| First Author | Feng Z | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 52 | Pages | 13240-13245 |
| PubMed ID | 30523118 | Mgi Jnum | J:268894 |
| Mgi Id | MGI:6272246 | Doi | 10.1073/pnas.1810897115 |
| Citation | Feng Z, et al. (2018) Modulation of HIF-2alpha PAS-B domain contributes to physiological responses. Proc Natl Acad Sci U S A 115(52):13240-13245 |
| abstractText | 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-2alpha 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-2alpha target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2alpha PAS-B domain suppressed HIF-2alpha activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF-2alpha 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-2alpha 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-2alpha in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders. |
