Rosiglitazone reduces fatty acid translocase and increases AMPK in skeletal muscle in aged rats: a possible mechanism to prevent high-fat-induced insulin resistance

Background As an agonist of peroxisome proliferator-activated receptor-gamma (PPAR gamma), rosiglitazone can prevent acute fatty acid-induced insulin resistance in rats, however, the precise mechanisms by which rosiglitazone alleviates insulin resistance induced by high-fat diet need to be further investigated. Methods Wistar rats aged 23-24 weeks were divided into three groups: (1) aged control group (OC), (2) high-fat diet (HF) group and (3) high-fat diet plus rosiglitazone maleate tablets (HF+Rosi) treatment group (n=20 in each group). Insulin sensitivity was evaluated by conscious hyperinsulinemic-euglycemic clamp technique. mRNA levels of fatty acid translocase (FAT/CD36), AMP-activated protein kinase alpha 1 (AMPK alpha 1), AMPK alpha 2 and acetyl CoA carboxylase (ACC) of rat skeletal muscle were determined using real-time PCR, while muscle carnitine palmitoyltransferase-1 (CPT-1 beta) was determined using semi-quantitative PCR. Protein expression levels of FAT/CD36, AMPK phosphorylation (reflecting AMPK activity), P-ACC (inversely related with ACC activity) and muscle CPT-1M in rat skeletal muscles were measured using Western blotting. Results Aged rats fed by diet rich in fat for more than 8 weeks led to significant increases of plasma lipids, skeletal muscle intramuscular triglyceride and long-chain fatty acyl-CoA (LCACoA) compared to aged rats fed by normal chow diet (OC) (P <0.05), which might correlate with the lower (reduced by 42.4%) whole body insulin sensitivity in HF rats. FAT/CD36 protein concentrations and mRNA levels increased in untreated HF aged rats (P <0.01) and high-fat diet induced a significant decrease in P-AMPK, P-ACC, CPT-1M protein concentrations and AMPK alpha 2 and CPT-1 beta mRNA levels in rat skeletal muscles (P <0.05). No change in AMPK alpha 1 mRNA levels was observed in the HF group. Conclusion High-fat diet in aged rats results in a lipid accumulation and subsequent insulin resistance, while rosiglitazone can alleviate the insulin resistance by reducing fatty acid uptake as well as enhancing lipometabolism. Chin Med J 2010;123(17):2384-2391