Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cell Metab. 2013 Dec 3;18(6):860-70. doi: 10.1016/j.cmet.2013.11.003.
The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.
黑皮质素受体 4（MC4R）是体重稳态的重要调节因子。然而，介导 MC4R 功能的神经递质仍知之甚少；因此，人们对 MC4R 神经通路的二级神经元知之甚少。单基因 1（Sim1）表达的脑区，包括下丘脑室旁核（PVH），代表了介导黑素细胞刺激素作用的关键脑区。我们在 Mc4r 基因敲除小鼠的 Sim1 神经元中条件性地恢复了 MC4R 的表达。恢复显著降低了 Mc4r 基因敲除小鼠的肥胖程度。选择性破坏这些相同的 Sim1 神经元中的谷氨酸释放完全逆转了抗肥胖作用。这种逆转是由于能量消耗减少和摄食量增加引起的。此外，选择性破坏成年 PVH 神经元中的谷氨酸释放会通过减少能量消耗和增加摄食量导致肥胖的快速发展。因此，这项研究确立了谷氨酸作为主要神经递质，调节 Sim1 神经元上的 MC4R 参与体重调节。
