Format

Send to

Choose Destination
Cell Metab. 2018 Jan 9;27(1):180-194.e6. doi: 10.1016/j.cmet.2017.12.005.

Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis.

Author information

1
UCSF Diabetes Center, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Morioka, Uchimaru, Japan.
2
UCSF Diabetes Center, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
3
UCSF Diabetes Center, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
4
UCSF Diabetes Center, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Tokyo, Japan.
5
Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Morioka, Uchimaru, Japan.
6
The Rockefeller University, Laboratory of Molecular Metabolism, New York, NY, USA.
7
UCSF Diabetes Center, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Electronic address: suneil.koliwad2@ucsf.edu.
8
UCSF Diabetes Center, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: shingo.kajimura@ucsf.edu.

Abstract

Adipose tissue fibrosis is a hallmark of malfunction that is linked to insulin resistance and type 2 diabetes; however, what regulates this process remains unclear. Here we show that the PRDM16 transcriptional complex, a dominant activator of brown/beige adipocyte development, potently represses adipose tissue fibrosis in an uncoupling protein 1 (UCP1)-independent manner. By purifying the PRDM16 complex, we identified GTF2IRD1, a member of the TFII-I family of DNA-binding proteins, as a cold-inducible transcription factor that mediates the repressive action of the PRDM16 complex on fibrosis. Adipocyte-selective expression of GTF2IRD1 represses adipose tissue fibrosis and improves systemic glucose homeostasis independent of body-weight loss, while deleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of transforming growth factor β-dependent pro-fibrosis genes by recruiting PRDM16 and EHMT1 onto their promoter/enhancer regions. These results suggest a mechanism by which repression of obesity-associated adipose tissue fibrosis through the PRDM16 complex leads to an improvement in systemic glucose homeostasis.

KEYWORDS:

EHMT1; GTF2IRD1; PRDM16; UCP1-independent; adipose tissue fibrosis; beige adipocyte; brown adipose tissue; diabetes; insulin resistance; obesity

PMID:
29320702
PMCID:
PMC5765755
DOI:
10.1016/j.cmet.2017.12.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center