Abstract
Hypoxia-inducible factor-2α (HIF2α) is a nuclear transcription factor that plays a critical role in cell survival including metabolic adaptation under hypoxia as well as normoxia, but whether HIF2α contributes to the control of whole-body metabolic balance is unclear. In this study, we found that the hypothalamic HIF2α protein level rapidly increases in young mice that are centrally stimulated with insulin. However, this insulin-induced HIF2α 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 HIF2α 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 HIF2α contributes to the action of central insulin in regulation of proopiomelanocortin (Pomc) gene expression and food intake. HIF2α 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 HIF2α responds to insulin, and the up-regulation is involved in adaptive metabolic regulation as age increases, whereas impairment of HIF2α in the hypothalamus contributes to weight gain and glucose disorders in age-dependent manners.
Highlights
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
Hypothalamic HIF2␣ up-regulation by insulin and its impairment at advanced age glucose infusion has been shown to increase HIF2␣ protein levels [8], it is unknown whether insulin influences hypothalamic HIF2␣, despite evidence that HIF1␣ mRNA and protein were shown to increase after insulin stimulation in human retinal epithelial cells [9]
Despite the young age of these animals, high-fat diet (HFD) feeding greatly diminished the ability of insulin to up-regulate the hypothalamic HIF2␣ protein, to a similar degree as seen in advanced age (Fig. 1, A and B)
Summary
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. We found that the hypothalamic HIF2␣ protein level rapidly increases in young mice that are centrally stimulated with insulin This insulininduced HIF2␣ up-regulation is substantially attenuated in mice of advanced age. Aging is associated with body composition changes including excess fat mass [11] It is unclear if metabolic disorders in advanced age are mediated through similar or different mechanisms compared with the dietary etiologies of diabetes such as chronic high-calorie feeding. Insulin signaling in the hypothalamus is important in metabolic regulation [17], but how it contributes to age-dependent metabolic changes is unclear In this context, this study investigates whether hypothalamic HIF2␣ responds to insulin and how this reaction is affected under different age and dietary conditions. Hypothalamic HIF2␣ in metabolic regulation dent Pomc gene expression, and how loss of HIF2␣ in Pomc neurons affects metabolic physiology at different ages
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