Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice
Wei Shen,
Suping Ren,
Yongyong Hou,
Zhuo Zuo,
Shengnan Liu,
Zhiyuan Liu,
Jingqi Fu,
Huihui Wang,
Bei Yang,
Rui Zhao,
Yanyan Chen,
Masayuki Yamamoto,
Yuanyuan Xu,
Qiang Zhang,
Jingbo Pi
Affiliations
Wei Shen
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Suping Ren
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Yongyong Hou
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Zhuo Zuo
Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Shengnan Liu
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Zhiyuan Liu
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Jingqi Fu
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Huihui Wang
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Bei Yang
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; School of Basic Medical Sciences, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Rui Zhao
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Yanyan Chen
The First Affiliated Hospital, China Medical University, No. 155 Nanjing North Road, Heping Area, Shenyang, Liaoning, 110001, China
Masayuki Yamamoto
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
Yuanyuan Xu
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China
Qiang Zhang
Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, GA, 30322, USA; Corresponding author.
Jingbo Pi
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China; Corresponding author. Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, China.
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.
