Control of feeding behavior by modified retrograde AAV to the gastrointestinal tract nerve afferents

Vagal afferents originating in the upper gastrointestinal (GI) tract convey critical satiety signals but have remained challenging to target with precision. Here, we exploited a modified retrograde AAV2/rh10 vector delivered to the gastric wall to selectively transduce stomach-innervating nodose ganglion neurons and express the excitatory DREADD receptor hM3Dq. Chemogenetic activation of these afferents in mice acutely suppressed food intake by over 50% and induced robust c-Fos expression in neurons of the nucleus tractus solitarius and ventromedial (VMH) and arcuate nuclei of the hypothalamus, while chronic stimulation during high-fat feeding attenuated diet-induced weight gain by nearly 40%. This minimally invasive, organ-targeted gene-delivery strategy affords reversible control over visceral sensory pathways and holds promise as a foundation for novel obesity and metabolic-disorder therapies.