Hypoxia-Inducible Factor Directs POMC Gene to Mediate Hypothalamic Nutrient Sensing and Energy Balance Regulation

Hypoxia-inducible factor (HIF) is a 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 HIF2alpha 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 HIF2alpha degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2alpha protein synthesis. Amino acid leucine and hormone insulin also activate HIF2alpha on protein levels through up-regulating mTOR/S6K pathway.;HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF deletion in POMC neurons. HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing, leucine sensing and insulin sensing and in turn caused energy imbalance to promote development of 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.