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Abstract
Hypoxia-inducible factor (HIF) is a nuclear transcription factor that responds to environmental and pathological hypoxia to induce metabolic adaptation, vascular growth, and cell survival. Here we found that HIF subunits and HIF2α in particular were normally expressed in the mediobasal hypothalamus of mice. Hypothalamic HIF was up-regulated by glucose to mediate the feeding control of hypothalamic glucose sensing. Two underlying molecular pathways were identified, including suppression of PHDs by glucose metabolites to prevent HIF2α degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2α protein synthesis. HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF inhibition in POMC neurons, revealing that HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing and caused energy imbalance to promote obesity development. The metabolic effects of HIF in hypothalamic POMC neurons were independent of leptin signaling or pituitary ACTH pathway. Hypothalamic gene delivery of HIF counteracted overeating and obesity under conditions of nutritional excess. In conclusion, HIF controls hypothalamic POMC gene to direct the central nutrient sensing in regulation of energy and body weight balance.
Highlights
Hypoxia-inducible factor (HIF) is the central nuclear transcription factor that is induced under environmental and pathological hypoxia [1,2]
Using a luciferase reporter system, we found that overexpression of HIF1a and HIF2a increased the activities of transfected POMC promoter by 12 folds and 26 folds, respectively (Figure 1B)
Supported by recent research that has shown that hypothalamic mammalian target of rapamycin (mTOR) [24,49] and S6 kinase (S6K) [50] restrict feeding and weight gain, we further evaluated if mTOR/S6K might participate in the action of hypothalamic HIF in regulation of feeding
Summary
Hypoxia-inducible factor (HIF) is the central nuclear transcription factor that is induced under environmental (e.g., high altitude) and pathological (e.g., cancer) hypoxia [1,2]. PHDs are suppressed, leading to HIFa protein stabilization and the transcriptional action of HIFa/b in inducing genes that classically regulate metabolic adaptation, vascular growth, and cell survival [1,2,3,4]. Among three HIFa isoforms (HIF1a, HIF2a, and HIF3a), HIF1a and HIF2a have been extensively studied in the literature [1,2,3,4]. While both HIF1a and HIF2a mediate hypoxia adaptation, HIF2a can control a distinct set of target genes [5,6]. The biological consequences of HIF2a versus HIF1a ablation in mice are different [7,8,9], suggesting that HIF2a and HIF1a have divergent physiological functions
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