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Age-dependent decline of hypothalamic HIF2α in response to insulin and its contribution to advanced age-associated metabolic disorders in mice.
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- Author(s): Wang Z;Wang Z; Khor S; Khor S; Cai D; Cai D
- Source:
The Journal of biological chemistry [J Biol Chem] 2019 Mar 29; Vol. 294 (13), pp. 4946-4955. Date of Electronic Publication: 2019 Feb 01.- Publication Type:
Journal Article; Research Support, N.I.H., Extramural- Language:
English - Source:
- Additional Information
- Source: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
- Publication Information: Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology - Subject Terms: Signal Transduction*; Aging/*metabolism ; Basic Helix-Loop-Helix Transcription Factors/*metabolism ; Glucose Intolerance/*metabolism ; Hypothalamus/*metabolism ; Insulin/*metabolism; Aging/genetics ; Aging/pathology ; Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Gene Expression Regulation ; Glucose Intolerance/genetics ; Glucose Intolerance/pathology ; Hypothalamus/pathology ; Insulin/genetics ; Mice ; Mice, Transgenic ; Pro-Opiomelanocortin/biosynthesis ; Pro-Opiomelanocortin/genetics
- 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.
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Physiol Behav. 2006 Dec 30;89(5):687-91. (PMID: 16979194) - Grant Information: P30 DK026687 United States DK NIDDK NIH HHS; R01 AG031774 United States AG NIA NIH HHS; R01 DK099136 United States DK NIDDK NIH HHS; T32 AG023475 United States AG NIA NIH HHS
- Contributed Indexing: Keywords: aging; cell signaling; diabetes; hypothalamus; hypoxia-inducible factor (HIF); insulin resistance; obesity
- Accession Number: 0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Insulin)
1B37H0967P (endothelial PAS domain-containing protein 1)
66796-54-1 (Pro-Opiomelanocortin) - Publication Date: Date Created: 20190203 Date Completed: 20191016 Latest Revision: 20210205
- Publication Date: 20240628
- Accession Number: PMC6442045
- Accession Number: 10.1074/jbc.RA118.005429
- Accession Number: 30709906
- Source:
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