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Cell Rep. 2014 Jun 26;7(6):1876-86. doi: 10.1016/j.celrep.2014.05.030. Epub 2014 Jun 12.

NUCKS is a positive transcriptional regulator of insulin signaling.

Author information

1
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
2
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138667, Singapore.
3
State Key Laboratory of Pharmaceutical Biotechnology, Hong Kong, China.
4
University of Osaka, Osaka 565-0871, Japan.
5
State Key Laboratory of Pharmaceutical Biotechnology, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China.
6
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138667, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: weiping_han@sbic.a-star.edu.sg.
7
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: vinayt@imcb.a-star.edu.sg.

Abstract

Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells. NUCKS knockout mice exhibit decreased insulin signaling and increased body weight/fat mass along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by a high-fat diet (HFD). Genome-wide ChIP-seq identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is downregulated in individuals with a high body mass index and in HFD-fed mice, and conversely, its levels increase upon starvation. Altogether, NUCKS is a physiological regulator of energy homeostasis and glucose metabolism that works by regulating chromatin accessibility and RNA polymerase II recruitment to the promoters of IR and other insulin pathway modulators.

PMID:
24931609
DOI:
10.1016/j.celrep.2014.05.030
[Indexed for MEDLINE]
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