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Loos CMM, Urschel KL. Current understanding of insulin dysregulation and its relationship with carbohydrate and protein metabolism in horses. Domest Anim Endocrinol 2025; 92:106940. [PMID: 40073599 DOI: 10.1016/j.domaniend.2025.106940] [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: 11/22/2024] [Revised: 02/28/2025] [Accepted: 03/06/2025] [Indexed: 03/14/2025]
Abstract
Insulin dysregulation (ID) is a common metabolic disorder in horses, characterized by hyperinsulinemia and/or peripheral insulin resistance. The critical role of hyperinsulinemia in endocrinopathic laminitis has driven research into the insulinotropic effects of dietary nutrients and the reciprocal impact of ID on nutrient metabolism. The relationship between ID and carbohydrate metabolism has been extensively studied; however, the effects of ID on protein metabolism in horses remain largely unexplored. This review begins with an overview of the importance of insulin in the regulation of muscle protein synthesis and degradation and then examines the current understanding of the interplay between ID and protein and carbohydrate metabolism in horses. Horses with ID exhibit altered resting plasma amino acid concentrations and shifts in postprandial amino acid dynamics. Recent work illustrated that ID horses had higher levels of plasma amino acids following a protein meal and delayed postprandial clearance from the blood compared to non-ID horses. The postprandial muscle synthetic response does not seem to be diminished in ID horses, but alterations in key cellular signaling molecules have been reported. ID horses display a pronounced hyperinsulinemic response following the consumption of feeds providing a range of protein, non-structural carbohydrate, starch and water-soluble carbohydrate intakes. Recent studies have shown that ID horses have an increased postprandial incretin response, contributing to the observed hyperinsulinemia. To minimize the postprandial insulin response, thresholds for carbohydrate consumption have recently been proposed. Similar thresholds should be established for protein to aid in the refinement of nutritional strategies to manage ID horses.
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Affiliation(s)
- C M M Loos
- Versele-Laga, Cavalor Equine Nutrition, Belgium.
| | - K L Urschel
- University of Kentucky, Department of Animal and Food Sciences, Lexington, KY, USA
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Loos CMM, Zhao S, Li L, Li J, Han W, Vanzant ES, McLeod KR. Essential oil supplementation improves insulin sensitivity and modulates the plasma metabolome of hyperinsulinemic horses. Front Vet Sci 2024; 11:1444581. [PMID: 39687851 PMCID: PMC11648227 DOI: 10.3389/fvets.2024.1444581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/04/2024] [Indexed: 12/18/2024] Open
Abstract
The objective of this study was to investigate the effect of essential oil (EO) supplementation on insulin sensitivity (IS) and the plasma metabolome in insulin dysregulated (ID) horses. Horses were blocked by degree of IS and assigned randomly to treatment: oral daily bolus (50 mL) of either a plant derived EO supplement or carrier (CON). Mares were housed in dry lots with ad libitum access to grass hay and supplemented individually twice daily with a concentrate to meet nutrient requirements for mature horses. Before and after 6 wks of treatment, mares underwent a combined glucose-insulin tolerance test (CGIT) and an oral sugar test (OST) on separate days. Global metabolome analysis was conducted on plasma samples before and after treatment. Although treatment did not affect (p > 0.4) AUC or glucose clearance during CGIT, there was a treatment*covariate interaction (p ≤ 0.08) for insulin concentrations at 75 min (INS75) and positive phase time (PT) with EO decreasing both INS75 (p ≤ 0.002) and PT (p = 0.05) in horses with more severe initial degree of ID. Similarly, EO treatment reduced (p ≤ 0.006) insulinemic response to the OST in horses exhibiting higher pre-treatment responses (treatment*covariate, p = 0.004). There were 702 metabolites identified that were uniquely changed with EO treatment. Pathway analysis and biomarkers showed EO-mediated changes in amino acid, linoleic acid, mesaconic acid, TCA-cyle intermediates and bile acid metabolism. The directional changes in these pathways or biomarkers are consistent with changes in inulin sensitivity in other models. These data show that EO shifted the plasma metabolome and improved insulin sensitivity in horses.
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Affiliation(s)
- Caroline M. M. Loos
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
| | - Shuang Zhao
- The Metabolomics Innovation Centre and Chemistry Department, University of Alberta, Edmonton, AB, Canada
| | - Liang Li
- The Metabolomics Innovation Centre and Chemistry Department, University of Alberta, Edmonton, AB, Canada
| | - Janet Li
- The Metabolomics Innovation Centre and Chemistry Department, University of Alberta, Edmonton, AB, Canada
| | - Wei Han
- The Metabolomics Innovation Centre and Chemistry Department, University of Alberta, Edmonton, AB, Canada
| | - Eric S. Vanzant
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
| | - Kyle R. McLeod
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, United States
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Selvarani R, Nguyen HM, Pazhanivel N, Raman M, Lee S, Wolf RF, Deepa SS, Richardson A. The role of inflammation induced by necroptosis in the development of fibrosis and liver cancer in novel knockin mouse models fed a western diet. GeroScience 2024:10.1007/s11357-024-01418-3. [PMID: 39514172 DOI: 10.1007/s11357-024-01418-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Non-resolving, chronic inflammation (inflammaging) is believed to play an important role in aging and age-related diseases. The goal of this study was to determine if inflammation induced by necroptosis arising from the liver plays a role in chronic liver disease (CLD) and liver cancer in mice fed a western diet (WD). Necroptosis was induced in liver using two knockin (KI) mouse models that overexpress genes involved in necroptosis (Ripk3 or Mlkl) specifically in liver (i.e., hRipk3-KI and hMlkl-KI mice). These mice and control mice (not overexpressing Ripk3 or Mlkl) were fed a WD (high in fat, sucrose, and cholesterol) starting at 2 months of age for 3, 6, and 12 months. Feeding the WD induced necroptosis in the control mice, which was further elevated in the hRipk3-KI and hMlkl-KI mice and was associated with a significant increase in inflammation in the livers of the hRipk3-KI and hMlkl-KI mice compared to control mice fed the WD. Overexpressing Ripk3 or Mlkl significantly increased steatosis and fibrosis compared to control mice fed the WD. Mice fed the WD for 12 months developed liver tumors (hepatocellular adenomas): 28% of the control mice developing tumors compared to 62% of the hRipk3-KI and hMlkl-KI mice. The hRipk3-KI and hMlkl-KI mice showed significantly more and larger tumor nodules. Our study provides the first direct evidence that inflammation induced by necroptosis arising from hepatocytes can lead to the progression of hepatic steatosis to fibrosis in obese mice that eventually results in an increased incidence in hepatocellular adenomas.
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Affiliation(s)
- Ramasamy Selvarani
- Biochemistry & Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Natesan Pazhanivel
- Department of Veterinary Pathology, TANUVAS, Chennai City, Tamilnadu, India
| | | | - Sunho Lee
- Biochemistry & Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Roman F Wolf
- Oklahoma Veteran Affairs Medical Center, Oklahoma City, OK, USA
| | - Sathyaseelan S Deepa
- Biochemistry & Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience & Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Arlan Richardson
- Biochemistry & Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Stephenson Cancer Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience & Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Veteran Affairs Medical Center, Oklahoma City, OK, USA.
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Mann G, Adegoke OAJ. Elevated BCAA catabolism reverses the effect of branched-chain ketoacids on glucose transport in mTORC1-dependent manner in L6 myotubes. J Nutr Sci 2024; 13:e66. [PMID: 39464407 PMCID: PMC11503859 DOI: 10.1017/jns.2024.66] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 08/13/2024] [Accepted: 08/30/2024] [Indexed: 10/29/2024] Open
Abstract
Plasma levels of branched-chain amino acids (BCAA) and their metabolites, branched-chain ketoacids (BCKA), are increased in insulin resistance. We previously showed that ketoisocaproic acid (KIC) suppressed insulin-stimulated glucose transport in L6 myotubes, especially in myotubes depleted of branched-chain ketoacid dehydrogenase (BCKD), the enzyme that decarboxylates BCKA. This suggests that upregulating BCKD activity might improve insulin sensitivity. We hypothesised that increasing BCAA catabolism would upregulate insulin-stimulated glucose transport and attenuate insulin resistance induced by BCKA. L6 myotubes were either depleted of BCKD kinase (BDK), the enzyme that inhibits BCKD activity, or treated with BT2, a BDK inhibitor. Myotubes were then treated with KIC (200 μM), leucine (150 μM), BCKA (200 μM), or BCAA (400 μM) and then treated with or without insulin (100 nM). BDK depletion/inhibition rescued the suppression of insulin-stimulated glucose transport by KIC/BCKA. This was consistent with the attenuation of IRS-1 (Ser612) and S6K1 (Thr389) phosphorylation but there was no effect on Akt (Ser473) phosphorylation. The effect of leucine or BCAA on these measures was not as pronounced and BT2 did not influence the effect. Induction of the mTORC1/IRS-1 (Ser612) axis abolished the attenuating effect of BT2 treatment on glucose transport in cells treated with KIC. Surprisingly, rapamycin co-treatment with BT2 and KIC further reduced glucose transport. Our data suggests that the suppression of insulin-stimulated glucose transport by KIC/BCKA in muscle is mediated by mTORC1/S6K1 signalling. This was attenuated by upregulating BCAA catabolic flux. Thus, interventions targeting BCAA metabolism may provide benefits against insulin resistance and its sequelae.
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Affiliation(s)
- Gagandeep Mann
- School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Olasunkanmi A. John Adegoke
- School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, ON, Canada
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Liu T, Zhang J, Chang F, Sun M, He J, Ai D. Role of endothelial Raptor in abnormal arteriogenesis after lower limb ischaemia in type 2 diabetes. Cardiovasc Res 2024; 120:1218-1234. [PMID: 38722901 DOI: 10.1093/cvr/cvae105] [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: 07/28/2023] [Revised: 03/08/2024] [Accepted: 03/17/2024] [Indexed: 09/03/2024] Open
Abstract
AIMS Proper arteriogenesis after tissue ischaemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type 2 diabetes mellitus (T2DM). Raptor is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischaemia-induced arteriogenesis during T2DM. METHODS AND RESULTS Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischaemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signalling in endothelial cells (ECs) and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that EC-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice. CONCLUSION Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischaemia-induced arteriogenesis in T2DM by mediating VEGFR2 signalling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM.
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Affiliation(s)
- Ting Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Jiachen Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Fangyuan Chang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Mengyu Sun
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jinlong He
- Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Ding Ai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
- Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
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Mentzinger J, Teixeira GF, Monnerat JADS, Velasco LL, Lucchetti BB, Martins MAC, Costa V, Andrade GPD, Magliano DC, Rocha HNM, da Nóbrega ACL, Medeiros RF, Rocha NG. Prenatal stress induces sex- and tissue-specific alterations in insulin pathway of Wistar rats offspring. Am J Physiol Heart Circ Physiol 2024; 327:H1055-H1066. [PMID: 39212771 DOI: 10.1152/ajpheart.00243.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 08/07/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND AND AIMS Prenatal stress may lead to tissue and sex-specific cardiometabolic disorders in the offspring through imbalances in the insulin signaling pathway. Therefore, we aimed to determine the sex-specific adaptations of prenatal stress on the insulin signaling pathway of cardiac and hepatic tissue of adult offspring Wistar rats. METHODS Wistar pregnant rats were divided into control and stress groups. Unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. After lactation, the dams were euthanized and blood was collected for corticosterone measurement and the offspring were separated into four groups according to sex and intervention (n=8/group). At 90 days old, the offspring were submitted to an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). After euthanasia blood collection was used for biochemical analysis and the left ventricle and liver were used for protein expression and histological analysis. RESULTS Stress increased maternal corticosterone levels, and in the offspring, decreased glucose concentration in both OGTT and ITT, reduced insulin receptor (Irβ) and insulin receptor substrate-1 (IRS1) activation and reduced insulin receptor inhibition (PTP1B) in the liver of male offspring at 90 days old, without repercussions in cardiac tissue. Moreover, female offspring submitted to prenatal stress exhibited reduced fatty acid uptake, with lower hepatic CD36 expression, reduced high density lipoprotein (cHDL) and increased Castelli risk indexes I and II. CONCLUSIONS Unpredictable prenatal stress evoked reduced insulin sensitivity and liver-specific impairment in insulin signaling activation in male while increasing markers of cardiovascular risk in females.
