Age-dependent decline of hypothalamic HIF2α in response to insulin and its contribution to advanced age-associated metabolic disorders in mice.

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: 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

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

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.
(© 2019 Wang et al.)

Adv Exp Med Biol. 2001;502:273-91. (PMID: 11950144)
J Mol Cell Biol. 2012 Jun;4(3):184-7. (PMID: 22474076)
Nat Med. 2014 Sep;20(9):1001-8. (PMID: 25086906)
Cell. 2012 Feb 3;148(3):399-408. (PMID: 22304911)
Nature. 1979 Nov 29;282(5738):503-5. (PMID: 116135)
Nutr Metab (Lond). 2007 Sep 01;4:18. (PMID: 17764572)
Physiol Behav. 2007 Nov 23;92(4):691-701. (PMID: 17585961)
Nat Genet. 1998 Jun;19(2):155-7. (PMID: 9620771)
Front Neurosci. 2013 Feb 22;7:19. (PMID: 23440036)
Cell. 2007 May 4;129(3):465-72. (PMID: 17482542)
Curr Opin Pharmacol. 2013 Dec;13(6):970-6. (PMID: 24075719)
Kidney Int. 2010 Jul;78(1):48-59. (PMID: 20375990)
J Physiol. 2009 May 15;587(Pt 10):2341-51. (PMID: 19332486)
J Clin Endocrinol Metab. 2003 Oct;88(10):4633-40. (PMID: 14557433)
Cell Metab. 2017 May 2;25(5):1091-1102.e4. (PMID: 28467927)
Nature. 2013 May 9;497(7448):211-6. (PMID: 23636330)
Nat Neurosci. 2002 Jun;5(6):566-72. (PMID: 12021765)
Trends Neurosci. 2013 Feb;36(2):65-73. (PMID: 23318157)
PLoS One. 2015 May 12;10(5):e0126804. (PMID: 25965336)
Annu Rev Psychol. 2000;51:255-77. (PMID: 10751972)
Nature. 2017 Aug 3;548(7665):52-57. (PMID: 28746310)
Nat Neurosci. 2005 May;8(5):571-8. (PMID: 15856065)
Physiol Behav. 2011 Apr 18;103(1):10-6. (PMID: 21241723)
Nat Neurosci. 2006 Jul;9(7):901-6. (PMID: 16783365)
J Biol Chem. 2002 Aug 2;277(31):27975-81. (PMID: 12032158)
Cell Metab. 2010 Apr 7;11(4):286-97. (PMID: 20374961)
Diabetologia. 2011 Aug;54(8):1946-56. (PMID: 21614571)
Curr Med Chem. 2009;16(34):4593-600. (PMID: 19903149)
Cell. 2008 Oct 3;135(1):61-73. (PMID: 18854155)
Endocrinology. 2007 Nov;148(11):5238-47. (PMID: 17673515)
Nat Med. 1999 Sep;5(9):1066-70. (PMID: 10470087)
Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5618-23. (PMID: 15800038)
PLoS Biol. 2011 Jul;9(7):e1001112. (PMID: 21814490)
Nature. 2006 Sep 21;443(7109):289-95. (PMID: 16988703)
Medicine (Baltimore). 2018 Jun;97(25):e11152. (PMID: 29924020)
Physiol Behav. 2006 Dec 30;89(5):687-91. (PMID: 16979194)

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

Keywords: aging; cell signaling; diabetes; hypothalamus; hypoxia-inducible factor (HIF); insulin resistance; obesity

0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Insulin)
1B37H0967P (endothelial PAS domain-containing protein 1)
66796-54-1 (Pro-Opiomelanocortin)

Date Created: 20190203 Date Completed: 20191016 Latest Revision: 20210205

20240628

PMC6442045

10.1074/jbc.RA118.005429

30709906