Inducible nitric oxide synthase-derived nitric oxide reduces vagal satiety signalling in obese mice.

Vagal afferents regulate feeding by transmitting satiety signals to the brain. Mice with diet-induced obesity have reduced vagal afferent sensitivity to satiety signals. We investigated whether inducible nitric oxide synthase (iNOS)-derived NO contributed to this reduction. C57BL/6J mice were fed a high- or low-fat diet for 6-8 weeks. Nodose ganglia and jejunum were analysed by immunoblotting for iNOS expression; NO production was measured using a fluorometric assay. Nodose neuron excitability and intestinal afferent sensitivity were evaluated by whole-cell patch clamp and in vitro afferent recording, respectively. Expression of iNOS and production of NO were increased in nodose ganglia and the small intestine in obese mice. Inhibition of iNOS in obese mice by pre-treatment with an iNOS inhibitor increased nodose neuron excitability via 2-pore-domain K+ channel leak currents, restored afferent sensitivity to satiety signals and reduced short-term energy intake. Obese mice given the iNOS inhibitor daily for 3 weeks had reduced energy intake and decreased body weight gain during the first week, compared to mice given saline, and lower amounts of epididymal fat at the end of 3 weeks. Inhibition of iNOS or blocking the action of iNOS-derived NO on vagal afferent pathways might comprise therapeutic strategies for hyperphagia and obesity.