Cannabinoid-1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure Through Sirtuin-1/Mechanistic Target of Rapamycin Complex 2 and 5'Adenosine Monophosphate-Activated Protein Kinase Signaling.

ABSTRACT: Endocannabinoids promote energy conservation in obesity, whereas cannabinoid-1 receptor (CB₁ R) blockade reverses body weight gain and insulin resistance and increases energy expenditure. Here we investigated the molecular mechanisms of the catabolic effects of CB₁ R blockade in the liver. Exposure of primary mouse hepatocytes and HepG2 cells to the CB₁ R agonist arachidonyl-2'-chloroethylamide inhibited the expression of Sirtuin-1 (Sirt1) and Rictor, a component of mechanistic target of rapamycin complex 2 (mTORC2) and suppressed insulin-induced Akt phosphorylation at serine 473. These effects were reversed by peripheral CB₁ R antagonist JD5037 in control hepatocytes but not in hepatocytes deficient in Sirt1 and/or Rictor, indicating that these

SUBMITTER: Liu J 

PROVIDER: S-EPMC6438767 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature