title: Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation.
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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Park
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D059305:Diet, High-Fat; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D005650:Fumarates / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005947:Glucose / Q000494:pharmacology* / Q000502:physiology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology / Q000502:physiology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000628:therapy; D010902:Pituitary Gland / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013386:Succinates / Q000494:pharmacology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005650:Fumarates; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020738:Leptin; D008156:Luciferases; D011333:Pro-Opiomelanocortin; D011393:Procollagen-Proline Dioxygenase; D013386:Succinates; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse