Hypoxia-inducible factors (HIFs) are transcription factors in the basic helix–loop–helix PER-ARNT-SIM (bHLH-PAS) protein family that contain internal hydrophobic cavities within their PAS-A and PAS-B domains. Among HIFs, the HIF-2α PAS-B domain contains a relatively large cavity exploited for the development of specific artificial ligands such as PT2399. Administration of PT2399 could suppress HIF-2α target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2α PAS-B domain suppressed HIF-2α activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF-2α hypoxia response. In contrast, the mutant mice did not phenocopy PT2399 intervention in wild-type mice under metabolic stress. Under a high-fat diet (HFD), the mutant mice exert enhanced adipogenesis and obtain larger adipose mass and body weight gain compared to wild type. However, administration of PT2399 along with HFD feeding sufficiently suppressed HFD-induced body weight and adipose mass increase through suppression of adipogenesis and lipogenesis. The accompanying decreased lipid accumulation in the liver and improved glucose tolerance in wild-type mice were not observed in the mutant mice indicating negative regulation of HIF-2α on obesity and a complex role for the PAS-B domain in metabolic regulation. Notably, short-term administration of PT2399 to obese mice decreased adipose mass and improved metabolic condition. These results indicate a regulatory role for HIF-2α in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders.

缺氧诱导因子（HIF）是基本螺旋-环-螺旋PER-ARNT-SIM（bHLH-PAS）蛋白家族中的转录因子，在其PAS-A和PAS-B结构域中包含内部疏水腔。在HIF中，HIF-2αPAS-B结构域包含一个相对较大的空腔，用于开发特定的人工配体（例如PT2399）。在缺氧条件下，给予PT2399可以抑制HIF-2α靶基因的表达，而不会影响小鼠的HIF-1活性。HIF-2αPAS-B结构域内的单个突变（S305M）抑制了HIF-2α活性，同时赋予了体内对PT2399的抗性，表明PAS-B结构域在HIF-2α缺氧反应中起着至关重要的作用。相反，突变小鼠在代谢应激下未对野生型小鼠进行PT2399干预。在高脂饮食（HFD）下，与野生型小鼠相比，突变型小鼠脂肪形成能力增强，脂肪量和体重增加。然而，通过抑制脂肪生成和脂肪生成，与HFD饲喂一起施用PT2399可以充分抑制HFD诱导的体重和脂肪增加。在突变型小鼠中未观察到伴随的肝脏中脂质积累的减少和野生型小鼠中葡萄糖耐量的改善，这表明HIF-2α对肥胖具有负调节作用，而PAS-B结构域在代谢调节中起着复杂的作用。值得注意的是，对肥胖小鼠短期施用PT2399可减少脂肪量并改善代谢状况。这些结果表明了HIF-2α在肥胖症发展中的调节作用，并提示了PT2399在肥胖症和相关代谢紊乱中的治疗机会。