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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
Author(s) -
Liu Jie,
Godlewski Grzegorz,
Jourdan Tony,
Liu Ziyi,
Cinar Resat,
Xiong Keming,
Kunos George
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30364
Subject(s) - endocrinology , medicine , sirtuin 1 , protein kinase b , amp activated protein kinase , biology , rimonabant , insulin resistance , mtorc1 , protein kinase a , chemistry , ampk , insulin , cannabinoid receptor , signal transduction , phosphorylation , biochemistry , receptor , agonist , downregulation and upregulation , gene
Endocannabinoids promote energy conservation in obesity, whereas cannabinoid‐1 receptor (CB 1 R) blockade reverses body weight gain and insulin resistance and increases energy expenditure. Here we investigated the molecular mechanisms of the catabolic effects of CB 1 R blockade in the liver. Exposure of primary mouse hepatocytes and HepG2 cells to the CB 1 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 CB 1 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 CB 1 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 CB 1 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 CB 1 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.