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 (LS GLP-1R ) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LS GLP-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 LS GLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LS GLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LS GLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.
Funding Information
  • Major Project of the Science and Technology Innovation 2030 of China (2021ZD0202103)
  • National Natural Science Foundation of China (82171492,32200827,82271534)
  • Guangdong Provincial Department of Science and Technology (2023B1515040009,2024A1515011612)
  • Science, Technology and Innovation Commission of Shenzhen (RCJC20200714114556103,ZDSYS20190902093601675,JCYJ20210324141201003)

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