Withaferin A promotes white adipose browning and prevents obesity through sympathetic nerve-activated Prdm16-FATP1 axis
The increasing prevalence of obesity causes demands for new strategies for obesity treatment. Withaferin A (WA) shows a great potential for obesity prevention by sensitizing leptin signaling in hypothalamus. However, the mechanism underlying weight- and adiposity-reducing effects of WA remains elusive. We report that WA induced white adipose tissue (WAT) browning, elevated energy expenditure (EE), decreased respiratory exchange ratio (RER), and prevented high-fat diet (HFD)-induced obesity. Sympathetic chemical denervation dampened WAT browning and impeded reduction of adiposity in WA-treated mice. WA up-regulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated WAT browning-inducing effects of WA, and restored weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis; and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on WAT browning.