Obesity is a major global health concern. Current anti-obesity therapies are either ineffective, or highly invasive and difficult to provide on a global scale. Therefore, there is a growing need for new treatments. High protein diets have been shown to be effective at promoting weight loss, improving glucose tolerance and supressing appetite, but compliance is low. Understanding the mechanisms underlying the beneficial effects of high protein diets could aid the development of new anti-obesity therapies.
Acute studies have shown protein loads to stimulate the secretion of anorectic hormones which can promote satiety and decrease food intake. However, the long-term effects of high protein intake on the regulation of gut hormones is less clear. This thesis presents a series of studies investigating the mechanisms which may mediate the effects of protein on energy and glucose homeostasis.
The long-term effects of high protein diets on the synthesis and secretion of gut hormones in mice was investigated, and a trend was observed for increased PYY expression in the jejunum, the site of protein digesta absorption.
Amino acids are products of protein digestion and have been suggested to regulate satiety and appetite in response to protein intake. Findings from our group have identified various appetite supressing amino acids including L-Cysteine, L-Arginine and L-Phenylalanine. The mechanism underlying L-Phenylalanine’s anorectic effects were further investigated.
L-Phenylalanine decreased food intake, without apparent behavioural side effects, increased neuronal activation in the dorsal vagal complex (DVC), and stimulated the secretion of anorectic gut hormones and pancreatic hormones. The secretion of GLP-1 and PYY were blunted by a calcium sensing receptor (CaSR) antagonist in vitro, suggesting the CaSR may mediate the anorectic effects of L-Phenylalanine.
Vagal afferents transmit peripheral sensory information from the gut to the central nervous system via nuclei in the DVC. The activation of the DVC in response L-Phenylalanine suggested the vagus nerve might be involved in mediating these responses. The CaSR is one of the few nutrient sensors expressed in the vagus. Knockdown of the CaSR in the vagal afferents of mice inhibited protein induced glucagon secretion. This suggests the CaSR may play an important role in an entero-pancreatic vagal circuit that requires further investigation. The effect of CaSR knockdown on L-Phenylalanine’s anorectic effects were inconclusive.
These studies examined the effects of L-Phenylalanine and high protein diets on appetite regulating hormones. They contribute to our understanding of the mechanism underlying the satiating effects of protein and identify vagally expressed CaSR as a potential nutrient sensor important in the regulation of pancreatic hormone secretion in response to protein intake. Further studies are required to determine the physiological importance of CaSR signalling in the vagus and the therapeutic potential of the CaSR system in the management of obesity.