Cannabinoid 1 receptor (CB1R) inverse-agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse-agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that deletion of CB1Rs in the VMH did not affect body weight in male and female mice fed chow or HFD. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse-agonists SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.

中文翻译：

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VMH 神经元中的 CB1R 调节葡萄糖稳态但不调节体重

大麻素 1 受体 (CB1R) 反向激动剂可减轻体重并改善葡萄糖稳态的几个参数。然而，这些药物也与有害的副作用有关。CB1R 表达广泛存在于大脑和外周组织中，但特定的表达位点是否可以介导 CB1R 药物的有益代谢作用，同时避免不良副作用，仍不清楚。有证据表明反向激动剂可能作用于中枢神经系统内的关键部位以改善新陈代谢。下丘脑腹内侧 (VMH) 是调节能量平衡和葡萄糖稳态的关键节点。为了确定在 VMH 神经元中表达的 CB1R 在调节代谢稳态中的作用，我们生成了 VMH 中缺乏 CB1R 的小鼠。我们发现 VMH 中 CB1R 的缺失不会影响喂食食物或 HFD 的雄性和雌性小鼠的体重。我们还发现，VMH 中 CB1R 的缺失不会改变由 CB1R 反向激动剂 SR141716 诱导的体重减轻反应。然而，我们确实发现 VMH 的 CB1R 在饮食诱导的肥胖雄性小鼠中调节葡萄糖稳态参数，而与体重无关。