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

Abstract

Key points Obesity is associated with disrupted satiety regulation. Mice with diet‐induced obesity have reduced vagal afferent neuronal excitability and a decreased afferent response to satiety signals. A low grade inflammation occurs in obesity with increased expression of inducible nitric oxide synthase (iNOS). Inhibition of iNOS in diet‐induced obese mice restored vagal afferent neuronal excitability, increased the afferent response to satiety mediators and distention of the gut, and reduced short‐term energy intake. A prolonged inhibition of iNOS reduced energy intake and body weight gain during the first week, and reduced amounts of epididymal fat after 3 weeks. We identified a novel pathway underlying disrupted satiety regulation in obesity. Blocking of this pathway might be clinically useful for the management of obesity. Abstract 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.

NO regulation of gut‐brain signalling in obesity

“…The study by Yu et al . () indicates a role for nitric oxide in the hyperphagia observed in high fat diet conditions and highlights the need for improved understanding of the dynamic role nitric oxide plays in modulating gastrointestinal vagal afferent signalling and the subcellular signalling pathways involved. This will ultimately lead to new peripheral targets for the pharmacotherapy of obesity.…”

“…Yu et al . () have taken these observations further and demonstrated that the dampened mechanosensitivity and chemosensitivity, observed in high fat diet‐induced obese mice, is reversed by addition of an iNOS inhibitor at least in subgroups of jejunal vagal afferent fibres. Further, they demonstrated that daily i.p.…”

“…This is disrupted in high fat diet-induced obesity and evidence suggests this is due to an excess production of nitric oxide as a result of upregulation of iNOS in response to the low-grade inflammation that occurs in the obese state. The study by Yu et al (2019) indicates a role for nitric oxide in the hyperphagia observed in high fat diet conditions and highlights the need for improved understanding of the dynamic role nitric oxide plays in modulating gastrointestinal vagal afferent signalling and the subcellular signalling pathways involved. This will ultimately lead to new peripheral targets for the pharmacotherapy of obesity.…”

“…Nonetheless, as outlined by Yu et al . () in this issue of The Journal of Physiology , nitric oxide has a dynamic role in the regulation of gastrointestinal vagal afferent mechanosensitivity, a role that is susceptible to disruption in high fat diet‐induced obesity.…”

“…More detailed information on the precise timing of nitric oxide synthesis with regard to nutritional status may provide a clearer understanding of the subtle role nitric oxide plays in peripheral appetite regulation. Nonetheless, as outlined by Yu et al (2019) in this issue of The Journal of Physiology, nitric oxide has a dynamic role in the regulation of gastrointestinal vagal afferent mechanosensitivity, a role that is susceptible to disruption in high fat diet-induced obesity.…”