1. Enhanced wild-Type mET Receptor levels in mouse hepatocytes attenuates insulin-mediated signaling
- Author
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Rada, Patricia, Lamballe, Fabienne, Cárcer, Guillermo de, Carceller-López, Elena, Hitos, Ana B., Sequera, Celia, Maina, Flavio, Valverde, Ángela M., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Fundación Ramón Areces, Instituto de Salud Carlos III, Institut National du Cancer (France), Aix-Marseille Université, Fondation de France, Fondation ARC pour la Recherche sur le Cancer, Instituto de Investigaciones Biomédicas Alberto Sols [Madrid], CSIC-UAM, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)
- Subjects
MET ,insulin signaling ,hepatocytes ,glucose homeostasis ,[SDV]Life Sciences [q-bio] ,General Medicine ,Glucose homeostasis ,Insulin signaling ,Mice ,Glucose ,Hepatocytes ,Animals ,Insulin ,Insulin Resistance ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Compelling evidence points to the MET receptor tyrosine kinase as a key player during liver development and regeneration. Recently, a role of MET in the pathophysiology of insulin resistance and obesity is emerging. Herein, we aimed to determine whether MET regulates hepatic insulin sensitivity. To achieve this, mice in which the expression of wild-type MET in hepatocytes is slightly enhanced above endogenous levels (Alb-R26Met mice) were analyzed to document glucose homeostasis, energy balance, and insulin signaling in hepatocytes. We found that Alb-R26Met mice exhibited higher body weight and food intake when compared to R26stopMet control mice. Metabolic analyses revealed that Alb-R26Met mice presented age-related glucose and pyruvate intolerance in comparison to R26stopMet controls. Additionally, in Alb-R26Met mice, high MET levels decreased insulin-induced insulin receptor (IR) and AKT phosphorylation compared to control mice. These results were corroborated in vitro by analyzing IR and AKT phosphorylation in primary mouse hepatocytes from Alb-R26Met and R26stopMet mice upon insulin stimulation. Moreover, co-immunoprecipitation assays revealed MET-IR interaction under both basal and insulin stimulation conditions; this effect was enhanced in Alb-R26Met hepatocytes. Altogether, our results indicate that enhanced MET levels alter hepatic glucose homeostasis, which can be an early event for subsequent liver pathologies., This work was supported by the Spanish Ministry of Science and Innovation with the help of European FEDER funding (RTI2018-094052-B-100), Comunidad de Madrid, Spain (S2017/BMD3684), and Fundación Ramón Areces and CIBERDEM (ISCIII) to Á.M.V. P.R. was a recipient of an International Mobility Grant from CIBERDEM (ISCIII). C.S. was supported by a FRM fellowship. F.M. is supported by research funding from Institut National du Cancer, ITMO Cancer Aviesan and INCa within the framework of the 2021–2030 Cancer Control Strategy on funds administered by Inserm, Canceropôle Provence Alpes Côte d’Azur, Institute for Cancer and Immunology (Aix-Marseille University), GEFLUC—Les Entreprises contre le Cancer, FdF (Fondation de France), ARC (Association pour la Recherche sur le Cancer), and SATT Sud-Est. The contribution of the Region Provence-AlpesCôte d’Azur and of the Aix-Marseille Univ to the IBDM animal facility is acknowledged.
- Published
- 2022