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Elman I. Treatments for weight gain in schizophrenia. Curr Opin Psychiatry 2025; 38:159-168. [PMID: 40009761 DOI: 10.1097/yco.0000000000000992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
PURPOSE OF REVIEW Obesity and related metabolic disorders are extremely common in psychiatric patients, particularly in those with schizophrenia. Elucidating this link's neurobiology may inform clinicians and researchers of rational therapeutic approaches necessary to optimize clinical outcomes. RECENT FINDINGS Current literature highlights the pivotal role of the inflammation-oxidative stress-insulin resistance loop in the pathophysiology of both metabolic and neuropsychiatric disorders. The concept of 'diabetophrenia' is put forward to highlight the overlapping neurobiological mechanisms underlying metabolic dysfunction and schizophrenia symptoms. Innovative treatments, including the combination of xanomeline with trospium and incretin-based medicines, demonstrate encouraging potential in addressing such complex health challenges. SUMMARY The nuanced dynamics of chronic inflammation and psychiatric symptomatology underscore the significance of addressing both metabolic and mental health factors in a cohesive fashion while considering unique psychosocial contexts, dietary preferences, and lifestyle choices. A multidisciplinary strategy is essential for incorporating counseling, dietary interventions, behavioral therapies, and pharmacotherapy into the management of schizophrenia. The ensuing enhanced collaboration among healthcare professionals may render obsolete the prevailing siloed conceptualizations of mental disorders, opening new vistas for generating synergistic insights into the mind-body systems and leading to improved health and quality of life for patients with schizophrenia and other psychiatric conditions.
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Affiliation(s)
- Igor Elman
- Department of Psychiatry, Cambridge Health Alliance, Harvard Medical School, Boston, Massachusetts, USA
- Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel
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2
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Yanık Çolak S, Andaç B, Özgün E, Yılmaz Bülbül B, Okur M, Yekdeş AC, Yıldız Ç, Çelik M. The Relationship Between Serum MG53 Levels and the Presence of Metabolic Syndrome and Its Components. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:582. [PMID: 40282872 PMCID: PMC12028786 DOI: 10.3390/medicina61040582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 02/26/2025] [Accepted: 03/19/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: MG53 is a myokine/cardiokine involved in membrane repair. Some preclinical studies suggest that it is associated with insulin resistance. Metabolic syndrome (MS) is manifested by dyslipidemia, hypertension (HT), visceral obesity, hyperinsulinism, and glucose intolerance. We aimed to evaluate the relationship between the MG53 protein and MS and its components. Materials and Methods: This study was conducted among 64 patients with MS and 64 age- and sex-matched healthy participants. MG53 levels were measured using Human-MG53, a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Cat# CSB-EL024511HU, Alfagen laboratory supplies, Cusabio, Bornova, İzmir.). Results: There was no significant connection between serum MG53 levels and the presence of MS (p = 0.969). We found no correlation between serum MG53 levels and the presence of HT, weight, waist circumference, body mass index, HDL-C, fasting blood glucose, and HbA1c levels. Conclusions: This study's results suggest no association between serum MG53 levels and MS parameters in the studied ethnic population. Due to the limited number and controversy of available studies on this subject, our findings may provide perspective for conducting studies with more diverse populations to obtain more comprehensive results.
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Affiliation(s)
- Serpil Yanık Çolak
- Department of Endocrinology and Metabolism, Trakya University Medical Faculty, Edirne 22000, Turkey; (B.A.)
| | - Burak Andaç
- Department of Endocrinology and Metabolism, Trakya University Medical Faculty, Edirne 22000, Turkey; (B.A.)
| | - Eray Özgün
- Department of Biochemistry, Trakya University Medical Faculty, Edirne 22000, Turkey
| | - Buket Yılmaz Bülbül
- Department of Endocrinology and Metabolism, Trakya University Medical Faculty, Edirne 22000, Turkey; (B.A.)
| | - Mine Okur
- Department of Endocrinology and Metabolism, Trakya University Medical Faculty, Edirne 22000, Turkey; (B.A.)
| | - Ali Cem Yekdeş
- Department of Public Health, Trakya University Medical Faculty, Edirne 22000, Turkey
| | - Çağla Yıldız
- Department of Internal Medicine, Trakya University Medical Faculty, Edirne 22000, Turkey
| | - Mehmet Çelik
- Department of Endocrinology and Metabolism, Trakya University Medical Faculty, Edirne 22000, Turkey; (B.A.)
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Mazzaferro E, Mujica E, Zhang H, Emmanouilidou A, Jenseit A, Evcimen B, Metzendorf C, Dethlefsen O, Loos RJ, Vienberg SG, Larsson A, Allalou A, den Hoed M. Functionally characterizing obesity-susceptibility genes using CRISPR/Cas9, in vivo imaging and deep learning. Sci Rep 2025; 15:5408. [PMID: 39948378 PMCID: PMC11825957 DOI: 10.1038/s41598-025-89823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 02/07/2025] [Indexed: 02/16/2025] Open
Abstract
Hundreds of loci have been robustly associated with obesity-related traits, but functional characterization of candidate genes remains a bottleneck. Aiming to systematically characterize candidate genes for a role in accumulation of lipids in adipocytes and other cardiometabolic traits, we developed a pipeline using CRISPR/Cas9, non-invasive, semi-automated fluorescence imaging and deep learning-based image analysis in live zebrafish larvae. Results from a dietary intervention show that 5 days of overfeeding is sufficient to increase the odds of lipid accumulation in adipocytes by 10 days post-fertilization (dpf, n = 275). However, subsequent experiments show that across 12 to 16 established obesity genes, 10 dpf is too early to detect an effect of CRISPR/Cas9-induced mutations on lipid accumulation in adipocytes (n = 1014), and effects on food intake at 8 dpf (n = 1127) are inconsistent with earlier results from mammals. Despite this, we observe effects of CRISPR/Cas9-induced mutations on ectopic accumulation of lipids in the vasculature (sh2b1 and sim1b) and liver (bdnf); as well as on body size (pcsk1, pomca, irs1); whole-body LDLc and/or total cholesterol content (irs2b and sh2b1); and pancreatic beta cell traits and/or glucose content (pcsk1, pomca, and sim1a). Taken together, our results illustrate that CRISPR/Cas9- and image-based experiments in zebrafish larvae can highlight direct effects of obesity genes on cardiometabolic traits, unconfounded by their - not yet apparent - effect on excess adiposity.
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Affiliation(s)
- Eugenia Mazzaferro
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Endrina Mujica
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Hanqing Zhang
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Anastasia Emmanouilidou
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Anne Jenseit
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Bade Evcimen
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Christoph Metzendorf
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden
| | - Olga Dethlefsen
- Science for Life Laboratory, National Bioinformatics Infrastructure, Stockholm University, Stockholm, Sweden
| | - Ruth Jf Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Anders Larsson
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala , Sweden
| | - Amin Allalou
- Department of Information Technology, Division of Visual Information and Interaction, Uppsala University, Uppsala , Sweden
- BioImage Informatics Facility at SciLifeLab, Uppsala, Sweden
| | - Marcel den Hoed
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala , Sweden.
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Bonnefond A, Florez JC, Loos RJF, Froguel P. Dissection of type 2 diabetes: a genetic perspective. Lancet Diabetes Endocrinol 2025; 13:149-164. [PMID: 39818223 DOI: 10.1016/s2213-8587(24)00339-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/11/2024] [Accepted: 10/30/2024] [Indexed: 01/18/2025]
Abstract
Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background, with family and twin studies indicating considerable heritability (ie, 31-72%). This Review explores type 2 diabetes from a genetic perspective, highlighting insights into its pathophysiology and the implications for precision medicine. More specifically, the traditional understanding of type 2 diabetes genetics has focused on a dichotomy between monogenic and polygenic forms. However, emerging evidence suggests a continuum that includes monogenic, oligogenic, and polygenic contributions, revealing their complementary roles in type 2 diabetes pathophysiology. Recent genetic studies provide deeper insights into disease mechanisms and pave the way for precision medicine approaches that could transform type 2 diabetes management. Additionally, the effect of environmental factors on type 2 diabetes, particularly from epigenetic modifications, adds another layer of complexity to understanding and addressing this multifaceted disease.
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Affiliation(s)
- Amélie Bonnefond
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ruth J F Loos
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Philippe Froguel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
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Yuan S, Yu Q, Luo M, Wu J, Wang L. Friend or Foe: The Paradoxical Roles of MG53 in Diabetes. Diabetes 2025; 74:145-152. [PMID: 39535840 DOI: 10.2337/db24-0556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes has gradually been elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) for ubiquitin-dependent degradation. Additionally, MG53 has been identified as a myokine/cardiokine that is secreted from striated muscles into the bloodstream, and circulating MG53 has further been shown to trigger insulin resistance by binding to the extracellular domain of the IR, thereby allosterically inhibiting insulin signaling. Conversely, findings have been reported from other studies that contradict these results. Specifically, no significant change in MG53 expression in striated muscles or serum has been observed in diabetic models, and the MG53-mediated degradation of IRS-1 may be insufficient to induce insulin resistance due to the compensatory roles of other IRS subtypes. Furthermore, sustained elevation of MG53 levels in serum or systemic administration of recombinant human MG53 (rhMG53) has shown no impact on metabolic function. In this article, we will fully characterize these two disparate views, strive to provide critical insights into their contrasts, and propose several specific experimental approaches that may yield additional evidence. Our goal is to encourage the scientific community to elucidate the effects of MG53 on metabolic diseases and the molecular mechanisms involved, thereby providing the theoretical basis for the treatment of metabolic diseases and the applications of rhMG53.
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Affiliation(s)
- Shuangshuang Yuan
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, and Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qin Yu
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, and Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Mao Luo
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, and Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jianbo Wu
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, and Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Liqun Wang
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, and Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, China
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Takahashi A, Furuta H, Nishi H, Kamei H, Takahashi SI, Hakuno F. Insulin Receptor Substrate-2 Regulates the Secretion of Growth Factors in Response to Amino Acid Deprivation. Int J Mol Sci 2025; 26:841. [PMID: 39859555 PMCID: PMC11766276 DOI: 10.3390/ijms26020841] [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: 12/27/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 01/27/2025] Open
Abstract
Insulin receptor substrates (IRSs) are well-known mediators of the insulin and insulin-like growth factor (IGF)-I signaling pathways. We previously reported that the protein levels of IRS-2, a molecular species of IRS, were upregulated in the livers of rats fed a protein-restricted diet. This study aimed to elucidate the physiological role of IRS-2, whose level increases in response to protein restriction in cultured hepatocyte models. Hepatocyte-derived cell lines subjected to amino acid deprivation showed increased IRS2 mRNA and IRS-2 protein levels due to increased IRS2 transcription and translation, respectively. Amino acid deprivation markedly increased vascular endothelial growth factor-D (VEGF-D) secretion. Remarkably, the amino acid deprivation-induced VEGF-D secretion was suppressed by IRS-2 knockdown and enhanced by IRS-2 overexpression. These results suggest that IRS-2 is an intercellular signaling molecule that extracellularly transmits information on amino acid deprivation stress by regulating the secretion of growth factors such as VEGF-D. Moreover, this function of IRS-2 is distinct from its currently accepted function as a mediator of the insulin/IGF-I signaling pathways. This study demonstrates that IRS-2 can modulate protein secretion in an insulin-independent manner and greatly expands our understanding of the role of IRS-2, which is upregulated in response to amino acid deprivation.
