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
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
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DOI：
10.1002/hep.30364
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发表时间：
2019-04-01
期刊：
影响因子：
13.5
通讯作者：
Kunos, George
中科院分区：
文献类型：
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作者：
Liu, Jie;Godlewski, Grzegorz;Kunos, George
内源性大麻素促进肥胖的能量保存，而大麻素-1受体（CB1R）阻断逆转体重增加和胰岛素抵抗并增加能量消耗。在这里，我们研究了CB1R阻断在肝脏中分解代谢作用的分子机制。将原代小鼠肝细胞和HepG2细胞暴露于CB1R激动剂花生四烯基-2'-氯乙胺可抑制Sirtuin-1 （Sirt1）和Rictor（雷帕霉素复合物2 （mTORC2）的一个机制靶点）的表达，并抑制胰岛素诱导的Akt在丝氨酸473位点的磷酸化。外周CB1R拮抗剂JD5037在对照肝细胞中逆转了这些作用，但在Sirt1和/或Rictor缺失的肝细胞中没有逆转，这表明这两种蛋白是CB1R介导的胰岛素信号抑制所必需的。给C57BL/6J小鼠喂食高脂肪饮食（HFD）可抑制肝脏Sirt1/mTORC2/Akt信号，利莫那班或JD5037可逆转野生型小鼠的抑制作用，但肝脏特异性Sirt1(-/-) （Sirt1- lko）小鼠的抑制作用，降至肝细胞特异性CB1R-/-小鼠的水平。野生型肥胖小鼠的高血糖和高胰岛素血症也有类似的减少，而Sirt1-LKO小鼠则没有，这可能是由于后者对hfd诱导的外周组织线粒体活性氧产生的逆转不足。相比之下，JD5037治疗在hfd喂养的野生型和Sirt1-LKO小鼠中同样有效，减少肝脏脂肪变性，增加脂肪酸β氧化，并通过肝激酶B1 （LKB1）激活5 '腺苷单磷酸活化蛋白激酶（AMPK），导致两种菌株的总能量消耗增加相似。结论：肥胖小鼠外周CB1R阻断通过肝脏Sirt1/mTORC2/Akt通路改善血糖控制，而通过LKB1/AMPK信号通路增加脂肪酸氧化。
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 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 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-/- 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 beta-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 CB1R 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.