Published on Sun Sep 12 2021

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.

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. We identified the FDA-approved rheumatoid arthritis

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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.