Journal
SCIENCE ADVANCES
Volume 5, Issue 4, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav4116
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Funding
- Ministry of Science and Technology of China [2014CB964704, 2014BAI02B01]
- National Natural Science Foundation of China [31671456, 31571211]
- Natural Science Foundation of Jiangsu Province of China [BK20161393]
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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 RalGAP alpha 1 is a critical regulator of muscle insulin action and governs both glucose and lipid homeostasis. A high-fat diet increased RalGAP alpha 1 protein but decreased its insulin-responsive Thr(735)-phospho-rylation in skeletal muscle. A RalGAP alpha 1(Thr735Ala) mutation impaired insulin-stimulated muscle assimilation of glucose and LCFAs and caused metabolic syndrome in mice. In contrast, skeletal muscle-specific deletion of RalGAP alpha 1 improved postprandial glucose and lipid control. Mechanistically, these mutations of RalGAP alpha 1 affected translocation of insulin-responsive glucose transporter GLUT4 and fatty acid translocase CD36 via RalA to affect glucose and lipid homeostasis. These data indicated RalGAP alpha 1 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.
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