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Affiliation(s)
- Ayaka Takahashi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
| | - Haruka Furuta
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
| | - Hiroki Nishi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Hiroyasu Kamei
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kanazawa 920-1192, Japan;
| | - Shin-Ichiro Takahashi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
| | - Fumihiko Hakuno
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
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7
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Toyoshima Y, Nakamura K, Taguchi Y, Tokita R, Takeuchi S, Osawa H, Teramoto N, Sugihara H, Yoshizawa F, Yamanouchi K, Minami S. Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats. Sci Rep 2025; 15:649. [PMID: 39779784 PMCID: PMC11711447 DOI: 10.1038/s41598-024-84234-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous study showed that the disruption of IRS-2 impairs body growth but not glucose tolerance or insulin sensitivity in rats, which led us to hypothesize that IRS-1 plays more pivotal roles in insulin functions than IRS-2. Here, we created IRS-1 knockout (KO) rats to elucidate the physiological roles of IRS-1 in rats. The body weight of IRS-1 KO rats at birth was lower than that of wild-type (WT) littermates, and postnatal growth of IRS-1 KO rats was severely impaired. Compared with WT rats, IRS-1 KO rats displayed insulin resistance but maintained euglycemia because of compensatory hyperinsulinemia. In addition, despite the increased activity of insulin-stimulated IRS-2-associated phosphatidylinositol-3 kinase (PI3K), insulin-induced phosphorylation of the kinases downstream of PI3K was suppressed in the liver and skeletal muscle of IRS-1 KO rats. Taken together, these results indicate that in rats, IRS-1 is essential for normal growth and the glucose-lowering effects of insulin. IRS-1 appears to be more important than IRS-2 for insulin functions in rats.
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Affiliation(s)
- Yuka Toyoshima
- Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, 350 Mine-machi, Utsunomiya, 321-8505, Tochigi, Japan.
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan.
| | - Katsuyuki Nakamura
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Department of Chemistry and Biomolecular Science, Biomolecular Science Course, Faculty of Engineering, Gifu University, Gifu, Japan
| | - Yusuke Taguchi
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan
| | - Reiko Tokita
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan
| | - Shiho Takeuchi
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Hayato Osawa
- Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, 350 Mine-machi, Utsunomiya, 321-8505, Tochigi, Japan
| | - Naomi Teramoto
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Hidetoshi Sugihara
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Fumiaki Yoshizawa
- Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, 350 Mine-machi, Utsunomiya, 321-8505, Tochigi, Japan
| | - Keitaro Yamanouchi
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Shiro Minami
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan
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Zieleniak A, Zurawska-Klis M, Laszcz K, Bulash K, Pacyga D, Cypryk K, Wozniak L, Wojcik M. Assessment of Changes in the Expression of Genes Involved in Insulin Signaling and Glucose Transport in Leukocytes of Women with Gestational Diabetes During Pregnancy and in the Postpartum Period. Int J Mol Sci 2024; 25:13094. [PMID: 39684804 DOI: 10.3390/ijms252313094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/28/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Not much is currently known about disturbances in insulin signaling and glucose transport in leukocytes of women with gestational diabetes mellitus (GDM) during and after pregnancy. In this study, the expression of insulin signaling (INSR, IRS1, IRS2 and PIK3R1)- and glucose transporter (SLC2A1, SLC2A3 and SLC2A4)-related genes in the leukocytes of 92 pregnant women was assayed using quantitative RT-PCR. The cohort consisted of 44 women without GDM (NGT group) and 48 with GDM (GDM group) at 24-28 weeks of gestation. GDM women were then tested again one year after childbirth (pGDM group: 14 women (29.2%) with abnormal glucose tolerance (AGT) and 34 women (70.8%) with normoglycemia). The GDM and NGT groups were closely matched for gestational age and parameters of obesity, such as pre-pregnancy body mass index (BMI), pregnancy weight, and gestational weight gain (GWG) (p > 0.05). Compared to the NGT group, the GDM and pGDM groups were hyperglycemic, but the GDM group featured a more highly insulin-resistant condition than the pGDM group, as reflected by higher fasting insulin (FI) levels and the values of the homeostasis model assessment for insulin resistance (HOMA-IR) (p < 0.05). In leukocytes from the GDM and pGDM groups, PIK3R1, SLC2A1, and SLC2A3 were upregulated and IRS1 was downregulated, with a larger magnitude in fold change (FC) values for PIK3R1 and IRS1 in the GDM group and for SLC2A1 and SLC2A3 in the pGDM group. The expression of SLC2A4 was unchanged in the GDM group but upregulated in the pGDM group, where it was inversely correlated with HOMA-IR (rho = -0.48; p = 0.007). Although the INSR and IRS2 levels did not significantly differ between the groups, the IRS2 transcript positively correlated with pregnancy weight, fasting plasma glucose, FI, and HOMA-IR in the GDM group. Our findings indicate that pronounced quantitative changes exist between the GDM and pGDM groups with respect to the expression of certain genes engaged in insulin signaling and glucose transport in leukocytes, with insulin resistance of a variable degree. These data also highlight the relationship of leukocyte SLC2A4 expression with insulin resistance in the postpartum period.
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Affiliation(s)
- Andrzej Zieleniak
- Department of Structural Biology, Faculty of Biomedical Sciences, Medical University of Lodz, 90-752 Lodz, Poland
| | - Monika Zurawska-Klis
- Department of Internal Diseases and Diabetology, Medical University of Lodz, 92-213 Lodz, Poland
| | - Karolina Laszcz
- Faculty of Biomedical Sciences, Medical University of Lodz, 90-752 Lodz, Poland
| | - Krystsina Bulash
- Faculty of Biomedical Sciences, Medical University of Lodz, 90-752 Lodz, Poland
| | - Dagmara Pacyga
- Faculty of Biomedical Sciences, Medical University of Lodz, 90-752 Lodz, Poland
| | - Katarzyna Cypryk
- Department of Internal Diseases and Diabetology, Medical University of Lodz, 92-213 Lodz, Poland
| | - Lucyna Wozniak
- Department of Structural Biology, Faculty of Biomedical Sciences, Medical University of Lodz, 90-752 Lodz, Poland
| | - Marzena Wojcik
- Department of Structural Biology, Faculty of Biomedical Sciences, Medical University of Lodz, 90-752 Lodz, Poland
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9
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Lee KE, Nishi M, Kim J, Murayama T, Dawson Z, Wang X, Zhou X, Tan T, Cai C, Takeshima H, Park KH. MG53's non-physiologic interaction with insulin receptor: lack of effect on insulin-stimulated Akt phosphorylation in muscle, heart and liver tissues. Front Endocrinol (Lausanne) 2024; 15:1425426. [PMID: 39355613 PMCID: PMC11442255 DOI: 10.3389/fendo.2024.1425426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/15/2024] [Indexed: 10/03/2024] Open
Abstract
Rationale MG53's known function in facilitating tissue repair and anti-inflammation has broad applications to regenerative medicine. There is controversy regarding MG53's role in the development of type 2 diabetes mellitus. Objective This study aims to address this controversy - whether MG53's myokine function contributes to inhibition of insulin signaling in muscle, heart, and liver tissues. Study design We determined the binding affinity of the recombinant human MG53 (rhMG53) to the insulin receptor extracellular domain (IR-ECD) and found low affinity of interaction with Kd (>480 nM). Using cultured C2C12 myotubes and HepG2 cells, we found no effect of rhMG53 on insulin-stimulated Akt phosphorylation (p-Akt). We performed in vivo assay with C57BL/6J mice subjected to insulin stimulation (1 U/kg, intraperitoneal injection) and observed no effect of rhMG53 on insulin-stimulated p-Akt in muscle, heart and liver tissues. Conclusion Overall, our data suggest that rhMG53 can bind to the IR-ECD, however has a low likelihood of a physiologic role, as the Kd for binding is ~10,000 higher than the physiologic level of MG53 present in the serum of rodents and humans (~10 pM). Our findings question the notion proposed by Xiao and colleagues - whether targeting circulating MG53 opens a new therapeutic avenue for type 2 diabetes mellitus and its complications.
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Affiliation(s)
- Kyung Eun Lee
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Miyuki Nishi
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Jongsoo Kim
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Takashi Murayama
- Department of Cellular and Molecular Pharmacology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Zachary Dawson
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Xiaoliang Wang
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Xinyu Zhou
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Tao Tan
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Chuanxi Cai
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Hiroshi Takeshima
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Ki Ho Park
- Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA, United States
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Dobson JR, Jacobson DA. Disrupted Endoplasmic Reticulum Ca 2+ Handling: A Harβinger of β-Cell Failure. BIOLOGY 2024; 13:379. [PMID: 38927260 PMCID: PMC11200644 DOI: 10.3390/biology13060379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/17/2024] [Accepted: 05/17/2024] [Indexed: 06/28/2024]
Abstract
The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca2+ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.
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Affiliation(s)
| | - David A. Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA;
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11
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Zhu Y, Yang M, Xu W, Zhang Y, Pan L, Wang L, Wang F, Lu Y. The collagen matrix regulates the survival and function of pancreatic islets. Endocrine 2024; 83:537-547. [PMID: 37999835 DOI: 10.1007/s12020-023-03592-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 10/30/2023] [Indexed: 11/25/2023]
Abstract
The extracellular matrix (ECM) provides an appropriate microenvironment for many kinds of cells, including pancreatic cells. Collagens are the most abundant components of the ECM. Type I, IV, V and VI collagen has been detected in pancreatic islets, and each type plays important role in the proliferation, survival, function and differentiation of pancreatic cells. In some cases, collagens show behaviours similar to those of growth factors and regulate the biological behaviour of β cells by binding with certain growth factors, including IGFs, EGFs and FGFs. The transcriptional coactivator YAP/TAZ has been widely recognised as a mechanosensor that senses changes in the physical characteristics of the ECM and inhibition of YAP/TAZ enhances insulin production and secretion. Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterised by the destruction of insulin-producing β cells. The crosstalk between collagens and immune cells plays a key role in the development and differentiation of immune cells. Further, Supplementation with collagens during islet transplantation is a promising strategy for improving the quality of the islets. But, excessive collagen deposition results in pancreatic fibrosis and pancreatic carcinoma. Targeting inhibit Piezo, autophagy or IL-6 may reduce excessive collagen deposition-induced pancreatic fibrosis and pancreatic carcinoma. This review provides insights into the treatment of T1DM to prolong life expectancy and provides the potential targets for treating collagen deposition-induced pancreatic fibrosis and pancreatic carcinoma.
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Affiliation(s)
- Yingying Zhu
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China
| | - Mei Yang
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China
| | - Wanli Xu
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China
| | - Yun Zhang
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China
| | - Linlin Pan
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China
| | - Lina Wang
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China
| | - Furong Wang
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China.
| | - Yanting Lu
- Traditional Chinese Medical college, Shandong University of Traditional Chinese Medicine, Jinan, 250300, Shandong, China.
