Modulation of neuropeptide W on gastric vagal afferents.

Abstract

Background: Gastric vagal afferents play an important role in the regulation of food intake in response to mechanical stimuli. In the stomach neuropeptide W (NPW) is secreted from G-cells. It is known that NPW is involved in central regulation of food intake and energy homeostasis, however, whether NPW can modulate gastric vagal afferents mechanosensitivity and how this role changes in different nutritional states, such as obesity, is not known. Furthermore, the role of different macronutrients in NPW expression and secretion in the stomach is not clear. Aims: This thesis aims to determine: 1) The modulatory effect of NPW on gastric vagal afferent mechanosensitivity under different states of nutrition including food restriction and high-fat diet-induced obese mice. 2) The modulatory effect of NPW on gastric vagal afferent mechanosensitivity in mice of different age and gender. 3) The macronutrients responsible for regulation of gastric NPW. Methods: An in vitro electrophysiology preparation was used to determine the effect of NPW on the mechanosensitivity of gastric mucosal and tension receptors in C57BL/6 mice fed ad libitum, fasted overnight, or fed with a high-fat diet. Expression of NPW in the gastric mucosa and GPR7 in the whole nodose ganglia was determined by quantitative RT-PCR (QRT-PCR). Expression of GPR7 in gastric vagal afferent neurons was determined by retrograde tracing and QRT-PCR. Plasma NPW levels were determined in healthy lean subjects after nutrient intake. Plasma and gastric NPW levels were determined in mice after feeding with different nutrients. Primary cell cultures of mouse gastric antral mucosal cells were used to investigate the signalling pathway of NPW expression. Results: In 20-week-old adult mice NPW selectively inhibited the responses of gastric vagal tension receptors to stretch. The inhibitory effect of NPW on gastric vagal tension receptors was gender consistent, but not observed in younger mice, high-fat diet-fed mice or food restricted mice. Protein and glucose intake increased gastric NPW transcript and protein levels in mice but had no effect on plasma NPW levels in human and mice. Protein and glucose are stimulants of gastric NPW expression, via distinct mechanisms. Conclusion: NPW modulates mechanosensitivity of gastric vagal afferents; an effect related to feeding status, age and gender. Gastric NPW is regulated by specific nutrients.