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

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Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis.
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jan-09 , DOI: 10.1016/j.cmet.2017.12.005
Yutaka Hasegawa ₁ , Kenji Ikeda ₂ , Yong Chen ₂ , Diana L Alba ₃ , Daniel Stifler ₃ , Kosaku Shinoda ₂ , Takashi Hosono ₄ , Pema Maretich ₂ , Yangyu Yang ₂ , Yasushi Ishigaki ₅ , Jingyi Chi ₆ , Paul Cohen ₆ , Suneil K Koliwad ₃ , Shingo Kajimura ₂

Affiliation

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.
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.
UCSF Diabetes Center, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
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.
Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Morioka, Uchimaru, Japan.
The Rockefeller University, Laboratory of Molecular Metabolism, New York, NY, USA.

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.

中文翻译：

通过PRDM16-GTF2IRD1复合物抑制脂肪组织纤维化可改善全身葡萄糖体内稳态。

脂肪组织纤维化是功能异常的标志，与胰岛素抵抗和2型糖尿病有关。但是，尚不清楚如何规范此过程。在这里，我们显示PRDM16转录复合体，棕色/米色脂肪细胞发育的主要激活因子，以非偶联蛋白1（UCP1）独立的方式有效抑制脂肪组织纤维化。通过纯化PRDM16复合物，我们确定了DNA结合蛋白TFII-I家族成员GTF2IRD1为介导PRDM16复合物对纤维化的抑制作用的冷诱导转录因子。GTF2IRD1的脂肪细胞选择性表达可抑制脂肪组织纤维化并改善全身葡萄糖稳态，而与体重减轻无关，而删除GTF2IRD1则以细胞自主方式促进纤维化。GTF2IRD1通过将PRDM16和EHMT1募集到它们的启动子/增强子区域来抑制转化生长因子β依赖性纤维化基因的转录。这些结果表明通过PRDM16复合物抑制肥胖相关的脂肪组织纤维化的机制导致全身葡萄糖稳态的改善。

更新日期：2018-01-09

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