The Notch-Pdgfrβ axis suppresses brown adipocyte progenitor differentiation in early postnatal mice

ABSTRACT De novo brown adipogenesis holds potential in combating the epidemics 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 observed that PDGFRβ+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRβ+ pericytes promotes brown adipogenesis through the downregulation of PDGFRβ. Furthermore, inhibition of Notch signaling in PDGFRβ+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFRβ axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health. Highlights PDGFRβ+ pericytes act as an essential developmental brown APC. TBX18+ pericytes contribute to brown adipogenesis in a depot-specific manner. Inhibiting Notch-Pdgfrβ axis promotes brown APC adipogenesis. Enhanced postnatal brown adipogenesis improves metabolic health in adult stage.