title: Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice.
abstract: OBJECTIVE
  Obesity, insulin resistance, and type 2 diabetes form a tightly correlated cluster of metabolic disorders in which adipose is one of the first affected tissues. The role of hypoxia and hypoxia-inducible factor 1 (HIF1) in the development of high-fat diet (HFD)-induced obesity and insulin resistance was investigated using animal models.
  
  
  METHODS
  Mice with adipocyte-specific targeted disruption of the genes encoding the HIF1 obligatory subunits Hif1α or Arnt (Hif1β) were generated using an aP2-Cre transgene with the Cre/LoxP system. The mice were fed an HFD for 12 weeks and their metabolic phenotypes were determined. Gene expression patterns in adipose tissues were also determined by microarray and quantitative PCR.
  
  
  RESULTS
  On an HFD, adipocyte-specific ARNT knockout mice and adipocyte-specific HIF1α knockout mice exhibit similar metabolic phenotypes, including reduced fat formation, protection from HFD-induced obesity, and insulin resistance compared with similarly fed wild-type controls. The cumulative food intake remained similar; however, the metabolic efficiency was lower in adipocyte-specific HIF1α knockout mice. Moreover, indirect calorimetry revealed respiratory exchange ratios were reduced in adipocyte-specific HIF1α knockout mice. Hyperinsulinemic-euglycemic clamp studies demonstrated that targeted disruption of HIF1α in adipocytes enhanced whole-body insulin sensitivity. The improvement of insulin resistance is associated with decreased expression of Socs3 and induction of adiponectin.
  
  
  CONCLUSIONS
  Inhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance. This study reveals that HIF1 could provide a novel potential therapeutic target for obesity and type 2 diabetes.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Tatyana
authors.initials: T
authors.lastname: Chanturiya
authors.forename: William
authors.initials: W
authors.lastname: Jou
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D002001:Adipose Tissue, Brown; D052436:Adipose Tissue, White; D050154:Adiposity / Q000502:physiology*; D000375:Aging; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000502:physiology*; D015309:Glucose Clamp Technique; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010101:Oxygen Consumption
chemical_list: C497397:Arnt protein, mouse; D004041:Dietary Fats; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator