NO regulation of gut‐brain signalling in obesity

Over the last century environmental and societal changes have resulted in obesity emerging as a major global health concern. This is due to consumption of high calorie and/or high fat diets along with a sedentary lifestyle. Since 1980 the prevalence of obesity has almost doubled worldwide and recent concern regards the rapid increase in the prevalence of severe obesity (BMI >35 kg/m²). In 2014, more than 39% of adults were overweight, with 13% being obese. This has resulted in an increased drive to understand the effects of high fat, high calorie diets on appetite regulation. Further, with the withdrawal of many centrally acting pharmacotherapies for obesity, due to adverse side‐effects, there is renewed interest in peripheral mechanisms of food intake regulation.

The upper gastrointestinal tract plays an important role in sensing the arrival, amount and nutrient composition of a meal. It responds to mechanical stimuli just from the presence of food in the gastrointestinal tract. The gut also responds to chemical stimuli, via the interaction of specific dietary nutrients with specialised ‘taste’ receptors on enteroendocrine cells within the small intestine. This interaction initiates an intracellular process that culminates in the release of a gut hormone(s). All these signals are then transmitted to the brain where information is processed and ultimately contributes to food intake regulation by modulating appetite as well as feedback control of gastrointestinal function, such as gut motility (e.g. gastric emptying). These signals are abnormally diminished in high fat diet‐induced obesity (Daly et al. 2011) and the mechanism for this decrease in peripheral satiety signalling is a point of interest as a potential target for the treatment of obesity.

Nitric oxide has been shown to be a critical regulator of cell and tissue function. Nitric oxide production is predominantly via the nitric oxide synthase (NOS) family of enzymes. The three isoforms of NOS include the constitutively active endothelial NOS (eNOS) and neuronal NOS (nNOS) and the inducible NOS (iNOS). iNOS is expressed in multiple cell types in response to inflammatory stimuli and when activated has the highest capacity to produce nitric oxide. In vagal afferent neurones it has been shown that nitric oxide decreases cell body excitability (Bielefeldt et al. 1999). Further, at the peripheral gastro‐oesophageal vagal afferent ending, the modulatory effect of nitric oxide on gastro‐oesophageal vagal afferent mechanosensitivity has been shown to depend on nutritional status. In mice fed ad libitum, endogenous nNOS‐derived nitric oxide inhibits the mechanosensitivity of a subset of gastro‐oesophageal vagal afferents, namely mucosal receptors. However, in fasted mice endogenous nitric oxide enhances the mechanosensitivity of gastro‐oesophageal vagal afferents (Kentish et al. 2014). These modulatory effects reflect the second messenger pathway utilized, which could conceivably depend on the amount of nitric oxide available. These effects are counterintuitive with regard to energy demand, as, for example, in fasted conditions energy demand is high and early satiety is therefore undesirable. 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.

Obesity is characterised as a low inflammatory state which could impact on iNOS expression and thus nitric oxide production. It has been shown that nitric oxide levels were increased in the small intestine of obese compared to control rats. Further, this was associated with an increase in iNOS mRNA and protein levels (Ou et al. 2012). Yu et al. (2019) 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. injection of the iNOS inhibitor l‐N ⁶‐(1‐Iminoethyl) lysine dihydrochloride (L‐NIL) decreased the hyperphagia observed in high fat diet‐induced obese mice by increasing the inter‐meal interval. However, this was not sustained and food intake and weight gain returned to the same level as the control treated high fat diet mice by the second week of treatment. This loss of effect of L‐NIL could be due to compensatory changes in the subcellular signalling pathways; however, this requires further investigation. Despite the lack of long term effects on food intake and weight gain, the accumulating evidence suggests that nitric oxide production plays a regulatory role in gastrointestinal vagal afferent function. 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.

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Competing interests

None declared.

Author contributions

Sole author.

Funding

No funding was received.