Gut hormone interactions in glucose homeostasis,
appetite control and bodyweight regulation.
Doctoral thesis, UCL (University College London).
Several hormones released from the gastrointestinal tract in response to caloric ingestion have been characterised in the regulation of glucose homeostasis, appetite control and bodyweight regulation. Ghrelin is released from the stomach and signals for hunger. Glucagon-like Peptide-1 (GLP-1), a product of the proglucagon gene, is released from the enteroendocrine L-cells of the distal gut and is primarily involved in glucose-dependent insulin secretion. Peptide tyrosine-tyrosine (PYY) is colocalised with proglucagon in both intestinal L-cells and pancreatic α-cells. Studies in Pyy null mice and humans have revealed a critical role for PYY in regulating appetite and bodyweight. However, to date the role of PYY in glucose homeostasis remains unclear. Controversy surrounds the effects dietary manipulations and bariatric surgery have on circulating gut hormone concentrations and subjective appetite. I first demonstrated that sample processing affects subsequent gut hormone measurements. To assess the potential interference of study design on study outcome, I investigated the effects of subject standardisation and study-associated stress on fasting gut hormone levels and appetite scores. To evaluate the temporal changes in gut hormones that occur with the development of obesity, I investigated tissue expression and circulating levels of gut hormones in mice exposed to a high-fat diet. I also compared the effects of weight loss through macronutrient modification, caloric restriction and bariatric surgery on gut hormones. The findings revealed a key role for PYY in mediating the weight loss and improved glucose homeostasis observed post-bariatric surgery. With further investigation, I delineated contrasting roles for the major PYY isoforms in glucose control systemically and locally within the pancreas through study of mice with tissuespecific deletion of Pyy in the pancreas as well as in vitro studies in isolated islets. A greater understanding of the dynamic properties and interactions between gut hormones is essential for the development of more focussed therapeutic strategies for the treatment of obesity and diabetes.
|Title:||Gut hormone interactions in glucose homeostasis, appetite control and bodyweight regulation|
Archive Staff Only