Sarcolipin, an Uncoupler of SERCA, Protects against Lipotoxicity and Insulin Resistance

Abstract

Obesity is strongly associated with insulin resistance and type 2 diabetes, and increased consumption of high-caloric diet combined with decreased physical activity have made type 2 diabetes a worldwide epidemic. Excess accumulation of lipid and fatty acid metabolites has been shown to interfere with insulin signaling in skeletal muscle. Increasing energy expenditure and mitochondrial metabolism in muscle is an attractive strategy to protect against fat-induced insulin resistance. We have previously shown that sarcolipin (SLN), an uncoupler of SERCA pump, promotes futile cycling, increases ATP utilization and heat generation thereby contributing to muscle thermogenesis. When fed with high-fat diet (HFD), Sln-KO mice developed massive obesity whereas SLN overexpression (SlnOE) mice showed resistance to obesity. In this study, we investigated if SLN based uncoupling mechanism can be targeted to enhance muscle energy expenditure and protects against fat-induced lipotoxicity and insulin resistance in skeletal muscle. Here we show that SLN overexpression increases fatty acid oxidation in skeletal muscle by reprogramming mitochondria and upregulation of enzymes involved in fatty acid transport and oxidation. Interestingly, SlnOE mice fed on high-fat diet did not show intramuscular lipid accumulation and display improved insulin sensitivity. On the other hand, Sln-KO mice show excessive lipid accumulation in muscle and defects in insulin-stimulated glucose uptake, a sign of insulin resistance. Insulin resistant phenotype of Sln-KO muscle was associated with the increased intramuscular concentration of diacylglycerols (DAG), ceramides and acylcarnitines. These results suggest that sarcolipin mediated uncoupling of SERCA is a novel therapeutic target to increase energy expenditure and prevent insulin resistance in skeletal muscle. Disclosure S.K. Maurya: None.