Investigating the mechanisms responsible for the effect of protein on appetite

Abstract

Obesity, its associated complications and mortality are major worldwide public health issues. Current treatments are poorly effective and are limited by risks and side-effects, and diet and lifestyle measures are poorly adhered to in the long-term. Protein has a satiating effect superior to that achieved with other macronutrients. High protein diets reduce food intake, increase weight loss and improve body composition in animal models and humans. However, they are difficult to adhere to in the longer-term and the exact mechanisms by which a high protein diet regulates food intake remain poorly understood. There is evidence that the amino acid products of protein digestion may regulate appetite and satiety. In vivo studies in rodents from our group have shown that specific amino acids, including L-arginine, can reduce food intake and stimulate the release of anorectic gut hormones. The work carried out in this thesis looked at the effect of L-arginine on appetite in humans. Further work was carried out to determine the metabolites that drive early gut hormone release in humans in response to meals rich in different macronutrients. Oral administration of the maximum dose of L-arginine considered to be a foodstuff by the Medicine Healthcare products Regulatory Agency was well-tolerated with no reported side-effects in a study carried out to determine tolerability. In combination with an ad libitum meal, L-arginine significantly elevated levels of the anorectic gut hormones glucagon-like peptide-1 and peptide YY in healthy human volunteers compared to vehicle treatment. There were possible delayed effects on energy intake and fat intake following oral L-arginine administration subsequent to the study period as observed in self-reported food diaries. Determining the specific metabolites generated by digestion of a high protein meal associated with gut hormone release could guide the targeting of future treatment options such as the creation of functional foods which manipulate intrinsic hunger and satiety mechanisms. Thus a study was carried out using metabolomics to analyse the metabolites present in the stomach and duodenum following ingestion of a high protein meal, and their correlation with gut hormone release. A high protein meal significantly elevated GLP-1 and glucagon. The increase in certain metabolites, some of which may be the products of microbial action, correlate with the increase in GLP-1 release following a high protein meal. Some of the metabolites identified in the duodenum were unexpected. The presence of SCFAs following the high protein meal was one of the findings from the metabolomics analysis, opening questions as to the importance of the gut microbiome in the upper gastrointestinal tract following a high protein meal. This study highlighted the utility of using metabolomics as a mechanistic tool to explore how particular diets may exert biological effects. Differences in metabolic profiles between the pre-meal and post-meal period could better our understanding of how diet influences appetite. Using this type of approach may provide a novel approach to the management of chronic conditions such as obesity. These studies demonstrate the effects of both L-arginine and a high protein meal on appetite-regulating hormones, and contribute to understanding the mechanism of how protein regulates appetite and its effect on glucose homeostasis. Further studies are now necessary to determine the potential of specific amino acids and protein metabolites as treatment options in the management of obesity.