Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat

Jon Dempersmier, Audrey Sambeat, Olga Gulyaeva, Sarah M. Paul, Carolyn S.S. Hudak, Helena F. Raposo, Hiu Yee KWAN, Chulho Kang, Roger H.F. Wong, Hei Sook Sul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

133 Citations (Scopus)

Abstract

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 wellas 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.

Original languageEnglish
Pages (from-to)235-246
Number of pages12
JournalMolecular Cell
Volume57
Issue number2
DOIs
Publication statusPublished - 22 Jan 2015

Scopus Subject Areas

  • Molecular Biology
  • Cell Biology

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