Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
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DOI：
10.1172/jci42551
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发表时间：
2010-08-01
影响因子：
15.9
通讯作者：
Kunos, George
中科院分区：
文献类型：
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作者：
Tam, Joseph;Vemuri, V. Kiran;Kunos, George
肥胖及其代谢后果是全球主要的公共卫生问题。肥胖与内源性大麻素系统的过度活跃有关，该系统参与食欲、脂肪生成和胰岛素抵抗的调节。大麻素-1受体（CB 1 R）拮抗剂在实验和人类肥胖中减轻体重并改善心脏代谢异常，但其治疗潜力受到神经精神副作用的限制。在这里，我们已经证明，CB 1 R中性拮抗剂主要局限于外围不影响行为反应介导的CB 1 R在遗传或饮食诱导的肥胖症小鼠的大脑，但它确实会导致不依赖于体重的改善葡萄糖稳态，脂肪肝和血脂谱。这些作用是由于外周组织（包括肝脏）中CB 1 R的阻断，如通过使用肝脏中有或没有CB 1 R转基因表达的CB 1 R缺陷小鼠所验证的。这些结果表明，靶向外周CB 1 R具有减轻肥胖患者心脏代谢风险的治疗潜力。
Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoicl system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.