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

Abstract Hypoxia-induced upregulation of HIF1α triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1α closely interacts with PPARγ, 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, HIF1α both promotes and represses lipid accumulation during adipogenesis. We show that the opposing roles of HIF1α are isolated from each other and depend on when HIF1α increases relative to the positive-feedback mediated upregulation of PPARγ that drives adipocyte differentiation. A theoretical model incorporating our findings resolves conflicting prior results and suggests that three network nodes before and after the isolation step have to be synergistically targeted in therapeutic strategies to revert hypoxia-mediated adipose tissue dysfunction in obesity. TeaserA systems biology approach detangles the effect of hypoxic and adipogenic regulators on lipid accumulation in adipocytes.