• Tzu-Chieh Chen, Daniel I Benjamin, Taiyi Kuo, Rebecca A Lee, Mei-Lan Li, Darryl J Mar, Damian E Costello, Daniel K Nomura, and Jen-Chywan Wang.
• Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720-3104, USA.
• Sci Signal. 2017 Jul 25; 10 (489).

AbstractChronic 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.Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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