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Liu J, Cheng Y, Liu Q, Long Q, Liang S, Sun W, Loomes KM, Gao X, Lin B, Liu X, Wu D, Hui HX. LETM-domain containing 1 (LETMD1) protects against obesity via enhancing UCP1-independent energy expenditure in human beige adipocytes. Theranostics 2025; 15:1914-1929. [PMID: 39897567 PMCID: PMC11780525 DOI: 10.7150/thno.104568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/11/2024] [Indexed: 02/04/2025] Open
Abstract
Rationale: Brown and beige adipocytes are specialized fat cells that dissipate energy in the form of heat, and hold therapeutic potential for obesity and metabolic diseases. Although in the classical viewpoint brown and beige adipocytes dissipate energy solely via uncoupling protein 1 (UCP1), emerging evidence suggests the importance of non-canonical UCP1-independent energy expenditure in regulating energy expenditure, especially in human beige adipocytes. Leucine zipper-, EF-hand-containing transmembrane protein 1 domain containing 1 (LETMD1) was recently identified as a key protein in maintaining UCP1 expression and the thermogenic activity of brown adipocytes in animal models. But the exact function of LETMD1 and its mechanism of action in human beige adipocytes are unclear. Methods: We tested the function of LETMD1 in human induced pluripotent stem cell (hiPSC)-derived beige adipocytes in vitro in both wildtype (WT) and UCP1 knockout (KO) background. Furthermore, human beige adipocytes harboring a doxycycline-inducible LETMD1 expression cassette were transplanted to NOD/SCID mice and the function of LETMD1 in human beige adipocytes was evaluated in the in vivo setting. RNA-Seq was conducted in normal and LETMD1-overexpressing human beige adipocytes to examine the genes and pathways regulated by LETMD1. Using a knock-in human iPSC line, a preclinical small molecule compound library was screened for compounds increasing LETMD1 expression in human beige adipocytes. The effects of the compound in inducing LETMD1 and UCP1-independent energy expenditure in beige adipocytes were examined in vitro and in animal models. Results: LETMD1 plays an essential role in engaging energy dissipation, in a manner independent of UCP1, in human beige adipocytes. Transplantation of LETMD1-overexpressing human beige adipocytes improved whole-body metabolism of the recipient mice independent of UCP1. Mechanistically LETMD1 enhances the transcription of PPARGC1A, a key regulator of mitochondrial biogenesis. The expression of genes related to UCP1-independent energy expenditure, including creatine futile cycle, was also stimulated upon LETMD1 overexpression. Using LETMD1 reporter human beige adipocytes, SP-8356 was identified as a compound significantly increasing LETMD1 expression. Oral administration of SP-8356 induced genes related to UCP1-independent energy expenditure in beige adipocytes, and counteracted body weight gain and metabolic disorders in mice. Conclusion: Increased LETMD1 action, either genetically or pharmacologically, enhances the non-canonical UCP1-independent energy expenditure in beige adipocytes.
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Affiliation(s)
- Jiaxing Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Ying Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Qing Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Qiaoyun Long
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Shiqing Liang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Sun
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
| | - Kerry M. Loomes
- School of Biological Sciences & Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
| | - Xuefei Gao
- School of Biomedical Sciences, Southern Medical University, Guangzhou, China
| | - Bin Lin
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xingguo Liu
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Donghai Wu
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Hannah Xiaoyan Hui
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-GIBH Joint Research Laboratory on Stem Cell and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China
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Ghosh A, Chénier I, Leung YH, Oppong AK, Peyot ML, Madiraju SRM, Al-Khairi I, Abubaker J, Al-Mulla F, Prentki M, Abu-Farha M. Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice. iScience 2024; 27:111292. [PMID: 39640567 PMCID: PMC11617963 DOI: 10.1016/j.isci.2024.111292] [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: 04/08/2024] [Revised: 08/28/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
Angiopoietin-like protein 8 (Angptl8), expressed in the liver and adipocytes, forms a complex with Angptl3 or Angptl4, which regulates lipoprotein lipase and triglyceride metabolism. However, the precise functions of adipocyte Angptl8 remain elusive. Here we report that adipocyte-specific inducible Angptl8-knockout (AT-A8-KO) male mice on normal diet showed minor phenotypic changes, but after a high-fat high fructose (HFHF) diet, exhibited decreased body weight gain and glycemia, elevated rectal temperature and early dark phase energy expenditure compared to the Cre controls. AT-A8-KO mice also displayed improved glucose tolerance, a trend for better insulin sensitivity, improved insulin-stimulated glucose uptake in adipose tissues, and reduced visceral adipose tissue crown-like structures, plasma MCP-1 and leptin levels. The results indicate the importance of adipose Angptl8 in the context of nutri-stress and obesity, as its deletion in mice promotes a metabolically healthy obese phenotype by slightly ameliorating obesity, improving glucose and energy homeostasis, and mitigating inflammation.
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Affiliation(s)
- Anindya Ghosh
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Isabelle Chénier
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Yat Hei Leung
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Abel K. Oppong
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Marie-Line Peyot
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - S. R. Murthy Madiraju
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Irina Al-Khairi
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Marc Prentki
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
- Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
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3
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Mirabelli M, Misiti R, Sicilia L, Brunetti FS, Chiefari E, Brunetti A, Foti DP. Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review. Int J Mol Sci 2024; 25:9802. [PMID: 39337290 PMCID: PMC11432683 DOI: 10.3390/ijms25189802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.
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Affiliation(s)
- Maria Mirabelli
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Roberta Misiti
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy;
- Operative Unit of Clinical Pathology, “Renato Dulbecco” Hospital, 88100 Catanzaro, Italy
| | - Luciana Sicilia
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Francesco S. Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Daniela P. Foti
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy;
- Operative Unit of Clinical Pathology, “Renato Dulbecco” Hospital, 88100 Catanzaro, Italy
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Greig JC, Tipping WJ, Graham D, Faulds K, Gould GW. New insights into lipid and fatty acid metabolism from Raman spectroscopy. Analyst 2024. [PMID: 39258960 DOI: 10.1039/d4an00846d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
One of the challenges facing biology is to understand metabolic events at a single cellular level. While approaches to examine dynamics of protein distribution or report on spatiotemporal location of signalling molecules are well-established, tools for the dissection of metabolism in single living cells are less common. Advances in Raman spectroscopy, such as stimulated Raman scattering (SRS), are beginning to offer new insights into metabolic events in a range of experimental systems, including model organisms and clinical samples, and across a range of disciplines. Despite the power of Raman imaging, it remains a relatively under-used technique to approach biological problems, in part because of the specialised nature of the analysis. To raise the profile of this method, here we consider some key studies which illustrate how Raman spectroscopy has revealed new insights into fatty acid and lipid metabolism across a range of cellular systems. The powerful and non-invasive nature of this approach offers a new suite of tools for biomolecular scientists to address how metabolic events within cells informs on or underpins biological function. We illustrate potential biological applications, discuss some recent advances, and offer a direction of travel for metabolic research in this area.
