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

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. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a new method combining monosynaptic rabies with single-cell transcriptomics to identify connected neurons in a genetically tractable manner: “RAMPANT” (Rabies Afferent Mapping by Poly-A Nuclear Transcriptomics). Applying RAMPANT to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons increases feeding and body weight and reduces liraglutide’s satiating effects. Our results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.