Hypoxia Inhibits Cavin-1 and Cavin-2 Expression and Down-Regulates Caveolae in Adipocytes

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.

Prognostic and Diagnostic Significance of SDPR-Cavin-2 in Hepatocellular Carcinoma

“…Comparing with cavin-1 and cavin-2, cavin-3's function was not well established and cavin-4 was related to caveolin-associated muscle disease [16,20]. In 2015, Regazzetti et al [21] found that cavin-1 and cavin-2 were necessary for the formation of caveolae. Therefore, researchers supposed that cavin-1 and cavin-2 may be related to tumorigenesis, one of the functions of caveolae.…”

Reactive oxygen species mediate angiotensin II-induced transcytosis of low-density lipoprotein across endothelial cells

“…Data indicate a correlation between the levels of cavin-1 (polymerase transcript release factor, PTRF) and caveolin-1 and the abundance of caveolae. Notably, cavin-1 can be recruited by caveolins to plasma membrane caveolar domains and is necessary for caveolae formation (43,44). In the present study, by determining the expression of these essential proteins involved in LDL transcytosis, including LDLR, caveolin-1, cavin-1 and clathrin, we observed that Ang II significantly upregulated the levels of LDLR, caveolin-1 and cavin-1, but Ang II exhibited no obvious effects on clathrin expression.…”

Cavin-2 Functions as a Suppressive Regulator in TNF-induced Mesenchymal Stromal Cell Inflammation and Angiogenic Phenotypes

“…Metabolic effects may also be expected upon modulation of Cavin-2 expression. Indeed, hypoxia was recently shown to inhibit Cavin-2 expression in adipocytes and to alter caveolar formation (37). This led to the inhibition of insulin signaling and the establishment of insulin resistance.…”