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

Abstract

Summary Uncoupling protein 1 (UCP1) mediates non-shivering thermogenesis and, upon cold exposure, is induced in BAT and subcutaneous white adipose tissue (iWAT). Here, by high-throughput screening using the UCP1 promoter, we identify Zfp516 as a novel 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, energy expenditure, and preventing diet-induced obesity. Zfp516 may represent a future target for obesity therapeutics.

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

“…Overall, we show that cold exposure induced fat browning and activated mitochondrial function; these results are consistent with previous studies (23)(24)(25). Therefore, we also suggest that BLC shows comparable effects to cold stimulation on fat browning.…”

“…4D). Previous studies have shown that activated mitochondrial function can be induced by cold stress or b-adrenergic stimuli as well as by the expression of brown adipocyte-specific genes (23)(24)(25). Exposure of mice to cold temperatures in this study resulted in an ;15-fold increase in UCP1 mRNA levels and a significant increase in UCP1 protein levels in the scWAT of mice compared with mice at room temperature ( Supplementary Fig.…”

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

“…Among them, the role of ZFP516 in BAT function and development has been studied (Dempersmier et al 2015). Interestingly, the BAT from ZFP516-null embryos displays strongly elevated myogenic gene expression but reduced or insignificant changes in WAT-selective gene expression, whereas we observed no significant change in myogenic gene expression but increased WAT-selective gene expression.…”

“…This is in apparent contradiction to the fact that ZFP516 and LSD1 appear to be in the same PRDM16 complex. Such a paradox may arise from the different genetic models being used; we used a conditional knockout, whereas Dempersmier et al (2015) used a global knockout. Therefore, this could be explained by the distinct roles of the ZFP516 and LSD1 at different stages of BAT development.…”

LSD1—a pivotal epigenetic regulator of brown and beige fat differentiation and homeostasis

“…Similar to the work of Zeng et al (2016), Sambeat et al (2016) showed that LSD1 ablation in brown fat resulted in impaired BAT development, increased fat mass, and decreased energy expenditure. A previous report demonstrated that Zfp516 interacts with PRDM16, suggesting that LSD1 forms a transcriptional complex to demethylate H3K9 (Dempersmier et al 2015). While LSD1 appears to be a broadly specific demethylase, its ability to selectively demethylate H3K9 on BAT loci and H3K4 on WAT loci suggests that gene selectivity is likely mediated via interactions with distinct DNA-binding transcription factors.…”