Hypoxia Decreases Insulin Signaling Pathways in Adipocytes

  1. Sophie Giorgetti-Peraldi1,2
  1. 1Team: Cellular and Molecular Physiopathology of Obesity and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) U 895, Mediterranean Research Centre for Molecular Medicine, Nice, France
  2. 2IFR 50, Faculty of Medicine, University of Nice Sophia Antipolis, Nice, France
  3. 3CNRS UMR 6543, Institute of Signaling, Biology, Development and Cancer, Nice, France
  1. Corresponding author: Sophie Giorgetti-Peraldi, peraldis{at}unice.fr

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.

RESEARCH DESIGN AND METHODS—The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O2) 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-1α or -2α or activation of HIF transcription factor with CoCl2 mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1α and -2α 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 4 November 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

    See accompanying commentary, p. 26.

    • Received April 4, 2008.
    • Accepted October 21, 2008.

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  1. Diabetes vol. 58 no. 1 95-103
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