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

Yutaka Hasegawa; Kenji Ikeda; Yong Chen; Diana L Alba; Daniel Stifler; Kosaku Shinoda; Takashi Hosono; Pema Maretich; Yangyu Yang; Yasushi Ishigaki; Jingyi Chi; Paul Cohen; Suneil K Koliwad; Shingo Kajimura

doi:10.1016/j.cmet.2017.12.005

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

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

Authors

Affiliations

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism
Adipose Tissue / metabolism*
Adipose Tissue / pathology*
Adipose Tissue, Brown / metabolism
Animals
Body Weight
DNA-Binding Proteins / metabolism*
Diet
Fibrosis
Gene Expression Regulation
Glucose / metabolism*
Histone-Lysine N-Methyltransferase / metabolism
Homeostasis*
Insulin Resistance
Mice, Transgenic
Muscle Proteins / metabolism*
Nuclear Proteins / metabolism*
Trans-Activators / metabolism*
Transcription Factors / metabolism*
Uncoupling Protein 1 / metabolism

Substances

DNA-Binding Proteins
Gtf2ird1 protein, mouse
Muscle Proteins
Nuclear Proteins
Prdm16 protein, mouse
Trans-Activators
Transcription Factors
Uncoupling Protein 1
GLP protein, mouse
Histone-Lysine N-Methyltransferase
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding