Le rôle de Gas6 dans le métabolisme du glucose
Introduction: Gas6 is a secreted protein which is gamma-carboxylated in a vitamin K dependent manner and functions as ligand for the TAM family of receptor tyrosine kinases: TYRO3, AXL and MERTK. A few studies in humans suggest a potential role for Gas6 in insulin resistance and obesity. Nevertheless, the mechanisms by which Gas6 influences insulin resistance remain unknown. Based on our preliminary data, we hypothesized that Gas6 regulates insulin sensitivity in muscle and adipose tissue through its interaction with its receptors. Methods and Results: We observed that Axl is the most highly expressed Gas6 receptor in adipocytes and myocytes. Moreover, we found that Axl and its downstream target AKT are phosphorylated in C2C12 myotubes following stimulation with recombinant Gas6. Importantly, these phosphorylation events are abrogated when cells where pre-treated with LDC1267, a TAM pharmacological inhibitors. In addition, Gas6-/- mice display an improved glucose tolerance, associated with increased insulin sensitivity when compared to wild-type mice. In contrast, Gas6 transgenic mice characterized by increased circulating Gas6 levels (ApoE-Gas6 Tg) have reduced insulin sensitivity. To further investigate the molecular events downstream of Gas6 and of its receptor in muscle cells, we characterized the Gas6/Axl-dependent transcriptome in myotubes using RNAseq. Interestingly, we found that key regulators of the insulin signaling pathway were modulated by Gas6 and Axl. Conclusion and Relevance: Together, these results support the notion that Gas6 is implicated in the regulation of insulin sensitivity in vivo. This function of Gas6 occurs through its interaction with Axl at the surface of myocytes.
Type 2 Diabetes Insulin resistance Metabolism Physiology Vitamin K