SUN-104 The Anti-Rheumatic Drug Auranofin Improves The Metabolic Phenotype Of Obesity

Obesity is associated with chronic low-grade inflammation, reflecting significant alterations in the composition of immune cell populations that reside in white adipose tissue (WAT). The ensuing pro-inflammatory environment likely impinges on the metabolic functions of adipocytes and may partially explain the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). We recently demonstrated ectopic expression of the microRNA miR-30a in the subcutaneous fat pad of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. We subsequently pursued the notion that pharmacological inhibitors of inflammation that exhibit a gene expression profile similar to ectopic miR-30a expression in WAT should represent new drugs for insulin resistance and T2DM. To this end, we used the Broad Connectivity Map to analyze a library of small molecules that induce mRNA profiles similar to that of exogenous miR-30a expression in WAT. Through this process, we nominated the rheumatoid arthritis compound auranofin. Treatment of obese mice with auranofin elevated energy expenditure producing weight loss and improvements in insulin sensitivity. Auranofin treatment also normalized other obesity-associated conditions, including hepatic steatosis and serum levels of leptin. Auranofin likely exerts this function by modulating an integrated gene program to oppose low-grade inflammation in WAT. These studies reveal important metabolic properties of anti-inflammatory treatments that may be purposed as therapies for insulin resistance and T2DM.