The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
Factor inhibiting HIF-1alpha (FIH) is an asparaginyl hydroxylase. Hydroxylation of HIF-alpha proteins by FIH blocks association of HIFs with the transcriptional coactivators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, and improved glucose and lipid homeostasis and are resistant to high-fat-diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, and enhanced insulin sensitivity and are also protected against high-fat-diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.
Zhang
Na
N
Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Fu
Zhenxing
Z
Linke
Sarah
S
Chicher
Johana
J
Gorman
Jeffrey J
JJ
Visk
DeeAnn
D
Haddad
Gabriel G
GG
Poellinger
Lorenz
L
Peet
Daniel J
DJ
Powell
Frank
F
Johnson
Randall S
RS
D000818:Animals; D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D005234:Fatty Liver / Q000209:etiology; D005947:Glucose / Q000378:metabolism; D006985:Hyperventilation / Q000209:etiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015430:Weight Gain
D004041:Dietary Fats; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D001216:Asparagine; D006899:Mixed Function Oxygenases; C551240:factor inhibiting hypoxia-inducible factor 1, mouse; D005947:Glucose
J Clin Invest. 2007 Jul;117(7):1926-32
17557118
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3368-73
18299578
Genes Dev. 2001 Oct 15;15(20):2675-86
11641274
Sci STKE. 2007 Oct 09;2007(407):cm8
17925579
Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14767-72
17003112
J Appl Physiol (1985). 2000 Sep;89(3):1142-50
10956362
Nat Genet. 2008 Feb;40(2):170-80
18176562
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5
8650183
Cell Death Differ. 2008 Apr;15(4):621-7
18259201
Mol Cell Biol. 2008 May;28(10):3386-400
18332118
Blood. 2008 Mar 15;111(6):3229-35
18056838
Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):821-6
11792862
Respir Physiol Neurobiol. 2008 Mar 20;161(1):95-9
18280799
Cell Metab. 2009 May;9(5):428-39
19416713
Int J Biochem Cell Biol. 2009 Jul;41(7):1563-71
19401150
Cell Metab. 2006 May;3(5):333-41
16679291
Cell. 2005 Aug 12;122(3):337-49
16096055
Cell Metab. 2009 Jan 7;9(1):11-22
19117543
J Clin Invest. 2006 Mar;116(3):581-9
16511590
Chem Commun (Camb). 2005 Nov 21;(43):5438-40
16261239
J Clin Invest. 2007 Apr;117(4):1068-77
17404621
Mol Cell Proteomics. 2009 Mar;8(3):535-46
18936059
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1583-8
11171994
Antioxid Redox Signal. 2010 Apr;12(4):481-501
19754349
Physiology (Bethesda). 2009 Apr;24:97-106
19364912
Cell. 2008 Apr 18;133(2):223-34
18423195
J Biol Chem. 2004 Mar 12;279(11):9899-904
14701857
Genes Dev. 2002 Jun 15;16(12):1466-71
12080085
Physiology (Bethesda). 2004 Aug;19:176-82
15304631
Mol Cell Biol. 2006 Nov;26(22):8336-46
16966370
Mol Cell Biol. 2009 Aug;29(16):4527-38
19528226
J Biol Chem. 2007 Aug 17;282(33):24027-38
17573339
Methods Enzymol. 2004;381:467-87
15063693
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9102-7
9256442
Biochem J. 2009 May 13;420(2):327-33
19245366
J Physiol. 2006 Dec 1;577(Pt 2):705-16
16973705
Mol Cell Biol. 2007 Sep;27(18):6407-19
17636018
Curr Pharm Des. 2009;15(33):3904-7
19671041