The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents.

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of peptide YY3-36 (PYY3-36), lithium chloride, glucagon-like peptide 1 (GLP-1), and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated do not mimic the behaviour of well-fed animals and that the intermeal interval is influenced by fullness. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating upper gut emptying can be as effective as anorectic drug administration.

L-Arginine Increases Postprandial Circulating GLP-1 and PYY Levels in Humans.

OBJECTIVE: The satiating effect of protein compared with other nutrients has been well described and is thought to be mediated, in part, by gut hormone release. Previously, it has been shown that oral L-arginine acts as a GLP-1 secretagogue both in vitro and in vivo in rodents. Here, the effect of L-arginine on gut hormone release in humans was investigated. METHODS: The hypothesis was tested in two separate studies. The first study assessed the tolerability of oral L-arginine in healthy human subjects. The second study assessed the effect of oral L-arginine on gut hormone release following an ad libitum meal. Subjects were given L-arginine, glycine (control amino acid), or vehicle control in a randomized double-blind fashion. RESULTS: At a dose of 17.1 mmol, L-arginine was well tolerated and stimulated the release of plasma GLP-1 (P < 0.05) and PYY (P < 0.001) following an ad libitum meal. Food diaries showed a trend toward lower energy intake and particularly fat intake following L-arginine treatment. CONCLUSIONS: L-arginine can significantly elevate GLP-1 and PYY in healthy human volunteers in combination with a meal. Further work is required to investigate whether L-arginine may have utility in the suppression of appetite and food intake.

The L-Cell in Nutritional Sensing and the Regulation of Appetite.

The gastrointestinal (GI) tract senses the ingestion of food and responds by signaling to the brain to promote satiation and satiety. Representing an important part of the gut-brain axis, enteroendocrine L-cells secrete the anorectic peptide hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) in response to the ingestion of food. The release of GLP-1 has multiple effects, including the secretion of insulin from pancreatic ß-cells, decreased gastric emptying, and increased satiation. PYY also slows GI motility and reduces food intake. At least part of the gut-brain response seems to be due to direct sensing of macronutrients by L-cells, by mechanisms including specific nutrient-sensing receptors. Such receptors may represent possible pathways to target to decrease appetite and increase energy expenditure. Designing drugs or functional foods to exploit the machinery of these nutrient-sensing mechanisms may offer a potential approach for agents to treat obesity and metabolic disease.

GPRC6a is not required for the effects of a high-protein diet on body weight in mice.

OBJECTIVE: The G-protein coupled receptor family C group 6 member A (GPRC6A) is activated by proteinogenic amino acids and may sense amino acids in the gastrointestinal tract and the brain. The study investigated whether GPRC6A was necessary for the effects of low- and high-protein diets on body weight and food intake in mice. METHODS: The role of GPRC6A in mediating the effects of a low-protein diet on body weight was investigated in GPRC6a knockout (GPRC6a-KO) and wild-type (WT) mice fed a control diet (18% protein) or a low-protein diet (6% protein) for 9 days. The role of GPRC6A in mediating the effects of a high-protein diet on body weight was investigated in GPRC6a-KO and WT mice fed a control diet (18% protein) or a high-protein diet (50% protein) for 5 weeks. RESULTS: A high-protein diet reduced body weight gain and food intake compared with a control diet in both WT and GPRC6a-KO mice. A low-protein diet decreased body weight gain in GPRC6a-KO mice. CONCLUSIONS: GPRC6A was not necessary for the effects of a low- or high-protein diet on body weight and likely does not play a role in protein-induced satiety.