Age-dependent decline of hypothalamic HIF2 in response to insulin and its contribution to advanced age-associated metabolic disorders in mice

Hypoxia-inducible factor-2 (HIF2) is a nuclear transcription factor that plays a critical role in cell survival including metabolic adaptation under hypoxia as well as normoxia, but whether HIF2 contributes to the control of whole-body metabolic balance is unclear. In this study, we found that the hypothalamic HIF2 protein level rapidly increases in young mice that are centrally stimulated with insulin. However, this insulin-induced HIF2 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 HIF2 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 HIF2 contributes to the action of central insulin in regulation of proopiomelanocortin (Pomc) gene expression and food intake. HIF2 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 HIF2 responds to insulin, and the up-regulation is involved in adaptive metabolic regulation as age increases, whereas impairment of HIF2 in the hypothalamus contributes to weight gain and glucose disorders in age-dependent manners.