Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis

Diabetes. 2017 Jun;66(6):1601-1610. doi: 10.2337/db16-0831. Epub 2017 Mar 14.


Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas 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 (also called 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 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of glucocorticoids. Thus, the inhibition of Pik3r1 in adipocytes could alleviate lipid disorders caused by excess glucocorticoid exposure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipose Tissue, White / metabolism
  • Animals
  • Blotting, Western
  • Class Ia Phosphatidylinositol 3-Kinase / genetics*
  • Dexamethasone / pharmacology
  • Fatty Acids, Nonesterified / metabolism
  • Gene Knockdown Techniques
  • Glucocorticoids / pharmacology
  • Insulin / metabolism
  • Lipid Droplets / drug effects
  • Lipid Droplets / metabolism*
  • Lipolysis*
  • Mice
  • Perilipin-1 / drug effects
  • Perilipin-1 / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Real-Time Polymerase Chain Reaction
  • Sterol Esterase / drug effects
  • Sterol Esterase / metabolism


  • Fatty Acids, Nonesterified
  • Glucocorticoids
  • Insulin
  • Perilipin-1
  • Plin1 protein, mouse
  • Dexamethasone
  • Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase
  • Pik3r1 protein, mouse
  • Sterol Esterase