. The purpose of this study was to examine changes in metabolic function in obese women with PCOS following heat therapy. Eighteen age- and BMI-matched obese women with PCOS (age: 27 ± 1 yr, BMI: 41.3 ± 1.1 kg/m-2) were assigned to heat therapy (HT) or time control (CON). HT participants underwent 30 one-hour hot tub sessions over 8-10 wk, while CON participants completed all testing but did not undergo heat therapy. Before (Pre), at the mid-point (Mid), and following (Post) 8-10 wk of heat therapy, metabolic health was assessed using a 2-h oral glucose tolerance test, a subcutaneous abdominal fat biopsy (Pre-Post only), and other blood markers relating to metabolic function. HT participants exhibited improved fasting glucose (Pre: 105 ± 3, Post: 89 ± 5mg/dl; P = 0.001), glucose area under the curve (AUC) (Pre: 18,698 ± 1,045, Post: 16,987 ± 1,017 mg·dl-1·min-1; P = 0.028) and insulin AUC (Pre: 126,924 ± 11,730, Post: 91,233 ± 14,429 IU l-1·min-1; P = 0.012). Adipocyte insulin signaling (p-AKT at Ser-473 with 1.2 nM insulin) increased in HT (Pre: 0.29 ± 0.14, Post: 0.93 ± 0.29 AU; P = 0.021). Additionally, serum testosterone declined in HT participants (Pre: 51 ± 7, Post: 34 ± 4 ng/dl; P = 0.033). No parameters changed over time in CON, and no change in BMI was observed in either group. HT substantially improved metabolic risk profile in obese women with PCOS. HT also reduced androgen excess and may improve PCOS symptomology.
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Affiliation(s)
- Brett R Ely
- Department of Human Physiology, University of Oregon , Eugene, Oregon
| | - Zachary S Clayton
- Department of Human Physiology, University of Oregon , Eugene, Oregon
| | - Carrie E McCurdy
- Department of Human Physiology, University of Oregon , Eugene, Oregon
| | - Joshua Pfeiffer
- PeaceHealth Medical Group, Oregon Bariatric Center , Springfield, Oregon
| | | | - Lindan N Comrada
- Department of Human Physiology, University of Oregon , Eugene, Oregon
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Abstract
A pivotal metabolic function of insulin is the stimulation of glucose uptake into muscle and adipose tissues. The discovery of the insulin-responsive glucose transporter type 4 (GLUT4) protein in 1988 inspired its molecular cloning in the following year. It also spurred numerous cellular mechanistic studies laying the foundations for how insulin regulates glucose uptake by muscle and fat cells. Here, we reflect on the importance of the GLUT4 discovery and chronicle additional key findings made in the past 30 years. That exocytosis of a multispanning membrane protein regulates cellular glucose transport illuminated a novel adaptation of the secretory pathway, which is to transiently modulate the protein composition of the cellular plasma membrane. GLUT4 controls glucose transport into fat and muscle tissues in response to insulin and also into muscle during exercise. Thus, investigation of regulated GLUT4 trafficking provides a major means by which to map the essential signaling components that transmit the effects of insulin and exercise. Manipulation of the expression of GLUT4 or GLUT4-regulating molecules in mice has revealed the impact of glucose uptake on whole-body metabolism. Remaining gaps in our understanding of GLUT4 function and regulation are highlighted here, along with opportunities for future discoveries and for the development of therapeutic approaches to manage metabolic disease.
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Affiliation(s)
- Amira Klip
- Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
| | - Timothy E McGraw
- Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10065
| | - David E James
- Charles Perkins Centre, School of Life and Environmental Sciences, Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia
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48
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Stöckli J, Zadoorian A, Cooke KC, Deshpande V, Yau B, Herrmann G, Kebede MA, Humphrey SJ, James DE. ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation. Mol Metab 2019; 25:83-94. [PMID: 31105056 PMCID: PMC6601125 DOI: 10.1016/j.molmet.2019.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 04/26/2019] [Accepted: 05/01/2019] [Indexed: 01/01/2023] Open
Abstract
Objective Insulin suppresses adipose tissue lipolysis after a meal, playing a key role in metabolic homeostasis. This is mediated via the kinase Akt and its substrate phosphodiesterase 3B (PDE3B). Once phosphorylated and activated, PDE3B hydrolyses cAMP leading to the inactivation of cAMP-dependent protein kinase (PKA) and suppression of lipolysis. However, several gaps have emerged in this model. Here we investigated the role of the PDE3B-interacting protein, α/β-hydrolase ABHD15 in this process. Methods Lipolysis, glucose uptake, and signaling were assessed in ABHD15 knock down and knock out adipocytes and fat explants in response to insulin and/or β-adrenergic receptor agonist. Glucose and fatty acid metabolism were determined in wild type and ABHD15−/− littermate mice. Results Deletion of ABHD15 in adipocytes resulted in a significant defect in insulin-mediated suppression of lipolysis with no effect on insulin-mediated glucose uptake. ABHD15 played a role in suppressing PKA signaling as phosphorylation of the PKA substrate Perilipin-1 remained elevated in response to insulin upon ABHD15 deletion. ABHD15−/− mice had normal glucose metabolism but defective fatty acid metabolism: plasma fatty acids were elevated upon fasting and in response to insulin, and this was accompanied by elevated liver triglycerides upon β-adrenergic receptor activation. This is likely due to hyperactive lipolysis as evident by the larger triglyceride depletion in brown adipose tissue in these mice. Finally, ABHD15 protein levels were reduced in adipocytes from mice fed a Western diet, further implicating this protein in metabolic homeostasis. Conclusions Collectively, ABHD15 regulates adipocyte lipolysis and liver lipid accumulation, providing novel therapeutic opportunities for modulating lipid homeostasis in disease.
