Webster Addison N, Becker Jordan J, Li Chia, Schwalbe Dana C, Kerspern Damien, Karolczak Eva O, Bundon Catherine B, Onoharigho Roberta A, Crook Maisie, Jalil Maira, Godschall Elizabeth N, Dame Emily G, Dawer Adam, Belmont-Rausch Dylan Matthew, Pers Tune H, Lutas Andrew, Habib Naomi, Güler Ali D, Krashes Michael J, Campbell John N
Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA.
Section on Motivational Processes Underlying Appetite, Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
Nat Metab. 2024 Dec;6(12):2354-2373. doi: 10.1038/s42255-024-01168-8. Epub 2024 Dec 3.
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) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRH neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRH 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。一种潜在机制是通过激活抑制弓状下丘脑（Arc）中促进饥饿的刺鼠相关肽（AgRP）神经元的神经元。为了识别这些传入神经元，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，我们在小鼠中脑基底和室旁下丘脑中识别出至少21种AgRP神经元的传入亚型，这是由我们的方法预测出来的。其中包括促甲状腺激素释放激素（TRH）弓状核（TRH）神经元，这是一种表达Glp1r基因并被GLP-1RA利拉鲁肽激活的抑制性神经元。激活TRH神经元会抑制AgRP神经元和进食，可能是以一种依赖于AgRP神经元的方式。沉默TRH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抑制食欲的一条通路。
