ABSTRACT

Brown adipose tissue (BAT) is a specialized type of adipose tissue which promotes energy expenditure. Considering the capacity of BAT for energy dissipation and its role in glucose and lipid metabolism, increasing BAT mass or activity could potentially be utilized to combat obesity and its related metabolic disorders. Adipose tissue is composed of adipocytes, adipocyte progenitors, vascular cells, immune cells, and neurons. Although adipocytes play the major role in maintaining energy balance, other cell types form the adipocyte niche and regulate adipose tissue function. Cold exposure increases BAT mass through de novo recruitment of brown adipocytes to enable maximal thermogenic activity. However, the source of cold-induced brown adipocytes and the molecular mechanism regulating BAT expansion is not known. To determine the cellular origin of brown adipocytes, we performed single-cell RNA-sequencing of BAT from mice housed at different temperatures. Our analysis identified two distinct types of adipocyte progenitors: the previously reported Sca1pos Pdgfrapos mesenchymal progenitors and a new vascular smooth muscle-derived adipocyte progenitor cell (SM-APC) population that contribute to de novo recruitment of thermogenic adipocytes in cold. Using flow cytometry and lineage tracing, we demonstrated that the SM-APCs were indeed distinct from the Pdgfrapos progenitors and could contribute to thermogenic brown adipocytes in response to cold challenge. Together, these findings reveal a novel cellular origin of thermogenic adipocytes and suggest a new model for the development of BAT that could be critical in designing strategies to increase the number of brown adipocytes in humans.