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Type: Thesis
Title: Obesity induced dysfunction of gastric vagal afferent signalling.
Author: Kentish, Stephen James
Issue Date: 2013
School/Discipline: School of Medicine
Abstract: Background: The stomach has the ability to respond to chemical and mechanical stimuli to mediate satiety through vagal pathways. Within the stomach specialised endocrine and epithelial cells synthesise and secrete leptin and ghrelin, which influence food intake through vagal afferent pathways. However, it remains to be determined if mechanosensitive gastric vagal afferent signalling is disrupted in obesity and whether this may play a role in the overconsumption of energy required for the maintenance of diet induced obesity. Furthermore, whether leptin can modulate mechanically sensitive gastric vagal afferents and whether any ability of leptin and ghrelin to modulate mechanically sensitive endings is altered in obesity has not been conclusively determined. Aims: To determine in lean mice and in high fat diet induced obese mice: 1) The effect of gastric peptides ghrelin and leptin on gastric vagal afferent mechanosensitivity. 2) The effect of gastric peptides on the expression of their own and other peptide receptors. 3) The reversibility of diet-induced obesity. Methods: Lean and diet-induced obese mice were created by feeding 8 week old female C57BL/6 mice a standard chow diet (N=4-20; 7% energy from fat) or a high-fat diet (N=4-20; 60% of energy from fat) respectively. An in vitro gastro-oesophageal vagal flat sheet preparation was utilised to determine the mechanosensitivity of vagal afferent endings and the effect of leptin, ghrelin and diet-induced obesity on this mechanosensitivity. Messenger RNA (mRNA) content in nodose ganglia was measured by QRT-PCR. Specific gastric vagal afferent cell bodies were identified by retrograde labelling and this technique was combined with QRT-PCR to determine mRNA content in specific gastric cell bodies. Anterograde tracing by injection of tracer into the nodose ganglia allowed visualisation of the distribution of gastric vagal afferents in relation to leptin and ghrelin positive cells. Nodose ganglia were cultured overnight in medium containing leptin, ghrelin or neuropeptide W (NPW) followed by QRTPCR to determine any homologous or heterologous receptor expression regulation. Results: Diet-induced obesity caused a reduction in the mechanosensitivity of gastric tension receptors. Furthermore, it increased the inhibitory effect of ghrelin on gastric vagal afferent mechanosensitivity and resulted in a switch in the effect of leptin from potentiating to inhibitory. The gut peptides leptin, ghrelin and NPW modified the mRNA content of their own and each other‘s receptors in a manner that was dependent on dietary group. Placing obese mice back on a chow diet resulted in an initial weight loss but subsequent increased food consumption and weight gain. The decrease in mechanosensitivity caused by the high fat diet was not reversible by placing diet-induced obese mice back on a chow diet and the effects of leptin were only partially reversed. Conclusions: Vagal afferent function is altered in diet-induced obesity to the extent that both the baseline response and the effects of leptin and ghrelin may act to facilitate increased food intake. Given the lack of reversibility of changes observed in diet-induced obesity this suggests that gastric vagal afferents may play a role in the maintenance of obesity and may act to oppose weight loss.
Advisor: Page, Amanda Jayne
Blackshaw, Laurence Ashley
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2013
Keywords: obesity; vagal afferents; gastric; leptin; ghrelin; satiety
Provenance: Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
Appears in Collections:Research Theses

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