<b>GAS6 and AXL promote insulin resistance by rewiring insulin signaling and increasing insulin receptor trafficking to endosomes</b>

<p dir="ltr"><b>ABSTRACT</b></p><p dir="ltr">Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations in <i>GAS6 </i>are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that <i>Gas6</i> deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity <i>in vivo</i>. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR form a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.</p><p><br></p><p dir="ltr"><b>ARTICLE HIGHLIGHTS</b></p><p dir="ltr">· GAS6 deficient mice are characterized by improved glucose tolerance, increased insulin sensitivity and are protected from diet-induced insulin resistance.</p><p dir="ltr">· The GAS6 receptor AXL is expressed in muscle cells and forms a complex with the insulin receptor.</p><p dir="ltr">· GAS6 reprograms insulin signaling by modulating the phosphorylation of proteins implicated in endocytosis, vesicle-mediated transport, and membrane trafficking.</p><p dir="ltr">· AXL and GAS6 promotes insulin receptor endocytosis following insulin treatment.</p>