Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity

Adipose precursor cells (APCs) exhibit regional variation in response to obesity, for unclear reasons. Here, we reveal that HIFα-induced PDGFRβ signaling within murine white adipose tissue (WAT) PDGFRβ+ cells drives inhibitory serine 112 (S112) phosphorylation of PPARγ, the master regulator of adipogenesis. Levels of PPARγ S112 phosphorylation in WAT PDGFRβ+ cells are depot dependent, with levels of PPARγ phosphorylation in PDGFRβ+ cells inversely correlating with their capacity for adipogenesis upon high-fat-diet feeding. HIFα suppression in PDGFRβ+ progenitors promotes subcutaneous and intra-abdominal adipogenesis, healthy WAT remodeling, and improved metabolic health in obesity. These metabolic benefits are mimicked by treatment of obese mice with the PDGFR antagonist Imatinib, which promotes adipocyte hyperplasia and glucose tolerance in a progenitor cell PPARγ-dependent manner. Our studies unveil a mechanism underlying depot-specific responses of APCs to high-fat feeding and highlight the potential for APCs to be targeted pharmacologically to improve metabolic health in obesity. [Display omitted] •PPARγ S112 phosphorylation underlies depot differences in preadipocyte activity•Mural cell HIFα drives PPARγ phosphorylation and suppression of adipogenesis•Inhibition of mural cell HIFα promotes adipogenesis and limits fibrosis in obesity•Anti-diabetic effects of Imatinib dependent on mural cell PPARγ and adipogenesis How adipocyte precursor cells are regulated to control depot-specific adipose tissue expansion in obesity remains unclear. Here, Shao et al. identify a HIFα-dependent regulatory mechanism controlling adipocyte progenitor activity in mice and demonstrate the ability of the anti-cancer drug Imatinib to promote metabolically beneficial adipogenesis in obesity.