Cannabinoid‐1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure via Sirt1/mTORC2 and AMPK Signaling

Abstract

Endocannabinoids promote energy conservation in obesity, whereas cannabinoid‐1 receptor (CB₁R) blockade reverses body weight gain and insulin resistance and increases energy expenditure. Here we investigated the molecular mechanisms of the catabolic effects of CB₁R blockade in the liver. Exposure of primary mouse hepatocytes and HepG2 cells to the CB₁R agonist ACEA inhibited the expression of Sirt1 and Rictor, a component of mTORC2, and suppressed insulin‐induced Akt phosphorylation at ser473. These effects were reversed by peripheral CB₁R antagonist JD5037 in control hepatocytes but not in hepatocytes deficient in Sirt1 and/or Rictor, indicating that these two proteins are required for the CB₁R‐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 CB₁R^‐/‐ (LCB₁R^‐/‐) mice. A similar attenuation of hyperglycemia and hyperinsulinemia in obese wild‐type but not Sirt1‐LKO mice could be attributed to insufficient reversal of HFD‐induced mitochondrial ROS 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 AMPK via LKB1, resulting in a similar increase in total energy expenditure in the two strains.

Conclusion

peripheral CB₁R blockade in obese mice improves glycemic control via the hepatic Sirt1/mTORC2/Akt pathway, whereas it increases fatty acid oxidation via LKB1/AMPK signaling.

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