LAUSR

The RalGAPα1/β complex links insulin signaling to glucose and lipid metabolism in skeletal muscle through RalA activation. How insulin stimulates postprandial uptake of glucose and long-chain fatty acids (LCFAs) into skeletal muscle and the mechanisms by which these events are dampened in diet-induced obesity are incompletely understood. Here, we show that RalGAPα1 is a critical regulator of muscle insulin action and governs both glucose and lipid homeostasis. A high-fat diet increased RalGAPα1 protein but decreased its insulin-responsive Thr735-phosphorylation in skeletal muscle. A RalGAPα1Thr735Ala mutation impaired insulin-stimulated muscle assimilation of glucose and LCFAs and caused metabolic syndrome in mice. In contrast, skeletal muscle–specific deletion of RalGAPα1 improved postprandial glucose and lipid control. Mechanistically, these mutations of RalGAPα1 affected translocation of insulin-responsive glucose transporter GLUT4 and fatty acid translocase CD36 via RalA to affect glucose and lipid homeostasis. These data indicated RalGAPα1 as a dual-purpose target, for which we developed a peptide-blockade for improving muscle insulin sensitivity. Our findings have implications for drug discovery to combat metabolic disorders.