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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

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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 4

Food consumption rapidly inhibits the activity of dLSGLP-1R neurons, but food seeking has no effect.

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Food consumption rapidly inhibits the activity of dLSGLP-1R neurons, but...
(A) Representative image displaying optic fiber position above GCaMP6-expressing LSGLP-1R neurons. Scale bar: 200 μm. (B) Raw trace illustrating real-time Ca2+ dynamics within dLSGLP-1R neurons of freely ambulating (moving) mice engaged in feeding. (C) Schematic diagram representing the food deprivation protocol used. (D and E) Comprehensive heatmaps (top) and per-animal stacked plots (bottom) depicting average GCaMP6 responses within dLSGLP-1R neurons, synchronized to the first and last bites during bouts of consumption across various food types (standard chow, high-sucrose, or high-fat) in individually fasted subjects (n = 10 animals). (F) Calculation of the valley and area under the curve (AUC) for GCaMP6 signals in individual subjects, assessed within a 10-second window immediately after the first bite. (G) Schematic illustration of the satiety protocol. (H and I) Heatmaps (top) and mean traces of GCaMP6 signals (bottom) from dLSGLP-1R neurons, correlating with the commencement (H) and cessation (I) of high-fat food ingestion in both fasted and sated mice (n = 7 animals). (J) Quantitative examination of the valley and AUC z scores associated with consumption-induced Ca2+ responses within dLSGLP-1R neurons across fasted and sated mice. (K) Stacked trace of dLSGLP-1R-GCaMP6 signals, aligned to the first bite during the initial third and the concluding third of bouts in mice, analyzed under both fasted and fed states (n = 7 animals). (L) Comparative analysis of the valley of dLSGLP-1R-GCaMP6 signals between initial and final feeding stages. (M) Stacked plot showcasing the response of dLSGLP-1R-GCaMP6 when fasted mice engaged in exploratory actions (n = 7 animals). *P < 0.05, **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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