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

Area of Science:

• Endocrinology
• Metabolism
• Molecular Biology

Background:

• Chronic exposure to glucocorticoids is a known cause of insulin resistance.
• Angiopoietin-like 4 (Angptl4) is a glucocorticoid-responsive gene involved in lipolysis.

Purpose of the Study:

• To investigate the role of Angptl4 in glucocorticoid-induced insulin resistance.
• To elucidate the molecular mechanisms linking glucocorticoids, Angptl4, and hepatic ceramide metabolism.

Main Methods:

• Utilized mouse models with targeted ablation or knockdown of Angptl4.
• Employed metabolomic profiling to analyze hepatic lipid profiles.
• Assessed glucose tolerance and insulin sensitivity in vivo.
• Investigated the activity of key signaling molecules like PP2A and PKCζ.

Main Results:

• Ablation of Angptl4 significantly attenuated glucocorticoid-induced insulin resistance and glucose intolerance.
• Glucocorticoid treatment increased hepatic ceramide synthesis via Angptl4-dependent induction of synthetic enzymes.
• Angptl4 mediated the activation of downstream effectors, protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ).
• Inhibition of ceramide synthesis or PKCζ prevented glucocorticoid-induced glucose intolerance, with no additive effect in Angptl4-deficient mice.

Conclusions:

• Angiopoietin-like 4 (Angptl4) plays a critical role in mediating glucocorticoid-induced insulin resistance.
• Glucocorticoid-augmented hepatic ceramide production, regulated by Angptl4, is a key driver of whole-body insulin resistance.
• PP2A and PKCζ are major downstream effectors of Angptl4 in this pathway.