Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Molecular Genetics, University of Utah, Salt Lake City, Utah.
Am J Physiol Endocrinol Metab. 2021 Jul 1;321(1):E146-E155. doi: 10.1152/ajpendo.00044.2021. Epub 2021 Jun 7.
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 the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist 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. Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.
大麻素 1 型受体 (CB1R) 反向激动剂可降低体重并改善多种血糖稳态参数。然而，这些药物也与有害的副作用有关。CB1R 在大脑和外周组织中广泛表达，但特定表达部位是否可以介导 CB1R 药物的有益代谢作用，同时避免不良副作用，尚不清楚。有证据表明，反向激动剂可能作用于中枢神经系统的关键部位，以改善代谢。腹内侧下丘脑 (VMH) 是调节能量平衡和血糖稳态的关键节点。为了确定 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 神经元中缺乏 CB1R 的小鼠。我们发现，VMH 中 CB1R 的缺失不会影响雄性和雌性 Chow 和高脂肪饮食喂养的小鼠的体重。我们还发现，VMH 中 CB1R 的缺失不会改变 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 中的 CB1R 调节肥胖雄性小鼠的血糖稳态参数，而与体重无关。大麻素 1 型受体 (CB1R) 调节代谢稳态，CB1R 反向激动剂可降低体重并改善血糖代谢参数。然而，调节代谢稳态的表达 CB1R 的细胞群体尚不清楚。CB1R 在腹内侧下丘脑核 (VMH) 中高度表达，VMH 是调节代谢的关键节点。我们使用 CRISPR/Cas9 技术生成了特异性缺乏 VMH 神经元中 CB1R 的小鼠，并发现 VMH 神经元中的 CB1R 对于葡萄糖代谢的调节是独立于体重调节所必需的。
