The rheumatoid arthritis drug auranofin lowers leptin levels and exerts antidiabetic effects in obese mice.

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM. [Display omitted] • The rheumatoid arthritis drug auranofin improves insulin sensitivity in obese mice • Auranofin accumulation in epididymal white fat drives whole-body glucose disposal • Metabolic benefits of auranofin require an intact leptin axis • Auranofin couples lipolytic competence to inhibition of leptin secretion The FDA-approved rheumatoid arthritis drug auranofin accumulates in white adipose tissue, improves insulin sensitivity, and normalizes fatty-liver disease in obesity. Beta-adrenergic receptor regulation of leptin secretion generates metabolic benefits superior to anti-inflammatory effects. Consequently, studies of auranofin reinforce that partial leptin reduction represents a relevant method for treating obesity. [ABSTRACT FROM AUTHOR]