High-Fat Diet Feeding Impairs Insulin Sensitivity Of Rats' Skeletal Muscle: Role Of AMPK And Gi Alpha

Background:High-fat diet is a single risk factor leading to insulin resistance and type 2 diabetes, also named as "lipotoxocity", which is characterized by increased body weight, elevated plasma FFA levels and abnormal accumulation of fat in insulin target organs. Although both epidemlogical and experimential researches have demonstrated the effects of high-fat exposure on insulin resistance in several insulin target organs, including skeletal muscles, liver, adipocytes etc, the precise mechanism is not fully eludiated yet.To date, both in vivo and in vitro studies have demonstrated that high-fat induced insulin resistance is accompanied with impaired activity or expression of several insulin signal moleculars, such as insulin receptor, insulin receptor substrate and GluT4 etc, and this was proposed as possible contributors to high-fat induced insulin resistance. However, the upstream mechanism underlying such impaired insulin signaling caused by high-fat exposure remains unclear.AMPK, AMP-activated protein kinase, is a key regulator of intracellular fatty acid metabolism. Stresses such as exercise, hypoxia, or prolonged starvation could activate AMPK via increasing intracellular AMP/ATP ratio. Once activated, its classical effect is to phosphorylate and inactivate acetyl-CoA carboxylase (ACC), resulting in a decrease in malonyl-CoA, thus relieving inhibition of CPT1 and facilitating FFA entry into mitochondria for P-oxidation. Besides regulating fatty acid oxidation, AMPK has been proved recently as a regulator of insulin signaling. For example, it was showed that AMPK-knockout mice became more insulin resistant, while those with AMPK overexpression exhibited enhanced insulin sensitivity. Recently, it was reported that AMPK activities in cultured skeletal muscle cells could be decreased by glucose...