<p>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.</p>

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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

摘要

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.