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Affiliation(s)
- Juliana Mentzinger
- Department of Physiology and Pharmacology, Universidade Federal Fluminense, Niteroi, Brazil
| | | | | | | | | | | | - Viviane Costa
- Department of Physiology and Pharmacology, Fluminense Federal University, Brazil
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García-Cruz VM, Arias C. Palmitic Acid Induces Posttranslational Modifications of Tau Protein in Alzheimer's Disease-Related Epitopes and Increases Intraneuronal Tau Levels. Mol Neurobiol 2024; 61:5129-5141. [PMID: 38167971 PMCID: PMC11249523 DOI: 10.1007/s12035-023-03886-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024]
Abstract
Metabolic diseases derived from an unhealthy lifestyle have been linked with an increased risk for developing cognitive impairment and even Alzheimer's disease (AD). Although high consumption of saturated fatty acids such as palmitic acid (PA) has been associated with the development of obesity and type II diabetes, the mechanisms connecting elevated neuronal PA levels and increased AD marker expression remain unclear. Among other effects, PA induces insulin resistance, increases intracellular calcium and reactive oxygen species (ROS) production, and reduces the NAD+/NADH ratio, resulting in decreased activity of the deacetylase Sirtuin1 (SIRT1) in neurons. These mechanisms may affect signaling pathways that impact the posttranslational modifications (PTMs) of the tau protein. To analyze the role played by PA in inducing the phosphorylation and acetylation of tau, we examined PTM changes in human tau in differentiated neurons from human neuroblastoma cells. We found changes in the phosphorylation state of several AD-related sites, namely, S199/202 and S214, that were mediated by a mechanism associated with the dysregulated activity of the kinases GSK3β and mTOR. PA also increased the acetylation of residue K280 and elevated total tau level after long exposure time. These findings provide information about the mechanisms by which saturated fatty acids cause tau PTMs that are similar to those observed in association with AD biochemical changes.
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Affiliation(s)
- Valeria Melissa García-Cruz
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, CDMX, 04510, México
| | - Clorinda Arias
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, CDMX, 04510, México.
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Abdualkader AM, Karwi QG, Lopaschuk GD, Al Batran R. The role of branched-chain amino acids and their downstream metabolites in mediating insulin resistance. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2024; 27:13040. [PMID: 39007094 PMCID: PMC11239365 DOI: 10.3389/jpps.2024.13040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024]
Abstract
Elevated levels of circulating branched-chain amino acids (BCAAs) and their associated metabolites have been strongly linked to insulin resistance and type 2 diabetes. Despite extensive research, the precise mechanisms linking increased BCAA levels with these conditions remain elusive. In this review, we highlight the key organs involved in maintaining BCAA homeostasis and discuss how obesity and insulin resistance disrupt the intricate interplay among these organs, thus affecting BCAA balance. Additionally, we outline recent research shedding light on the impact of tissue-specific or systemic modulation of BCAA metabolism on circulating BCAA levels, their metabolites, and insulin sensitivity, while also identifying specific knowledge gaps and areas requiring further investigation. Finally, we summarize the effects of BCAA supplementation or restriction on obesity and insulin sensitivity.
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Affiliation(s)
- Abdualrahman Mohammed Abdualkader
- Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada
- Montreal Diabetes Research Center, Montréal, QC, Canada
- Cardiometabolic Health, Diabetes and Obesity Research Network, Montréal, QC, Canada
| | - Qutuba G. Karwi
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Gary D. Lopaschuk
- Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada
| | - Rami Al Batran
- Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada
- Montreal Diabetes Research Center, Montréal, QC, Canada
- Cardiometabolic Health, Diabetes and Obesity Research Network, Montréal, QC, Canada
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Burbano de Lara S, Kemmer S, Biermayer I, Feiler S, Vlasov A, D'Alessandro LA, Helm B, Mölders C, Dieter Y, Ghallab A, Hengstler JG, Körner C, Matz-Soja M, Götz C, Damm G, Hoffmann K, Seehofer D, Berg T, Schilling M, Timmer J, Klingmüller U. Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease. Mol Syst Biol 2024; 20:187-216. [PMID: 38216754 PMCID: PMC10912216 DOI: 10.1038/s44320-023-00007-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 12/06/2023] [Accepted: 12/08/2023] [Indexed: 01/14/2024] Open
Abstract
Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
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Affiliation(s)
- Sebastian Burbano de Lara
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
| | - Svenja Kemmer
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Institute of Physics, University of Freiburg, Freiburg, Germany
- FDM - Freiburg Center for Data Analysis and Modeling, University of Freiburg, Freiburg, Germany
| | - Ina Biermayer
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
| | - Svenja Feiler
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of General, Visceral and Transplant Surgery, Heidelberg University, Heidelberg, Germany
| | - Artyom Vlasov
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lorenza A D'Alessandro
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara Helm
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christina Mölders
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
| | - Yannik Dieter
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ahmed Ghallab
- Systems Toxicology, Leibniz Research Center for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
| | - Jan G Hengstler
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Systems Toxicology, Leibniz Research Center for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany
| | - Christiane Körner
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Division of Hepatology, Clinic of Oncology, Gastroenterology, Hepatology, and Pneumology, University Hospital Leipzig, 04103, Leipzig, Germany
| | - Madlen Matz-Soja
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Division of Hepatology, Clinic of Oncology, Gastroenterology, Hepatology, and Pneumology, University Hospital Leipzig, 04103, Leipzig, Germany
| | - Christina Götz
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital Leipzig, Leipzig University, 04103, Leipzig, Germany
| | - Georg Damm
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital Leipzig, Leipzig University, 04103, Leipzig, Germany
| | - Katrin Hoffmann
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Department of General, Visceral and Transplant Surgery, Heidelberg University, Heidelberg, Germany
| | - Daniel Seehofer
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital Leipzig, Leipzig University, 04103, Leipzig, Germany
| | - Thomas Berg
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany
- Division of Hepatology, Clinic of Oncology, Gastroenterology, Hepatology, and Pneumology, University Hospital Leipzig, 04103, Leipzig, Germany
| | - Marcel Schilling
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Jens Timmer
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany.
- Institute of Physics, University of Freiburg, Freiburg, Germany.
- FDM - Freiburg Center for Data Analysis and Modeling, University of Freiburg, Freiburg, Germany.
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
| | - Ursula Klingmüller
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Liver Systems Medicine against Cancer (LiSyM-Krebs), Heidelberg, Germany.
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10
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Martínez Báez A, Ayala G, Pedroza-Saavedra A, González-Sánchez HM, Chihu Amparan L. Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways. Curr Issues Mol Biol 2024; 46:634-649. [PMID: 38248343 PMCID: PMC10814773 DOI: 10.3390/cimb46010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/23/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
Insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) are signaling adaptor proteins that participate in canonical pathways, where insulin cascade activation occurs, as well as in non-canonical pathways, in which phosphorylation of substrates is carried out by a diverse array of receptors including integrins, cytokines, steroid hormones, and others. IRS proteins are subject to a spectrum of post-translational modifications essential for their activation, encompassing phosphorylation events in distinct tyrosine, serine, and threonine residues. Tyrosine residue phosphorylation is intricately linked to the activation of the insulin receptor cascade and its interaction with SH2 domains within a spectrum of proteins, including PI3K. Conversely, serine residue phosphorylation assumes a different function, serving to attenuate the effects of insulin. In this review, we have identified over 50 serine residues within IRS-1 that have been reported to undergo phosphorylation orchestrated by a spectrum of kinases, thereby engendering the activation or inhibition of different signaling pathways. Furthermore, we delineate the phosphorylation of over 10 distinct tyrosine residues at IRS-1 or IRS-2 in response to insulin, a process essential for signal transduction and the subsequent activation of PI3K.
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Affiliation(s)
- Anabel Martínez Báez
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| | - Guadalupe Ayala
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| | - Adolfo Pedroza-Saavedra
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
| | - Hilda M. González-Sánchez
- CONAHCYT—Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico;
| | - Lilia Chihu Amparan
- Infection Disease Research Center, National Institute of Public Health, Cuernavaca 62100, Mexico; (A.M.B.); (G.A.); (A.P.-S.)
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11
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Engin A. Protein Kinases in Obesity, and the Kinase-Targeted Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:199-229. [PMID: 39287853 DOI: 10.1007/978-3-031-63657-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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12
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Tobias DK, Hamaya R, Clish CB, Liang L, Deik A, Dennis C, Bullock K, Zhang C, Hu FB, Manson JE. Type 2 diabetes metabolomics score and risk of progression to type 2 diabetes among women with a history of gestational diabetes mellitus. Diabetes Metab Res Rev 2024; 40:e3763. [PMID: 38287718 PMCID: PMC10842268 DOI: 10.1002/dmrr.3763] [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: 05/06/2022] [Revised: 09/08/2023] [Accepted: 11/05/2023] [Indexed: 01/31/2024]
Abstract
BACKGROUND Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D-metabolite pattern with a risk of progression to T2D among high-risk women with a history of gestational diabetes mellitus (GDM). METHODS The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age-matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1-5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic regression models adjusting for body mass index at the blood draw, and other established T2D risk factors. RESULTS The percentage of women progressing to T2D ranged from 10% in the bottom T2D metabolomics score quartile to 78% in the highest score quartile. Adjusting for established T2D risk factors, women in the highest quartile had more than a 20-fold greater diabetes risk than women in the lowest quartile (odds ratios [OR] = 23.1 [95% CI = 8.6, 62.1]; p for trend<0.001). The continuous T2D metabolomics score was strongly and positively associated with incident T2D (adjusted OR = 2.7 per SD [95% CI = 1.9, 3.7], p < 0.0001). CONCLUSIONS A pattern of plasma metabolites among high-risk women is associated with a markedly elevated risk of progression to T2D later in life.
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Affiliation(s)
- Deirdre K. Tobias
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Nutrition Department, Harvard TH Chan School of Public Health, Boston, MA
| | - Rikuta Hamaya
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Epidemiology Department, Harvard TH Chan School of Public Health, Boston, MA
| | | | - Liming Liang
- Biostatistics Department, Harvard TH Chan School of Public Health, Boston, MA
| | - Amy Deik
- Broad Institute of MIT and Harvard, Cambridge, MA
| | | | | | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Frank B. Hu
- Nutrition Department, Harvard TH Chan School of Public Health, Boston, MA
- Epidemiology Department, Harvard TH Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - JoAnn E. Manson
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Epidemiology Department, Harvard TH Chan School of Public Health, Boston, MA
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13
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Hayes E, Winston N, Stocco C. Molecular crosstalk between insulin-like growth factors and follicle-stimulating hormone in the regulation of granulosa cell function. Reprod Med Biol 2024; 23:e12575. [PMID: 38571513 PMCID: PMC10988955 DOI: 10.1002/rmb2.12575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/11/2024] [Accepted: 03/20/2024] [Indexed: 04/05/2024] Open
Abstract
Background The last phase of folliculogenesis is driven by follicle-stimulating hormone (FSH) and locally produced insulin-like growth factors (IGFs), both essential for forming preovulatory follicles. Methods This review discusses the molecular crosstalk of the FSH and IGF signaling pathways in regulating follicular granulosa cells (GCs) during the antral-to-preovulatory phase. Main findings IGFs were considered co-gonadotropins since they amplify FSH actions in GCs. However, this view is not compatible with data showing that FSH requires IGFs to stimulate GCs, that FSH renders GCs sensitive to IGFs, and that FSH signaling interacts with factors downstream of AKT to stimulate GCs. New evidence suggests that FSH and IGF signaling pathways intersect at several levels to regulate gene expression and GC function. Conclusion FSH and locally produced IGFs form a positive feedback loop essential for preovulatory follicle formation in all species. Understanding the mechanisms by which FSH and IGFs interact to control GC function will help design new interventions to optimize follicle maturation, perfect treatment of ovulatory defects, improve in vitro fertilization, and develop new contraceptive approaches.
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Affiliation(s)
- Emily Hayes
- Department of Physiology and BiophysicsUniversity of Illinois Chicago College of MedicineChicagoIllinoisUSA
| | - Nicola Winston
- Department of Obstetrics and GynecologyUniversity of Illinois Chicago College of MedicineChicagoIllinoisUSA
| | - Carlos Stocco
- Department of Physiology and BiophysicsUniversity of Illinois Chicago College of MedicineChicagoIllinoisUSA
- Department of Obstetrics and GynecologyUniversity of Illinois Chicago College of MedicineChicagoIllinoisUSA
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14
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Xourafa G, Korbmacher M, Roden M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol 2024; 20:27-49. [PMID: 37845351 DOI: 10.1038/s41574-023-00898-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2023] [Indexed: 10/18/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.
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Affiliation(s)
- Georgia Xourafa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany
| | - Melis Korbmacher
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany.
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
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15
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Elliehausen CJ, Anderson RM, Diffee GM, Rhoads TW, Lamming DW, Hornberger TA, Konopka AR. Geroprotector drugs and exercise: friends or foes on healthy longevity? BMC Biol 2023; 21:287. [PMID: 38066609 PMCID: PMC10709984 DOI: 10.1186/s12915-023-01779-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Physical activity and several pharmacological approaches individually combat age-associated conditions and extend healthy longevity in model systems. It is tantalizing to extrapolate that combining geroprotector drugs with exercise could extend healthy longevity beyond any individual treatment. However, the current dogma suggests that taking leading geroprotector drugs on the same day as exercise may limit several health benefits. Here, we review leading candidate geroprotector drugs and their interactions with exercise and highlight salient gaps in knowledge that need to be addressed to identify if geroprotector drugs can have a harmonious relationship with exercise.
