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

Mol Cell. 2015 Jan 22;57(2):235-46. doi: 10.1016/j.molcel.2014.12.005. Epub 2015 Jan 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / physiology*
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / physiology*
  • Animals
  • Cold-Shock Response
  • DNA-Binding Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Ion Channels / genetics*
  • Ion Channels / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Muscle Development
  • Phenotype
  • Promoter Regions, Genetic
  • Protein Binding
  • Thermogenesis
  • Trans-Activators / physiology*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Uncoupling Protein 1


  • DNA-Binding Proteins
  • Ion Channels
  • Mitochondrial Proteins
  • PRDM16 protein, human
  • Trans-Activators
  • Transcription Factors
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Zfp516 protein, mouse