Journal:
Cell Metabolism
Publication Date:
Tue, 2018-01-09
Institutions:
1UCSF Diabetes Center, San Francisco, CA, USA
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA
3Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
4Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
5The Rockefeller University, Laboratory of Molecular Metabolism, New York, NY, USA
6Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Morioka, Uchimaru, Japan
7Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Tokyo, Japan
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 b-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.
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