Shenzhen Key Laboratory of Drug Addiction, Shenzhen Neher Neural Plasticity Laboratory, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China.
J Clin Invest. 2024 Sep 3;134(17):e178239. doi: 10.1172/JCI178239.
Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.
利拉鲁肽是一种胰高血糖素样肽-1（GLP-1）类似物，已被批准用于肥胖症治疗，但促进其治疗效果的确切神经元位置仍难以捉摸。在这里，我们发现侧隔核（LSGLP-1R）中的 GLP-1 受体阳性（GLP-1R-阳性）神经元在介导利拉鲁肽的厌食和减肥作用方面发挥着关键作用。利拉鲁肽能强烈激活 LSGLP-1R 神经元，而这些神经元的化学遗传激活则显著抑制进食。靶向敲低 LS 中的 GLP-1 受体，但不在下丘脑，极大地削弱了利拉鲁肽抑制进食和降低体重的能力。在自然进食过程中，LSGLP-1R 神经元的活性迅速下降，而 LSGLP-1R 神经元的突触失活则减弱了利拉鲁肽引发的厌食作用。总之，这些发现为 LSGLP-1R 神经元在能量平衡的生理调节中的功能作用提供了重要的见解，并描绘了它们在介导利拉鲁肽的药理学疗效中的重要作用。
