Role of Notch Signaling in Regulating Pericyte Contribution to Brown Adipose Tissue Development

De novo brown adipogenesis holds potential in combating the epidemic of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here through in vivo lineage tracing, we found that PDGFRβ+ pericytes give rise to developmental but not adult brown adipocytes. In contrast, Tbx18+ pericytes contribute to brown adipogenesis during development and the adult stage in a depot-specific mode. Mechanistically, Notch inhibition in PDGFRβ+ pericytes promotes brown adipogenesis through the downregulation of Pdgfrβ. Furthermore, inhibition of Notch signaling in PDGFRβ+ pericytes mitigates HFHS-induced glucose and metabolic impairment in both developmental and adult stages. Finally, Notch signaling regulates developmental beige adipogenesis through promoting beige APC differentiation whereas it regulates adult cold-induced beige adipogenesis through regulating pericyte secretome. Collectively, these findings show that Notch/PDGFRβ axis regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.