Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Cell Syst. 2023 Dec 20;14(12):1074-1086.e7. doi: 10.1016/j.cels.2023.10.010. Epub 2023 Nov 22.
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 regarding how this interaction controls the excessive lipid accumulation that drives adipocyte dysfunction. To directly address these conflicts, we established a differentiation system that recapitulated prior seemingly opposing observations made across different experimental settings. Using single-cell imaging and coarse-grained mathematical modeling, we show how HIF1α can both promote and repress lipid accumulation during adipogenesis. Our model predicted and our experiments confirmed that the opposing roles of HIF1α are isolated from each other by the positive-feedback-mediated upregulation of PPARγ that drives adipocyte differentiation. Finally, we identify three factors: strength of the differentiation cue, timing of hypoxic perturbation, and strength of HIF1α expression changes that, when considered together, provide an explanation for many of the previous conflicting reports.
缺氧诱导因子 1α 的上调触发肥胖患者脂肪组织功能障碍和胰岛素抵抗。HIF1α 与过氧化物酶体增殖物激活受体 γ（PPARγ）密切相互作用，后者是脂肪细胞分化和脂质积累的主要调节剂，但关于这种相互作用如何控制驱动脂肪细胞功能障碍的过量脂质积累，存在相互矛盾的结果。为了直接解决这些冲突，我们建立了一个分化系统，该系统再现了先前在不同实验环境中观察到的似乎相互矛盾的结果。使用单细胞成像和粗粒度数学建模，我们展示了 HIF1α 如何在脂肪生成过程中促进和抑制脂质积累。我们的模型预测并通过实验证实，HIF1α 的拮抗作用彼此隔离，这是由促进脂肪细胞分化的 PPARγ 的正反馈介导的上调所驱动的。最后，我们确定了三个因素：分化信号的强度、缺氧干扰的时间以及 HIF1α 表达变化的强度，当综合考虑时，这些因素可以解释许多先前相互矛盾的报告。
