bioRxiv : the preprint server for biology · 2024
Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Webster Addison Nicole, Becker Jordan J, Li Chia, Schwalbe Dana Catharine, Kerspern Damien, Karolczak Eva O, Bundon Catherine, Onoharigho Roberta A, Crook Maisie, Jalil Maira, Godschall Elizabeth Nora, Dame Emily G, Dawer Adam, Belmont-Rausch Dylan Matthew, Pers Tune H, Lutas Andrew, Habib Naomi, Guler Ali D, Krashes Michael J, Campbell John Nelson
Аннотация
Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit 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-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons, inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating Trh+ Arc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing Trh+ Arc neurons causes over-eating 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.