Age-dependent progenitor switching shapes adult brown adipose tissue heterogeneity

The ontogeny of brown adipose tissue (BAT) begins during embryogenesis and continues into the postnatal period and throughout adulthood. Distinct populations of adipose progenitor cells (APCs) have been identified to support BAT development and thermogenesis; however, the division of labor and temporal relationship between different APCs, particularly during adulthood and aging, remain undetermined. Here, we showed that Pdgfra+ APCs establish BAT in early life but have a limited contribution to brown adipogenesis in adult mice housed at room temperature. Using integrative single-cell analysis and lineage tracing, we identified a distinct population of Myl1-expressing cells that emerge in an age-dependent manner and function as committed BAT progenitors in adult and middle-aged mice. Myl1+ APC-derived brown adipocytes possess a unique molecular signature that links to more dependence on oxidative phosphorylation over glycolysis, thus contributing to heterogeneous metabolic activity in adult BAT. The ablation of Myl1+ descendants or the blockade of Myl1+ APC differentiation leads to BAT paucity and impaired glucose metabolism in adult mice. Collectively, our results support a progenitor switching model in which distinct APC populations control sequential brown adipogenesis and shape BAT heterogeneity.