Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation

Hai Zhang, Guo Zhang, Frank J. Gonzalez, Sung min Park, Dongsheng Cai

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1001112
JournalPLoS Biology
Volume9
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Pro-Opiomelanocortin
Energy balance
energy balance
hypoxia
Genes
Glucose
glucose
Neurons
genes
AMP-Activated Protein Kinases
neurons
Transcription
Metabolites
Leptin
Adrenocorticotropic Hormone
Nutrients
obesity
Transcription Factors
Obesity
Chemical activation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation. / Zhang, Hai; Zhang, Guo; Gonzalez, Frank J.; Park, Sung min; Cai, Dongsheng.

In: PLoS Biology, Vol. 9, No. 7, e1001112, 07.2011.

Research output: Contribution to journalArticle

Zhang, Hai ; Zhang, Guo ; Gonzalez, Frank J. ; Park, Sung min ; Cai, Dongsheng. / Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation. In: PLoS Biology. 2011 ; Vol. 9, No. 7.
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