GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats

Mar 6, 2020Science translational medicine

Inhibitory neurons in the brainstem control appetite reduction by liraglutide in rats through GLP-1 receptors

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Abstract

Knockdown of NTS GLP-1 receptors significantly reduced the effects of liraglutide on food intake and body weight in male rats.

Liraglutide acts through central GLP-1 receptors in the hypothalamus and hindbrain to suppress food intake and body weight.
The anorectic effects of liraglutide are mediated by GLP-1 receptors specifically in the nucleus tractus solitarius (NTS).
Surgical lesioning of the area postrema did not diminish liraglutide's effects, indicating its role is not primary in this context.
Inhibition of GABAergic neurons in the NTS also reduced the anorectic effects of liraglutide, revealing a specific neuronal population involved.
Chronic administration of liraglutide maintained its weight-reducing effects, but this was attenuated by targeted knockdown of NTS GLP-1 receptors.

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The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is approved for the treatment of obesity; however, there is still much to be learned regarding the neuronal sites of action that underlie its suppressive effects on food intake and body weight. Peripherally administered liraglutide in rats acts in part through central GLP-1Rs in both the hypothalamus and the hindbrain. Here, we extend findings supporting a role for hindbrain GLP-1Rs in mediating the anorectic effects of liraglutide in male rats. To dissociate the contribution of GLP-1Rs in the area postrema (AP) and the nucleus tractus solitarius (NTS), we examined the effects of liraglutide in both NTS AAV-shRNA-drivenknockdown and AP-lesioned animals. Knockdown of NTS GLP-1Rs, but not surgical lesioning of the AP, attenuated the anorectic and body weight-reducing effects of acutely delivered liraglutide. In addition, NTS c-Fos responses were maintained in AP-lesioned animals. Moreover, NTSknockdown was sufficient to attenuate the intake- and body weight-reducing effects of chronic daily administered liraglutide over 3 weeks. Development of improved obesity pharmacotherapies requires an understanding of the cellular phenotypes targeted by GLP-1R agonists. Fluorescence in situ hybridization identifiedtranscripts in NTS GABAergic neurons, which when inhibited using chemogenetics, attenuated the food intake- and body weight-reducing effects of liraglutide. This work demonstrates the contribution of NTS GLP-1Rs to the anorectic potential of liraglutide and highlights a phenotypically distinct (GABAergic) population of neurons within the NTS that express the GLP-1R and are involved in the mediation of liraglutide signaling. Glp1r Glp1r Glp1r

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GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats

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