The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet–induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated 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 the WAT browning–inducing effects of WA and restored the 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 white adipose browning.

B.G. and J.L. contributed equally to this work.

This article contains supplementary material online at https://doi.org/10.2337/figshare.16915426.

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