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GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats.
Science Translational Medicine ( IF 17.1 ) Pub Date : 2020-03-04 , DOI: 10.1126/scitranslmed.aay8071
Samantha M Fortin 1 , Rachele K Lipsky 1, 2 , Rinzin Lhamo 1 , Jack Chen 1 , Eun Kim 1 , Tito Borner 2 , Heath D Schmidt 1, 2 , Matthew R Hayes 1, 2
Affiliation  

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-driven Glp1r knockdown 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, NTS Glp1r knockdown 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 identified Glp1r transcripts 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.

中文翻译:

孤束核中的 GABA 神经元表达 GLP-1 受体并介导利拉鲁肽对大鼠的厌食作用。

胰高血糖素样肽-1受体(GLP-1R)激动剂利拉鲁肽被批准用于治疗肥胖症;然而,关于其对食物摄入和体重的抑制作用的神经元作用位点,仍有很多东西有待了解。大鼠外周给药的利拉鲁肽部分通过下丘脑和后脑的中枢 GLP-1R 发挥作用。在这里,我们扩展了支持后脑 GLP-1R 在介导雄性大鼠利拉鲁肽的厌食作用中的作用的发现。为了分离 GLP-1R 在后区 (AP) 和孤束核 (NTS) 中的作用,我们检查了利拉鲁肽在 NTS AAV-shRNA 驱动的 Glp1r 敲低和 AP 损伤动物中的作用。NTS GLP-1R 的敲低,而不是 AP 的手术损伤,减弱了急性递送的利拉鲁肽的厌食和减轻体重的作用。此外,NTS c-Fos 反应在 AP 损伤的动物中得以维持。此外,NTS Glp1r 敲低足以减弱长期每日服用利拉鲁肽超过 3 周的摄入量和体重减少作用。开发改进的肥胖药物疗法需要了解 GLP-1R 激动剂针对的细胞表型。荧光原位杂交鉴定了 NTS GABA 能神经元中的 Glp1r 转录本,当使用化学遗传学抑制该转录本时,会减弱利拉鲁肽的食物摄入和体重减轻作用。这项工作证明了 NTS GLP-1R 对利拉鲁肽的厌食潜力的贡献,并强调了 NTS 内表达 GLP-1R 并参与利拉鲁肽信号传导的表型独特(GABA 能)神经元群体。
更新日期:2020-03-06
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