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12
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Ahmed M, Biswas T, Mondal S. The strategic involvement of IRS in cancer progression. Biochem Biophys Res Commun 2023; 680:141-160. [PMID: 37738904 DOI: 10.1016/j.bbrc.2023.09.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
Insulin Receptor Substrate (IRS), an intracellular molecule devoid of an intrinsic kinase activity, is activated upon binding to IR which thereby works as a scaffold, organizing all signaling complexes and initiating the signaling process downstream. The level of IRS proteins and their stability in the cell is mostly maintained through the phosphorylation status of their tyrosine and serine residues. IRS is positively regulated by phosphorylation of its Tyr residues whereas a Ser residue phosphorylation attenuates it, although there exist some exceptions as well. Other post-translational modifications like O-linked glycosylation, N-linked glycosylation and acetylation also play a prominent role in IRS regulation. Since the discovery of the Warburg effect, people have been curious to find out all possible signaling networks and molecules that could lead to cancer and no doubt, the insulin signaling pathway is identified as one such pathway, which is highly deregulated in cancers. Eminent studies reveal that IRS is a pertinent regulator of cancer and is highly overexpressed in the five most commonly occurring cancers namely- Prostate, Ovarian, Breast, Colon and Lung cancers. IRS1 and IRS2 family members are actively involved in the progression, invasion and metastasis of these cancers. Recently, less studied IRS4 has also emerged as a contributor in ovarian, breast, colorectal and lung cancer, but no such studies related to IRS4 are found in Prostate cancer. The involvement of other IRS family members in cancer is still undiscovered and so paves the way for further exploration. This review is a time-lapse study of IRSs in the context of cancer done over the past two decades and it highlights all the major discoveries made till date, in these cancers from the perspective of IRS.
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Affiliation(s)
- Mehnaz Ahmed
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India
| | - Tannishtha Biswas
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India
| | - Susmita Mondal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India.
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13
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Chen Q, Jiang FJ, Gao X, Li XY, Xia P. Steatotic hepatocyte-derived extracellular vesicles promote β-cell apoptosis and diabetes via microRNA-126a-3p. Liver Int 2023; 43:2560-2570. [PMID: 37337778 DOI: 10.1111/liv.15654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 06/08/2023] [Accepted: 06/10/2023] [Indexed: 06/21/2023]
Abstract
Extracellular vesicles (EVs) have emerged as a unique mediator of interorgan communications, playing important roles in the pathophysiologic process of various diseases, including diabetes and other metabolic diseases. Here, we reported that the EVs released by steatotic hepatocytes exerted a detrimental effect on pancreatic β cells, leading to β-cell apoptosis and dysfunction. The effect was profoundly attributable to an up-regulation of miR-126a-3p in the steatotic hepatocyte-derived EVs. Accordingly, overexpression of miR-126a-3p promoted, whereas inhibition of miR-126a-3p prevented β-cell apoptosis, through a mechanism related to its target gene, insulin receptor substrate-2. Moreover, inhibition of miR-126a-3p by its specific antagomir was able to partially reverse the loss of β-cell mass and ameliorate hyperglycaemia in diabetic mice. Thus, the findings reveal a novel pathogenic role of steatotic hepatocyte-derived EVs, which mechanistically links nonalcoholic fatty liver disease to the development of diabetes.
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Affiliation(s)
- Qi Chen
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fang-Jie Jiang
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Ying Li
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pu Xia
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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14
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Sano T, Ochiai T, Nagayama T, Nakamura A, Kubota N, Kadowaki T, Wakabayashi T, Iwatsubo T. Genetic Reduction of Insulin Signaling Mitigates Amyloid-β Deposition by Promoting Expression of Extracellular Matrix Proteins in the Brain. J Neurosci 2023; 43:7226-7241. [PMID: 37699718 PMCID: PMC10601373 DOI: 10.1523/jneurosci.0071-23.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 08/16/2023] [Accepted: 09/03/2023] [Indexed: 09/14/2023] Open
Abstract
The insulin/IGF-1 signaling (IIS) regulates a wide range of biological processes, including aging and lifespan, and has also been implicated in the pathogenesis of Alzheimer's disease (AD). We and others have reported that reduced signaling by genetic ablation of the molecules involved in IIS (e.g., insulin receptor substrate 2 [IRS-2]) markedly mitigates amyloid plaque formation in the brains of mouse models of AD, although the molecular underpinnings of the amelioration remain unsolved. Here, we revealed, by a transcriptomic analysis of the male murine cerebral cortices, that the expression of genes encoding extracellular matrix (ECM) was significantly upregulated by the loss of IRS-2. Insulin signaling activity negatively regulated the phosphorylation of Smad2 and Smad3 in the brain, and suppressed TGF-β/Smad-dependent expression of a subset of ECM genes in brain-derived cells. The ECM proteins inhibited Aβ fibril formation in vitro, and IRS-2 deficiency suppressed the aggregation process of Aβ in the brains of male APP transgenic mice as revealed by injection of aggregation seeds in vivo Our results propose a novel mechanism in AD pathophysiology whereby IIS modifies Aβ aggregation and amyloid pathology by altering the expression of ECM genes in the brain.SIGNIFICANCE STATEMENT The insulin/IGF-1 signaling (IIS) has been recognized as a regulator of aging, a leading risk factor for the onset of Alzheimer's disease (AD). In AD mouse models, genetic deletion of key IIS molecules markedly reduces the amyloid plaque formation in the brain, although the molecular underpinnings of this amelioration remain elusive. We found that the deficiency of insulin receptor substrate 2 leads to an increase in the expression of various extracellular matrices (ECMs) in the brain, potentially through TGF-β/Smad signaling. Furthermore, some of those ECMs exhibited the potential to inhibit amyloid plaque accumulation by disrupting the formation of Aβ fibrils. This study presents a novel mechanism by which IIS regulates Aβ accumulation, which may involve altered brain ECM expression.
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Affiliation(s)
- Toshiharu Sano
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Toshitaka Ochiai
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
- Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Company, LTD, Kyoto, 607-8042, Japan
| | - Takeru Nagayama
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Ayaka Nakamura
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
- Department of Clinical Nutrition Therapy, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
- Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Tomoko Wakabayashi
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
- Department of Innovative Dementia Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Takeshi Iwatsubo
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
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15
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Guijarro LG, Justo Bermejo FJ, Boaru DL, De Castro-Martinez P, De Leon-Oliva D, Fraile-Martínez O, Garcia-Montero C, Alvarez-Mon M, Toledo-Lobo MDV, Ortega MA. Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes? Cancers (Basel) 2023; 15:4651. [PMID: 37760618 PMCID: PMC10526421 DOI: 10.3390/cancers15184651] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/06/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes "(IRS-4 or IRS4)", or the combination of these terms with the word "(cancer)" or "(human)", for searches. Terms related to specific tumor pathologies ("breast", "ovary", "colon", "lung", "lymphoma", etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets.
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Affiliation(s)
- Luis G. Guijarro
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
| | | | - Diego Liviu Boaru
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Patricia De Castro-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Diego De Leon-Oliva
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Oscar Fraile-Martínez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Cielo Garcia-Montero
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Melchor Alvarez-Mon
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
- Immune System Diseases-Rheumatology, Oncology Service and Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, 28806 Alcala de Henares, Spain
| | - María del Val Toledo-Lobo
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Biomedicine and Biotechnology, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Miguel A. Ortega
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (D.L.B.); (D.D.L.-O.); (O.F.-M.); (C.G.-M.); (M.A.-M.); (M.A.O.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain
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Andaç B, Özgün E, Bülbül BY, Çolak SY, Okur M, Yekdeş AC, Öcal E, Tapan ME, Çelik M. Association of MG53 with presence of type 2 diabetes mellitus, glycemic control, and diabetic complications. PLoS One 2023; 18:e0291333. [PMID: 37699054 PMCID: PMC10497120 DOI: 10.1371/journal.pone.0291333] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 08/27/2023] [Indexed: 09/14/2023] Open
Abstract
OBJECTIVES Mitsugumin 53 (MG53) is a myokine that acts as a membrane repair protein in tissues. Data on the effect of MG53 on insulin signaling and type 2 diabetes mellitus (T2 DM) are still unknown; most are from preclinical studies. Nevertheless, some researchers have argued that it may be a new pathogenic factor, and therapies targeting MG53 may be a new avenue for T2 DM. Our study aims to evaluate the relationship of circulating MG53 levels with the presence of diabetes, diabetic complications, and glycemic control. METHODS We conducted a case-control study with 107 patients with T2 DM and 105 subjects without insulin resistance-related disease. Concurrent blood samples were used for serum MG53 levels and other biochemical laboratory data. MG53 concentration was measured using Human-MG53, an enzyme-linked immunosorbent assay kit (Cat# CSB-EL024511HU). RESULTS We found no difference in MG53 levels between the diabetic and control groups (p = 0.914). Furthermore, when the subjects were divided into tertiles according to their MG53 levels, we did not find any difference between the groups in terms of the presence of diabetes (p = 0.981). Additionally, no correlation was observed between weight, BMI, waist circumference, systolic and diastolic blood pressure, fasting blood glucose, HbA1c, albumin excretion in the urine, e-GFR levels, and MG53. Finally, MG53 levels were similar between the groups with and without microvascular and macrovascular complications of diabetes. CONCLUSION Our research finding provides insightful clinical evidence of lack of association between the levels of MG53 and T2 DM or glycemic control, at least in the studied population of Turkeys ethnicity. However, further clinical studies are warranted to establish solid evidence of the link between MG53, insulin resistance and glycemic control in a wider population elsewhere in the world.
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Affiliation(s)
- Burak Andaç
- Department of Endocrinology and Metabolism, Medical Faculty, Trakya University, Edirne, Turkey
| | - Eray Özgün
- Department of Biochemistry, Medical Faculty, Trakya University, Edirne, Turkey
| | - Buket Yılmaz Bülbül
- Department of Endocrinology and Metabolism, Medical Faculty, Trakya University, Edirne, Turkey
| | - Serpil Yanık Çolak
- Department of Endocrinology and Metabolism, Medical Faculty, Trakya University, Edirne, Turkey
| | - Mine Okur
- Department of Endocrinology and Metabolism, Medical Faculty, Trakya University, Edirne, Turkey
| | - Ali Cem Yekdeş
- Department of Public Health, Medical Faculty, Trakya University, Edirne, Turkey
| | - Eftal Öcal
- Department of Internal Medicine, Medical Faculty, Trakya University, Edirne, Turkey
| | - Mehmet Emin Tapan
- Department of Internal Medicine, Medical Faculty, Trakya University, Edirne, Turkey
| | - Mehmet Çelik
- Department of Endocrinology and Metabolism, Medical Faculty, Trakya University, Edirne, Turkey
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Wang Y, Li J, Xiang Q, Tang L. INSR and ISR‑1 gene polymorphisms and the susceptibility of essential hypertension: A meta‑analysis. Exp Ther Med 2023; 25:251. [PMID: 37153892 PMCID: PMC10161195 DOI: 10.3892/etm.2023.11950] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/08/2023] [Indexed: 05/10/2023] Open
Abstract
INSR and ISR-1 may be candidate genes for essential hypertension (EH). However, the genetic association between the INSR and ISR-1 gene polymorphisms and EH risk remains contradictory. To determine a more precise association of the INSR and ISR-1 gene polymorphisms and EH, the present study performed a meta-analysis. Eligible studies up to Jan 2021 were retrieved from multiple databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the genetic associations between the allele, dominant and recessive models of INSR Nsil, RsaI and ISR-1 G972R polymorphisms and EH susceptibility. A total of 10 case-control studies encompassing 2,782 subjects including 1,289 cases and 1,493 controls were evaluated for the present meta-analysis. Neither of the allele, dominant and recessive models of INSR Nsil and ISR-1 G972R polymorphisms was associated with EH risk (P>0.05). While the allele [P=0.0008, OR=0.58, (95% CI)=(0.42, 0.80)], dominant [P=0.02, OR=0.59, (95% CI)=(0.38, 0.92)] and recessive models [P=0.003, OR=0.38, (95% CI)=(0.20, 0.72)] of INSR Rsal polymorphism were associated with decreased risk of EH. Subgroup analysis according to ethnicity showed that the significant associations between the allele, dominant and recessive models of INSR Rsal polymorphism and EH risk were observed in Caucasian populations, but not in Asian populations (P>0.05). In conclusion, the INSR Rsal polymorphism is probably a protective factor for EH. To identify the result, additional case-control designed research with larger numbers of subjects are required.
