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Citation

  • Authors: Regazzetti, C., Dumas, K., Lacas-Gervais, S., Pastor, F., Peraldi, P., Bonnafous, S., Dugail, I., Le Lay, S., Valet, P., Le Marchand-Brustel, Y., Tran, A., Gual, P., Tanti, J. F., Cormont, M., Giorgetti-Peraldi, S.
  • Year: 2015
  • Journal: Endocrinology 156 789-801
  • Applications: in vitro / siRNA / INTERFERin
  • Cell type: 3T3-L1
    Description: Murine embryonic fibroblasts
    Known as: NIH/3T3-L1, NIH-3T3-L1

Method

40 pmol of siRNA.

Abstract

During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.

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