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Affiliation(s)
- Justin C Greig
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, UK.
| | | | - Duncan Graham
- Pure and Applied Chemistry, University of Strathclyde, UK
| | - Karen Faulds
- Pure and Applied Chemistry, University of Strathclyde, UK
| | - Gwyn W Gould
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, UK.
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5
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Zhao Y, Li X, Yu W, Lin W, Wei W, Zhang L, Liu D, Ma H, Chen J. Differential expression of ADRB1 causes different responses to norepinephrine in adipocytes of Duroc-Landrace-Yorkshire pigs and min pigs. J Therm Biol 2024; 123:103906. [PMID: 38970835 DOI: 10.1016/j.jtherbio.2024.103906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 02/11/2024] [Accepted: 06/23/2024] [Indexed: 07/08/2024]
Abstract
Research has shown that pigs from different regions exhibit varying responses to cold stimuli. Typically, cold stimuli induce browning of white adipose tissue mediated by adrenaline, promoting non-shivering thermogenesis. However, the molecular mechanisms underlying differential response of pig breeds to norepinephrine are unclear. The aim of this study was to investigate the differences and molecular mechanisms of the effects of norepinephrine (NE) treatment on adipocytes of Min pigs (a cold-resistant pig breed) and Duroc-Landrace-Yorkshire (DLY) pigs. Real time-qPCR, western blot, and immunofluorescence were performed following NE treatment on cell cultures of adipocytes originating from Min pigs (n = 3) and DLY pigs (n = 3) to assess the expressions of adipogenesis markers, beige fat markers, and mitochondrial biogenesis markers. The results showed that NE did not affect browning of adipocytes in DLY pigs, whereas promoted browning of adipocytes in Min pigs. Further, the expression of ADRB1 (Adrenoceptor Beta 1, ADRB1) was higher in subcutaneous adipose tissue and adipocytes of Min pigs than those of DLY pigs. Overexpression of ADRB1 in DLY pig adipocytes enhanced sensitivity to NE, exhibiting decreased adipogenesis markers, upregulated beige fat markers, and increased mitochondrial biogenesis. Conversely, adipocytes treated with ADRB1 antagonist in Min pigs resulted in decreased cellular sensitivity to NE. Further studies revealed differential CpG island methylation in ADRB1 promoter region, with lower methylation levels in Min pigs compared to DLY pigs. In conclusion, differential methylation of the ADRB1 promoter region leads to different ADRB1 expression, resulting in varying responsiveness to NE in adipocytes of two pig breeds. Our results provide new insights for further analysis of the differential cold responsiveness in pig breeds from different regions.
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Affiliation(s)
- Yuelei Zhao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Xuexin Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wensai Yu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Weimin Lin
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wei Wei
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Lifan Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Di Liu
- Institute of Animal Husbandry Research, HeiLongJiang Academy of Agricultural Sciences, Harbi, 150086, China
| | - Hong Ma
- Institute of Animal Husbandry Research, HeiLongJiang Academy of Agricultural Sciences, Harbi, 150086, China
| | - Jie Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
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6
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Geiser A, Foylan S, Tinning PW, Bryant NJ, Gould GW. GLUT4 dispersal at the plasma membrane of adipocytes: a super-resolved journey. Biosci Rep 2023; 43:BSR20230946. [PMID: 37791639 PMCID: PMC10600063 DOI: 10.1042/bsr20230946] [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: 09/07/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/05/2023] Open
Abstract
In adipose tissue, insulin stimulates glucose uptake by mediating the translocation of GLUT4 from intracellular vesicles to the plasma membrane. In 2010, insulin was revealed to also have a fundamental impact on the spatial distribution of GLUT4 within the plasma membrane, with the existence of two GLUT4 populations at the plasma membrane being defined: (1) as stationary clusters and (2) as diffusible monomers. In this model, in the absence of insulin, plasma membrane-fused GLUT4 are found to behave as clusters. These clusters are thought to arise from exocytic events that retain GLUT4 at their fusion sites; this has been proposed to function as an intermediate hub between GLUT4 exocytosis and re-internalisation. By contrast, insulin stimulation induces the dispersal of GLUT4 clusters into monomers and favours a distinct type of GLUT4-vesicle fusion event, known as fusion-with-release exocytosis. Here, we review how super-resolution microscopy approaches have allowed investigation of the characteristics of plasma membrane-fused GLUT4 and further discuss regulatory step(s) involved in the GLUT4 dispersal machinery, introducing the scaffold protein EFR3 which facilitates localisation of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) to the cell surface. We consider how dispersal may be linked to the control of transporter activity, consider whether macro-organisation may be a widely used phenomenon to control proteins within the plasma membrane, and speculate on the origin of different forms of GLUT4-vesicle exocytosis.
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Affiliation(s)
- Angéline Geiser
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Shannan Foylan
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Peter W Tinning
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Nia J Bryant
- Department of Biology, University of York, Heslington, York, U.K
| | - Gwyn W Gould
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
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Su Y, Ye L, Hu C, Zhang Y, Liu J, Shao L. Periodontitis as a promoting factor of T2D: current evidence and mechanisms. Int J Oral Sci 2023; 15:25. [PMID: 37321994 PMCID: PMC10272210 DOI: 10.1038/s41368-023-00227-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/12/2023] [Accepted: 04/26/2023] [Indexed: 06/17/2023] Open
Abstract
Periodontitis is an infectious disease caused by an imbalance between the local microbiota and host immune response. Epidemiologically, periodontitis is closely related to the occurrence, development, and poor prognosis of T2D and is recognized as a potential risk factor for T2D. In recent years, increasing attention has been given to the role of the virulence factors produced by disorders of the subgingival microbiota in the pathological mechanism of T2D, including islet β-cell dysfunction and insulin resistance (IR). However, the related mechanisms have not been well summarized. This review highlights periodontitis-derived virulence factors, reviews how these stimuli directly or indirectly regulate islet β-cell dysfunction. The mechanisms by which IR is induced in insulin-targeting tissues (the liver, visceral adipose tissue, and skeletal muscle) are explained, clarifying the influence of periodontitis on the occurrence and development of T2D. In addition, the positive effects of periodontal therapy on T2D are overviewed. Finally, the limitations and prospects of the current research are discussed. In summary, periodontitis is worthy of attention as a promoting factor of T2D. Understanding on the effect of disseminated periodontitis-derived virulence factors on the T2D-related tissues and cells may provide new treatment options for reducing the risk of T2D associated with periodontitis.