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Affiliation(s)
- Yan Wang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Jianming Li
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Academics Working Station, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Qin Xiang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Academics Working Station, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Liang Tang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Academics Working Station, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Correspondence to: Professor Liang Tang, Department of Basic Biology, Changsha Medical College, 1501 Leifeng Road, Wangcheng, Changsha, Hunan 410219, P.R. China
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18
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Scalia P, Williams SJ, Fujita-Yamaguchi Y, Giordano A. Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation. Cell Cycle 2023; 22:1-37. [PMID: 36005738 PMCID: PMC9769454 DOI: 10.1080/15384101.2022.2108117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.
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Affiliation(s)
- Pierluigi Scalia
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states,CONTACT Pierluigi Scalia ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA9102, USA
| | - Stephen J Williams
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states
| | - Yoko Fujita-Yamaguchi
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Antonio Giordano
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,School of Medical Biotechnology, University of Siena, Italy
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19
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Lee JS, Tocheny CE, Shaw LM. The Insulin-like Growth Factor Signaling Pathway in Breast Cancer: An Elusive Therapeutic Target. LIFE (BASEL, SWITZERLAND) 2022; 12:life12121992. [PMID: 36556357 PMCID: PMC9782138 DOI: 10.3390/life12121992] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/30/2022]
Abstract
In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important for normal mammary gland biology, and dysregulation of their expression and function drives breast cancer risk and progression through activation of downstream signaling effectors, often in a subtype-dependent manner. The IGF signaling pathway has also been implicated in resistance to current therapeutic strategies, including ER and HER2 targeting drugs. Unfortunately, efforts to target IGF signaling for the treatment of breast cancer have been unsuccessful, due to a number of factors, most significantly the adverse effects of disrupting IGF signaling on normal glucose metabolism. We highlight here the recent discoveries that provide enthusiasm for continuing efforts to target IGF signaling for the treatment of breast cancer patients.
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Affiliation(s)
| | | | - Leslie M. Shaw
- Correspondence: ; Tel.: +1-508-856-8675; Fax: +1-508-856-1310
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20
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Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart. Mol Cell Biol 2022; 42:e0016322. [PMID: 36125265 PMCID: PMC9583714 DOI: 10.1128/mcb.00163-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion. Heart failure was characterized by cardiomyocyte loss and disarray, increased proapoptotic signaling, and increased autophagy. Suppression of autophagy by activating mTOR signaling did not prevent heart failure. Transcriptional profiling revealed reduced serum response factor (SRF) transcriptional activity and decreased mRNA levels of genes encoding sarcomere and gap junction proteins as early as 3 days post-gene deletion, in concert with ultrastructural evidence of sarcomere disruption and intercalated discs within 1 week after gene deletion. These data confirm conserved roles for constitutive insulin and IGF1 signaling in suppressing autophagic and apoptotic signaling in the adult heart. The present study also identifies an unexpected role for insulin and IGF1 signaling in regulating an SRF-mediated transcriptional program, which maintains expression of genes encoding proteins that support sarcomere integrity in the adult heart, reduction of which results in rapid development of heart failure.
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21
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Sasako T, Umehara T, Soeda K, Kaneko K, Suzuki M, Kobayashi N, Okazaki Y, Tamura-Nakano M, Chiba T, Accili D, Kahn CR, Noda T, Asahara H, Yamauchi T, Kadowaki T, Ueki K. Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice. Nat Commun 2022; 13:5655. [PMID: 36198696 PMCID: PMC9535008 DOI: 10.1038/s41467-022-33008-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/19/2022] [Indexed: 01/23/2023] Open
Abstract
Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1/4, but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan.
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Affiliation(s)
- Takayoshi Sasako
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan ,grid.45203.300000 0004 0489 0290Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Toshihiro Umehara
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kotaro Soeda
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan ,grid.45203.300000 0004 0489 0290Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuma Kaneko
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Miho Suzuki
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoki Kobayashi
- grid.45203.300000 0004 0489 0290Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yukiko Okazaki
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Miwa Tamura-Nakano
- grid.45203.300000 0004 0489 0290Communal Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tomoki Chiba
- grid.265073.50000 0001 1014 9130Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Domenico Accili
- grid.21729.3f0000000419368729Columbia University College of Physicians & Surgeons, Department of Medicine, New York, NY USA
| | - C. Ronald Kahn
- grid.38142.3c000000041936754XJoslin Diabetes Center, Harvard Medical School, Boston, MA USA
| | - Tetsuo Noda
- grid.410807.a0000 0001 0037 4131Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan
| | - Hiroshi Asahara
- grid.265073.50000 0001 1014 9130Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshimasa Yamauchi
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Kadowaki
- grid.26999.3d0000 0001 2151 536XDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan ,grid.410813.f0000 0004 1764 6940Toranomon Hospital, Tokyo, Japan
| | - Kohjiro Ueki
- grid.45203.300000 0004 0489 0290Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan ,grid.26999.3d0000 0001 2151 536XDepartment of Molecular Diabetetology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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22
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Shin J, Toyoda S, Nishitani S, Onodera T, Fukuda S, Kita S, Fukuhara A, Shimomura I. SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1. Metabolism 2022; 133:155236. [PMID: 35688210 PMCID: PMC9173833 DOI: 10.1016/j.metabol.2022.155236] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/11/2022] [Accepted: 06/01/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. METHODS To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. RESULTS We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, liver, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in liver, adipose tissue, and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which was previously reported to be associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and was frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. CONCLUSIONS The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.
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Affiliation(s)
- Jihoon Shin
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
| | - Shinichiro Toyoda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shigeki Nishitani
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Toshiharu Onodera
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shiro Fukuda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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23
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Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes. Cell Discov 2022; 8:60. [PMID: 35764611 PMCID: PMC9240053 DOI: 10.1038/s41421-022-00426-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301–600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases.
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24
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Meng X, Huang Z, Inoue A, Wang H, Wan Y, Yue X, Xu S, Jin X, Shi GP, Kuzuya M, Cheng XW. Cathepsin K activity controls cachexia-induced muscle atrophy via the modulation of IRS1 ubiquitination. J Cachexia Sarcopenia Muscle 2022; 13:1197-1209. [PMID: 35098692 PMCID: PMC8978007 DOI: 10.1002/jcsm.12919] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 11/22/2021] [Accepted: 12/14/2021] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Cachexia is a complicated metabolic disorder that is characterize by progressive atrophy of skeletal muscle. Cathepsin K (CTSK) is a widely expressed cysteine protease that has garnered attention because of its enzymatic and non-enzymatic functions in signalling in various pathological conditions. Here, we examined whether CTSK participates in cancer-induced skeletal muscle loss and dysfunction, focusing on protein metabolic imbalance. METHODS Male 9-week-old wild-type (CTSK+/+ , n = 10) and CTSK-knockout (CTSK-/- , n = 10) mice were injected subcutaneously with Lewis lung carcinoma cells (LLC; 5 × 105 ) or saline, respectively. The mice were then subjected to muscle mass and muscle function measurements. HE staining, immunostaining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting were used to explore the CTSK expression and IRS1/Akt pathway in the gastrocnemius muscle at various time points. In vitro measurements included CTSK expression, IRS1/Akt pathway-related target molecule expressions, and the diameter of C2C12 myotubes with or without LLC-conditioned medium (LCM). An IRS1 ubiquitin assay, and truncation, co-immunoprecipitation, and co-localization experiments were also performed. RESULTS CTSK+/+ cachectic animals exhibited loss of skeletal muscle mass (muscle weight loss of 15%, n = 10, P < 0.01), muscle dysfunction (grip strength loss > 15%, n = 10, P < 0.01), and fibre area (average area reduction > 30%, n = 5, P < 0.01). Compared with that of non-cachectic CTSK+/+ mice, the skeletal muscle of cachectic CTSK+/+ mice exhibited greater degradation of insulin receptor substrate 1 (IRS1, P < 0.01). In this setting, cachectic muscles exhibited decreases in the phosphorylation levels of protein kinase B (Akt308 , P < 0.01; Akt473 , P < 0.05) and anabolic-related proteins (the mammalian target of rapamycin, P < 0.01) and increased levels of catabolism-related proteins (muscle RING-finger protein-1, P < 0.01; MAFbx1, P < 0.01) in CTSK+/+ mice (n = 3). Although there was no difference in LLC tumour growth (n = 10, P = 0.44), CTSK deletion mitigated the IRS1 degradation, loss of the skeletal muscle mass (n = 10, P < 0.01), and dysfunction (n = 10, P < 0.01). In vitro, CTSK silencing prevented the IRS1 ubiquitination and loss of the myotube myosin heavy chain content (P < 0.01) induced by LCM, and these changes were accelerated by CTSK overexpression even without LCM. Immunoprecipitation showed that CTSK selectively acted on IRS1 in the region of amino acids 268 to 574. The results of co-transfection of IRS1-N-FLAG or IRS1-C-FLAG with CTSK suggested that CTSK selectively cleaves IRS1 and causes ubiquitination-related degradation of IRS1. CONCLUSIONS These results demonstrate that CTSK plays a novel role in IRS1 ubiquitination in LLC-induced muscle wasting, and suggest that CTSK could be an effective therapeutic target for cancer-related cachexia.
