| First Author | Chen Q | Year | 2019 |
| Journal | Sci Adv | Volume | 5 |
| Issue | 4 | Pages | eaav4116 |
| PubMed ID | 30989113 | Mgi Jnum | J:287672 |
| Mgi Id | MGI:6415836 | Doi | 10.1126/sciadv.aav4116 |
| Citation | Chen Q, et al. (2019) Targeting RalGAPalpha1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control. Sci Adv 5(4):eaav4116 |
| abstractText | 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 RalGAPalpha1 is a critical regulator of muscle insulin action and governs both glucose and lipid homeostasis. A high-fat diet increased RalGAPalpha1 protein but decreased its insulin-responsive Thr(735)-phosphorylation in skeletal muscle. A RalGAPalpha1(Thr735Ala) mutation impaired insulin-stimulated muscle assimilation of glucose and LCFAs and caused metabolic syndrome in mice. In contrast, skeletal muscle-specific deletion of RalGAPalpha1 improved postprandial glucose and lipid control. Mechanistically, these mutations of RalGAPalpha1 affected translocation of insulin-responsive glucose transporter GLUT4 and fatty acid translocase CD36 via RalA to affect glucose and lipid homeostasis. These data indicated RalGAPalpha1 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. |
