Resveratrol ameliorates high-fat diet-induced insulin resistance and fatty acid oxidation via ATM-AMPK axis in skeletal muscle.

Resveratrol (RSV) is a polyphenolic phytoalexin that exhibits diverse pharmacological actions, including its effect on the insulin resistance. However, the mechanism through which RSV improves insulin resistance is not fully understood yet. The aim of this study was to determine the mechanism through which RSV ameliorates insulin resistance in skeletal muscle of high-fat diet (HFD)-induced mouse model, as well as palmitic acid (PA) treated L6 cells, with a specific focus on the response of RSV on fatty acid oxidation.Male C57BL6/J mice were randomly divided into three groups: normal diet-fed mice (ND), the high-fat diet-fed mice (HFD), HFD supplemented with RSV (100 mg/kg body weight [BW]/day orally; n = 10). Fasting plasma glucose, insulin, total cholesterol, triglyceride (TG), and free fatty acid levels were determined. The intraperitoneal glucose tolerance test was used to measure blood glucose and area under the curve. The quantitative insulin sensitivity index was calculated to assess insulin resistance. Skeletal muscles were collected for histology study and protein expression measurement. L6 cells were cultured with PA and the glucose concentration in the culture medium, and the intracellular TG levels were tested. RSV, chloroquine, palmitoyltransferase and Ku-55933 were administered to differentiate L6 cells.The HFD fed mice showed increased BW, hyperglycemia, and hyperlipidemia. The expressions of ataxia telangiectasia mutated (ATM), 5' adenosine monophosphate-activated protein kinase (AMPK), carnitine palmitoyltransferase 1, cytochrome oxidase subunit IV protein were significantly decreased in the skeletal muscles of HFD fed mice and PA-treated L6 cells. All these effects induced by HFD and PA were reversed by RSV treatment.ATM is a key factor to improve HFD-induced lipid metabolism and insulin resistance in skeletal muscles. The effects of RSV on ameliorating HFD-induced abnormal lipid metabolism and insulin resistance mediated through ATM-AMPK pathway may due to its improvement in fatty acid oxidation efficiency and sequential reduction in ROS production in skeletal muscle. These results provide important theoretical evidence for the application of RSV in the prevention and treatment of diabetes mellitus and related metabolic diseases.