A dynamic HIF1α- PPARγ circuit controls a paradoxical adipocyte regulatory landscape

Hypoxia-induced upregulation of HIF1alpha; triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1alpha; closely interacts with PPARgamma;, the master regulator of adipocyte differentiation and lipid accumulation, but there are conflicting results how this co-regulation controls the excessive lipid accumulation that drives adipocyte dysfunction. Using single-cell imaging and modeling, we find that, surprisingly, HIF1alpha; both promotes and represses lipid accumulation during adipogenesis. We show that the opposing roles of HIF1alpha; are isolated from each other and depend on when HIF1alpha; increases relative to the positive-feedback mediated upregulation of PPARgamma; that drives adipocyte differentiation. A theoretical model incorporating our findings resolves the conflicting prior results and predicts that therapeutic strategies based on proper timing and three-point regulation can revert hypoxia-mediated adipose tissue dysfunction in obesity. ### Competing Interest Statement The authors have declared no competing interest.