Commitment of adipose-resident c-kit+ progenitors to brown adipocytes contributes to adipose tissue homeostasis and remodeling

The global incidence of obesity-related metabolic disorders and their comorbidities continue to increase along with a demand for innovative therapeutic interventions. An in-depth understanding of de novo thermogenic adipogenesis is vital to harness the potential of these adipocytes. Here, we combine genetic lineage tracing and single-nucleus RNA Sequencing to demonstrate that adult adipose-resident c-Kit⁺ cells are previously unidentified brown adipocyte progenitor cells (APCs). c-Kit⁺ APCs differentiate into brown adipocytes but not white adipocytes in adipose tissue homeostasis as well as in cold exposure-, high-fat diet (HFD)- and aging-induced adipose remodeling. More importantly, the vital role of c-Kit⁺ APCs in the generation of brown adipocytes is indicated by decreased brown fat, impaired thermogenic capacity, and excessive fat accumulation in c-Kit mutant mice of both genders. In conclusion, the present study demonstrates that adult c-Kit⁺ APCs give rise to brown adipocytes which are responsible for fat homeostasis and remodeling. Thus, c-Kit⁺ progenitors may be an innovative and crucial target for obesity and metabolic diseases.