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Affiliation(s)
- Yuan Su
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Leilei Ye
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Chen Hu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanli Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Jia Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Longquan Shao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
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GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes. Sci Rep 2022; 12:20535. [PMID: 36446811 PMCID: PMC9708847 DOI: 10.1038/s41598-022-24736-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/18/2022] [Indexed: 11/30/2022] Open
Abstract
The regulated translocation of the glucose transporter, GLUT4, to the surface of adipocytes and muscle is a key action of insulin. This is underpinned by the delivery and fusion of GLUT4-containing vesicles with the plasma membrane. Recent studies have revealed that a further action of insulin is to mediate the dispersal of GLUT4 molecules away from the site of GLUT4 vesicle fusion with the plasma membrane. Although shown in adipocytes, whether insulin-stimulated dispersal occurs in other cells and/or is exhibited by other proteins remains a matter of debate. Here we show that insulin stimulates GLUT4 dispersal in the plasma membrane of adipocytes, induced pluripotent stem cell-derived cardiomyocytes and HeLa cells, suggesting that this phenomenon is specific to GLUT4 expressed in all cell types. By contrast, insulin-stimulated dispersal of TfR was not observed in HeLa cells, suggesting that the mechanism may be unique to GLUT4. Consistent with dispersal being an important physiological mechanism, we observed that insulin-stimulated GLUT4 dispersal is reduced under conditions of insulin resistance. Adipocytes of different sizes have been shown to exhibit distinct metabolic properties: larger adipocytes exhibit reduced insulin-stimulated glucose transport compared to smaller cells. Here we show that both GLUT4 delivery to the plasma membrane and GLUT4 dispersal are reduced in larger adipocytes, supporting the hypothesis that larger adipocytes are refractory to insulin challenge compared to their smaller counterparts, even within a supposedly homogeneous population of cells.
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Bremner SK, Al Shammari WS, Milligan RS, Hudson BD, Sutherland C, Bryant NJ, Gould GW. Pleiotropic effects of Syntaxin16 identified by gene editing in cultured adipocytes. Front Cell Dev Biol 2022; 10:1033501. [PMID: 36467416 PMCID: PMC9716095 DOI: 10.3389/fcell.2022.1033501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 08/01/2023] Open
Abstract
Adipocytes play multiple roles in the regulation of glucose metabolism which rely on the regulation of membrane traffic. These include secretion of adipokines and serving as an energy store. Central to their energy storing function is the ability to increase glucose uptake in response to insulin, mediated through translocation of the facilitative glucose transporter GLUT4 to the cell surface. The trans-Golgi reticulum localized SNARE protein syntaxin 16 (Sx16) has been identified as a key component of the secretory pathway required for insulin-regulated trafficking of GLUT4. We used CRISPR/Cas9 technology to generate 3T3-L1 adipocytes lacking Sx16 to understand the role of the secretory pathway on adipocyte function. GLUT4 mRNA and protein levels were reduced in Sx16 knockout adipocytes and insulin stimulated GLUT4 translocation to the cell surface was reduced. Strikingly, neither basal nor insulin-stimulated glucose transport were affected. By contrast, GLUT1 levels were upregulated in Sx16 knockout cells. Levels of sortilin and insulin regulated aminopeptidase were also increased in Sx16 knockout adipocytes which may indicate an upregulation of an alternative GLUT4 sorting pathway as a compensatory mechanism for the loss of Sx16. In response to chronic insulin stimulation, Sx16 knockout adipocytes exhibit elevated insulin-independent glucose transport and significant alterations in lactate metabolism. We further show that the adipokine secretory pathways are impaired in Sx16 knockout cells. Together this demonstrates a role for Sx16 in the control of glucose transport, the response to elevated insulin, cellular metabolic profiles and adipocytokine secretion.
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Affiliation(s)
- Shaun K. Bremner
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - Woroud S. Al Shammari
- The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, United Kingdom
| | - Roderick S. Milligan
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - Brian D. Hudson
- The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, United Kingdom
| | - Calum Sutherland
- Department of Cellular Medicine, Ninewells Hospital, University of Dundee, Glasgow, United Kingdom
| | - Nia J. Bryant
- Department of Biology, University of York, York, United Kingdom
| | - Gwyn W. Gould
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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Livingstone R, Bryant NJ, Boyle JG, Petrie JR, Gould G. Diabetes is accompanied by changes in the levels of proteins involved in endosomal
GLUT4
trafficking in obese human skeletal muscle. Endocrinol Diabetes Metab 2022; 5:e361. [PMID: 35964329 PMCID: PMC9471587 DOI: 10.1002/edm2.361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/11/2022] [Accepted: 07/18/2022] [Indexed: 12/27/2022] Open
Abstract
Introduction The regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin‐stimulated glucose transport. Insulin‐stimulated glucose transport is impaired in skeletal muscle of patients with type‐2 diabetes, and this may arise because of impaired intracellular trafficking of GLUT4. However, molecular details of any such impairment have not been described. We hypothesized that GLUT4 and/or levels of proteins involved in intracellular GLUT4 trafficking may be impaired in skeletal muscle in type‐2 diabetes and tested this in obese individuals without and without type‐2 diabetes. Methods We recruited 12 participants with type‐2 diabetes and 12 control participants. All were overweight or obese with BMI of 25–45 kg/m2. Insulin sensitivity was measured using an insulin suppression test (IST), and vastus lateralis biopsies were taken in the fasted state. Cell extracts were immunoblotted to quantify levels of a range of proteins known to be involved in intracellular GLUT4 trafficking. Results Obese participants with type‐2 diabetes exhibited elevated fasting blood glucose and increased steady state glucose infusion rates in the IST compared with controls. Consistent with this, skeletal muscle from those with type‐2 diabetes expressed lower levels of GLUT4 (30%, p = .014). Levels of Syntaxin4, a key protein involved in GLUT4 vesicle fusion with the plasma membrane, were similar between groups. By contrast, we observed reductions in levels of Syntaxin16 (33.7%, p = 0.05), Sortilin (44%, p = .006) and Sorting Nexin‐1 (21.5%, p = .039) and −27 (60%, p = .001), key proteins involved in the intracellular sorting of GLUT4, in participants with type‐2 diabetes. Conclusions We report significant reductions of proteins involved in the endosomal trafficking of GLUT4 in skeletal muscle in obese people with type 2 diabetes compared with age‐ and weight‐matched controls. These abnormalities of intracellular GLUT4 trafficking may contribute to reduced whole body insulin sensitivity.
