GLP-1R–positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice
Zijun Chen, … , Yixiao Luo, Yingjie Zhu
Zijun Chen, … , Yixiao Luo, Yingjie Zhu
Published September 3, 2024
Citation Information: J Clin Invest. 2024;134(17):e178239. https://doi.org/10.1172/JCI178239.
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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 3

Silencing of LSGLP-1R neurons enhances consumption and reduces liraglutide’s effects on food intake and body weight.

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Silencing of LSGLP-1R neurons enhances consumption and reduces liragluti...
(A) Representative image showing specific expression of TeNT-2A-EGFP in LSGLP-1R neurons. Scale bars: left, 200 μm; right, 50 μm. (B) Left: Images of EYFP- and TeNT-expressing mice after 6 weeks on high-fat diet. Right: Quantification of body weight gain in mice after high-fat diet. Two-way repeated-measures ANOVA; standard chow: F(1,15) = 7.203, P = 0.0170. Šidák’s post hoc analysis. Means ± SEM. (C and D) Left: Scheme depicting free consumption of a standard chow and a high-sucrose food paradigm. Right: Quantification of daily solid food intake in EYFP- and TeNT-expressing mice. Unpaired, 2-tailed t test; chow: t(29) = 0.1347, P = 0.8970; high-sucrose food: t(17) = 3.529, P = 3.529. Means ± SEM. (E) Oral glucose tolerance test (oGTT) results for TeNT- and EYFP-expressing mice. Two-way repeated-measures ANOVA; F(5,60) = 0.7675, P = 0.5769. Inset: Area under the curve (AUC) over 2 hours during oGTT. Unpaired, 2-tailed t test; t(12) = 1.352, P = 0.2014. Means ± SEM. (F) Schematic showing Ensure solution self-administration (fixed ratio 1) paradigm. (G) Lick patterns for individual mice. (H) The TeNT group had a greater number of pokes at the active port and greater Ensure solution consumption than the EYFP group. Two-way repeated-measures ANOVA; F(1,21) = 119.2, P < 0.0001. Šidák’s post hoc analysis. Unpaired, 2-tailed t test; t(21) = 13.32, P < 0.0001. Means ± SEM. (I–L) Silencing of LSGLP-1R neurons attenuated the anorectic and body weight–reducing effect of acutely delivered systemic liraglutide during standard chow or high-sucrose diet over varying durations and dosages. Food intake (2 hours, left panels; 24 hours, middle panels): 2-way repeated-measures ANOVA, followed by Šidák’s post hoc test. Body weight (right panels): unpaired, 2-tailed t test. Means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.