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

Research output: Contribution to journalArticle

36 Scopus citations

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. Hasegawa et al. identify GTF2IRD1 as a cold-inducible transcription factor that represses adipose tissue fibrosis through a PRDM16-EHMT1 complex. Repression of adipose tissue fibrosis by the complex improves systemic glucose homeostasis independent of UCP1-mediated thermogenesis and body weight. In humans, GTF2IRD1 expression inversely correlates with subcutaneous WAT fibrosis and visceral adiposity.

Original languageEnglish (US)
Pages (from-to)180-194.e6
JournalCell metabolism
Volume27
Issue number1
DOIs
StatePublished - Jan 9 2018
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis'. Together they form a unique fingerprint.

  • Cite this

    Hasegawa, Y., Ikeda, K., Chen, Y., Alba, D. L., Stifler, D., Shinoda, K., Hosono, T., Maretich, P., Yang, Y., Ishigaki, Y., Chi, J., Cohen, P., Koliwad, S. K., & Kajimura, S. (2018). Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis. Cell metabolism, 27(1), 180-194.e6. https://doi.org/10.1016/j.cmet.2017.12.005