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Affiliation(s)
- Rachel Livingstone
- Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK
- Institute of Molecular Cell and Systems Biology University of Glasgow Glasgow UK
| | | | | | - John R. Petrie
- Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK
| | - Gwyn W. Gould
- Institute of Molecular Cell and Systems Biology University of Glasgow Glasgow UK
- Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UK
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11
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Rychtrmoc D, Staňková P, Kučera O, Červinková Z. Comparison of two anti-diabetic monoestolides regarding effects on intact murine liver tissue. Arch Physiol Biochem 2022; 128:985-992. [PMID: 32208934 DOI: 10.1080/13813455.2020.1743322] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 01/24/2020] [Accepted: 01/27/2020] [Indexed: 12/14/2022]
Abstract
CONTEXT Monoestolides belonging to the fatty acid-hydroxy fatty acid (FAHFA) family have recently emerged as promising insulin sensitizers. OBJECTIVE To investigate and compare impact of two selected FAHFA isomers, namely 9-hexadecanoyloxy-octadecanoic acid [9-PAHSA] and 9-(9Z-octadecenoyloxy)-octadecanoic acid [9-OAHSA], on intact livers in C57BL/6J mice. MATERIALS AND METHODS Short-term in vivo study with intragastric gavage of 13 mg/kg of substances. Morphological, biochemical and high-resolution respirometric assessment of plasma and liver tissue or homogenates thereof. RESULTS The 9-OAHSA-gavaged mice had the highest final total body weight, the lowest free fatty acid circulating levels and the highest plasma activities of both ALT and AST. No significant changes of ambient glycaemia were found, however 9-PAHSA-gavaged mice tended to have lower glycaemia than other animals. Respirometry proved no substance-dependent differences. DISCUSSION AND CONCLUSION 9-PAHSA was more metabolically beneficial and less hepatotoxic than 9-OAHSA. Bioenergetic machinery of liver homogenates seemed unaffected at our FAHFA dose.
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Affiliation(s)
- David Rychtrmoc
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Pavla Staňková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Zuzana Červinková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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12
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Ramírez-Moreno E, Arias-Rico J, Jiménez-Sánchez RC, Estrada-Luna D, Jiménez-Osorio AS, Zafra-Rojas QY, Ariza-Ortega JA, Flores-Chávez OR, Morales-Castillejos L, Sandoval-Gallegos EM. Role of Bioactive Compounds in Obesity: Metabolic Mechanism Focused on Inflammation. Foods 2022; 11:foods11091232. [PMID: 35563955 PMCID: PMC9101148 DOI: 10.3390/foods11091232] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 02/01/2023] Open
Abstract
Obesity is a disease characterized by an inflammatory process in the adipose tissue due to diverse infiltrated immune cells, an increased secretion of proinflammatory molecules, and a decreased secretion of anti-inflammatory molecules. On the other hand, obesity increases the risk of several diseases, such as cardiovascular diseases, diabetes, and cancer. Their treatment is based on nutritional and pharmacological strategies. However, natural products are currently implemented as complementary and alternative medicine (CAM). Polyphenols and fiber are naturally compounds with potential action to reduce inflammation through several pathways and play an important role in the prevention and treatment of obesity, as well as in other non-communicable diseases. Hence, this review focuses on the recent evidence of the molecular mechanisms of polyphenols and dietary fiber, from Scopus, Science Direct, and PubMed, among others, by using key words and based on recent in vitro and in vivo studies.
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Affiliation(s)
- Esther Ramírez-Moreno
- Academic Area of Nutrition, Interdisciplinary Research Center, Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (E.R.-M.); (Q.Y.Z.-R.); (J.A.A.-O.)
| | - José Arias-Rico
- Academic Area of Nursing; Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (J.A.-R.); (R.C.J.-S.); (D.E.-L.); (A.S.J.-O.); (O.R.F.-C.); (L.M.-C.)
| | - Reyna Cristina Jiménez-Sánchez
- Academic Area of Nursing; Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (J.A.-R.); (R.C.J.-S.); (D.E.-L.); (A.S.J.-O.); (O.R.F.-C.); (L.M.-C.)
| | - Diego Estrada-Luna
- Academic Area of Nursing; Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (J.A.-R.); (R.C.J.-S.); (D.E.-L.); (A.S.J.-O.); (O.R.F.-C.); (L.M.-C.)
| | - Angélica Saraí Jiménez-Osorio
- Academic Area of Nursing; Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (J.A.-R.); (R.C.J.-S.); (D.E.-L.); (A.S.J.-O.); (O.R.F.-C.); (L.M.-C.)
| | - Quinatzin Yadira Zafra-Rojas
- Academic Area of Nutrition, Interdisciplinary Research Center, Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (E.R.-M.); (Q.Y.Z.-R.); (J.A.A.-O.)
| | - José Alberto Ariza-Ortega
- Academic Area of Nutrition, Interdisciplinary Research Center, Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (E.R.-M.); (Q.Y.Z.-R.); (J.A.A.-O.)
| | - Olga Rocío Flores-Chávez
- Academic Area of Nursing; Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (J.A.-R.); (R.C.J.-S.); (D.E.-L.); (A.S.J.-O.); (O.R.F.-C.); (L.M.-C.)
| | - Lizbeth Morales-Castillejos
- Academic Area of Nursing; Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (J.A.-R.); (R.C.J.-S.); (D.E.-L.); (A.S.J.-O.); (O.R.F.-C.); (L.M.-C.)
| | - Eli Mireya Sandoval-Gallegos
- Academic Area of Nutrition, Interdisciplinary Research Center, Institute of Health Sciences, Circuit Actopan Tilcuautla s/n, Ex hacienda La Concepción, San Agustin Tlaxiaca, Pachuca 42160, Mexico; (E.R.-M.); (Q.Y.Z.-R.); (J.A.A.-O.)
- Correspondence:
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13
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Dong Y, Betancourt A, Belfort MA, Yallampalli C. Lipid dysfunction and adrenomedullin expression in omental versus subcutaneous adipose tissues in diabetic pregnancies. PLoS One 2022; 17:e0265419. [PMID: 35390031 PMCID: PMC8989323 DOI: 10.1371/journal.pone.0265419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 03/01/2022] [Indexed: 11/19/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy but the underlying mechanism remains obscure. The aims of this study are to examine if omental adipose tissue (OMAT) and subcutaneous AT (SCAT) differentially express proinflammatory and lipid metabolic adipokines, and if so, whether their regional differences have implications on lipid metabolism in GDM. Paired samples of OMAT and SCAT were excised from pregnant women in scheduled Cesarean sections with non-obese (NOBS), obese (OBS) and GDM. The results showed that the mRNA of monocyte chemoattractant protein (MCP)-1, macrophage marker CD68, and cytokines IL-6, IL-8, and TNF-α are increased in OMAT from GDM women compared to that in NOBS and OBS women (P<0.05). Glucose and TNF-α dose-dependently enhanced ADM and its receptor components CRLR and RAMPs in human adipocytes. Immunofluorescence showed that ADM and its receptor components are higher in OMAT from GDM women compared to non-GDM women. Further, basal lipolysis was greater in OMAT than in SCAT and ADM stimulates further glycerol release in OMAT, but not in SCAT, and these increases are reduced by ADM antagonist, ADM22-52. We therefore conclude that elevated ADM and its receptor expressions by OMAT, but not by SCAT appear to contribute to the lipid dysregulation in GDM women, and manipulation of ADM may represent one of the novel approaches in minimizing the risk of GDM-related fetal overgrowth.
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Affiliation(s)
- Yuanlin Dong
- Department of Obstetrics and Gynecology, Baylor College of Medicine/Texas Children’s Hospital, Houston, Texas, United States of America
| | - Ancizar Betancourt
- Department of Obstetrics and Gynecology, Baylor College of Medicine/Texas Children’s Hospital, Houston, Texas, United States of America
| | - Michael A. Belfort
- Department of Obstetrics and Gynecology, Baylor College of Medicine/Texas Children’s Hospital, Houston, Texas, United States of America
| | - Chandrasekhar Yallampalli
- Department of Obstetrics and Gynecology, Baylor College of Medicine/Texas Children’s Hospital, Houston, Texas, United States of America
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14
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Jarosinski MA, Chen YS, Varas N, Dhayalan B, Chatterjee D, Weiss MA. New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals. J Clin Endocrinol Metab 2022; 107:909-928. [PMID: 34850005 PMCID: PMC8947325 DOI: 10.1210/clinem/dgab849] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Indexed: 11/19/2022]
Abstract
Design of "first-generation" insulin analogues over the past 3 decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool kit-integrating protein sequence, chemical modification, and formulation-has thus led to improved prandial and basal formulations for the treatment of diabetes mellitus. Although PK/PD changes were modest in relation to prior formulations of human and animal insulins, significant clinical advantages in efficacy (mean glycemia) and safety (rates of hypoglycemia) were obtained. Continuing innovation is providing further improvements to achieve ultrarapid and ultrabasal analogue formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogues seek to exploit therapeutic mechanisms: glucose-responsive ("smart") analogues, pathway-specific ("biased") analogues, and organ-targeted analogues. Smart insulin analogues and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogues may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will affect use and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale, and potential clinical applications.
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Affiliation(s)
- Mark A Jarosinski
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yen-Shan Chen
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nicolás Varas
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Balamurugan Dhayalan
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Deepak Chatterjee
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Michael A Weiss
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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15
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Hu X, Liu Z, Lu Y, Chi X, Han K, Wang H, Wang Y, Ma L, Xu B. Glucose metabolism enhancement by 10-hydroxy-2-decenoic acid via the PI3K/AKT signaling pathway in high-fat-diet/streptozotocin induced type 2 diabetic mice. Food Funct 2022; 13:9931-9946. [DOI: 10.1039/d1fo03818d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Here, we used high fat diet (HFD) combined with streptozotocin (STZ) injection to establish a diabetes model, with the aim of exploring the hypoglycemic effects of 10-hydroxy-2-decenoic acid (10-HDA), and...
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16
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Black HL, Livingstone R, Mastick CC, Al Tobi M, Taylor H, Geiser A, Stirrat L, Kioumourtzoglou D, Petrie JR, Boyle JG, Bryant NJ, Gould GW. Knockout of Syntaxin-4 in 3T3-L1 adipocytes reveals new insight into GLUT4 trafficking and adiponectin secretion. J Cell Sci 2021; 135:273617. [PMID: 34859814 PMCID: PMC8767277 DOI: 10.1242/jcs.258375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 11/18/2021] [Indexed: 11/20/2022] Open
Abstract
Adipocytes are key to metabolic regulation, exhibiting insulin-stimulated glucose transport that is underpinned by the insulin-stimulated delivery of glucose transporter type 4 (SLC2A4, also known and hereafter referred to as GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, and increase cell surface GLUT4 levels. Adipocytokines, such as adiponectin, are secreted via a similar mechanism. We used genome editing to knock out syntaxin-4, a protein reported to mediate fusion between GLUT4-containing vesicles and the plasma membrane in 3T3-L1 adipocytes. Syntaxin-4 knockout reduced insulin-stimulated glucose transport and adiponectin secretion by ∼50% and reduced GLUT4 levels. Ectopic expression of haemagglutinin (HA)-tagged GLUT4 conjugated to GFP showed that syntaxin-4-knockout cells retain significant GLUT4 translocation capacity, demonstrating that syntaxin-4 is dispensable for insulin-stimulated GLUT4 translocation. Analysis of recycling kinetics revealed only a modest reduction in the exocytic rate of GLUT4 in knockout cells, and little effect on endocytosis. These analyses demonstrate that syntaxin-4 is not always rate limiting for GLUT4 delivery to the cell surface. In sum, we show that syntaxin-4 knockout results in reduced insulin-stimulated glucose transport, depletion of cellular GLUT4 levels and inhibition of adiponectin secretion but has only modest effects on the translocation capacity of the cells. This article has an associated First Person interview with Hannah L. Black and Rachel Livingstone, joint first authors of the paper. Summary: Syntaxin-4 knockout reduces insulin-stimulated glucose transport, depletes levels of cellular GLUT4 and inhibits secretion of adiponectin but only modestly affects the translocation capacity of the cells.
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Affiliation(s)
- Hannah L Black
- Department of Biology and York Biomedical Research Institute, University of York. Heslington, York, YO10 5DD, UK
| | - Rachel Livingstone
- Henry Welcome Laboratory for Cell Biology, Institute for Molecular, Cellular and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Cynthia C Mastick
- Henry Welcome Laboratory for Cell Biology, Institute for Molecular, Cellular and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.,Department of Biology, University of Nevada Reno, 1664 N. Virginia Street, Reno, NV 89557, USA
| | - Mohammed Al Tobi
- Henry Welcome Laboratory for Cell Biology, Institute for Molecular, Cellular and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Holly Taylor
- Strathclyde Institute for Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, UK
| | - Angéline Geiser
- Strathclyde Institute for Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, UK
| | - Laura Stirrat
- Strathclyde Institute for Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, UK
| | - Dimitrios Kioumourtzoglou
- Department of Biology and York Biomedical Research Institute, University of York. Heslington, York, YO10 5DD, UK
| | - John R Petrie
- Institute of Cardiovascular and Medical Sciences, University of Glasgow. Glasgow G12 8QQ, UK
| | - James G Boyle
- Institute of Cardiovascular and Medical Sciences, University of Glasgow. Glasgow G12 8QQ, UK.,School of Medicine, Dentistry and Nursing, University of Glasgow. Glasgow G12 8QQ, UK
| | - Nia J Bryant
- Department of Biology and York Biomedical Research Institute, University of York. Heslington, York, YO10 5DD, UK
| | - Gwyn W Gould
- Strathclyde Institute for Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, UK
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17
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Abstract
The Akt isoforms-AS160-GLUT4 axis is the primary axis that governs glucose homeostasis in the body. The first step on the path to insulin resistance is deregulated Akt isoforms. This could be Akt isoform expression, its phosphorylation, or improper isoform-specific redistribution to the plasma membrane in a specific tissue system. The second step is deregulated AS160 expression, its phosphorylation, improper dissociation from glucose transporter storage vesicles (GSVs), or its inability to bind to 14-3-3 proteins, thus not allowing it to execute its function. The final step is improper GLUT4 translocation and aberrant glucose uptake. These processes lead to insulin resistance in a tissue-specific way affecting the whole-body glucose homeostasis, eventually progressing to an overt diabetic phenotype. Thus, the relationship between these three key proteins and their proper regulation comes out as the defining axis of insulin signaling and -resistance. This review summarizes the role of this central axis in insulin resistance and disease in a new light.
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Affiliation(s)
- Medha Sharma
- Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi, 110016, India
| | - Chinmoy Sankar Dey
- Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi, 110016, India.
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18
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Reilly AM, Yan S, Huang M, Abhyankar SD, Conley JM, Bone RN, Stull ND, Horan DJ, Roh HC, Robling AG, Ericsson AC, Dong XC, Evans-Molina C, Ren H. A high-fat diet catalyzes progression to hyperglycemia in mice with selective impairment of insulin action in Glut4-expressing tissues. J Biol Chem 2021; 298:101431. [PMID: 34801552 PMCID: PMC8689209 DOI: 10.1016/j.jbc.2021.101431] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 11/09/2021] [Accepted: 11/16/2021] [Indexed: 12/18/2022] Open
Abstract
Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in β-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.
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Affiliation(s)
- Austin M Reilly
- Stark Neurosciences Research Institute, Medical Neuroscience Graduate Program, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Shijun Yan
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Menghao Huang
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Surabhi D Abhyankar
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jason M Conley
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Robert N Bone
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Natalie D Stull
- Indiana Biosciences Research Institute, Indianapolis, Indiana, USA
| | - Daniel J Horan
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hyun C Roh
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Alexander G Robling
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Aaron C Ericsson
- Metagenomics Center, University of Missouri, Columbia, Missouri, USA
| | - Xiaocheng C Dong
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Carmella Evans-Molina
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Hongxia Ren
- Stark Neurosciences Research Institute, Medical Neuroscience Graduate Program, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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19
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Koh HCE, van Vliet S, Pietka TA, Meyer GA, Razani B, Laforest R, Gropler RJ, Mittendorfer B. Subcutaneous Adipose Tissue Metabolic Function and Insulin Sensitivity in People With Obesity. Diabetes 2021; 70:2225-2236. [PMID: 34266892 PMCID: PMC8576507 DOI: 10.2337/db21-0160] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 07/08/2021] [Indexed: 11/13/2022]
Abstract
We used stable isotope-labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [18F]fluorodeoxyglucose and [15O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that 1) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive. We found that high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT but, rather, was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than in lean participants. In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants, even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest that several putative SAT factors commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance.
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Affiliation(s)
- Han-Chow E Koh
- Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO
| | - Stephan van Vliet
- Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO
| | - Terri A Pietka
- Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO
| | - Gretchen A Meyer
- Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO
| | - Babak Razani
- Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Richard Laforest
- Department of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Robert J Gropler
- Department of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Bettina Mittendorfer
- Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO
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20
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Jarosinski MA, Dhayalan B, Chen YS, Chatterjee D, Varas N, Weiss MA. Structural principles of insulin formulation and analog design: A century of innovation. Mol Metab 2021; 52:101325. [PMID: 34428558 PMCID: PMC8513154 DOI: 10.1016/j.molmet.2021.101325] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. SCOPE OF REVIEW Pioneering crystallographic analyses-beginning with Hodgkin's solving of the 2-Zn insulin hexamer-elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia. MAJOR CONCLUSIONS Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.
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Affiliation(s)
- Mark A Jarosinski
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA
| | - Balamurugan Dhayalan
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA
| | - Yen-Shan Chen
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA
| | - Deepak Chatterjee
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA
| | - Nicolás Varas
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA
| | - Michael A Weiss
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA; Department of Chemistry, Indiana University, Bloomington, 47405, IN, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, 47907, IN, USA.
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21
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Khandelwal R, Dassanayake AS, Conjeevaram HS, Singh SP. Non-alcoholic fatty liver disease in diabetes: When to refer to the hepatologist? World J Diabetes 2021; 12:1479-1493. [PMID: 34630901 PMCID: PMC8472504 DOI: 10.4239/wjd.v12.i9.1479] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. A strong relationship exists between NAFLD and diabetes mellitus. There is growing evidence of a mechanistically complex and strong association between the two diseases. Current data also shows that one disease actually leads to worsening of the other and vice versa. Understanding of the various pathophysiological mechanisms involved, natural history and spectrum of these two diseases is essential not only for early diagnosis and management but also for prevention of severe disease forms. Despite the tremendous progress made in recent times in acquiring knowledge about these highly prevalent diseases, the guidelines and recommendations for screening and management of diabetics with NAFLD remain ambiguous. An interdisciplinary approach is required to not only raise awareness of the prevalence of NAFLD in diabetics but also for better patient management. This can help attenuate the development of significant complications, such as cirrhosis, decompensation and hepatocellular carcinoma in these patients, thereby halting NAFLD in its tracks. This review focuses on the pivotal role of primary care physicians and endocrinologists in identification of NAFLD in diabetics in early stages and the role of proactive screening for prompt referral to hepatologist.
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Affiliation(s)
- Reshu Khandelwal
- Department of Gastroenterology, Srirama Chandra Bhanja (SCB) Medical College and Hospital, Cuttack 753007, Odisha, India
| | - Anuradha S Dassanayake
- Department of Medicine, Colombo North Centre for Liver Disease, University of Kelaniya, Kelaniya 11600, Sri Lanka
| | - Hari S Conjeevaram
- Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
| | - Shivaram P Singh
- Department of Gastroenterology, Srirama Chandra Bhanja (SCB) Medical College and Hospital, Cuttack 753007, Odisha, India
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22
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Yoon SY, Ahn D, Hwang JY, Kang MJ, Chung SJ. Linoleic acid exerts antidiabetic effects by inhibiting protein tyrosine phosphatases associated with insulin resistance. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104532] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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23
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Long Y, Wang YC, Yuan DZ, Dai XH, Liao LC, Zhang XQ, Zhang LX, Ma YD, Lei Y, Cui ZH, Zhang JH, Nie L, Yue LM. GLUT4 in Mouse Endometrial Epithelium: Roles in Embryonic Development and Implantation. Front Physiol 2021; 12:674924. [PMID: 34248664 PMCID: PMC8267529 DOI: 10.3389/fphys.2021.674924] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/23/2021] [Indexed: 12/21/2022] Open
Abstract
GLUT4 is involved in rapid glucose uptake among various kinds of cells to contribute to glucose homeostasis. Prior data have reported that aberrant glucose metabolism by GLUT4 dysfunction in the uterus could be responsible for infertility and increased miscarriage. However, the expression and precise functions of GLUT4 in the endometrium under physiological conditions remain unknown or controversial. In this study, we observed that GLUT4 exhibits a spatiotemporal expression in mouse uterus on pregnant days 1–4; its expression especially increased on pregnant day 4 during the window of implantation. We also determined that estrogen, in conjunction with progesterone, promotes the expression of GLUT4 in the endometrial epithelium in vivo or in vitro. GLUT4 is an important transporter that mediates glucose transport in endometrial epithelial cells (EECs) in vitro or in vivo. In vitro, glucose uptake decreased in mouse EECs when the cells were treated with GLUT4 small interfering RNA (siRNA). In vivo, the injection of GLUT4-siRNA into one side of the mouse uterine horns resulted in an increased glucose concentration in the uterine fluid on pregnant day 4, although it was still lower than in blood, and impaired endometrial receptivity by inhibiting pinopode formation and the expressions of leukemia inhibitory factor (LIF) and integrin ανβ3, finally affecting embryonic development and implantation. Overall, the obtained results indicate that GLUT4 in the endometrial epithelium affects embryo development by altering glucose concentration in the uterine fluid. It can also affect implantation by impairing endometrial receptivity due to dysfunction of GLUT4.
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Affiliation(s)
- Yun Long
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.,Department of Physiology, Chongqing Three Gorges Medical College, Chongqing, China
| | - Yi-Cheng Wang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Dong-Zhi Yuan
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Xin-Hua Dai
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Lin-Chuan Liao
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Xue-Qin Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Li-Xue Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Yong-Dan Ma
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Yi Lei
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Zhi-Hui Cui
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jin-Hu Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Li Nie
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Li-Min Yue
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
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24
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Lyu K, Zhang D, Song J, Li X, Perry RJ, Samuel VT, Shulman GI. Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation. JCI Insight 2021; 6:139946. [PMID: 33411692 PMCID: PMC7934919 DOI: 10.1172/jci.insight.139946] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 12/29/2020] [Indexed: 12/17/2022] Open
Abstract
White adipose tissue (WAT) insulin action has critical anabolic function and is dysregulated in overnutrition. However, the mechanism of short-term high-fat diet-induced (HFD-induced) WAT insulin resistance (IR) is poorly understood. Based on recent evidences, we hypothesize that a short-term HFD causes WAT IR through plasma membrane (PM) sn-1,2-diacylglycerol (sn-1,2-DAG) accumulation, which promotes protein kinase C-ε (PKCε) activation to impair insulin signaling by phosphorylating insulin receptor (Insr) Thr1160. To test this hypothesis, we assessed WAT insulin action in 7-day HFD-fed versus regular chow diet-fed rats during a hyperinsulinemic-euglycemic clamp. HFD feeding caused WAT IR, reflected by impaired insulin-mediated WAT glucose uptake and lipolysis suppression. These changes were specifically associated with PM sn-1,2-DAG accumulation, higher PKCε activation, and impaired insulin-stimulated Insr Tyr1162 phosphorylation. In order to examine the role of Insr Thr1160 phosphorylation in mediating lipid-induced WAT IR, we examined these same parameters in InsrT1150A mice (mouse homolog for human Thr1160) and found that HFD feeding induced WAT IR in WT control mice but not in InsrT1150A mice. Taken together, these data demonstrate the importance of the PM sn-1,2-DAG/PKCε/Insr Thr1160 phosphorylation pathway in mediating lipid-induced WAT IR and represent a potential therapeutic target to improve WAT insulin sensitivity.
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Affiliation(s)
- Kun Lyu
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Dongyan Zhang
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Joongyu Song
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Xiruo Li
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Rachel J Perry
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Varman T Samuel
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA
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25
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Zammouri J, Vatier C, Capel E, Auclair M, Storey-London C, Bismuth E, Mosbah H, Donadille B, Janmaat S, Fève B, Jéru I, Vigouroux C. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne) 2021; 12:803189. [PMID: 35046902 PMCID: PMC8763341 DOI: 10.3389/fendo.2021.803189] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.
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Affiliation(s)
- Jamila Zammouri
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
| | - Camille Vatier
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Emilie Capel
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
| | - Martine Auclair
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
| | - Caroline Storey-London
- Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Pediatric Endocrinology Department, National Competence Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Elise Bismuth
- Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Pediatric Endocrinology Department, National Competence Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Héléna Mosbah
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Bruno Donadille
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Sonja Janmaat
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Bruno Fève
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Isabelle Jéru
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
- Genetics Department, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Paris, France
| | - Corinne Vigouroux
- Sorbonne University, Inserm UMR_S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France
- Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
- Genetics Department, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Paris, France
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26
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Alghamdi F, Alshuweishi Y, Salt IP. Regulation of nutrient uptake by AMP-activated protein kinase. Cell Signal 2020; 76:109807. [DOI: 10.1016/j.cellsig.2020.109807] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023]
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27
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Building GLUT4 Vesicles: CHC22 Clathrin's Human Touch. Trends Cell Biol 2020; 30:705-719. [PMID: 32620516 DOI: 10.1016/j.tcb.2020.05.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 12/18/2022]
Abstract
Insulin stimulates glucose transport by triggering regulated delivery of intracellular vesicles containing the GLUT4 glucose transporter to the plasma membrane. This process is defective in diseases such as type 2 diabetes (T2DM). While studies in rodent cells have been invaluable in understanding GLUT4 traffic, evolutionary plasticity must be considered when extrapolating these findings to humans. Recent work has identified species-specific distinctions in GLUT4 traffic, notably the participation of a novel clathrin isoform, CHC22, in humans but not rodents. Here, we discuss GLUT4 sorting in different species and how studies of CHC22 have identified new routes for GLUT4 trafficking. We further consider how different sorting-protein complexes relate to these routes and discuss other implications of these pathways in cell biology and disease.
