Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety

期刊论文
发表日期：

2024年12月3日

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Addison N. Webster,
Jordan J. Becker,
Chia Li,
Dana C. Schwalbe,
Damien Kerspern,
Eva O. Karolczak,
Catherine B. Bundon,
Roberta A. Onoharigho,
Maisie Crook,
Maira Jalil,
Elizabeth N. Godschall,
Emily G. Dame,
Adam Dawer,
Dylan Matthew Belmont-Rausch,
Tune H. Pers,
Andrew Lutas,
Naomi Habib,
Ali D. Güler,
Michael J. Krashes,
John N. Campbell

摘要

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.