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Affiliation(s)
- Xiangkun Meng
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Zhe Huang
- Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, China.,Department of Human Cord Stem Cell Therapy, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Aiko Inoue
- Institute of Innovation for Future Society, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hailong Wang
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ying Wan
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xueling Yue
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shengnan Xu
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xueying Jin
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Guo-Ping Shi
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Masafumi Kuzuya
- Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Institute of Innovation for Future Society, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xian Wu Cheng
- Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, China.,Department of Human Cord Stem Cell Therapy, Graduate School of Medicine, Nagoya University, Nagoya, Japan
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25
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Zhang Y, Wang H, Tu W, Abbas Raza SH, Cao J, Huang J, Wu H, Fan C, Wang S, Zhao Y, Tan Y. Comparative Transcriptome Analysis Provides Insight into Spatio-Temporal Expression Characteristics and Genetic Regulatory Network in Postnatal Developing Subcutaneous and Visceral Fat of Bama Pig. Front Genet 2022; 13:844833. [PMID: 35432468 PMCID: PMC9008487 DOI: 10.3389/fgene.2022.844833] [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: 12/28/2021] [Accepted: 03/04/2022] [Indexed: 12/23/2022] Open
Abstract
The depot differences between Subcutaneous Fat (SAF) and Visceral Fat (VAF) are critical for human well-being and disease processes in regard to energy metabolism and endocrine function. Miniature pigs (Sus scrofa) are ideal biomedical models for human energy metabolism and obesity due to the similarity of their lipid metabolism with that of humans. However, the regulation of differences in fat deposition and development remains unclear. In this study, the development of SAF and VAF was characterized and compared in Bama pig during postnatal development (infancy, puberty and adulthood), using RNA sequencing techniques (RNA-Seq). The transcriptome of SAF and VAF was profiled and isolated from 1-, 3- and 6 months-old pigs and identified 23,636 expressed genes, of which 1,165 genes were differentially expressed between the depots and/or developmental stages. Upregulated genes in SAF showed significant function and pathway enrichment in the central nervous system development, lipid metabolism, oxidation-reduction process and cell adhesion, whereas genes involved in the immune system, actin cytoskeleton organization, male gonad development and the hippo signaling pathway were preferentially expressed in VAF. Miner analysis of short time-series expression demonstrated that differentiation in gene expression patterns between the two depots corresponded to their distinct responses in sexual development, hormone signaling pathways, lipid metabolism and the hippo signaling pathway. Transcriptome analysis of SAF and VAF suggested that the depot differences in adipose tissue are not only related to lipid metabolism and endocrine function, but are closely associated with sexual development and organ size regulation.
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Affiliation(s)
- Yingying Zhang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
- *Correspondence: Yingying Zhang, ; Yongsong Tan,
| | - Hongyang Wang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Weilong Tu
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | | | - Jianguo Cao
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Ji Huang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Huali Wu
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Chun Fan
- Shanghai Laboratory Animal Research Center, Shanghai, China
| | | | - Ying Zhao
- Shanghai Laboratory Animal Research Center, Shanghai, China
| | - Yongsong Tan
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
- *Correspondence: Yingying Zhang, ; Yongsong Tan,
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26
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Thyroid-Stimulating Hormone Inhibits Insulin Receptor Substrate-1 Expression and Tyrosyl Phosphorylation in 3T3-L1 Adipocytes by Increasing NF-κB DNA-Binding Activity. DISEASE MARKERS 2022; 2022:7553670. [PMID: 35320949 PMCID: PMC8938072 DOI: 10.1155/2022/7553670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 02/04/2023]
Abstract
Background. Abundant evidence indicates that thyroid-stimulating hormone (TSH) levels are associated with insulin resistance in adipocytes. However, the potential mechanism of the association remains uncertain. The objective of this study was to determine the potential role of TSH in the suppression of insulin receptor substrate-1 (IRS-1) expression and IRS-1 tyrosyl phosphorylation, which might contribute to insulin resistance. Methods. Mouse 3T3-L1 preadipocytes were differentiated into adipocytes. After treatment with 0.01, 0.1, and 1.0 mIU/ml bovine TSH, the TNF-α concentration in the medium was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB) DNA-binding activity was quantified by electrophoretic mobility shift assay (EMSA). IRS-1 levels in adipocytes were quantified by Western blotting, and tyrosine phosphorylation was measured by immunoprecipitation. Results. TSH induced TNF-α secretion in a dose-dependent manner. There was a significant positive correlation between NF-κB DNA-binding activity and TNF-α secretion. This effect and correlation were weakened by BAY 11-7082 (a nuclear NF-κB inhibitor) and H89 (an inhibitor of cyclic adenosine monophosphate- (cAMP-) dependent protein kinase A (PKA)). Treatment of cultured adipocytes with TSH inhibited insulin-stimulated IRS-1 tyrosyl phosphorylation but promoted TSH-dependent secretion of TNF-α and activation of NF-κB DNA-binding activity. The effects of TSH were significantly inhibited by BAY 11-7082 and H89 and were completely blocked by the TNF-α antagonist WP9QY. Conclusion. TSH inhibited IRS-1 protein expression and tyrosyl phosphorylation in 3T3-L1 adipocytes by stimulating TNF-α production via promotion of NF-κB DNA-binding activity. TSH might play a pivotal role in the development of insulin resistance.
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27
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Jurgens SJ, Choi SH, Morrill VN, Chaffin M, Pirruccello JP, Halford JL, Weng LC, Nauffal V, Roselli C, Hall AW, Oetjens MT, Lagerman B, vanMaanen DP, Aragam KG, Lunetta KL, Haggerty CM, Lubitz SA, Ellinor PT. Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank. Nat Genet 2022; 54:240-250. [PMID: 35177841 PMCID: PMC8930703 DOI: 10.1038/s41588-021-01011-w] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 12/22/2021] [Indexed: 12/30/2022]
Abstract
Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.
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Affiliation(s)
- Sean J. Jurgens
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Seung Hoan Choi
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Valerie N. Morrill
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Mark Chaffin
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - James P. Pirruccello
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Jennifer L. Halford
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Lu-Chen Weng
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Victor Nauffal
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Carolina Roselli
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amelia W. Hall
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | | | - Braxton Lagerman
- Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA
| | - David P. vanMaanen
- Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA
| | | | - Krishna G. Aragam
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Kathryn L. Lunetta
- NHLBI and Boston University’s Framingham Heart Study, Framingham, MA, USA.,Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Christopher M. Haggerty
- Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.,Heart Institute, Geisinger, Danville, PA, USA
| | - Steven A. Lubitz
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.,Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick T. Ellinor
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.,Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.,
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28
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Zhao J, Zhao X, Shen X, Zhang Y, Zhang Y, Ye L, Li D, Zhu Q, Yin H. CircCCDC91 regulates chicken skeletal muscle development by sponging miR-15 family via activating IGF1-PI3K/AKT signaling pathway. Poult Sci 2022; 101:101803. [PMID: 35334442 PMCID: PMC8956820 DOI: 10.1016/j.psj.2022.101803] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 09/20/2021] [Accepted: 02/21/2022] [Indexed: 11/25/2022] Open
Abstract
Circular RNAs (circRNAs) has been reported in various tissues of animals and associated with multiple biological processes. From our previous sequencing data, we found a novel circRNA, circCCDC91 which was generated from exon 2 to 8 of the CCDC91 gene. We observed that circCCDC91 was differentially expressed in the chicken breast muscle among 4 different embryonic developmental time points (embryonic day 10 [E10], E13, E16, and E19). Therefore, we assumed that circCCDC91 have a potential function in chicken skeletal muscle development. In this study, we firstly verify the annular structure and expression pattern of circCCDC91, and further investigate on whether circCCDC91 could promote chicken skeletal development. Mechanistically, circCCDC91 could absorb miR-15a, miR-15b-5p, and miR-15c-5p to modulate the expression of Insulin receptor substrate1 (IRS1), as well as activate insulin-1ike growth factor 1-phosphatidylinositol 3-kinase/AKT (IGF1-PI3K/AKT) signaling pathway. In addition, circCCDC91 could rescue skeletal muscle atrophy by activating IGF1-PI3K/AKT pathway. Taken together, the findings in this study revealed that the newly identified circCCDC91 promotes myoblasts proliferation and differentiation, and alleviates skeletal muscle atrophy by directly binding to miR-15 family via activating IGF1-PI3K/AKT signaling pathway in chicken.
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Affiliation(s)
- Jing Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Xiyu Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Xiaoxu Shen
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Yun Zhang
- College of Management, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Yao Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Lin Ye
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Diyan Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Qing Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Huadong Yin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China.
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Metabolism of Imidazole Dipeptides, Taurine, Branched-Chain Amino Acids, and Polyamines of the Breast Muscle Are Affected by Post-Hatch Development in Chickens. Metabolites 2022; 12:metabo12010086. [PMID: 35050208 PMCID: PMC8778354 DOI: 10.3390/metabo12010086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/08/2022] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
To explore metabolic characteristics during the post-hatch developmental period, metabolomic analyses of breast muscle and plasma were performed in chickens. The most significant growth-related changes in metabolite levels were observed between seven and 28 days of age. Some of these metabolites are essential nutrients or reported as growth-promoting metabolites. In the muscle, two imidazole dipeptides—carnosine and its methylated metabolite, anserine—increased with the development. These dipeptide levels may be, in part, regulated transcriptionally because in the muscle mRNA levels of carnosine synthase and carnosine methylation enzyme increased. In contrast, taurine levels in the muscle decreased. This would be substrate availability-dependent because some upstream metabolites decreased in the muscle or plasma. In branched-chain amino acid metabolism, valine, leucine, and isoleucine decreased in the muscle, while some of their downstream metabolites decreased in the plasma. The polyamines, putrescine and spermidine, decreased in the muscle. Furthermore, mRNA levels associated with insulin/insulin-like growth factor 1 signaling, which play important roles in muscle growth, increased in the muscle. These results indicate that some metabolic pathways would be important to clarify metabolic characteristics and/or growth of breast muscle during the post-hatch developmental period in chickens.
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Confettura AD, Cuboni E, Ammar MR, Jia S, Gomes GM, Yuanxiang P, Raman R, Li T, Grochowska KM, Ahrends R, Karpova A, Dityatev A, Kreutz MR. Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease. Transl Neurodegener 2022; 11:2. [PMID: 34986876 PMCID: PMC8734066 DOI: 10.1186/s40035-021-00277-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown. METHODS We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms. RESULTS We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'. CONCLUSIONS Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.
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Affiliation(s)
| | - Eleonora Cuboni
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Mohamed Rafeet Ammar
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Shaobo Jia
- German Center for Neurodegenerative Diseases (DZNE), 39120, Magdeburg, Germany
| | - Guilherme M Gomes
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany
| | - PingAn Yuanxiang
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Rajeev Raman
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Tingting Li
- Leibniz-Institut Für Analytische Wissenschaften-ISAS-e.V., 44227, Dortmund, Germany
| | - Katarzyna M Grochowska
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany.,Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Robert Ahrends
- Leibniz-Institut Für Analytische Wissenschaften-ISAS-e.V., 44227, Dortmund, Germany.,Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090, Wien, Austria
| | - Anna Karpova
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany
| | - Alexander Dityatev
- German Center for Neurodegenerative Diseases (DZNE), 39120, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany.,Medical Faculty, Otto-von-Guericke University, 39120, Magdeburg, Germany
| | - Michael R Kreutz
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany. .,German Center for Neurodegenerative Diseases (DZNE), 39120, Magdeburg, Germany. .,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany. .,Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
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31
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Zasu A, Hishima F, Thauvin M, Yoneyama Y, Kitani Y, Hakuno F, Volovitch M, Takahashi SI, Vriz S, Rampon C, Kamei H. NADPH-Oxidase Derived Hydrogen Peroxide and Irs2b Facilitate Re-oxygenation-Induced Catch-Up Growth in Zebrafish Embryo. Front Endocrinol (Lausanne) 2022; 13:929668. [PMID: 35846271 PMCID: PMC9283716 DOI: 10.3389/fendo.2022.929668] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/31/2022] [Indexed: 11/30/2022] Open
Abstract
Oxygen deprivation induces multiple changes at the cellular and organismal levels, and its re-supply also brings another special physiological status. We have investigated the effects of hypoxia/re-oxygenation on embryonic growth using the zebrafish model: hypoxia slows embryonic growth, but re-oxygenation induces growth spurt or catch-up growth. The mitogen-activated kinase (MAPK)-pathway downstream insulin-like growth factor (IGF/Igf) has been revealed to positively regulate the re-oxygenation-induced catch-up growth, and the role of reactive oxygen species generated by environmental oxygen fluctuation is potentially involved in the phenomenon. Here, we report the role of NADPH-oxidase (Nox)-dependent hydrogen peroxide (H2O2) production in the MAPK-activation and catch-up growth. The inhibition of Nox significantly blunted catch-up growth and MAPK-activity. Amongst two zebrafish insulin receptor substrate 2 genes (irs2a and irs2b), the loss of irs2b, but not its paralog irs2a, resulted in blunted MAPK-activation and catch-up growth. Furthermore, irs2b forcedly expressed in mammalian cells allowed IGF-MAPK augmentation in the presence of H2O2, and the irs2b deficiency completely abolished the somatotropic action of Nox in re-oxygenation condition. These results indicate that redox signaling alters IGF/Igf signaling to facilitate hypoxia/re-oxygenation-induced embryonic growth compensation.
