Vascular smooth muscle-derived Trpv1+ progenitors are a source of cold-induced thermogenic adipocytes

Abstract

Brown adipose tissue (BAT) and related beige fat function in energy expenditure in part due to their role in thermoregulation. The prominent capacity of thermogenic fat to enhance fuel utilization and energy expenditure makes it an attractive target for treating obesity and metabolic disorders. While prolonged cold exposure increases BAT mass through de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we sought to investigate the cellular origin of cold-induced brown adipocytes using single-cell RNA sequencing. We identify two distinct types of adipocyte progenitors that contribute to de novo recruitment of brown adipocytes in response to cold challenge. One population is the previously-known Pdgfr-expressing mesenchymal progenitors, while the other is a previously-unidentified vascular smooth muscle-derived adipocyte progenitor (VSM-APC) population, which expresses the temperature-sensitive ion channel transient receptor potential cation channel subfamily V member 1 (Trpv1). Using flow cytometry and lineage tracing, we demonstrate that the Trpv1-positive VSM-APCs are distinct from the Pdgfr-positive progenitors, and can give rise to thermogenic adipocytes in response to cold. Together, these findings illustrate the landscape of the thermogenic adipose niche at the single cell resolution and identify a new cellular origin for the development of brown and beige adipocytes.