Inserm (P.C., L.B., O.G.-Q., C.A., S.C., M.E., T.L.-L., D.G., A.C., G.M., D.C.) and Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, unit 862, F-33000 Bordeaux, France; and Department of Biochemistry and Molecular Biology I and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) (L.B.), School of Biology, Complutense University-Instituto Universitario de Investigación Neuroquímica, 28040 Madrid, Spain.
Endocrinology. 2015 Feb;156(2):411-8. doi: 10.1210/en.2014-1437. Epub 2014 Dec 2.
The paraventricular nucleus of the hypothalamus (PVN) regulates energy balance by modulating not only food intake, but also energy expenditure (EE) and brown adipose tissue thermogenesis. To test the hypothesis that cannabinoid type 1 (CB1) receptor in PVN neurons might control these processes, we used the Cre/loxP system to delete CB1 from single-minded 1 (Sim1) neurons, which account for the majority of PVN neurons. On standard chow, mice lacking CB1 receptor in Sim1 neurons (Sim1-CB1-knockout [KO]) had food intake, body weight, adiposity, glucose metabolism, and EE comparable with wild-type (WT) (Sim1-CB1-WT) littermates. However, maintenance on a high-fat diet revealed a gene-by-diet interaction whereby Sim1-CB1-KO mice had decreased adiposity, improved insulin sensitivity, and increased EE, whereas feeding behavior was similar to Sim1-CB1-WT mice. Additionally, high-fat diet-fed Sim1-CB1-KO mice had increased mRNA expression of the β3-adrenergic receptor, as well as of uncoupling protein-1, cytochrome-c oxidase subunit IV and mitochondrial transcription factor A in the brown adipose tissue, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using β-blockers suggested that modulation of β-adrenergic transmission play an important role in determining EE changes observed in Sim1-CB1-KO. Finally, chemical sympathectomy abolished the obesity-resistant phenotype of Sim1-CB1-KO mice. Altogether, these findings reveal a diet-dependent dissociation in the CB1 receptor control of food intake and EE, likely mediated by the PVN, where CB1 receptors on Sim1-positive neurons do not impact food intake but hinder EE during dietary environmental challenges that promote body weight gain.
下丘脑室旁核（PVN）通过调节摄食、能量消耗（EE）和棕色脂肪组织产热，来调节能量平衡。为了验证 PVN 神经元中的大麻素 1 型（CB1）受体是否可以控制这些过程，我们使用 Cre/loxP 系统删除单胺氧化酶 1（Sim1）神经元中的 CB1 受体，Sim1 神经元占 PVN 神经元的大多数。在标准饮食中，缺乏 Sim1 神经元中 CB1 受体的小鼠（Sim1-CB1-KO）的摄食量、体重、肥胖程度、葡萄糖代谢和 EE 与野生型（WT）（Sim1-CB1-WT）同窝仔鼠相当。然而，在高脂肪饮食下，出现了基因-饮食的相互作用，即 Sim1-CB1-KO 小鼠的肥胖程度降低、胰岛素敏感性提高、EE 增加，而摄食行为与 Sim1-CB1-WT 小鼠相似。此外，高脂肪饮食喂养的 Sim1-CB1-KO 小鼠的β3-肾上腺素能受体、解偶联蛋白-1、细胞色素 c 氧化酶亚基 IV 和线粒体转录因子 A 的 mRNA 表达增加，所有这些分子变化都提示产热增加。使用β-阻滞剂的药理学研究表明，β-肾上腺素能传递的调节在决定 Sim1-CB1-KO 中观察到的 EE 变化中起着重要作用。最后，化学性交感神经切除术消除了 Sim1-CB1-KO 小鼠肥胖抗性表型。总之，这些发现揭示了 CB1 受体对摄食和 EE 的控制在饮食依赖上的分离，这可能是由 PVN 介导的，在 PVN 中，Sim1 阳性神经元上的 CB1 受体不影响摄食，但在促进体重增加的饮食环境挑战中阻碍 EE。