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Affiliation(s)
- Ayaka Zasu
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Noto, Japan
| | - Futa Hishima
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Noto, Japan
| | - Marion Thauvin
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Centre national de la recherche scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
- Sorbonne Université, Ecole Doctorale 515-Complexité du Vivant, Paris, France
| | - Yosuke Yoneyama
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoichiro Kitani
- Noto Marine Laboratory, Division of Marine Environmental Studies, Institute of Nature and Environmental Technology, Kanazawa University, Noto, Japan
| | - Fumihiko Hakuno
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Michel Volovitch
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Centre national de la recherche scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
- Department of Biology, École Normale Supérieure, Paris Sciences et Lettres (PSL) Research University, Paris, France
- Laboratoire des BioMolécules (LBM), Département de Chimie, Sorbonne Université, École Normale Supérieure, Paris Sciences et Lettres (PSL) University, Sorbonne Université, Centre national de la recherche scientifique (CNRS), Paris, France
| | - Shin-Ichiro Takahashi
- Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Sophie Vriz
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Centre national de la recherche scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
- Laboratoire des BioMolécules (LBM), Département de Chimie, Sorbonne Université, École Normale Supérieure, Paris Sciences et Lettres (PSL) University, Sorbonne Université, Centre national de la recherche scientifique (CNRS), Paris, France
- Université Paris-Cité, Faculty of Sciences, Paris, France
| | - Christine Rampon
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Centre national de la recherche scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
- Laboratoire des BioMolécules (LBM), Département de Chimie, Sorbonne Université, École Normale Supérieure, Paris Sciences et Lettres (PSL) University, Sorbonne Université, Centre national de la recherche scientifique (CNRS), Paris, France
- Université Paris-Cité, Faculty of Sciences, Paris, France
| | - Hiroyasu Kamei
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Noto, Japan
- *Correspondence: Hiroyasu Kamei,
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32
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Ochiai T, Sano T, Nagayama T, Kubota N, Kadowaki T, Wakabayashi T, Iwatsubo T. Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease. Neurobiol Dis 2021; 159:105510. [PMID: 34537327 DOI: 10.1016/j.nbd.2021.105510] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/27/2021] [Accepted: 09/14/2021] [Indexed: 01/03/2023] Open
Abstract
Insulin signaling has been implicated in the metabolism as well as aging and longevity. Type 2 diabetes mellitus and its core pathology, insulin resistance, has also been implicated in the development of Alzheimer's disease (AD) and amyloid-β deposition in humans. By contrast, genetic ablation of the insulin/IGF-1 signaling (IIS) pathway components, e.g. insulin receptor substrate (IRS)-2, has been documented to suppress amyloid-β accumulation in the brains of transgenic mice overexpressing AD mutant β-amyloid precursor protein (APP). Therefore, the brain IIS may be a key modifiable molecular target in the pathophysiology of AD. IRS-1 and IRS-2 are critical nodes in IIS as substrates for insulin receptor and IGF-1 receptor, although the functional differences between IRS-1 and IRS-2 in the adult brain are yet to be explored. To examine their relative contribution to the brain IIS activity and AD pathomechanism, we generated APP transgenic mice lacking either IRS-1 or IRS-2. IRS-1 deficiency had little effects on the brain IIS pathway associated with compensatory activation of IRS-2, whereas IRS-2 deficiency was not fully compensated by activation of IRS-1, and the downstream activation of Akt also was significantly compromised. Pathological analyses of the cortical tissues showed that the biochemical levels of soluble and insoluble amyloid-β, the amyloid-β histopathology, and tau phosphorylation were not affected by the absence of IRS-1, in contrast to the marked alteration in IRS-2 deleted mice. These results suggest the predominance of IRS-2 in the brain IIS, and support the hypothesis that reduced IIS exerts anti-amyloid effects in the brain.
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Affiliation(s)
- Toshitaka Ochiai
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., LTD., Kyoto, Japan
| | - Toshiharu Sano
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeru Nagayama
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Nutrition Therapy, The University of Tokyo, Tokyo, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan
| | - Tomoko Wakabayashi
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Innovative Dementia Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Takeshi Iwatsubo
- Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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33
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Ding Y, Li G, Zhou Z, Deng T. Molecular mechanisms underlying hepatitis C virus infection-related diabetes. Metabolism 2021; 121:154802. [PMID: 34090869 DOI: 10.1016/j.metabol.2021.154802] [Citation(s) in RCA: 8] [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: 03/23/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022]
Abstract
Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.
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Affiliation(s)
- Yujin Ding
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410011, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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34
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Hayashi T, Kubota T, Mariko I, Takamoto I, Aihara M, Sakurai Y, Wada N, Miki T, Yamauchi T, Kubota N, Kadowaki T. Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus. Diabetes 2021; 70:1640-1653. [PMID: 33980693 DOI: 10.2337/db20-0482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/07/2021] [Indexed: 11/13/2022]
Abstract
Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.
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Affiliation(s)
- Takanori Hayashi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Clinical Nutrition, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, Japan
| | - Tetsuya Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Clinical Nutrition, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, Japan
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
- Division of Cardiovascular Medicine, Toho University, Ohashi Hospital, Tokyo, Japan
| | - Inoue Mariko
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Clinical Nutrition, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, Japan
| | - Iseki Takamoto
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masakazu Aihara
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshitaka Sakurai
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuhiro Wada
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Clinical Nutrition, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, Japan
| | - Takashi Miki
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Clinical Nutrition, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, Japan
- Department of Clinical Nutrition Therapy, The University of Tokyo, Tokyo, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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35
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Wang X, Li X, Ong H, Tan T, Park KH, Bian Z, Zou X, Haggard E, Janssen PM, Merritt RE, Pawlik TM, Whitson BA, Mokadam NA, Cao L, Zhu H, Cai C, Ma J. MG53 suppresses NFκB activation to mitigate age-related heart failure. JCI Insight 2021; 6:e148375. [PMID: 34292883 PMCID: PMC8492351 DOI: 10.1172/jci.insight.148375] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 07/21/2021] [Indexed: 11/17/2022] Open
Abstract
Aging is associated with chronic oxidative stress and inflammation that impact the tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here we demonstrate that the expression of MG53 is reduced in failing human heart and aging mouse heart, concomitant with elevated NFκB activation. We evaluate the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements reveal beneficial effects of rhMG53 treatment in improving heart function of aging mice. Biochemical and histological studies demonstrate the cardioprotective effects of rhMG53 are linked to suppression of NFκB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administrations of rhMG53 in aged mice do not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
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Affiliation(s)
- Xiaoliang Wang
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Xiuchun Li
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Hannah Ong
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Tao Tan
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Ki Ho Park
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Zehua Bian
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Xunchang Zou
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, United States of America
| | - Erin Haggard
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Paul M Janssen
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, United States of America
| | - Robert E Merritt
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Bryan A Whitson
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Nahush A Mokadam
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Lei Cao
- The Ohio State University, Columbus, United States of America
| | - Hua Zhu
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Chuanxi Cai
- Department of Surgery, The Ohio State University, Columbus, United States of America
| | - Jianjie Ma
- Department of Surgery, The Ohio State University, Columbus, United States of America
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36
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Zhong W, Benissan-Messan DZ, Ma J, Cai C, Lee PHU. Cardiac effects and clinical applications of MG53. Cell Biosci 2021; 11:115. [PMID: 34183055 PMCID: PMC8240287 DOI: 10.1186/s13578-021-00629-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/11/2021] [Indexed: 12/18/2022] Open
Abstract
Heart disease remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for treatment and prevention. Mitsugumin 53 (MG53), also known as TRIM72, is a TRIM family protein that was found to be involved in cell membrane repair and primarily found in striated muscle. Its role in skeletal muscle regeneration and myogenesis has been well documented. However, accumulating evidence suggests that MG53 has a potentially protective role in heart tissue, including in ischemia/reperfusion injury of the heart, cardiomyocyte membrane injury repair, and atrial fibrosis. This review summarizes the regulatory role of MG53 in cardiac tissues, current debates regarding MG53 in diabetes and diabetic cardiomyopathy, as well as highlights potential clinical applications of MG53 in treating cardiac pathologies.
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Affiliation(s)
- Weina Zhong
- Department of Surgery, The Ohio State University, Columbus, OH, USA
| | | | - Jianjie Ma
- Department of Surgery, The Ohio State University, Columbus, OH, USA
| | - Chuanxi Cai
- Department of Surgery, The Ohio State University, Columbus, OH, USA.
| | - Peter H U Lee
- Department of Surgery, The Ohio State University, Columbus, OH, USA.
- Department of Pathology and Laboratory Medicine, Brown University, Campus Box G-E5, 70 Ship Street, Providence, RI, 02912, USA.
- Department of Cardiothoracic Surgery, Southcoast Health, Fall River, MA, USA.
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Lero MW, Shaw LM. Diversity of insulin and IGF signaling in breast cancer: Implications for therapy. Mol Cell Endocrinol 2021; 527:111213. [PMID: 33607269 PMCID: PMC8035314 DOI: 10.1016/j.mce.2021.111213] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/02/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022]
Abstract
This review highlights the significance of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway in cancer and assesses its potential as a therapeutic target. Our emphasis is on breast cancer, but this pathway is central to the behavior of many cancers. An understanding of how IR/IGF-1R signaling contributes to the function of the normal mammary gland provides a foundation for understanding its aberrations in breast cancer. Specifically, dysregulation of the expression and function of ligands (insulin, IGF-1 and IGF-2), receptors and their downstream signaling effectors drive breast cancer initiation and progression, often in a subtype-dependent manner. Efforts to target this pathway for the treatment of cancer have been hindered by several factors including a lack of biomarkers to select patients that could respond to targeted therapy and adverse effects on normal metabolism. To this end, we discuss ongoing efforts aimed at overcoming such obstacles.
