| First Author | Wang Z | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 13 | Pages | 4946-4955 |
| PubMed ID | 30709906 | Mgi Jnum | J:280322 |
| Mgi Id | MGI:6316570 | Doi | 10.1074/jbc.RA118.005429 |
| Citation | Wang Z, et al. (2019) Age-dependent decline of hypothalamic HIF2alpha in response to insulin and its contribution to advanced age-associated metabolic disorders in mice. J Biol Chem 294(13):4946-4955 |
| abstractText | Hypoxia-inducible factor-2alpha (HIF2alpha) is a nuclear transcription factor that plays a critical role in cell survival including metabolic adaptation under hypoxia as well as normoxia, but whether HIF2alpha contributes to the control of whole-body metabolic balance is unclear. In this study, we found that the hypothalamic HIF2alpha protein level rapidly increases in young mice that are centrally stimulated with insulin. However, this insulin-induced HIF2alpha up-regulation is substantially attenuated in mice of advanced age. This attenuation is comparable with the effect of high-calorie feeding in young mice. Of note, unlike high-calorie feeding conditions, age-dependent HIF2alpha attenuation occurs without impaired activation of the hypothalamic IR/IRS-2/AKT/FOXO1 pathway in response to insulin. Molecular and physiological analyses revealed that hypothalamic HIF2alpha contributes to the action of central insulin in regulation of proopiomelanocortin (Pomc) gene expression and food intake. HIF2alpha knockout in POMC neurons led to age-dependent excess weight gain and fat increase, a phenotype that was associated with a mild degree of glucose intolerance and insulin resistance. In conclusion, hypothalamic HIF2alpha responds to insulin, and the up-regulation is involved in adaptive metabolic regulation as age increases, whereas impairment of HIF2alpha in the hypothalamus contributes to weight gain and glucose disorders in age-dependent manners. |