Insulin was unable to suppress lipolysis in the absence of ABHD15 in adipocytes in vitro, ex vivo and in mice in vivo. The lipolysis defect was associated with defective signalling via protein kinase A and its substrate Perilipin-1. The defect was specific for lipolysis with no impairment in insulin signalling or insulin-stimulated glucose uptake. Deletion of ABHD15 caused a significant increase in fatty acid deposition in liver in response to stress.
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Affiliation(s)
- Jacqueline Stöckli
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Armella Zadoorian
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Kristen C Cooke
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Vinita Deshpande
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Belinda Yau
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Gaia Herrmann
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Melkam A Kebede
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - Sean J Humphrey
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia
| | - David E James
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
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49
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Spradley FT, Smith JA, Alexander BT, Anderson CD. Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. Am J Physiol Endocrinol Metab 2018; 315:E795-E814. [PMID: 29509436 PMCID: PMC6293166 DOI: 10.1152/ajpendo.00394.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intrauterine growth restriction (IUGR) is linked to increased risk for chronic disease. Placental ischemia and insufficiency in the mother are implicated in predisposing IUGR offspring to metabolic dysfunction, including hypertension, insulin resistance, abnormalities in glucose homeostasis, and nonalcoholic fatty liver disease (NAFLD). It is unclear whether these metabolic disturbances contribute to the developmental origins of exaggerated cardiovascular-renal disease (CVRD) risk accompanying IUGR. IUGR impacts the pancreas, adipose tissue, and liver, which are hypothesized to program for hepatic insulin resistance and subsequent NAFLD. NAFLD is projected to become the major cause of chronic liver disease and contributor to uncontrolled type 2 diabetes mellitus, which is a leading cause of chronic kidney disease. While NAFLD is increased in experimental models of IUGR, lacking is a full comprehension of the mechanisms responsible for programming of NAFLD and whether this potentiates susceptibility to liver injury. The use of well-established and clinically relevant rodent models, which mimic the clinical characteristics of IUGR, metabolic disturbances, and increased blood pressure in the offspring, will permit investigation into mechanisms linking adverse influences during early life and later chronic health. The purpose of this review is to propose mechanisms, including those proinflammatory in nature, whereby IUGR exacerbates the pathogenesis of NAFLD and how these adverse programmed outcomes contribute to exaggerated CVRD risk. Understanding the etiology of the developmental origins of chronic disease will allow investigators to uncover treatment strategies to intervene in the mother and her offspring to halt the increasing prevalence of metabolic dysfunction and CVRD.
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Affiliation(s)
- Frank T Spradley
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Jillian A Smith
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Barbara T Alexander
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Christopher D Anderson
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
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50
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Fujimoto Y, Hashimoto O, Shindo D, Sugiyama M, Tomonaga S, Murakami M, Matsui T, Funaba M. Metabolic changes in adipose tissues in response to β 3 -adrenergic receptor activation in mice. J Cell Biochem 2018; 120:821-835. [PMID: 30191605 DOI: 10.1002/jcb.27443] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 07/16/2018] [Indexed: 12/31/2022]
Abstract
Brown and beige adipocytes dissipate energy as heat. Thus, the activation of brown adipocytes and the emergence of beige adipocytes in white adipose tissue (WAT) are suggested to be useful for preventing and treating obesity. Although β3 -adrenergic receptor activation is known to stimulate lipolysis and activation of brown and beige adipocytes, fat depot-dependent changes in metabolite concentrations are not fully elucidated. The current study examined the effect of treatment with CL-316,243, a β3 -adrenergic receptor agonist, on the relative abundance of metabolites in interscapular brown adipose tissue (iBAT), inguinal WAT (ingWAT), and epididymal WAT (epiWAT). Intraperitoneal injection of CL-316,243 (1 mg/kg) for 3 consecutive days increased the relative abundance of several glycolysis-related metabolites in all examined fat depots. The cellular concentrations of metabolites involved in the citric acid cycle and of free amino acids were also increased in epiWAT by CL-316,243. CL-316,243 increased the expression levels of several enzymes and transporters related to glucose metabolism and amino acid catabolism in ingWAT and iBAT but not in epiWAT. CL-316,243 also induced the emergence of more beige adipocytes in ingWAT than in epiWAT. Furthermore, adipocytes surrounded by macrophages were detected in the epiWAT of mice given CL-316,243. The current study reveals the fat depot-dependent modulation of cellular metabolites in CL-316,243-treated mice, presumably resulting from differential regulation of cell metabolism in different cell populations.
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Affiliation(s)
- Yusuke Fujimoto
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Osamu Hashimoto
- Laboratory of Experimental Animal Science, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Daichi Shindo
- Laboratory of Experimental Animal Science, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Makoto Sugiyama
- Laboratory of Veterinary Anatomy, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Shozo Tomonaga
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Masaru Murakami
- Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara, Japan
| | - Tohru Matsui
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Masayuki Funaba
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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