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 1

GLP-1R–expressing neurons in the LS are activated by liraglutide.

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GLP-1R–expressing neurons in the LS are activated by liraglutide. (A) Re...
(A) Representative image showing c-Fos expression in the dorsal lateral septum (dLS) following i.p. injection of either saline or liraglutide. Scale bars: left, 200 μm; right, 50 μm. (B) Left: Quantification of GLP-1R+ neuron densities across various brain regions. Right: Quantification of c-Fos+ neurons in corresponding brain regions after i.p. injection of saline or liraglutide. VP, ventral pallidum; LH, lateral hypothalamic area; PVN, paraventricular hypothalamic nucleus; Arc, arcuate hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; APN, anterior pretectal nucleus; Pn, pontine nuclei; DG, dentate gyrus; ECu, external cuneate nucleus; LRt, lateral reticular nucleus; AP, area postrema. (C) Representative image illustrating position of infusion cannula above GLP-1R–positive neurons. Scale bar: 500 μm. (D) Representative image showing c-Fos expression in LSGLP-1R neurons. Scale bar: 50 μm. (E) Quantification of c-Fos+ GLP-1R+ (left) and c-Fos+ GLP-1R– cells (right) after administration of saline or liraglutide. Unpaired, 2-tailed t test; left: t(5) = 3.454, P = 0.0182; right: t(5) = 0.2629, P = 0.8031. Means ± SEM. (F) Schematic of whole-cell recording from tdTomato–positive neurons in GLP-1R-ires-Cre:Ai14 slices. (G) Representative trace of spontaneous excitatory postsynaptic currents in LSGLP-1R neurons before and after liraglutide application. (H) Left: Cumulative amplitude probability plots. Inset and right: Pooled data; n = 7 cells from 2 animals; paired 2-tailed t test; t(6) = 4.017/1.256, P = 0.0070/0.2557. *P < 0.05, **P < 0.01.