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

• Published in: Cell metabolism 2018-01, Vol.27 (1), p.180-194.e6
• Main Authors: Hasegawa, Yutaka, Ikeda, Kenji, Chen, Yong, Alba, Diana L., Stifler, Daniel, Shinoda, Kosaku, Hosono, Takashi, Maretich, Pema, Yang, Yangyu, Ishigaki, Yasushi, Chi, Jingyi, Cohen, Paul, Koliwad, Suneil K., Kajimura, Shingo
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Adipose Tissue - metabolism; Adipose Tissue - pathology; adipose tissue fibrosis; Adipose Tissue, Brown - metabolism; Animals; beige adipocyte; Body Weight; brown adipose tissue; diabetes; Diet; DNA-Binding Proteins - metabolism; EHMT1; Fibrosis; Gene Expression Regulation; Glucose - metabolism; GTF2IRD1; Histone-Lysine N-Methyltransferase - metabolism; Homeostasis; Insulin Resistance; Mice, Transgenic; Muscle Proteins - metabolism; Nuclear Proteins - metabolism; obesity; PRDM16; Trans-Activators - metabolism; Transcription Factors - metabolism; UCP1-independent; Uncoupling Protein 1 - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.12.005

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. [Display omitted] •GTF2IRD1 is a transcription factor that forms a complex with PRDM16 and EHMT1•A PRDM16-GTF2IRD1 complex cell-autonomously represses adipose tissue fibrosis•Repression of adipose tissue fibrosis improves systemic glucose homeostasis•GTF2IRD1 expression inversely correlates with subcutaneous WAT fibrosis in humans 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.