Objective:High-protein diets (HPDs) are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which HPDs exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may have a role in appetite regulation and satiety. We investigated the effects of l-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents.Methods:We investigated the effects of the aromatic amino-acid and calcium-sensing receptor (CaSR) agonist l-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal (GI) hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral l-Phe administration on glucose tolerance in rats.Results:Oral administration of l-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal l-Phe also reduced food intake in rats. l-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal l-Phe in rats, and l-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade.Conclusions:l-Phe reduced food intake, stimulated GLP-1 and PYY release, and reduced plasma ghrelin in rodents. Our data provide evidence that the anorectic effects of l-Phe are mediated via the CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.

AimsTo investigate the anorectic effect of L‐arginine (L‐Arg) in rodents.MethodsWe investigated the effects of L‐Arg on food intake, and the role of the anorectic gut hormones glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY), the G‐protein‐coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents.ResultsOral gavage of L‐Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet‐induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L‐Arg stimulated GLP‐1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP‐1 and PYY receptors did not influence the anorectic effect of L‐Arg. L‐Arg‐mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L‐Arg suppressed food intake in rats.Conclusions L‐Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L‐Arg is unlikely to be mediated by GLP‐1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L‐Arg suppressed food intake in rats, suggesting that L‐Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L‐Arg suppresses food intake and its utility in the treatment of obesity.

The goal of this study was to determine if there is a basal release of nitric oxide that affects long-term arterial pressure regulation in dogs. Studies were conducted over a 23-day period in eight conscious dogs with indwelling catheters. Nitric oxide synthesis was blocked by continuous intravenous infusion of nitro-L-arginine-methyl ester at 37.1 nmol/kg per minute for 11 days. Arterial pressure increased to 120±4% of control on the first day, decreased for a few days, and then increased to a maximum value of 122±6% of control on day 7. Bradycardia was sustained throughout the entire nitro-arginine period. Blockade of nitric oxide synthesis was evidenced by attenuated pressure and flow responses to systemic acetylcholine infusion. The pressor response to phenylephrine was increased for only 1 day, and the hypotensive effects of nitroprusside were enhanced. Also, the variability of arterial pressure was significantly increased during nitro-arginine. Sodium and water balances were positive the first day of nitro-arginine infusion but were unchanged for the entire nitro-arginine period. In conclusion, the data suggest that blockade of the basal release of nitric oxide in dogs causes an increase in the long-term level of arterial pressure without any sustained sodium or water retention. (Hypertension 1993;22:40-48) KEY WORDS • endothelium • vasodilation • arginine • nitric oxide • hypertension, essential I n 1980 Furchgott and Zawadzki 1 found that acetyl-choline-induced relaxation of vascular strips or rings was dependent on the presence of an intact endothelium. A substance released from the endothe-lium, later known as endothelium-derived relaxing factor (EDRF), was primarily responsible for this relaxation. Furchgott 2 later suggested that EDRF was nitric oxide (NO), and Ignarro et al 3 speculated that EDRF might be NO or a related compound. Other investigators have confirmed that NO is an integral part of EDRF, and specific NO synthesis inhibitors have been successfully developed. 4 The two major inhibitors of NO production are JV G-monomethyl L-arginine (L-NMMA) and Af G-nitro-L-arginine-methyl ester (L-NAME), and they both act by competitive inhibition of NO synthase. This inhibition prevents the conversion of L-arginine to NO. Of these two inhibitors, L-NAME is much more potent and causes acute vasoconstriction in a number of vascular beds, whereas D-NAME does not. 5 Most experiments on NO synthesis blockade have been performed in vitro on vascular rings. However, more recently, administration of NO synthesis blockers resulted in acute increases in arterial pressure in rats, 6 ' 7 guinea pigs, 8 and rabbits. 9 In addition, studies by Gar-diner et al 5 and Baylis et al 10 showed that administration of L-NAME for several hours to conscious rats resulted in increases in arterial pressure. More recently, several longer experiments have been performed in which NOson, MS 39216-4505 (Dr Manning). synthesis inhibitors were administered to rats orally for periods lasting between 9 hours and 6 months, and mean arter...

ObjectiveThe 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.MethodsThe 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.ResultsA 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.ConclusionsGPRC6A 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.