PDF(Pubmed)
Abstract：
Brown adipose tissue (BAT) is a major site of non-shivering thermogenesis in mammals and plays an important role in energy homeostasis. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a master regulator of cellular metabolic homeostasis and numerous stress responses, has been found to function as a critical driver in BAT thermogenic adaption to cold or obesity by providing proteometabolic quality control. Our recent studies using adipocyte-specific Nfe2l1 knockout [Nfe2l1(f)-KO] mice demonstrated that NFE2L1-dependent transcription of lipolytic genes is crucial for white adipose tissue (WAT) homeostasis and plasticity. In the present study, we found that Nfe2l1(f)-KO mice develop an age-dependent whitening and shrinking of BAT, with signatures of down-regulation of proteasome, impaired mitochondrial function, reduced thermogenesis, pro-inflammation, and elevated regulatory cell death (RCD). Mechanistic studies revealed that deficiency of Nfe2l1 in brown adipocytes (BAC) primarily results in down-regulation of lipolytic genes, which decelerates lipolysis, making BAC unable to fuel thermogenesis. These changes lead to BAC hypertrophy, inflammation-associated RCD, and consequently cold intolerance. Single-nucleus RNA-sequencing of BAT reveals that deficiency of Nfe2l1 induces significant transcriptomic changes leading to aberrant expression of a variety of genes involved in lipid metabolism, proteasome, mitochondrial stress, inflammatory responses, and inflammation-related RCD in distinct subpopulations of BAC. Taken together, our study demonstrated that NFE2L1 serves as a vital transcriptional regulator that controls the lipid metabolic homeostasis in BAC, which in turn determines the metabolic dynamics, cellular heterogeneity and subsequently cell fates in BAT.
摘要：
棕色脂肪组织（BAT）是哺乳动物非发抖产热的主要部位，在能量稳态中起着重要作用。核因子-红系2相关因子1（NFE2L1，也称为Nrf1），细胞代谢稳态和许多应激反应的主要调节剂，通过提供蛋白质代谢质量控制，已发现在BAT对感冒或肥胖的热适应中起关键驱动因素。我们最近使用脂肪细胞特异性Nfe2l1敲除[Nfe2l1（f）-KO]小鼠进行的研究表明，NFE2L1依赖的脂解基因转录对于白色脂肪组织（WAT）稳态和可塑性至关重要。在本研究中,我们发现Nfe2l1(f)-KO小鼠发展出年龄依赖性的BAT增白和收缩,带有蛋白酶体下调的标志，线粒体功能受损，减少产热，促炎症，和升高的调节性细胞死亡（RCD）。机制研究表明，棕色脂肪细胞（BAC）中Nfe2l1的缺乏主要导致脂解基因的下调，减缓脂肪分解，使BAC无法为产热提供燃料。这些变化导致BAC肥大,炎症相关RCD,因此，冷不容忍。BAT的单核RNA测序显示，Nfe2l1的缺乏诱导显著的转录组变化，导致多种参与脂质代谢的基因的异常表达。蛋白酶体,线粒体应激，炎症反应，和BAC不同亚群的炎症相关RCD。一起来看,我们的研究表明，NFE2L1作为一个重要的转录调节因子，控制BAC中的脂质代谢稳态，这反过来又决定了代谢动力学，BAT中的细胞异质性和随后的细胞命运。
