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.

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 two proteins are required for the CB₁ R-mediated inhibition of insulin signaling. Feeding C57BL/6J mice a high-fat diet (HFD) inhibited hepatic Sirt1/mTORC2/Akt signaling, and the inhibition was reversed by rimonabant or JD5037 in wild-type but not liver-specific Sirt1^-/- (Sirt1-LKO) mice, to levels observed in hepatocyte-specific CB₁ R^-/- mice. A similar attenuation of hyperglycemia and hyperinsulinemia in wild-type mice with obesity but not in Sirt1-LKO mice could be attributed to insufficient reversal of HFD-induced mitochondrial reactive oxygen species generation in peripheral tissues in the latter. In contrast, JD5037 treatment was equally effective in HFD-fed wild-type and Sirt1-LKO mice in reducing hepatic steatosis, increasing fatty acid β-oxidation, and activating 5'adenosine monophosphate-activated protein kinase (AMPK) through liver kinase B1 (LKB1), resulting in a similar increase in total energy expenditure in the two strains. Conclusion: Peripheral CB₁ R blockade in mice with obesity improves glycemic control through the hepatic Sirt1/mTORC2/Akt pathway, whereas it increases fatty acid oxidation through LKB1/AMPK signaling.