Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes 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 we 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 induces Nrf1 in BAT to increase proteasomal activity and that this is 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 Nfe2l1 (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 by treatment with 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.

中文翻译：

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棕色脂肪组织产热适应需要 Nrf1 介导的蛋白酶体活性。


脂肪细胞具有显着的适应能力，可以应对营养过剩、禁食或寒冷暴露，因此它们是维持适当代谢健康的重要细胞类型。尽管内质网 (ER) 是细胞稳态的关键细胞器，但介导 ER 适应脂肪细胞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) 生热功能需要适应性增加蛋白酶体活性，以确保细胞蛋白质质量控​​制，并且我们鉴定了内质网定位的转录因子核因子红细胞 2 样 1（Nfe2l1，也称为 Nrf1）作为这一过程的关键驱动力。我们发现冷适应会诱导 BAT 中的 Nrf1 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生热活性状态时。在小鼠中，在产热条件下，棕色脂肪细胞特异性缺失 Nfe2l1 (Nrf1) 会导致 ER 应激、组织炎症、线粒体功能显着减弱以及 BAT 变白。在遗传性肥胖和饮食性肥胖的小鼠模型中，通过外源表达 Nrf1 或用 BAT 中的蛋白酶体激活剂 PA28α 处理来刺激蛋白酶体活性，可改善胰岛素敏感性。总之，Nrf1 成为棕色脂肪细胞功能的新型守护者，为适应寒冷或肥胖提供增强的蛋白质代谢质量控制。