Lipid-induced Muscle Insulin Resistance Is Mediated by GGPPS via Modulation of the RhoA/Rho Kinase Signaling Pathway

摘要: Elevated circulating free fatty acid levels are important contributors to insulin resistance in the muscle and liver, but underlying mechanisms require further elucidation. Here, we show that geranylgeranyl diphosphate synthase 1 (GGPPS), which is a branch point enzyme mevalonic pathway, promotes lipid-induced through activation of RhoA/Rho kinase signaling pathway. We have found metabolic perturbation would increase GGPPS expression skeletal muscles db/db mice high fat diet-fed mice. To address effects activity muscle, generated with specific deletions their tissue. Heterozygous knock-out improved systemic sensitivity glucose homeostasis fed both normal chow diets. These alterations were accompanied by activated PI3K/Akt enhanced uptake muscle. Further investigation showed acid-stimulated was able enhance geranylgeranylation RhoA, induced inhibitory phosphorylation IRS-1 (Ser-307) increasing Rho activity. results implicate crucial role GGPPS/RhoA/Rho kinase/IRS-1 pathway it mediates obese Therefore, may represent potential pharmacological target for prevention treatment obesity-related type 2 diabetes.