High-Fat Diet And Leptin Treatment Alter Skeletal Muscle Insulin-Stimulated Phosphatidylinositol 3-Kinase Activity And Glucose Transport

The aim of this investigation was to evaluate if leptin treatment enhances insulin-stimulated glucose transport in normal (experimental group [EXP]-1) and insulin-resistant skeletal muscle (EXP-2) by altering components of the insulin-signaling cascade and/or glucose transport pathway. In EXP-1, Sprague Dawley rats were assigned to control-chow fed (CON-CF) or leptin treated-chow fed (LEP-CF) groups. Animals were implanted with miniosmotic pumps, which delivered 0.5 mg leptin/kg/d to the LEP-CF animals and vehicle to CON-CF animals for 14 days. For EXP-2, Sprague-Dawley rats consumed normal (CON) or high-fat diets for 3 months. After the dietary lead in, the high-fat diet group was further subdivided into high-fat (HF) and high-fat, leptin-treated (HF-LEP) animals. HF-LEP animals were injected with leptin (0.5 mg leptin/kg/d) for 12 days, while the CON and HF animals were injected with vehicle. After the treatment periods, all animals were prepared for and subjected to hind limb perfusion. In EXP-1, leptin treatment increased insulin-stimulated skeletal muscle glucose transporter (GLUT4) translocation, which appeared to be due to increased phosphatidylinositol 3-kinase (PI3-K) activation and Akt phosphorylation. In EXP-2, the high-fat diet reduced insulin-stimulated glucose transport, in part, by impairing insulin-stimulated PI3-K activation and glucose transporter translocation. Leptin treatment reversed high-fat-diet-induced insulin resistance in skeletal muscle by restoring insulin receptor substrate (IRS)-1-associated PI3-K activity, total GLUT4 protein concentration, and glucose transporter translocation. Collectively, these findings suggest that leptin treatment will enhance components of both the insulin-signaling cascade and glucose transport effector system in normal and insulin-resistant skeletal muscle.