title: Hypoxia decreases insulin signaling pathways in adipocytes.
abstract: OBJECTIVE
  Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes.
  
  
  METHODS
  The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O(2)) or modulation of hypoxia-inducible factor (HIF) expression. Insulin signaling was monitored through the phosphorylation state of several key partners of the pathway and glucose transport.
  
  
  RESULTS
  In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor. In 3T3-L1 adipocytes, this inhibition of insulin receptor phosphorylation is followed by a decrease in the phosphorylation state of protein kinase B and AS160, as well as an inhibition of glucose transport in response to insulin. These processes were reversible under normoxic conditions. The mechanism of inhibition seems independent of protein tyrosine phosphatase activities. Overexpression of HIF-1alpha or -2alpha or activation of HIF transcription factor with CoCl(2) mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1alpha and -2alpha by small interfering RNA inhibited it.
  
  
  CONCLUSIONS
  We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients.
authors.affiliation: Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Institut National de la Santé et de la Recherche Médicale U 895, Mediterranean Research Centre for Molecular Medicine, Nice, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Regazzetti
authors.forename: Pascal
authors.initials: P
authors.lastname: Peraldi
authors.forename: Thierry
authors.initials: T
authors.lastname: Grémeaux
authors.forename: Rosanna
authors.initials: R
authors.lastname: Najem-Lendom
authors.forename: Issam
authors.initials: I
authors.lastname: Ben-Sahra
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bost
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
authors.forename: Sophie
authors.initials: S
authors.lastname: Giorgetti-Peraldi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D015687:Cell Hypoxia; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D005947:Glucose; D005990:Glycerol; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D053583:Interleukin-1beta; D015850:Interleukin-6; D017027:Protein Tyrosine Phosphatases; D017382:Reactive Oxygen Species; D011972:Receptor, Insulin; D000099162:Endothelial PAS Domain-Containing Protein 1; C018021:cobaltous chloride