Azoxystrobin, A Mitochondrial Complex â…¢ Inhibitor,Exerts Beneficial Effects On Metabolic Syndrome In Vito And In Vitro

Background:Several anti-diabetic drugs such as metformin and TZDs have been shown to exert beneficial effects for metabolic syndrome through inhibiton of mitochondrial respiration. Although much progress has been made toward understanding the role of mitochondrial inhibitors in ameliorating metabolic diseases, the potential effects of these inhibitors on mitochondrial respiratory chain complex â…¢ remain unclear.Methods:First we evaluated the metabolic effects of AZOX, a Qo inhibitor of complex â…¢, in different metabolic cells, such as L6myotubes,3T3-L1adipocytes, HepG2cells and mouse primary hepatocytes. Second, the pharmacokinetics in rats was assessed and acute effects on energy consumption and the respiratory quotient in C57BL/6J mice were tested with TSE system. Last we investigated the metabolic effects of AZOX in the high-fat diet-fed mouse model with insulin resistance.Results:AZOX increased glucose uptake in L6myotubes and3T3-L1adipocytes, and inhibited de novo lipogenesis in HepG2cells and mouse primary hepatocytes. Our study indicated that these alterations in lipid and glucose metabolism may dependent on AMP-activated protein kinase (AMPK) signaling pathway. AZOX also inhibited the3T3-L1differentiation and reduced the maintenance of3T3-L1mature adipocytes. Preliminary pharmacokinetic study indicated that AZOX had10.6%oral absorption and short plasma half-life (2.52h). The acute administration of AZOX in mice increased the respiratory exchange ratio. Chronic treatment of AZOX reduced body weight (especially fat mass) and resulted in decreased triacylglycerol accumulation in liver and skeletal muscle. AZOX treatment caused a significant improvement in glucose tolerance and insulin sensitivity in high-fat diet-fed mice.Conclusions:Taken together, AZOX, a Qo inhibitor of mitochondrial respiratory complex â…¢, exerts the whole-body beneficial effects on the regulation of glucose and lipid homeostasis in high-fat diet-fed mice. Our findings provide a proof for a Qo inhibitor of mitochondrial respiratory complex â…¢ as a novel approach for the treatment of metabolic syndrome.