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

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 journal › Journal article › peer-review

188 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 language	English
Pages (from-to)	235-246
Number of pages	12
Journal	Molecular Cell
Volume	57
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2014.12.005
Publication status	Published - 22 Jan 2015

Scopus Subject Areas

Molecular Biology
Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2014.12.005

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@article{376764cb6c6b488198dbac0755fd593e,

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

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.",

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

note = "Funding Information: We thank Dr. S. Kajimura for GST-PRDM16 constructs and Dr. P. Tontonoz for the V5-PRDM16 construct. We thank D. Hunerdosse, J. Niliwat, W. Orenella, N. Chien, J. Zheng, X. Liang, E. Esquivel, and J. Chong for technical assistance. The work was supported in part by DK095338 to H.S.S. H.F.R. is a recipient of a doctoral fellowship from The State of Sao Paulo Research Foundation (FAPEPS 2011/20136-9). ",

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doi = "10.1016/j.molcel.2014.12.005",

language = "English",

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journal = "Molecular Cell",

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T1 - Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat

AU - Dempersmier, Jon

AU - Sambeat, Audrey

AU - Gulyaeva, Olga

AU - Paul, Sarah M.

AU - Hudak, Carolyn S.S.

AU - Raposo, Helena F.

AU - KWAN, Hiu Yee

AU - Kang, Chulho

AU - Wong, Roger H.F.

AU - Sul, Hei Sook

N1 - Funding Information: We thank Dr. S. Kajimura for GST-PRDM16 constructs and Dr. P. Tontonoz for the V5-PRDM16 construct. We thank D. Hunerdosse, J. Niliwat, W. Orenella, N. Chien, J. Zheng, X. Liang, E. Esquivel, and J. Chong for technical assistance. The work was supported in part by DK095338 to H.S.S. H.F.R. is a recipient of a doctoral fellowship from The State of Sao Paulo Research Foundation (FAPEPS 2011/20136-9).

PY - 2015/1/22

Y1 - 2015/1/22

N2 - 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.

AB - 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.

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ER -

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

Abstract

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