Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.
Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.
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DOI：
10.1038/nm.4481
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发表时间：
2018-03
期刊：
影响因子：
82.9
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
Bartelt A;Widenmaier SB;Schlein C;Johann K;Goncalves RLS;Eguchi K;Fischer AW;Parlakgül G;Snyder NA;Nguyen TB;Bruns OT;Franke D;Bawendi MG;Lynes MD;Leiria LO;Tseng YH;Inouye KE;Arruda AP;Hotamisligil GS
脂肪细胞对营养过剩、禁食或寒冷暴露具有显著的适应能力，因此是维持适当代谢健康的重要细胞类型。虽然内质网（ER）是细胞内稳态的关键细胞器，但介导脂肪细胞中ER适应代谢挑战的机制尚不清楚。在这里，我们表明，棕色脂肪组织（BAT）产热功能需要蛋白酶体活性的适应性增加，以确保细胞蛋白质的质量控制，并确定ER定位的转录因子核因子红细胞-2，像-1（Nfe 2l 1，也称为Nrf 1）作为这一过程的关键驱动程序。我们发现，冷适应诱导BAT中的Nrf 1增加蛋白酶体活性，这对于维持ER稳态和细胞完整性至关重要，特别是当细胞处于高产热活性状态时。在小鼠中，在产热条件下，棕色脂肪细胞特异性缺失Nrf 1导致ER应激、组织炎症、线粒体功能显著降低和BAT变白。在遗传性和饮食性肥胖的小鼠模型中，通过在BAT中外源表达Nrf 1或蛋白酶体激活剂PA 28 α来刺激蛋白酶体活性，可改善胰岛素敏感性。总之，Nrf 1作为棕色脂肪细胞功能的新监护人出现，为适应寒冷或肥胖提供增加的蛋白质代谢质量控制。
Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and thus are an important cell type to maintain proper metabolic health. While the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER in adipocytes to metabolic challenges are unclear. Here, we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and identify the ER-localized transcription factor nuclear factor erythroid-2, like-1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induced Nrf1 in BAT to increase proteasomal activity, and that this was crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown adipocyte-specific deletion of Nrf1 resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.
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影响因子：
16.6
作者：
Berbée JF;Boon MR;Khedoe PP;Bartelt A;Schlein C;Worthmann A;Kooijman S;Hoeke G;Mol IM;John C;Jung C;Vazirpanah N;Brouwers LP;Gordts PL;Esko JD;Hiemstra PS;Havekes LM;Scheja L;Heeren J;Rensen PC
通讯作者：
Rensen PC
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R
影响因子：
4.3
作者：
Clarke, Kieran J.;Adams, Alison E.;Porter, Richard K.
通讯作者：
Porter, Richard K.