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.
D019325:3-O-Methylglucose / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage*; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D020738:Leptin / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D019325:3-O-Methylglucose; D004041:Dietary Fats; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526296:Irs1 protein, rat; C495694:Slc2a4 protein, rat; C494920:Akt1 protein, rat