Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity
A recent publication in Cell Stem Cell led by Dr. Mengle Shao at Dr. Rana Gupta’s lab at UT Southwestern identified a novel mechanism underlying adipose progenitor cell activity regulation by the hypoxia-inducible factor-1α (HIF-1α). Adipose precursor cells (APCs) exhibit regional variation in response to obesity, for unclear reasons. Here, this study reveals 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. These findings 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. Other CADA members, including Dr. Bo Shan, Dr. Shangang Zhao, Dr. Yu An, and Dr. Yibo Wu, also made contributions to this work.