Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, while superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (a.k.a. p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by glucocorticoids in wild type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice. Our data demonstrated a novel role of Pik3r1, independent of its regulatory function of phosphoinositide 3-kinase, in mediating the metabolic action of glucocorticoids. Thus, the inhibition of Pik3r1 in adipocyte could alleviate lipid disorders caused by excess glucocorticoid exposure.
+ These authors contributed equally to this work
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0831/-/DC1.
- Received July 7, 2016.
- Accepted March 9, 2017.
- © 2017 by the American Diabetes Association.