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Affiliation(s)
- Christian J Elliehausen
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Rozalyn M Anderson
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Gary M Diffee
- Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA
| | - Timothy W Rhoads
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
- Division of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Dudley W Lamming
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Troy A Hornberger
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Adam R Konopka
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
- Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
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16
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Vijiaratnam N, Foltynie T. How should we be using biomarkers in trials of disease modification in Parkinson's disease? Brain 2023; 146:4845-4869. [PMID: 37536279 PMCID: PMC10690028 DOI: 10.1093/brain/awad265] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/18/2023] [Accepted: 07/22/2023] [Indexed: 08/05/2023] Open
Abstract
The recent validation of the α-synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson's disease has formed the backbone for a proposed staging system for incorporation in Parkinson's disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson's disease patients into trials (as distinct from patients with non-Parkinson's disease parkinsonism or non-Parkinson's disease tremors). There remain, however, further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson's disease, namely: optimizing the distinction between different α-synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; a sensitive means of confirming target engagement; and the early prediction of longer-term clinical benefit. For example, levels of CSF proteins such as the lysosomal enzyme β-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer's disease-like pathology (detectable through CSF levels of amyloid-β42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline in Parkinson's disease even in its later stages. The exploitation of additional biomarkers to the α-synuclein seed amplification assay will, therefore, greatly add to our ability to plan trials and assess the disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson's disease. However, correlation with clinical progression does not necessarily equate to causation, and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson's disease.
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Affiliation(s)
- Nirosen Vijiaratnam
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
| | - Thomas Foltynie
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
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17
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Shastry A, Dunham-Snary K. Metabolomics and mitochondrial dysfunction in cardiometabolic disease. Life Sci 2023; 333:122137. [PMID: 37788764 DOI: 10.1016/j.lfs.2023.122137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/21/2023] [Accepted: 09/29/2023] [Indexed: 10/05/2023]
Abstract
Circulating metabolites are indicators of systemic metabolic dysfunction and can be detected through contemporary techniques in metabolomics. These metabolites are involved in numerous mitochondrial metabolic processes including glycolysis, fatty acid β-oxidation, and amino acid catabolism, and changes in the abundance of these metabolites is implicated in the pathogenesis of cardiometabolic diseases (CMDs). Epigenetic regulation and direct metabolite-protein interactions modulate metabolism, both within cells and in the circulation. Dysfunction of multiple mitochondrial components stemming from mitochondrial DNA mutations are implicated in disease pathogenesis. This review will summarize the current state of knowledge regarding: i) the interactions between metabolites found within the mitochondrial environment during CMDs, ii) various metabolites' effects on cellular and systemic function, iii) how harnessing the power of metabolomic analyses represents the next frontier of precision medicine, and iv) how these concepts integrate to expand the clinical potential for translational cardiometabolic medicine.
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Affiliation(s)
- Abhishek Shastry
- Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Kimberly Dunham-Snary
- Department of Medicine, Queen's University, Kingston, ON, Canada; Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada.
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18
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Leroux AE, Biondi RM. The choreography of protein kinase PDK1 and its diverse substrate dance partners. Biochem J 2023; 480:1503-1532. [PMID: 37792325 DOI: 10.1042/bcj20220396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/24/2023] [Accepted: 08/31/2023] [Indexed: 10/05/2023]
Abstract
The protein kinase PDK1 phosphorylates at least 24 distinct substrates, all of which belong to the AGC protein kinase group. Some substrates, such as conventional PKCs, undergo phosphorylation by PDK1 during their synthesis and subsequently get activated by DAG and Calcium. On the other hand, other substrates, including members of the Akt/PKB, S6K, SGK, and RSK families, undergo phosphorylation and activation downstream of PI3-kinase signaling. This review presents two accepted molecular mechanisms that determine the precise and timely phosphorylation of different substrates by PDK1. The first mechanism involves the colocalization of PDK1 with Akt/PKB in the presence of PIP3. The second mechanism involves the regulated docking interaction between the hydrophobic motif (HM) of substrates and the PIF-pocket of PDK1. This interaction, in trans, is equivalent to the molecular mechanism that governs the activity of AGC kinases through their HMs intramolecularly. PDK1 has been instrumental in illustrating the bi-directional allosteric communication between the PIF-pocket and the ATP-binding site and the potential of the system for drug discovery. PDK1's interaction with substrates is not solely regulated by the substrates themselves. Recent research indicates that full-length PDK1 can adopt various conformations based on the positioning of the PH domain relative to the catalytic domain. These distinct conformations of full-length PDK1 can influence the interaction and phosphorylation of substrates. Finally, we critically discuss recent findings proposing that PIP3 can directly regulate the activity of PDK1, which contradicts extensive in vitro and in vivo studies conducted over the years.
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Affiliation(s)
- Alejandro E Leroux
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina
| | - Ricardo M Biondi
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina
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19
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Konopka AR, Lamming DW. Blazing a trail for the clinical use of rapamycin as a geroprotecTOR. GeroScience 2023; 45:2769-2783. [PMID: 37801202 PMCID: PMC10643772 DOI: 10.1007/s11357-023-00935-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/04/2023] [Indexed: 10/07/2023] Open
Abstract
Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
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Affiliation(s)
- Adam R Konopka
- Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.
