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

Roberta Marongiu; Jingjing Wang; Santiago R Unda; Julie Barbera; Leandra Velazquez; Rosemary Li; Maria Jimenez-Gonzalez; William Tower; Neranjan de Silva; Rachel Retik; Sarah A Stanley; Michael G Kaplitt

doi:10.1038/s41598-025-31377-4

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

Sci Rep. 2025 Dec 14;16(1):1773. doi: 10.1038/s41598-025-31377-4.

Authors

Roberta Marongiu^{1

2

3}, Jingjing Wang^#¹, Santiago R Unda^#¹, Julie Barbera¹, Leandra Velazquez¹, Rosemary Li⁴, Maria Jimenez-Gonzalez⁴, William Tower¹, Neranjan de Silva¹, Rachel Retik¹, Sarah A Stanley^{4

5}, Michael G Kaplitt^{6

7}

Affiliations

¹ Department of Neurological Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA.
² Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, USA.
³ Department of Genetics, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁴ Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Neurological Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA. mik2002@med.cornell.edu.
⁷ Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, USA. mik2002@med.cornell.edu.

^# Contributed equally.

Abstract

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.

Keywords: AAV vectors; Neuronal modulation; Nodose ganglion; Nucleus tractus solitarius; Vagal afferent.

MeSH terms

Animals
Dependovirus* / genetics
Diet, High-Fat
Eating
Feeding Behavior* / physiology
Gastrointestinal Tract* / innervation
Gastrointestinal Tract* / physiology
Gene Transfer Techniques
Genetic Vectors / genetics
Male
Mice
Mice, Inbred C57BL
Neurons, Afferent* / metabolism
Nodose Ganglion / metabolism
Nodose Ganglion / physiology
Solitary Nucleus / metabolism