Combinatorial therapies are under intense investigation for the development of more efficient anti-obesity drugs, however little is known about how they act in brain to produce enhanced anorexia and weight loss.

Objectives

The goal of this study was to identify the brain sites and neuronal populations engaged during the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents.

Methods

We measured acute and long-term feeding and body weight responses, and neuronal activation pattern throughout the neuraxis and in specific neuronal subsets in response to GLP-1R and CCK1R agonists administered alone or in combination in lean and high-fat fed mice. We used PhosphoTRAP to obtain unbiased molecular markers for neuronal populations selectively activated by the combination of the two agonists.

Results

The initial anorectic response to GLP-1R and CCK1R co-agonism was mediated by a reduction in meal size but over a few hours, a reduction in meal number accounted for the sustained feeding suppressive effect. The nucleus of the solitary tract (NTS) is one of the few brain sites where GLP-1R and CCK1R signaling interact to produce enhanced neuronal activation. None of the previously categorized NTS neuronal subpopulations relevant to feeding behaviour were implicated in this increased activation. However, we identified NTS/AP Calcrl⁺ neurons as targets of this treatment.

Conclusions

Collectively these studies indicate that circuit-level integration of GLP-1R and CCK1R coagonism in discrete brain nuclei including the NTS produces enhanced rapid and sustained appetite suppression and weight loss.

中文翻译：

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支持 GLP-1/CCK 联合治疗的摄食抑制作用的行为和神经化学机制

正在对联合疗法进行深入研究，以开发更有效的抗肥胖药物，但人们对它们如何在大脑中发挥作用以产生增强的厌食症和体重减轻知之甚少。

目标

本研究的目的是确定在共同给药 GLP-1R 和 CCK1R 激动剂（肥胖啮齿动物的有效联合疗法）期间参与的大脑部位和神经元群体。

方法

我们测量了急性和长期喂养和体重反应，以及整个神经轴和特定神经元亚群中的神经元激活模式，以响应在瘦肉和高脂喂养的小鼠中单独或联合使用 GLP-1R 和 CCK1R 激动剂。我们使用 PhosphoTRAP 来获得由两种激动剂的组合选择性激活的神经元群体的无偏分子标记。

结果

对 GLP-1R 和 CCK1R 共激动的最初厌食反应是通过减少膳食大小来介导的，但在几个小时内，膳食数量的减少解释了持续的摄食抑制作用。孤束核 (NTS) 是 GLP-1R 和 CCK1R 信号相互作用以产生增强的神经元激活的少数大脑部位之一。先前分类的与进食行为相关的 NTS 神经元亚群中没有一个与这种增加的激活有关。然而，我们将 NTS/AP Calcrl ⁺神经元确定为这种治疗的目标。

结论

总的来说，这些研究表明 GLP-1R 和 CCK1R 在包括 NTS 在内的离散脑核中的电路级整合产生增强的快速和持续的食欲抑制和体重减轻。