title: Adipose HIF-1α causes obesity by suppressing brown adipose tissue thermogenesis.
abstract: Hypoxia-inducible factor-1α (HIF-1α) in adipose tissue is known to promote obesity. We hypothesized that HIF-1α interferes with brown fat thermogenesis, thus decreasing energy expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1α in adipose tissues (HIF-1α++) at usual temperature (22 °C), where brown fat is somewhat active, or at thermoneutrality (30 °C), where brown fat is minimally active. HIF-1α++ mice or control litter mates were separated into room temperature (22 °C) or thermoneutrality (30 °C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 °C, HIF-1α++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1α++ mice, oxygen consumption decreased ~50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α). In conclusion, adipose HIF-1α overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature.
  
  
  
  Constitutive HIF-1α activation in adipose tissue promotes weight gain in mice. The weight gain is associated with reduced brown adipose tissue function and oxygen consumption. Reduced oxygen consumption may be mediated by reductions in mitochondria.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA. jjun2@jhmi.edu.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jun
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Devera
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Dileep
authors.initials: D
authors.lastname: Unnikrishnan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bevans-Fonti
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Aman
authors.initials: A
authors.lastname: Rathore
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Haris
authors.initials: H
authors.lastname: Younas
authors.affiliation: Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.affiliation: Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA.
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D004435:Eating; D004734:Energy Metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010101:Oxygen Consumption; D022722:Thermogenesis; D015430:Weight Gain
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Brown adipose; HIF; Hypoxia; Obesity; Thermogenesis