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

doi:10.1016/j.molcel.2014.12.005

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.

Authors

Affiliations

¹ Department of Nutritional Science & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Nutritional Science & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Nutritional Science & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Molecular Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Department of Nutritional Science & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: hsul@berkeley.edu.

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 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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding