Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key determining metabolic state and fate decision of brown adipocytes in mice [scRNA-seq]
Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) in mammals and might play an important role in human obesity and energy homeostasis. Recent single-cell/nucleus RNA-sequencing studies have revealed heterogeneity in thermogenesis among brown adipocytes, such as the findings of low thermogenesis and regulated thermogenesis in brown adipocytes. Activating and enhancing function adipocytes (BAC) has acquired attention as a possible therapeutic intervention for metabolic diseases. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of multiple cellular functions and responds to various stress in many cells and tissues. NFE2L1 acts as a guardian role in BAC function providing increased proteometabolic quality control for adapting to cold or obesity. Our previous studies demonstrated that NFE2L1-dependent lipolytic activity is crucial for white adipose tissue (WAT) plasticity and lipid homeostasis. ?To further clarify the role of NFE2L1 in adipocytes, we focused on the phenotype and gene expression profiling of BAT in adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice. We found that deletion of Nfe2l1 decreased core body temperature and cold intolerance under cold exposure. Compared with floxed mice, the BAT of Nfe2l1(f)-KO mice expressed substantially lower levels of many genes related to lipolysis, thermogenesis, oxidative capacity of mitochondria, cellular respiration while higher genes related to inflammation, pyroptosis. By snRNA-seq, we found that Nfe2l1-knockout resulted in increased antigen processing and presentation (APP), necroptosis and NOD-like receptor signal pathway (NOD) signaling pathways in most subpopulations of BAC, with devastating effects on a normal subpopulation of BAC with low thermogenesis and high necroptosis genes expression. Absent of Nfe2l1 impairs the function of BAC, causing a morphological “whitening” phenotype with adipocyte hypertrophy and severe inflammation. Moreover, the adipose inflammation and pyroptosis in Nfe2l1(f)-KO mice could be mitigated by cold exposure or ß3-agonist treatment. These findings provided a deeper insight into the function of NFE2L1 in the metabolic programming of brown adipocytes. Overall design: Single-nucleus RNA-sequencing profiles of BAT from Flox and Nfe2l1(f)-KO mice at 4 weeks.