The role of short chain fatty acids in appetite regulation

Abstract

The current obesity epidemic poses a major challenge to public health. Apart from bariatric surgery, a safe and effective long-term treatment for obesity has yet to be identified. Therefore, an improved understanding of the physiology of energy homeostasis is now more critical than ever. Epidemiologically, there is an inverse association between consumption of fermentable fibre and weight gain. This is supported by experimental studies, which demonstrate that increasing the consumption of fermentable fibre can reduce appetite and body weight. It is thought that these effects may be attributable, at least in part, to the bacterial fermentation of fibre in the colon yielding short chain fatty acids (SCFAs). SCFAs have been identified as ligands for the G-protein coupled receptors GPR41 and GPR43. There are fundamental gaps in our current understanding of the physiological roles of SCFAs and their receptors in energy homeostasis, and of their specific effects in different endocrine tissues. This thesis investigates the effects of colonic SCFAs on anorectic gut hormone release from enteroendocrine L cells, and the role of GPR43 in mediating these effects. I established mouse and human primary L cell models in our laboratory and used them to demonstrate that SCFAs, and particularly propionate, stimulate the release of anorectic gut hormones peptide YY (PYY) and glucagon-like peptide 1 (GLP-1). I confirmed that colonic administration of propionate increases plasma gut hormone concentrations in vivo, in rats and mice. I then explored the mechanisms underlying propionate-induced gut hormone release in vitro. I demonstrated that Gpr43-/- L cells exhibit significantly attenuated PYY and GLP-1 secretion in response to propionate; a result which was also confirmed for the first time in vivo using Gpr43-/- mice. These findings suggest that colonic SCFA signalling via GPR43 may play an important physiological role. Further investigation is now required to characterise the intracellular signalling mechanisms underlying GPR43-activated gut hormone secretion and to determine the wider role of GPR43 in energy homeostasis.