Nutrient sensing is essential for both short and long-term energy homeostasis and is in part mediated by the vagus nerve. The processes and mechanisms involved in nutrient sensing require proper synthesis and secretion of gut-derived peptides originating from enteroendocrine cells found along the length of the gastrointestinal tract to transmit both humoral and neural signals along the gut-brain axis. The vagal afferent pathway acts as a conduit that relays the plethora of gut-derived endocrine messages that are ultimately integrated in feeding centers found in the hypothalamus. In this dissertation, we tested the hypothesis that the response to nutrients along the vagal afferent pathway is compromised in diet-induced obesity and Type 2 Diabetes Mellitus (T2DM). Impairment of mechanisms involved in nutrient sensing may be associated with reduced satiety signaling leading to hyperphagia and body weight gain seen in metabolic disease. We used three animal models to investigate the interactions between gut hormones, along the vagus nerve in response to acute nutrient stimuli or long-term high-fat diet maintenance. Firstly, we examined the role of orexigenic ghrelin signaling via GHSR1a in CCK1R-/- mice and found increased GHSR1a expression in nodose neurons to be associated with altered meal patterns in CCK1R-/- mice. Secondly, we looked at the effect of long term high-fat feeding on the ghrelin system (hormone, GOAT, GHSR1a) along the vagal afferents and central arcuate nucleus (ARC) in polygenic Sprague-Dawley rats, where approximately half of them become diet-induced obese (DIO) while the others remain diet-resistant (DR). The data suggest that elevated levels of GHSR1a in the stomach, pancreas and nodose neurons may be driving the hyperphagia and body weight gain seen in DIO rats, which is unchanged in the ARC. Lastly, we found that glucose-sensing in gut endocrine cells along the vagal afferent pathway in the novel UCD T2DM rat model is attenuated in T2DM. Together, these findings demonstrate the neuroplasticity of the vagal afferents under metabolic compromise leading to reduced gut endocrine and neural function and impaired regulation of gut chemosensing and food intake.
|Advisor:||Raybould, Helen E.|
|Commitee:||Adams, Sean H., Ramsey, Jon J.|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 71/12, Dissertation Abstracts International|
|Subjects:||Endocrinology, Neurobiology, Physiology|
|Keywords:||Diet-induced obesity, Gastrointestinal tract, Gut hormones, Metabolic disease, Nutrient sensing, Plasticity, Type 2 diabetes mellitus, Vagus nerve|
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