Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis.
Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis.
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通过 PRDM16-GTF2IRD1 复合物抑制脂肪组织纤维化可改善系统性葡萄糖稳态
DOI：
10.1016/j.cmet.2017.12.005
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发表时间：
2018-01-09
期刊：
影响因子：
29
通讯作者：
Kajimura S
中科院分区：
文献类型：
--
作者：
Hasegawa Y;Ikeda K;Chen Y;Alba DL;Stifler D;Shinoda K;Hosono T;Maretich P;Yang Y;Ishigaki Y;Chi J;Cohen P;Koliwad SK;Kajimura S
脂肪组织纤维化是与胰岛素抵抗和2型糖尿病相关的功能障碍的标志；然而，调控这一过程的因素仍不清楚。在这里，我们发现PRDM16转录复合物，棕色/米色脂肪细胞发育的主要激活因子，以不依赖于ucp1的方式有效抑制脂肪组织纤维化。通过纯化PRDM16复合体，我们确定了GTF2IRD1， TFII-I dna结合蛋白家族的成员，作为介导PRDM16复合体对纤维化的抑制作用的冷诱导转录因子。脂肪细胞选择性表达GTF2IRD1可抑制脂肪组织纤维化，改善不依赖于体重减轻的全身葡萄糖稳态，而消耗GTF2IRD1可以细胞自主方式促进纤维化。GTF2IRD1通过将PRDM16和EHMT1募集到启动子/增强子区域，抑制TGF-β依赖性促纤维化基因的转录。这些结果表明，通过PRDM16复合物抑制肥胖相关脂肪组织纤维化导致全身葡萄糖稳态改善的机制。Hasegawa等人发现GTF2IRD1是一种冷诱导转录因子，通过PRDM16-EHMT1复合物抑制脂肪组织纤维化。该复合物对脂肪组织纤维化的抑制改善了独立于ucp1介导的产热和体重的全身葡萄糖稳态。在人类中，GTF2IRD1的表达与皮下WAT纤维化和内脏肥胖呈负相关。
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 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 depleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of TGF-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.
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影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
影响因子：
29
作者：
Harms MJ;Ishibashi J;Wang W;Lim HW;Goyama S;Sato T;Kurokawa M;Won KJ;Seale P
通讯作者：
Seale P
影响因子：
10.5
作者：
Kajimura, Shingo;Seale, Patrick;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
64.5
作者：
Cohen P;Levy JD;Zhang Y;Frontini A;Kolodin DP;Svensson KJ;Lo JC;Zeng X;Ye L;Khandekar MJ;Wu J;Gunawardana SC;Banks AS;Camporez JP;Jurczak MJ;Kajimura S;Piston DW;Mathis D;Cinti S;Shulman GI;Seale P;Spiegelman BM
通讯作者：
Spiegelman BM
影响因子：
15.9
作者：
Koliwad, Suneil K.;Streeper, Ryan S.;Farese, Robert V., Jr.
通讯作者：
Farese, Robert V., Jr.