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.
Highlights
Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for growth factors, hormones, and cytokines
We have previously reported the generation of the Rosa26LacZ-stop-Met mice, which allowed wild-type MET levels to increase in a temporal and spatial-regulated manner [12]
This genetic setting allows exploring the impact of hepatocyte-specific modest MET upregulation in whole-body glucose homeostasis
Summary
Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for growth factors, hormones, and cytokines. RTKs induce rapid signaling responses at the plasma membrane that are transmitted to intracellular compartments to modulate the expression of genes relevant to fundamental biological processes including cell proliferation, migration, survival, differentiation, and metabolism [1,2]. MET is a well-known RTK family member widely expressed in many tissues including liver, pancreas, prostate, kidney, and muscle [3,4]. Canonical activation of MET by its cognate ligand hepatocyte growth factor (HGF) triggers a cascade of molecular events including MAPK and AKT signaling pathways, both being common downstream targets of metabolic signaling. Growing evidence points to a special interest of the HGF/MET axis in the crosstalk with insulin resistance and obesity-related molecular signatures. Treatment of obese rats with the combination of recombinant
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