The effects of amino acids on gut hormone release and appetite

Abstract

Obesity is a major health concern and a public health burden. Current pharmacological treatments have limited efficacy and are associated with significant side effects. Diets and life style changes remain the most effective strategy for treatment of obesity, but are often difficult to adhere to. High protein diets are among the most satiating diets, associated with the greatest satiety and weight loss, and with better weight management. The exact mechanisms by which high protein diets exert their effects are unclear. However, evidence suggests that amino acids produced as a result of protein digestion may play a role in appetite regulation and satiety. Preliminary studies within our group demonstrated that specific amino acids can reduce food intake in rodents. The work carried out in this thesis examined the effect of the amino acids L-arginine and L-phenylalanine on appetite and explored the potential mechanisms by which these effects are mediated. In addition, the thesis investigated the effect of microencapsulation of these amino acids on their ability to suppress appetite. Oral gavage of L-arginine significantly reduced food intake in mice and rats. This effect was not associated with any abnormal behavioural side effects. L-arginine significantly stimulated GLP-1 and PYY release from a murine primary intestinal culture, and oral L-arginine also significantly elevated plasma GLP-1 and PYY in rats. However, the anorectic effect of L-arginine appears unlikely to be mediated by changes in these gut hormones. L-arginine significantly reduced food intake in GPRC6A knockout and wild-type mice, suggesting its anorectic effect is not mediated by GPRC6A. Oral gavage of L-phenylalanine significantly reduced food intake in mice and rats. Oral administration of L-phenylalanine also elevated circulating GLP-1 and PYY levels and suppressed plasma ghrelin levels in rats. Direct ileal administration of L-phenylalanine reduced food intake in rats, and this effect was blocked by a calcium sensing receptor antagonist. Chronic administration of L-phenylalanine also reduced food intake and body weight in diet-induced obese mice. Encapsulated L-arginine and L-phenylalanine reduced food intake in rats. Specific encapsulation processes appeared to delay the anorectic effect of these amino acids. However, there was no significant difference in the magnitude of response compared to the un-encapsulated forms. Encapsulation may be a viable approach to facilitate targeted delivery of the amino acids in the gastrointestinal tract, but further matrix optimization is required to improve the controlled release of the amino acids in the gut. These studies demonstrate the anorectic properties of L-arginine and L-phenylalanine, and contribute to the current understanding of amino acid sensing in the gut. Further studies are now required to determine the therapeutic potential of specific amino acids as novel treatments for obesity.