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Affiliation(s)
- Michael W Lero
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Leslie M Shaw
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
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Dearden L, Bouret SG, Ozanne SE. Nutritional and developmental programming effects of insulin. J Neuroendocrinol 2021; 33:e12933. [PMID: 33438814 DOI: 10.1111/jne.12933] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/24/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023]
Abstract
The discovery of insulin in 1921 was a major breakthrough in medicine and for therapy in patients with diabetes. The dramatic rise in the prevalence of overweight and obesity has been tightly linked to an increased prevalence of gestational diabetes mellitus (GDM), which poses major health concerns. Babies born to GDM mothers are more likely to develop obesity, type 2 diabetes and cardiovascular disease later in life. Evidence accumulated during the past two decades has revealed that high levels insulin, such as those observed during GDM, can have a widespread effect on the development and function of a variety of organs. This review summarises our current knowledge on the role of insulin in the placenta, cardiovascular system and brain during critical periods of development, as well as how it can contribute to lifelong metabolic regulation. We also discuss possible intervention strategies to ameliorate and hopefully reverse the developmental defects associated with obesity and GDM.
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Affiliation(s)
- Laura Dearden
- MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
| | - Sebastien G Bouret
- Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition Research Center, Lille, France
- University of Lille, Lille, France
| | - Susan E Ozanne
- MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
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Xie Y, Xiao L, Li S. Effects of Metformin on Reproductive, Endocrine, and Metabolic Characteristics of Female Offspring in a Rat Model of Letrozole-Induced Polycystic Ovarian Syndrome With Insulin Resistance. Front Endocrinol (Lausanne) 2021; 12:701590. [PMID: 34484117 PMCID: PMC8414830 DOI: 10.3389/fendo.2021.701590] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/17/2021] [Indexed: 01/28/2023] Open
Abstract
The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased INSR expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased FSHR expression and increased LHCGR expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that FSHR and LHCGR dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in INSR, FSHR, and LHCGR expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients.
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Affiliation(s)
- Yidong Xie
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Li Xiao
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Shangwei Li
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- *Correspondence: Shangwei Li,
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Roles of Insulin Receptor Substrates (IRS) in renal function and renal hemodynamics. PLoS One 2020; 15:e0242332. [PMID: 33270683 PMCID: PMC7714100 DOI: 10.1371/journal.pone.0242332] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 10/30/2020] [Indexed: 12/17/2022] Open
Abstract
We have reported previously that renal hemodynamic abnormalities exist in the prediabetic stage of type II diabetic rats. At this prediabetic stage these rats have hyperinsulinemia, insulin resistance and metabolic syndrome. It is well known that insulin resistance is frequently associated with renal abnormalities, but the mechanism underlying this association has remained speculative. Although insulin is known to modify renal hemodynamics, little is known about the roles of insulin receptor substrates (IRS1, IRS2) in the renal actions of insulin. To address this issue, the effects of insulin on renal function and renal hemodynamics were investigated in C57BL/6 (WT: wild type), insulin receptor substrate 1- knockout (IRS1–/–), and IRS2-knockout (IRS2–/–) mice. IRS2–/–mice had elevated glucose level as expected. 24-h urine collections and serum creatinine revealed that creatinine clearance did not significantly differ between these groups. Albuminuria was found in IRS1–/–and IRS2–/–groups. We examined the effects on the IRS during the administration of Losartan, which is widely used for diabetic nephropathy. After the administration of Losartan the IRS displayed improved renal hemodynamics. Moreover, the subjects were also given Pioglitazone, which improves insulin resistance. Losartan significantly reduced albuminuria in both groups. Pioglitazone also showed similar results. We assessed the autoregulatory responses of the total renal blood flow (RBF), the superficial (SBF) and the deep renal cortical blood flow (DBF) with stepwise reductions of renal perfusion pressure (RPP), which was induced by a manual clamp on the abdominal aorta. During the clamp induced reductions of the RPP by 10 to 20mm HG, RBF, SBF and the DBF fell significantly more in the IRS1 and IRS2 than in the WT mice. Furthermore micropuncture studies showded that compared to the WT tubuloglomerular feedback (TGF) responses of the stop flow pressure (Psf) were reduced in both the IRS1 -/- and IRS2 -/-. The results of the IRS1 and IRS2 mice displayed the pressence of hemodynamic abnormalities. Losartan and Pioglitazone have shown the potential to improve these abnormalities. In conclusion the results indicate that IRS plays a major role in the stimulation of renal functions and renal hemodynamics in type type II diabetes.
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Sethi A, Foulds N, Ehtisham S, Ahmed SH, Houghton J, Colclough K, Didi M, Flanagan SE, Senniappan S. Heterozygous Insulin Receptor (INSR) Mutation Associated with Neonatal Hyperinsulinemic Hypoglycaemia and Familial Diabetes Mellitus: Case Series. J Clin Res Pediatr Endocrinol 2020; 12:420-426. [PMID: 31989990 PMCID: PMC7711633 DOI: 10.4274/jcrpe.galenos.2019.2019.0106] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: An SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients.
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Affiliation(s)
- Aashish Sethi
- Alder Hey Children’s Hospital, Department of Paediatric Endocrinology, Liverpool, UK
| | - Nicola Foulds
- Wessex Clinical Genetics Services, Clinical Genetics, Southampton, UK
| | - Sarah Ehtisham
- Mediclinic City Hospital, Deparment of Paediatric Endocrinology, Dubai, UAE
| | - Syed Haris Ahmed
- Countess of Chester Hospital, Department of Endocrinology, Chester, UK
| | - Jayne Houghton
- Royal Devon and Exeter NHS Foundation Trust, Department of Molecular Genetics, Exeter, UK
| | - Kevin Colclough
- Royal Devon and Exeter NHS Foundation Trust, Department of Molecular Genetics, Exeter, UK
| | - Mohammed Didi
- Alder Hey Children’s Hospital, Department of Paediatric Endocrinology, Liverpool, UK
| | - Sarah E. Flanagan
- University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK
| | - Senthil Senniappan
- Alder Hey Children’s Hospital, Department of Paediatric Endocrinology, Liverpool, UK,* Address for Correspondence: Alder Hey Children’s Hospital, Department of Paediatric Endocrinology, Liverpool, UK Phone: +01512525281 E-mail:
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Fang L, Guo J, Wang Q, Ou K, Zou M, Lv L, Chen M, Wang C. Chronic Exposure to Environmental Level Phenanthrene Induces Non-Obesity-Dependent Insulin Resistance in Male Mice. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2020; 54:15225-15234. [PMID: 33171048 DOI: 10.1021/acs.est.0c04171] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Epidemiological evidence shows that the body burden of polycyclic aromatic hydrocarbons (PAHs) is related to the disruption of glucose homeostasis. However, the contribution of PAHs to the development of diabetes remains poorly documented. In the current work, male Kunming mice received phenanthrene (Phe) (5, 50, and 500 ng/kg) by gavage administration once every 2 days for 28 weeks. The significant elevation of homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA-β cell, accompanied by hyperinsulinemia, indicated the occurrence of insulin resistance. The suppression of the insulin receptor signaling pathway in skeletal muscle might be responsible for glucose intolerance. Under the nonobese state, the serum levels of resistin, tumor necrosis factor-α, and interleukin-6 were elevated, whereas the levels of adiponectin were reduced. These changes in adipocytokine levels were consistent with their transcription in white adipose tissue. The promoter methylation levels of Retn (encoding resistin) and Adipoq (encoding adiponectin) were inversely correlated with their mRNA levels, indicating that Phe exposure could cause the disruption of adipocytokine secretion via epigenetic modification. The results would be helpful for understanding the pathogenesis in the development of T2DM caused by nonobesogenic pollutants.
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Affiliation(s)
- Lu Fang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, PR China
| | - Jiaojiao Guo
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, PR China
| | - Qian Wang
- College of Environment & Ecology, Xiamen University, Xiamen 361102, PR China
| | - Kunlin Ou
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, PR China
| | - Minwen Zou
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, PR China
| | - Liangju Lv
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, PR China
| | - Meng Chen
- College of Environment & Ecology, Xiamen University, Xiamen 361102, PR China
| | - Chonggang Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, PR China
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Benissan-Messan DZ, Zhu H, Zhong W, Tan T, Ma J, Lee PHU. Multi-Cellular Functions of MG53 in Muscle Calcium Signaling and Regeneration. Front Physiol 2020; 11:583393. [PMID: 33240103 PMCID: PMC7677405 DOI: 10.3389/fphys.2020.583393] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/09/2020] [Indexed: 12/28/2022] Open
Abstract
Since its identification in 2009, multiple studies have indicated the importance of MG53 in muscle physiology. The protein is produced in striated muscles but has physiologic implications reaching beyond the confines of striated muscles. Roles in muscle regeneration, calcium homeostasis, excitation-contraction coupling, myogenesis, and the mitochondria highlight the protein's wide-reaching impact. Numerous therapeutic applications could potentially emerge from these physiologic roles. This review summarizes the current literature regarding the role of MG53 in the skeletal muscle. Therapeutic applications are discussed.
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Affiliation(s)
| | - Hua Zhu
- Department of Surgery, The Ohio State University, Columbus, OH, United States
| | - Weina Zhong
- Department of Surgery, The Ohio State University, Columbus, OH, United States
| | - Tao Tan
- Department of Surgery, The Ohio State University, Columbus, OH, United States
| | - Jianjie Ma
- Department of Surgery, The Ohio State University, Columbus, OH, United States
| | - Peter H. U. Lee
- Department of Surgery, The Ohio State University, Columbus, OH, United States
- Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States
- Department of Cardiothoracic Surgery, Southcoast Health, Fall River, MA, United States
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Zhao MT, Ye S, Su J, Garg V. Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration. Front Cell Dev Biol 2020; 8:594226. [PMID: 33178704 PMCID: PMC7593613 DOI: 10.3389/fcell.2020.594226] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 09/25/2020] [Indexed: 12/20/2022] Open
Abstract
In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.
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Affiliation(s)
- Ming-Tao Zhao
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Shiqiao Ye
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States
| | - Juan Su
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States
| | - Vidu Garg
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States.,Department of Molecular Genetics, The Ohio State University, Columbus, OH, United States
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da Silva Rosa SC, Nayak N, Caymo AM, Gordon JW. Mechanisms of muscle insulin resistance and the cross-talk with liver and adipose tissue. Physiol Rep 2020; 8:e14607. [PMID: 33038072 PMCID: PMC7547588 DOI: 10.14814/phy2.14607] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 12/18/2022] Open
Abstract
Insulin resistance is a metabolic disorder affecting multiple tissues and is a precursor event to type 2 diabetes (T2D). As T2D affects over 425 million people globally, there is an imperative need for research into insulin resistance to better understand the underlying mechanisms. The proposed mechanisms involved in insulin resistance include both whole body aspects, such as inflammation and metabolic inflexibility; as well as cellular phenomena, such as lipotoxicity, ER stress, and mitochondrial dysfunction. Despite numerous studies emphasizing the role of lipotoxicity in the pathogenesis of insulin resistance, an understanding of the interplay between tissues and these proposed mechanisms is still emerging. Furthermore, the tissue-specific and unique responses each of the three major insulin target tissues and how each interconnect to regulate the whole body insulin response has become a new priority in metabolic research. With an emphasis on skeletal muscle, this mini-review highlights key similarities and differences in insulin signaling and resistance between different target-tissues, and presents the latest findings related to how these tissues communicate to control whole body metabolism.
