Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue

Authors: SONG, ANYING - City Of Hope Medical Center; DAI, WENTING - City Of Hope Medical Center; JANG, MIN JEE - California Institute Of Technology; MEDRANO, LEONARD - City Of Hope Medical Center; LI, ZHUO - City Of Hope Medical Center; ZHAO, HU - Texas A&M University; SHAO, MENGLE - University Of Texas Southwestern Medical Center; TAN, JIAYI - City Of Hope Medical Center; LI, AIMIN - City Of Hope Medical Center; NING, TINGLU - City Of Hope Medical Center; MILLER, MARCIA - City Of Hope Medical Center; ARMSTRONG, BRIAN - City Of Hope Medical Center; HUSS, JANICE - City Of Hope Medical Center; ZHU, YI - Children'S Nutrition Research Center (CNRC); LIU, YONG - Wuhan University; GRADINARU, VIVIANA - California Institute Of Technology; WU, XIWEI - City Of Hope Medical Center; JIANG, LEI - City Of Hope Medical Center; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center; WANG, QIONG - City Of Hope Medical Center

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/25/2019
Publication Date: 11/25/2019
Citation: Song, A., Dai, W., Jang, M., Medrano, L., Li, Z., Zhao, H., Shao, M., Tan, J., Li, A., Ning, T., Miller, M.M., Armstrong, B., Huss, J.M., Zhu, Y., Liu, Y., Gradinaru, V., Wu, X., Jiang, L., Scherer, P.E., Wang, Q.A. 2019. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. Journal of Clinical Investigation. 130(1):247-257. https://doi.org/10.1172/JCI129167.
DOI: https://doi.org/10.1172/JCI129167

Interpretive Summary: Brown adipose tissue (BAT) is a thermogenic organ that is thought to play an important role in human energy homeostasis. Brown adipose tissue is the main site of adaptive thermogenesis, wherein this tisse exerts beneficial metabolic effects on obesity. This paper identifies a high degree of functional heterogeneity of brown adipocytes in the depot and suggests future strategies that promote the low-thermogenic brown adipocytes to high-thermogenic cells may enhance brown adipose tissue thermogenesis and improve metabolic function.The results presented here offer critical insight toward our understanding of how brown adipose tissue thermogenesis is regulated at the cellular level. Future studies will need to address the metabolic functions and lineages of the low-thermogenic brown adipocyte subpopulation.

Technical Abstract: Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high-fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.