- Division of Geriatrics and Gerontology, Department of Medicine, Geriatric Research Education and Clinical Center (GRECC), William S. Middleton Memorial Veterans Hospital, University of Wisconsin-Madison, 2500 Overlook Terrace, Madison, WI, 53705, USA.
| | - Dudley W Lamming
- William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA
- Division of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
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20
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Blandino-Rosano M, Louzada RA, Werneck-De-Castro JP, Lubaczeuski C, Almaça J, Rüegg MA, Hall MN, Leibowitz G, Bernal-Mizrachi E. Raptor levels are critical for β-cell adaptation to a high-fat diet in male mice. Mol Metab 2023; 75:101769. [PMID: 37423392 PMCID: PMC10391668 DOI: 10.1016/j.molmet.2023.101769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/19/2023] [Accepted: 06/29/2023] [Indexed: 07/11/2023] Open
Abstract
OBJECTIVE The essential role of raptor/mTORC1 signaling in β-cell survival and insulin processing has been recently demonstrated using raptor knock-out models. Our aim was to evaluate the role of mTORC1 function in adaptation of β-cells to insulin resistant state. METHOD Here, we use mice with heterozygous deletion of raptor in β-cells (βraHet) to assess whether reduced mTORC1 function is critical for β-cell function in normal conditions or during β-cell adaptation to high-fat diet (HFD). RESULTS Deletion of a raptor allele in β-cells showed no differences at the metabolic level, islets morphology, or β-cell function in mice fed regular chow. Surprisingly, deletion of only one allele of raptor increases apoptosis without altering proliferation rate and is sufficient to impair insulin secretion when fed a HFD. This is accompanied by reduced levels of critical β-cell genes like Ins1, MafA, Ucn3, Glut2, Glp1r, and specially PDX1 suggesting an improper β-cell adaptation to HFD. CONCLUSION This study identifies that raptor levels play a key role in maintaining PDX1 levels and β-cell function during the adaptation of β-cell to HFD. Finally, we identified that Raptor levels regulate PDX1 levels and β-cell function during β-cell adaptation to HFD by reduction of the mTORC1-mediated negative feedback and activation of the AKT/FOXA2/PDX1 axis. We suggest that Raptor levels are critical to maintaining PDX1 levels and β-cell function in conditions of insulin resistance in male mice.
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Affiliation(s)
- Manuel Blandino-Rosano
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA; Miami VA Health Care System, Miami, FL, USA.
| | - Ruy Andrade Louzada
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Joao Pedro Werneck-De-Castro
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA; Miami VA Health Care System, Miami, FL, USA
| | - Camila Lubaczeuski
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Joana Almaça
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Markus A Rüegg
- Biozentrum, University of Basel, CH-4056, Basel, Switzerland
| | - Michael N Hall
- Biozentrum, University of Basel, CH-4056, Basel, Switzerland
| | - Gil Leibowitz
- Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ernesto Bernal-Mizrachi
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA; Miami VA Health Care System, Miami, FL, USA.
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Kakehi S, Tamura Y, Ikeda SI, Kaga N, Taka H, Nishida Y, Kawamori R, Watada H. Physical inactivity induces insulin resistance in plantaris muscle through protein tyrosine phosphatase 1B activation in mice. Front Physiol 2023; 14:1198390. [PMID: 37389126 PMCID: PMC10300557 DOI: 10.3389/fphys.2023.1198390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/05/2023] [Indexed: 07/01/2023] Open
Abstract
Inactivity causes insulin resistance in skeletal muscle and exacerbates various lifestyle-related diseases. We previously found that 24-h hindlimb cast immobilization (HCI) of the predominantly slow-twitch soleus muscle increased intramyocellular diacylglycerol (IMDG) and insulin resistance by activation of lipin1, and HCI after a high-fat diet (HFD) further aggravated insulin resistance. Here, we investigated the effects of HCI on the fast-twitch-predominant plantaris muscle. HCI reduced the insulin sensitivity of plantaris muscle by approximately 30%, and HCI following HFD dramatically reduced insulin sensitivity by approximately 70% without significant changes in the amount of IMDG. Insulin-stimulated phosphorylation levels of insulin receptor (IR), IR substrate-1, and Akt were reduced in parallel with the decrease in insulin sensitivity. Furthermore, tyrosine phosphatase 1B (PTP1B), a protein known to inhibit insulin action by dephosphorylating IR, was activated, and PTP1B inhibition canceled HCI-induced insulin resistance. In conclusion, HCI causes insulin resistance in the fast-twitch-predominant plantaris muscle as well as in the slow-twitch-predominant soleus muscle, and HFD potentiates these effects in both muscle types. However, the mechanism differed between soleus and plantaris muscles, since insulin resistance was mediated by the PTP1B inhibition at IR in plantaris muscle.
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Affiliation(s)
- Saori Kakehi
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Shin-ichi Ikeda
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Naoko Kaga
- Division of Proteomics and Biomolecular Science, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hikari Taka
- Division of Proteomics and Biomolecular Science, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuya Nishida
- Department of Metabolism and Endocrinology, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
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22
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Sonsalla MM, Lamming DW. Geroprotective interventions in the 3xTg mouse model of Alzheimer's disease. GeroScience 2023; 45:1343-1381. [PMID: 37022634 PMCID: PMC10400530 DOI: 10.1007/s11357-023-00782-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 03/23/2023] [Indexed: 04/07/2023] Open
Abstract
Alzheimer's disease (AD) is an age-associated neurodegenerative disease. As the population ages, the increasing prevalence of AD threatens massive healthcare costs in the coming decades. Unfortunately, traditional drug development efforts for AD have proven largely unsuccessful. A geroscience approach to AD suggests that since aging is the main driver of AD, targeting aging itself may be an effective way to prevent or treat AD. Here, we discuss the effectiveness of geroprotective interventions on AD pathology and cognition in the widely utilized triple-transgenic mouse model of AD (3xTg-AD) which develops both β-amyloid and tau pathologies characteristic of human AD, as well as cognitive deficits. We discuss the beneficial impacts of calorie restriction (CR), the gold standard for geroprotective interventions, and the effects of other dietary interventions including protein restriction. We also discuss the promising preclinical results of geroprotective pharmaceuticals, including rapamycin and medications for type 2 diabetes. Though these interventions and treatments have beneficial effects in the 3xTg-AD model, there is no guarantee that they will be as effective in humans, and we discuss the need to examine these interventions in additional animal models as well as the urgent need to test if some of these approaches can be translated from the lab to the bedside for the treatment of humans with AD.
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Affiliation(s)
- Michelle M Sonsalla
- Department of Medicine, University of Wisconsin-Madison, 2500 Overlook Terrace, VAH C3127 Research 151, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA
- Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Dudley W Lamming
- Department of Medicine, University of Wisconsin-Madison, 2500 Overlook Terrace, VAH C3127 Research 151, Madison, WI, 53705, USA.
- William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.
- Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, 53706, USA.
