title: Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity.
abstract: Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jung-Whan
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborne
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ai
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Lipomics Technologies, Inc., West Sacramento, CA 95691, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Watkins
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, 171 77, Sweden; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK. Electronic address: rsj33@cam.ac.uk.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jolefsky@ucsd.edu.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D033742:Adenine Nucleotide Translocator 2 / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D033742:Adenine Nucleotide Translocator 2; D051792:Basic Helix-Loop-Helix Proteins; D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; D009569:Nitric Oxide; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse