Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)⁺ Arc (TRH^Arc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRH^Arc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRH^Arc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite.

利拉鲁肽和其他胰高血糖素样肽 1 受体激动剂 （GLP-1RAs） 是有效的减肥药物，但它们如何抑制食欲仍不清楚。一种可能的机制是通过激活抑制弓状下丘脑 （Arc） 促进饥饿的 Agouti 相关肽 （AgRP） 神经元的神经元。为了识别这些传入子，我们开发了一种将基于狂犬病的连接组学与单核转录组学相结合的方法。在这里，我们在小鼠中下丘脑和室旁下丘脑中鉴定了至少 21 种 AgRP 神经元的传入亚型，这些亚型由我们的方法预测。其中包括促甲状腺激素释放激素 （TRH）⁺ Arc （TRH^Arc） 神经元，表达 Glp1r 基因并被 GLP-1RA 利拉鲁肽激活的抑制性神经元。激活 TRH^Arc 神经元会抑制 AgRP 神经元和摄食，可能以 AgRP 神经元依赖性方式。沉默 TRH^Arc 神经元会导致暴饮暴食和体重增加，并减弱利拉鲁肽对体重的影响。我们的结果证明了一种广泛适用的分子连接组学方法，全面识别了 AgRP 神经元的局部输入，并揭示了 GLP-1RAs 抑制食欲的回路。