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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 Thr-phosphorylation in skeletal muscle. A RalGAPα1 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.

Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control