title: The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
abstract: 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.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: Fu
authors.forename: Sarah
authors.initials: S
authors.lastname: Linke
authors.forename: Johana
authors.initials: J
authors.lastname: Chicher
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gorman
authors.forename: DeeAnn
authors.initials: D
authors.lastname: Visk
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
authors.forename: Frank
authors.initials: F
authors.lastname: Powell
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: 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
chemical_list: 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
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