The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ

Insulin resistance associated with glucocorticoid treatment may be alleviated by inhibiting the synthesis of ceramides or their effectors. Using glucocorticoids without insulin resistance Inflammation can be reduced with chronic glucocorticoid treatment, which unfortunately is associated with the development of insulin resistance. Glucocorticoids induce the production of the secreted protein Angptl4 and of ceramides, a family of lipid mediators. Chen et al. showed that Angptl4 was necessary to induce the expression of genes encoding factors involved in ceramide synthesis in the livers of glucocorticoid-treated mice. Furthermore, Angptl4 was required to stimulate the activity of two downstream effectors of ceramides: PP2A and PKCζ. These results suggest that inhibiting this pathway may alleviate the insulin resistance that occurs with chronic glucocorticoid treatment. Chronic glucocorticoid exposure is associated with the development of insulin resistance. We showed that glucocorticoid-induced insulin resistance was attenuated upon ablation of Angptl4, a glucocorticoid target gene encoding the secreted protein angiopoietin-like 4, which mediates glucocorticoid-induced lipolysis in white adipose tissue. Through metabolomic profiling, we revealed that glucocorticoid treatment increased hepatic ceramide concentrations by inducing enzymes in the ceramide synthetic pathway in an Angptl4-dependent manner. Angptl4 was also required for glucocorticoids to stimulate the activities of the downstream effectors of ceramide, protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ). We further showed that knockdown of PP2A or inhibition of PKCζ or ceramide synthesis prevented glucocorticoid-induced glucose intolerance in wild-type mice. Moreover, the inhibition of PKCζ or ceramide synthesis did not further improve glucose tolerance in Angptl4−/− mice, suggesting that these molecules were major downstream effectors of Angptl4. Overall, our study demonstrates the key role of Angptl4 in glucocorticoid-augmented hepatic ceramide production that induces whole-body insulin resistance.