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Affiliation(s)
- Simone C. da Silva Rosa
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
- The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) ThemeUniversity of ManitobaWinnipegCanada
- Children’s Hospital Research Institute of Manitoba (CHRIM)University of ManitobaWinnipegCanada
| | - Nichole Nayak
- The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) ThemeUniversity of ManitobaWinnipegCanada
- Children’s Hospital Research Institute of Manitoba (CHRIM)University of ManitobaWinnipegCanada
- College of NursingUniversity of ManitobaWinnipegCanada
| | - Andrei Miguel Caymo
- The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) ThemeUniversity of ManitobaWinnipegCanada
- Children’s Hospital Research Institute of Manitoba (CHRIM)University of ManitobaWinnipegCanada
| | - Joseph W. Gordon
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
- The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) ThemeUniversity of ManitobaWinnipegCanada
- Children’s Hospital Research Institute of Manitoba (CHRIM)University of ManitobaWinnipegCanada
- College of NursingUniversity of ManitobaWinnipegCanada
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Defour M, Michielsen CCJR, O'Donovan SD, Afman LA, Kersten S. Transcriptomic signature of fasting in human adipose tissue. Physiol Genomics 2020; 52:451-467. [PMID: 32866087 DOI: 10.1152/physiolgenomics.00083.2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Little is known about gene regulation by fasting in human adipose tissue. Accordingly, the objective of this study was to investigate the effects of fasting on adipose tissue gene expression in humans. To that end, subcutaneous adipose tissue biopsies were collected from 11 volunteers 2 and 26 h after consumption of a standardized meal. For comparison, epididymal adipose tissue was collected from C57Bl/6J mice in the ab libitum-fed state and after a 16 h fast. The timing of sampling adipose tissue roughly corresponds with the near depletion of liver glycogen. Transcriptome analysis was carried out using Affymetrix microarrays. We found that, 1) fasting downregulated numerous metabolic pathways in human adipose tissue, including triglyceride and fatty acid synthesis, glycolysis and glycogen synthesis, TCA cycle, oxidative phosphorylation, mitochondrial translation, and insulin signaling; 2) fasting downregulated genes involved in proteasomal degradation in human adipose tissue; 3) fasting had much less pronounced effects on the adipose tissue transcriptome in humans than mice; 4) although major overlap in fasting-induced gene regulation was observed between human and mouse adipose tissue, many genes were differentially regulated in the two species, including genes involved in insulin signaling (PRKAG2, PFKFB3), PPAR signaling (PPARG, ACSL1, HMGCS2, SLC22A5, ACOT1), glycogen metabolism (PCK1, PYGB), and lipid droplets (PLIN1, PNPLA2, CIDEA, CIDEC). In conclusion, although numerous genes and pathways are regulated similarly by fasting in human and mouse adipose tissue, many genes show very distinct responses to fasting in humans and mice. Our data provide a useful resource to study adipose tissue function during fasting.
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Affiliation(s)
- Merel Defour
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Charlotte C J R Michielsen
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Shauna D O'Donovan
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Lydia A Afman
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
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Kamei H. Oxygen and embryonic growth: the role of insulin-like growth factor signaling. Gen Comp Endocrinol 2020; 294:113473. [PMID: 32247621 DOI: 10.1016/j.ygcen.2020.113473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/05/2020] [Accepted: 03/28/2020] [Indexed: 01/03/2023]
Abstract
Oxygen is indispensable for the efficient release of chemical energy from nutrient molecules in cells. Therefore, the local oxygen tension is one of the most critical factors affecting physiological processes. In most viviparous species, many pathological conditions result in abnormal oxygen tension in the uterus, which modifies the growth and development of the fetus. Insulin-like growth factor (IGF/Igf) is one of the most important hormones for the regulation of somatic growth in animals. Changes in oxygen levels modulate the activity of the IGF/Igf signaling system, which in turn regulates the embryonic growth rate. In general, there are serious difficulties associated with monitoring and studying rodent embryos in utero. The zebrafish is a convenient experimental model to study the relationship between embryonic growth and environmental conditions. Most importantly, the fish model makes it possible to rapidly evaluate embryonic growth and development under entirely controlled environments without interfering with the mother organism. In this review, firstly an overview is given of the fluctuation of environmental oxygen, the IGF-system, and the advantages of the zebrafish model for studying embryonic growth. Then, the relationships of dynamic environmental oxygen and embryonic growth rate are outlined with a specific focus on the changes in the IGF/Igf-system in the zebrafish model. This review will shed light on the fine-tuning mechanisms of the embryonic IGF/Igf-system under different oxygen levels, including constant normoxia, hypoxia, and re-oxygenation.
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Affiliation(s)
- Hiroyasu Kamei
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, 11-4-1, Ossaka, Noto, Ishikawa 927-0552, Japan.
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Wang C, An Y, Wang Y, Shen K, Wang X, Luan W, Ma F, Ni L, Liu M, Yu L. Insulin-like growth factor-I activates NFκB and NLRP3 inflammatory signalling via ROS in cancer cells. Mol Cell Probes 2020; 52:101583. [PMID: 32360740 DOI: 10.1016/j.mcp.2020.101583] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 12/17/2022]
Abstract
Previous studies have demonstrated that insulin-like growth factor-I (IGF-1) and reactive oxygen species (ROS) are involved in the development and progression of various cancers. However, their regulatory mechanism remains unknown. In this study, we treated cancer cells (HeLa, HepG2 and SW1116 cells) and normal cells (NCM-460) with IGF-1 at different concentrations and for different times and found that cancer cells produced large amounts of cytoplasmic ROS in cancer cells but not in normal cells. Further mechanistic analysis demonstrated that IGF-1 activated NFκB and NLRP3 inflammatory signalling in HeLa cells; systematic analysis indicated that IGF-1 activates NFκB and NLRP3, and the activation was cytosolic ROS- and NADPH oxidase 2 (NOX2)-dependent. Additionally, through coimmunoprecipitation experiments, we found that the IRS-1/COX2/mPGES-1/MAPKs/RAC2/NOX2 pathway nexus was involved in IGF-1-induced NFκB and NLRP3 production. Finally, we validated the regulatory mechanisms through IRS-1, mPGES-1 or NOX2 inhibition using their respective selective inhibitors or shRNA knockdown. Taken together, this is the first report on the mechanism by which IGF-1 activates NFκB and NLRP3 inflammatory signalling via ROS. These findings pave the way for an in-depth study of the role of IGF-1 and ROS in inflammation associated with the development and progression of cancer.
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Affiliation(s)
- Chao Wang
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Yanan An
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Yang Wang
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Keshu Shen
- Jilin Hepatobiliary Hospital, Changchun, 130062, China
| | - Xuefei Wang
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Wenjing Luan
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Fangxue Ma
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Lihui Ni
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Mingyuan Liu
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
| | - Lu Yu
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China.
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Man XF, Hu N, Tan SW, Tang HN, Guo Y, Tang CY, Liu YQ, Tang J, Zhou CL, Wang F, Zhou HD. Insulin receptor substrate-1 inhibits high-fat diet-induced obesity by browning of white adipose tissue through miR-503. FASEB J 2020; 34:12308-12323. [PMID: 32721050 DOI: 10.1096/fj.201903283rr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/13/2020] [Accepted: 07/01/2020] [Indexed: 12/18/2022]
Abstract
Genetic variation of insulin receptor substrate 1 (IRS-1) was found to modulate the insulin resistance of adipose tissues, but the underlying mechanism was not clear. To investigate how the IRS-1 was involved in the browning of white adipose tissue through miRNA, we identified a mutated Irs-1 (Irs-1-/- ) mice model and found that this mice had a reduced subcutaneous WAT (sWAT) and increased brown adipose tissue (BAT) in the interscapular region. So we isolated the bone marrow stromal cells and analyzed differentially expressed miRNAs and adipogenesis-related genes with miRNA arrays and PCR arrays. Irs-1-/- mice showed decreased miR-503 expression, but increased expression of its target, bone morphogenetic protein receptor type 1a (BMPR1a). Overexpression of miR-503 in preadipocytes downregulated BMPR1a and impaired adipogenic activity through the phosphotidylinositol 3-kinase (PI3K/Akt) pathway, while the inhibitor had the opposite effect. In both Irs-1-/- and cold-induced models, sWAT exhibited BAT features, and showed tissue-specific increased BMPR1a expression, PI3K expression, and Akt phosphorylation. Thus, our results showed that IRS-1 regulated brown preadipocyte differentiation and induced browning in sWAT through the miR-503-BMPR1a pathway, which played important roles in high-fat diet-induced obesity.
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Affiliation(s)
- Xiao-Fei Man
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China.,Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nan Hu
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shu-Wen Tan
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao-Neng Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yue Guo
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chen-Yi Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ya-Qing Liu
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jun Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ci-La Zhou
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fang Wang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hou-De Zhou
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
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50
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Toyoshima Y, Nakamura K, Tokita R, Teramoto N, Sugihara H, Kato H, Yamanouchi K, Minami S. Disruption of insulin receptor substrate-2 impairs growth but not insulin function in rats. J Biol Chem 2020; 295:11914-11927. [PMID: 32631952 DOI: 10.1074/jbc.ra120.013095] [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: 02/19/2020] [Revised: 07/01/2020] [Indexed: 11/06/2022] Open
Abstract
Insulin receptor substrate (IRS)-2, along with IRS-1, is a key signaling molecule that mediates the action of insulin and insulin-like growth factor (IGF)-I. The activated insulin and IGF-I receptors phosphorylate IRSs on tyrosine residues, leading to the activation of downstream signaling pathways and the induction of various physiological functions of insulin and IGF-I. Studies using IRS-2 knockout (KO) mice showed that the deletion of IRS-2 causes type 2 diabetes due to peripheral insulin resistance and impaired β-cell function. However, little is known about the roles of IRS-2 in other animal models. Here, we created IRS-2 KO rats to elucidate the physiological functions of IRS-2 in rats. The body weights of IRS-2 KO rats at birth were lower compared with those of their WT littermates. The postnatal growth of both male and female IRS-2 KO rats was also suppressed. Compared with male WT rats, the glucose and insulin tolerance of male IRS-2 KO rats were slightly enhanced, whereas a similar difference was not observed between female WT and IRS-2 KO rats. Besides the modestly increased insulin sensitivity, male IRS-2 KO rats displayed the enhanced insulin-induced activation of the mTOR complex 1 pathway in the liver compared with WT rats. Taken together, these results indicate that in rats, IRS-2 plays important roles in the regulation of growth but is not essential for the glucose-lowering effects of insulin.
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Affiliation(s)
- Yuka Toyoshima
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kosugi-machi, Nakahara-ku, Kawasaki, Japan
| | - Katsuyuki Nakamura
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Reiko Tokita
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kosugi-machi, Nakahara-ku, Kawasaki, Japan
| | - Naomi Teramoto
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Hidetoshi Sugihara
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Hisanori Kato
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Keitaro Yamanouchi
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Shiro Minami
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kosugi-machi, Nakahara-ku, Kawasaki, Japan
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