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28
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Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch 2020; 472:1273-1298. [PMID: 32591906 PMCID: PMC7462924 DOI: 10.1007/s00424-020-02417-x] [Citation(s) in RCA: 274] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 12/13/2022]
Abstract
A family of facilitative glucose transporters (GLUTs) is involved in regulating tissue-specific glucose uptake and metabolism in the liver, skeletal muscle, and adipose tissue to ensure homeostatic control of blood glucose levels. Reduced glucose transport activity results in aberrant use of energy substrates and is associated with insulin resistance and type 2 diabetes. It is well established that GLUT2, the main regulator of hepatic hexose flux, and GLUT4, the workhorse in insulin- and contraction-stimulated glucose uptake in skeletal muscle, are critical contributors in the control of whole-body glycemia. However, the molecular mechanism how insulin controls glucose transport across membranes and its relation to impaired glycemic control in type 2 diabetes remains not sufficiently understood. An array of circulating metabolites and hormone-like molecules and potential supplementary glucose transporters play roles in fine-tuning glucose flux between the different organs in response to an altered energy demand.
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29
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Zhu QF, Yan JW, Ni J, Feng YQ. FAHFA footprint in the visceral fat of mice across their lifespan. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158639. [DOI: 10.1016/j.bbalip.2020.158639] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 01/20/2020] [Accepted: 01/23/2020] [Indexed: 12/30/2022]
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30
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Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice. Biomaterials 2020; 239:119839. [PMID: 32065973 DOI: 10.1016/j.biomaterials.2020.119839] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 01/29/2020] [Accepted: 02/01/2020] [Indexed: 12/28/2022]
Abstract
Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKCς) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Leprdb mice. In contrast, AAC2 established glycemic control altering food intake in leptin-deficient Lepob mice. Therefore, AAC2 activated the LepR and acted in a cytokine-like manner distinct from leptin. In a monogenic Ins2Akita mouse model for the phenotypes associated with type 1 diabetes, AAC2 rescued systemic glucose uptake in these mice without an increase in insulin levels and adiposity, as seen in insulin-treated Ins2Akita mice. In contrast to insulin, AAC2 treatment increased brain mass and reduced anxiety-related behavior in Ins2Akita mice. Our data suggests that the unique mechanism of action for AAC2, activating LepR/PKCς/GLUT1 axis, offers an effective strategy to broaden glycemic control for the prevention of diabetic complications of the nervous system and, possibly, other insulin insensitive or resistant tissues.
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31
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Iizuka K, Takao K, Yabe D. ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue. Front Endocrinol (Lausanne) 2020; 11:587189. [PMID: 33343508 PMCID: PMC7744659 DOI: 10.3389/fendo.2020.587189] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/09/2020] [Indexed: 12/22/2022] Open
Abstract
Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.
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Affiliation(s)
- Katsumi Iizuka
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan
- Center for Nutritional Support and Infection Control, Gifu University Hospital, Gifu, Japan
- *Correspondence: Katsumi Iizuka,
| | - Ken Takao
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Daisuke Yabe
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan
- Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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32
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Duan J, Chen Z, Wu Y, Zhu B, Yang L, Yang C. Metabolic remodeling induced by mitokines in heart failure. Aging (Albany NY) 2019; 11:7307-7327. [PMID: 31498116 PMCID: PMC6756899 DOI: 10.18632/aging.102247] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 08/22/2019] [Indexed: 04/11/2023]
Abstract
The prevalence rates of heart failure (HF) are greater than 10% in individuals aged >75 years, indicating an intrinsic link between aging and HF. It has been recognized that mitochondrial dysfunction contributes to the pathology of HF. Mitokines are a type of cytokines, peptides, or signaling pathways produced or activated by the nucleus or the mitochondria through cell non-autonomous responses during cellular stress. In addition to promoting the communication between the mitochondria and the nucleus, mitokines also exert a systemic regulatory effect by circulating to distant tissues. It is noteworthy that increasing evidence has demonstrated that mitokines are capable of reducing the metabolic-related HF risk factors and are associated with HF severity. Consequently, mitokines might represent a potential therapy target for HF.
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Affiliation(s)
- Jiahao Duan
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Zijun Chen
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Yeshun Wu
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Bin Zhu
- Department of Critical Care Medicine, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Ling Yang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Chun Yang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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33
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Claveles Casas FN, Barrera FS, Lopez CM, Chacon I. del V, Di Sciullo MP, Ramirez DC, Gomez Mejiba SE. Therapeutic targets to reduce the contribution of pulmonary neutrophilic inflammation towards obesity-associated co-morbidities: a mini-review. OPEN JOURNAL OF PHARMACEUTICAL SCIENCE AND RESEARCH 2019; 1:123-133. [PMID: 39450269 PMCID: PMC11500055 DOI: 10.36811/ojpsr.2019.110006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
Epidemiology and experimental models have shown a close link between adipose tissue inflammation, systemic inflammation and pulmonary neutrophilic inflammation, which predispose obese patients to pulmonary diseases, obesity-associated co-morbidities and cancer. Increased content and activation of neutrophils in the lung microvasculature, resulting from peripheral activation of neutrophils, and increased adhesion of neutrophils to the lung microvasculature are important factors explaining the increased susceptibility of obese patients towards respiratory diseases and loss of insulin sensitivity. Mechanism-based therapies to break this link are urgently needed to reduce pulmonary damage in obesity, due to the growing prevalence of obesity world-wide. Current research suggests that these approaches should be focused on, one or more of the following: reduction of macrophage activation at the adipose tissue, healthy growing of adipose tissue by induction of Nrf-2, inhibition of NF-κB activation, reduction of circulating neutrophil activation, blocking adhesins/selectins, inhibition of neutrophil activation by targeting NADPH oxidase-2 activation, inhibition of myeloperoxidase activity and scavenging of hypochlorous acid. These strategies are expected to reduce adipose tissue inflammation, peripheral inflammation, pulmonary neutrophilic inflammation and obesity-associated co-morbidities.
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Affiliation(s)
- FN Claveles Casas
- Laboratory of Experimental & Translational Medicine. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
- Laboratory of Experimental Therapeutics & Nutrition. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
| | - FS Barrera
- Laboratory of Experimental Therapeutics & Nutrition. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
| | - CM Lopez
- Laboratory of Experimental & Translational Medicine. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
| | - V Chacon I. del
- Laboratory of Experimental Therapeutics & Nutrition. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
| | | | - DC Ramirez
- Laboratory of Experimental & Translational Medicine. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
| | - SE Gomez Mejiba
- Laboratory of Experimental Therapeutics & Nutrition. IMIBIO-SL, CONICET-National University of San Luis, San Luis, 5700 San Luis, Argentina
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