Hypoxia decreases insulin signaling pathways in adipocytes

  1. Claire Regazzetti1,2,
  2. Pascal Peraldi2,3,
  3. Thierry Grémeaux1,2,
  4. Rosanna Najem-Lendom1,2,
  5. Issam Ben-Sahra1,2,
  6. Mireille Cormont1,2,
  7. Frédéric Bost1,2,
  8. Yannick Le Marchand-Brustel1,2,
  9. Jean-François Tanti1,2 and
  10. Sophie Giorgetti-Peraldi (peraldis{at}unice.fr)1,2
  1. 1INSERM U 895, Mediterranean Research Centre for Molecular Medicine, Team: Cellular and Molecular Physiopathology of obesity and diabetes F- 06204 Nice, France
  2. 2University of Nice Sophia Antipolis, Faculty of Medicine, IFR 50, F-06204 Nice, France
  3. 3CNRS UMR 6543, Institute of Signaling, Biology, development and Cancer, F-06108, Nice, France

    Abstract

    Objective: Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated if this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on insulin signaling pathway in adipocytes.

    Research design and Methods: Hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic condition (1% O2) or modulation of 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 the decrease in the phosphorylation state of PKB 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 phosphatases activities. Overexpression of HIF-1α or HIF-2α, or activation of HIF transcription factor with CoCl2 mimicked the effect of hypoxia on insulin signaling while downregulation of HIF-1α and HIF-2α by siRNA inhibited it.

    Conclusion: We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes which is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism which participates in insulin resistance in adipose tissue of obese patients.

    Footnotes

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