GLP-1R–positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice
Zijun Chen, Xiaofei Deng, Cuijie Shi, Haiyang Jing, Yu Tian, Jiafeng Zhong, Gaowei Chen, Yunlong Xu, Yixiao Luo, Yingjie Zhu
Zijun Chen, Xiaofei Deng, Cuijie Shi, Haiyang Jing, Yu Tian, Jiafeng Zhong, Gaowei Chen, Yunlong Xu, Yixiao Luo, Yingjie Zhu
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Research Article Metabolism Neuroscience

GLP-1R–positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice

Abstract

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.

Authors

Zijun Chen, Xiaofei Deng, Cuijie Shi, Haiyang Jing, Yu Tian, Jiafeng Zhong, Gaowei Chen, Yunlong Xu, Yixiao Luo, Yingjie Zhu

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Figure 5

Activation of LSGLP-1R neurons suppresses food consumption and lowers feeding motivation.

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Activation of LSGLP-1R neurons suppresses food consumption and lowers fe...
(A) Representative illustration demonstrating specific hM3D-mCherry expression within LSGLP-1R neurons. Scale bars: left, 200 μm; right, 50 μm. (B) Left: Representative depiction of robust c-Fos expression. Right: Statistical comparison. Unpaired, 2-tailed t test; t(6)= 23.53, P < 0.0001. Means ± SEM. Scale bar: 50 μm. (C) Paradigm for analyzing food consumption. (D) Effects of CNO injection on reduction of standard chow or high-sucrose food intake specifically in hM3D-expressing mice but not in mCherry-expressing mice. Two-way repeated-measures ANOVA (standard chow, F(1,17) = 22.07, P = 0.0002; high-sucrose food, F(1,17) = 8.784, P = 0.0087) followed by Šidák’s post hoc test. Means ± SEM. (E) Oral glucose tolerance test (oGTT) results for hM3D- and mCherry-expressing mice. Two-way repeated-measures ANOVA; F(5,75) = 0.2521, P = 0.9375. Inset: AUC over 2 hours during oGTT. Unpaired, 2-tailed t test; t(15) = 0.06426, P = 0.9496. Means ± SEM. (F) Paradigm for analyzing long-term chronic effects of chemogenetic activation of LSGLP-1R neurons on food intake and body weight. (G) Prolonged activation of LSGLP-1R neurons suppresses food intake. Two-way repeated-measures ANOVA (F(1,10) = 14.19, P = 0.0037) followed by Šidák’s post hoc test. Means ± SEM. (H) Prolonged activation of LSGLP-1R neurons suppresses body weight. Two-way repeated-measures ANOVA (F(1,10) = 8.782, P = 0.0142) followed by Šidák’s post hoc test. Means ± SEM. (I) Representative image displaying specific ChR2-mCherry expression within LSGLP-1R neurons, accompanied by fiber tracks situated above. Scale bars: left, 500 μm; right, 50 μm. (J) Schematic diagram depicting the poke-based Ensure solution intake paradigm. (K) Optogenetic stimulation of LSGLP-1R neurons resulted in a decline in the number of pokes at the active port and in consumption of Ensure solution. Left: Two-way repeated-measures ANOVA; F(1,20) = 12.27, P = 0.0022. Šidák’s post hoc analysis. Right: Paired, 2-tailed t test; t(5) = 4.932, P = 0.0044. **P < 0.01, ***P < 0.001, ****P < 0.0001.