Brown adipose tissue (BAT) is the major thermogenic organ, which promotes energy expenditure through a process called adaptive thermogenesis. Central to the inherent thermogenic activity of brown adipocytes is uncoupling protein 1(UCP1). Other than mature adipocytes, several other cell types form the adipose niche and play important roles in BAT function and remodeling. Prolonged cold exposure increases BAT mass and activity through de novo recruitment of brown adipocytes as well as coordinated expansion of other cells within the adipose niche 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 composition of BAT and its remodeling in response to ambient temperature, we performed single-cell RNA-sequencing (scRNA-seq) of the stromal vascular fraction of BAT from mice housed at different temperatures. The unsupervised clustering identified 19 major cell types, including several sub-populations of adipose progenitors, endothelial cells, immune cells, vascular smooth muscles, and Schwann cells. The transcriptional profile of each cell type in mice housed at different temperatures revealed the dynamic remodeling of brown adipocyte niche in response to environmental challenges. Among them, we identified a novel population of brown adipose progenitors derived from BAT endothelium. These endothelial-derived adipose progenitors have a distinct gene expression profile, which distinguishes them from the previously known Pdgfra-expressing adipose progenitors. Using an inducible genetic reporter, we validated the induction of UCP1 and other thermogenic gene program in the endothelial-derived adipose progenitors upon cold exposure.
In summary, scRNA-seq of BAT provides a high-resolution map of brown adipose niche and suggests the critical contribution of each cell type to BAT functions, homeostasis, and turn-over.
F. Shamsi: None. M. Piper: None. L. Ho: None. T. Huang: None. Y. Tseng: Consultant; Self; Boehringer Ingelheim International GmbH.
American Diabetes Association (1-18-PDF-169 to F.S.); National Institutes of Health (R01DK077097, R01DK102898, P30DK036836); Harvard Stem Cell Institute