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23
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Liebscher G, Vujic N, Schreiber R, Heine M, Krebiehl C, Duta-Mare M, Lamberti G, de Smet CH, Hess MW, Eichmann TO, Hölzl S, Scheja L, Heeren J, Kratky D, Huber LA. The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue. Mol Metab 2023; 71:101705. [PMID: 36907508 PMCID: PMC10074977 DOI: 10.1016/j.molmet.2023.101705] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/28/2023] [Accepted: 03/06/2023] [Indexed: 03/13/2023] Open
Abstract
OBJECTIVE In brown adipose tissue (iBAT), the balance between lipid/glucose uptake and lipolysis is tightly regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) complex, which serves to translate the nutrient status of the cell to the respective kinase. However, the role of LAMTOR in metabolically active iBAT has been elusive. METHODS Using an AdipoqCRE-transgenic mouse line, we deleted LAMTOR2 (and thereby the entire LAMTOR complex) in adipose tissue (LT2 AKO). To examine the metabolic consequences, we performed metabolic and biochemical studies in iBAT isolated from mice housed at different temperatures (30 °C, room temperature and 5 °C), after insulin treatment, or in fasted and refed condition. For mechanistic studies, mouse embryonic fibroblasts (MEFs) lacking LAMTOR 2 were analyzed. RESULTS Deletion of the LAMTOR complex in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake, which led to massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was abrogated by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient MEFs. CONCLUSIONS We identified a homeostatic circuit for the maintenance of iBAT metabolism that links the LAMTOR-mTORC1 pathway to PI3K-mTORC2-AKT signaling downstream of the insulin receptor.
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Affiliation(s)
- Gudrun Liebscher
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Nemanja Vujic
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria
| | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria
| | - Markus Heine
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Caroline Krebiehl
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Madalina Duta-Mare
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria
| | - Giorgia Lamberti
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Cedric H de Smet
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Michael W Hess
- Institute of Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, 6020 Innsbruck, Austria
| | - Thomas O Eichmann
- Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria
| | - Sarah Hölzl
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Dagmar Kratky
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria; BioTechMed-Graz, Mozartgasse 12, 8010 Graz, Austria
| | - Lukas A Huber
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
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24
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Huang SL, Xie W, Ye YL, Liu J, Qu H, Shen Y, Xu TF, Zhao ZH, Shi Y, Shen JH, Leng Y. Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice. Acta Pharmacol Sin 2023; 44:596-609. [PMID: 36085523 PMCID: PMC9958036 DOI: 10.1038/s41401-022-00985-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 08/18/2022] [Indexed: 11/09/2022]
Abstract
Promotion of hepatic glycogen synthesis and inhibition of hepatic glucose production are effective strategies for controlling hyperglycemia in type 2 diabetes mellitus (T2DM), but agents with both properties were limited. Herein we report coronarin A, a natural compound isolated from rhizomes of Hedychium gardnerianum, which simultaneously stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes. We showed that coronarin A (3, 10 μM) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3β phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 μM) or PI3K inhibitor LY294002 (10 μM) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 μM) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, β-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with β-catenin inhibitor IWR-1-endo (10 μM) or ERK inhibitor SCH772984 (1 μM) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3β and ERK/Wnt/β-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 μM) decreased the phosphorylation of mTOR and S6K1, the downstream target of mTORC1, which further inhibited the serine phosphorylation of IRS1, and subsequently increased the tyrosine phosphorylation of IRS1. In type 2 diabetic ob/ob mice, chronic administration of coronarin A significantly reduced the non-fasting and fasting blood glucose levels and improved glucose tolerance, accompanied by the inhibited hepatic mTOR/S6K1 signaling and activated IRS1 along with enhanced PI3K/Akt/GSK3β and ERK/Wnt/β-catenin pathways. These results demonstrate the anti-hyperglycemic effect of coronarin A with a novel mechanism by inhibiting mTORC1/S6K1 to increase IRS1 activity, and highlighted coronarin A as a valuable lead compound for the treatment of T2DM.
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Affiliation(s)
- Su-Ling Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Wei Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yang-Liang Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jia Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hui Qu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yu Shen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Ti-Fei Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Zhuo-Hui Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yu Shi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jian-Hua Shen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Ying Leng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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25
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Rigamonti AE, Frigerio G, Caroli D, De Col A, Cella SG, Sartorio A, Fustinoni S. A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study. Nutrients 2023; 15:529. [PMID: 36771236 PMCID: PMC9921209 DOI: 10.3390/nu15030529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Metabolomics applied to assess the response to a body weight reduction program (BWRP) may generate valuable information concerning the biochemical mechanisms/pathways underlying the BWRP-induced cardiometabolic benefits. The aim of the present study was to establish the BWRP-induced changes in the metabolomic profile that characterizes the obese condition. In particular, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to determine a total of 188 endogenous metabolites in the plasma samples of a cohort of 42 adolescents with obesity (female/male = 32/10; age = 15.94 ± 1.33 year; body mass index standard deviation score (BMI SDS) = 2.96 ± 0.46) who underwent a 3-week BWRP, including hypocaloric diet, physical exercise, nutritional education, and psychological support. The BWRP was capable of significantly improving body composition (e.g., BMI SDS, p < 0.0001), glucometabolic homeostasis (e.g., glucose, p < 0.0001), and cardiovascular function (e.g., diastolic blood pressure, p = 0.016). A total of 64 metabolites were significantly reduced after the intervention (at least p < 0.05), including 53 glycerophospholipids (23 PCs ae, 21 PCs aa, and 9 lysoPCs), 7 amino acids (tyrosine, phenylalanine, arginine, citrulline, tryptophan, glutamic acid, and leucine), the biogenic amine kynurenine, 2 sphingomyelins, and (free) carnitine (C0). On the contrary, three metabolites were significantly increased after the intervention (at least p < 0.05)-in particular, glutamine, trans-4-hydroxyproline, and the octadecenoyl-carnitine (C18:1). In conclusion, when administered to adolescents with obesity, a short-term BWRP is capable of changing the metabolomic profile in the plasma.
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Affiliation(s)
- Antonello E. Rigamonti
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Gianfranco Frigerio
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Avenue Du Swing, L-4367 Belvaux, Luxembourg
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Alessandra De Col
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Silvano G. Cella
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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26
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Keerthana CK, Rayginia TP, Shifana SC, Anto NP, Kalimuthu K, Isakov N, Anto RJ. The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment. Front Immunol 2023; 14:1114582. [PMID: 36875093 PMCID: PMC9975160 DOI: 10.3389/fimmu.2023.1114582] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.
