Accumulation of auranofin in white adipose tissues lowers leptin levels and exerts anti-diabetic effects
Cox, A. R.; Masschelin, P. M.; Saha, P.; Felix, J. B.; Sharp, R.; Lian, Z.; Xia, Y.; Chernis, N.; Bader, D. A.; Kim, K. H.; Li, X.; Yoshino, J.; Li, X.; Sun, Z.; Wu, H.; Coarfa, C.; Moore, D. D.; Klein, S.; Sun, K.; Hartig, S. M.
Show abstract
Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and frequently coincides with insulin resistance and type 2 diabetes (T2D). However, pharmacological targeting of WAT inflammation lacks durable therapeutic effects. Through a computational screen, we identified the FDA-approved rheumatoid arthritis drug auranofin is a putative small molecule for obesity treatment. We discovered that allometrically scaled safe auranofin doses homed to WAT and improved insulin sensitivity in obese wild-type mice. Auranofin treatment also normalized other obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia. Surprisingly, the anti-diabetic effects of auranofin required leptin lowering and beta-adrenergic receptors in WAT. These metabolic benefits of leptin reduction were superior to any immune impacts of auranofin in WAT. Our studies reveal 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 T2D.
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