Cold-Inducible Zfp516 Activates UCP1 Transcription to Promote Browning of White Fat and Development of Brown Fat

Uncoupling protein 1 (UCP1) mediates nonshivering thermogenesis and, upon cold exposure, is induced in brown adipose tissue (BAT) and subcutaneous white adipose tissue (iWAT). Here, by high-throughput screening using the UCP1 promoter, we identify Zfp516 as a transcriptional activator of UCP1 as well as PGC1α, thereby promoting a BAT program. Zfp516 itself is induced by cold and sympathetic stimulation through the cAMP-CREB/ATF2 pathway. Zfp516 directly binds to the proximal region of the UCP1 promoter, not to the enhancer region where other transcription factors bind, and interacts with PRDM16 to activate the UCP1 promoter. Although ablation of Zfp516 causes embryonic lethality, knockout embryos still show drastically reduced BAT mass. Overexpression of Zfp516 in adipose tissue promotes browning of iWAT even at room temperature, increasing body temperature and energy expenditure and preventing diet-induced obesity. Zfp516 may represent a future target for obesity therapeutics. [Display omitted] •Zfp516 binds UCP1 promoter to drive transcription•Zfp516 expression is regulated by cold/sympathetic stimuli•Zfp516 promotes the browning of iWAT and prevents diet-induced obesity•Zfp516 ablation leads to defective brown fat formation in mice Using high-throughput screening, Dempersmier et al. identify Zfp516 as a cold-inducible regulator of UCP1 transcription. Using both transgenic and knockout mouse models, they show that Zfp516 promotes browning of iWAT to prevent diet-induced obesity and is required for BAT development.