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Affiliation(s)
- Chenicheri Kizhakkeveettil Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.,Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, India
| | - Tennyson Prakash Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.,Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, India
| | | | - Nikhil Ponnoor Anto
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Kalishwaralal Kalimuthu
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Noah Isakov
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
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27
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Vratarić M, Šenk V, Bursać B, Gligorovska L, Ignjatović D, Kovačević S, Veličković N, Djordjevic A. Fructose diet ameliorate effects of macrophage migration inhibitory factor deficiency on prefrontal cortex inflammation, neural plasticity, and behavior in male mice. Biofactors 2023; 49:90-107. [PMID: 34767656 DOI: 10.1002/biof.1802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/26/2021] [Indexed: 12/11/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that represents a link between diet-induced inflammation and insulin resistance. Our aim was to examine whether fructose diet affects inflammation and insulin signaling in the prefrontal cortex (PFC) of Mif knockout mice (MIF-KO), and their possible link to neural plasticity and behavior. We analyzed nuclear factor κB (NF-κB) and glucocorticoid signaling, expression of F4/80, IL-1β, TNF-α, TLR-4, MyD88, arginase 1 (Arg-1), mannose receptor (Mrc-1), and leukemia inhibitory factor (Lif) to assess inflammation in the PFC of C57/BL6J and MIF-KO mice consuming 20% fructose solution for 9 weeks. Insulin receptor (IR), IRS-1 serine phosphorylations (307 and 1101) and activity of PKCα, Akt, GSK-3β and AMPKα were used to analyze insulin signaling. Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA levels, together with synapthophysin and PSD-95 protein level and calcium calmodulin-dependent kinase 2 (CaMKII) activity, were used as plasticity markers. Behavior was examined in elevated plus maze, light dark box and novel object recognition test. The results showed concomitant increase of Tnf-α, Tlr-4, MyD88 and M2 microglia markers (Arg-1, Mrc-1, Lif) in the PFC of MIF-KO, paralleled with unchanged glucocorticoid and insulin signaling. Increase of BDNF and IGF-1 was paralleled with increased CaMKII activity, decreased PSD-95 protein level, anxiogenic behavior, and impaired memory in MIF-KO mice. Fructose feeding restored these parameters in the PFC to the control level and mitigated behavioral changes, suggesting that ameliorating effects of fructose on neuroinflammation and behavior depend on the presence of MIF.
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Affiliation(s)
- Miloš Vratarić
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Vladimir Šenk
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Biljana Bursać
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Ljupka Gligorovska
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Djurdjica Ignjatović
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Sanja Kovačević
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Nataša Veličković
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Ana Djordjevic
- Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
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28
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Santos AL, Sinha S. Ageing, Metabolic Dysfunction, and the Therapeutic Role of Antioxidants. Subcell Biochem 2023; 103:341-435. [PMID: 37120475 DOI: 10.1007/978-3-031-26576-1_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
The gradual ageing of the world population has been accompanied by a dramatic increase in the prevalence of obesity and metabolic diseases, especially type 2 diabetes. The adipose tissue dysfunction associated with ageing and obesity shares many common physiological features, including increased oxidative stress and inflammation. Understanding the mechanisms responsible for adipose tissue dysfunction in obesity may help elucidate the processes that contribute to the metabolic disturbances that occur with ageing. This, in turn, may help identify therapeutic targets for the treatment of obesity and age-related metabolic disorders. Because oxidative stress plays a critical role in these pathological processes, antioxidant dietary interventions could be of therapeutic value for the prevention and/or treatment of age-related diseases and obesity and their complications. In this chapter, we review the molecular and cellular mechanisms by which obesity predisposes individuals to accelerated ageing. Additionally, we critically review the potential of antioxidant dietary interventions to counteract obesity and ageing.
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Affiliation(s)
- Ana L Santos
- IdISBA - Fundación de Investigación Sanitaria de las Islas Baleares, Palma, Spain.
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29
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Dong Y, Chen J, Zhang Y, Wang Z, Shang J, Zhao Z. Development and validation of diagnostic models for immunoglobulin A nephropathy based on gut microbes. Front Cell Infect Microbiol 2022; 12:1059692. [PMID: 36569195 PMCID: PMC9774022 DOI: 10.3389/fcimb.2022.1059692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022] Open
Abstract
Background Immunoglobulin A nephropathy (IgAN) is a highly prevalent glomerular disease. The diagnosis potential of the gut microbiome in IgAN has not been fully evaluated. Gut microbiota, serum metabolites, and clinical phenotype help to further deepen the understanding of IgAN. Patients and methods Cohort studies were conducted in healthy controls (HC), patients of IgA nephropathy (IgAN) and non-IgA nephropathy (n_IgAN). We used 16S rRNA to measure bacterial flora and non-targeted analysis methods to measure metabolomics; we then compared the differences in the gut microbiota between each group. The random forest method was used to explore the non-invasive diagnostic value of the gut microbiome in IgAN. We also compared serum metabolites and analyzed their correlation with the gut microbiome. Results The richness and diversity of gut microbiota were significantly different among IgAN, n_IgAN and HC patients. Using a random approach, we constructed the diagnosis model and analysed the differentiation between IgAN and n_IgAN based on gut microbiota. The area under the receiver operating characteristic curve for the diagnosis was 0.9899. The metabolic analysis showed that IgAN patients had significant metabolic differences compared with HCs. In IgAN, catechol, l-tryptophan, (1H-Indol-3-yl)-N-methylmethanamine, and pimelic acid were found to be enriched. In the correlation analysis, l-tryptophan, blood urea nitrogen and Eubacterium coprostanoligenes were positively correlated with each other. Conclusion Our study demonstrated changes in the gut microbiota and established models for the non-invasive diagnosis of IgAN from HC and n_IgAN. We further demonstrated a close correlation between the gut flora, metabolites, and clinical phenotypes of IgAN. These findings provide further directions and clues in the study of the mechanism of IgAN.
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Affiliation(s)
- Yijun Dong
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Jiaojiao Chen
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Yiding Zhang
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhihui Wang
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Jin Shang
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,Nephrology Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,Laboratory Animal Platform of Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China,*Correspondence: Zhanzheng Zhao, ; Jin Shang,
| | - Zhanzheng Zhao
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,Nephrology Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,Laboratory Animal Platform of Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China,*Correspondence: Zhanzheng Zhao, ; Jin Shang,
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Ortiz-Huidobro RI, Larqué C, Velasco M, Chávez-Maldonado JP, Sabido J, Sanchez-Zamora YI, Hiriart M. Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats. Cell Commun Signal 2022; 20:154. [PMID: 36224569 PMCID: PMC9554987 DOI: 10.1186/s12964-022-00965-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/17/2022] [Indexed: 11/23/2022] Open
Abstract
Background Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage.
Methods We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey’s tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. Results We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. Conclusions Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner.
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