l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents

Alamshah, Amin; Spreckley, Eleanor; Norton, Mariana; Kinsey‐Jones, James S.; Amin, Anjali; Ramgulam, Anya; Cao, Ye; Johnson, Ralph H.; Saleh, Keenan; Akalestou, Elina; Malik, Zainab; González-Abuín, Noemi; Jomard, Anne; Amarsi, Risha; Moolla, Ahmad; Sargent, Pippa; Gray, Gary; Bloom, Stephen R.; Murphy, Kevin G.

doi:10.1038/ijo.2017.164

Cited by 96 publications

(88 citation statements)

References 49 publications

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“…Similar results have been reported in previous studies, several amino acids such as l-Phe, l-Gln, and l-Arg induce gut hormone secretion in the murine small intestine, and this effect is enhanced by another CaSR agonist NPS R568 and is inhibited by NPS 2143 (Mace et al, 2012). In addition, Alamshah et al (2017) demonstrated that ileal administration of l-Phe stimulated GLP-1 and PYY release and reduced food intake in rats. However, the addition of CaSR inhibitor NPS 2143 attenuated the hormone release and anorectic effect induced by l-Phe in rats.…”

Section: Misukonissupporting

confidence: 91%

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Sensing of L‐Arginine by Gut‐Expressed Calcium Sensing Receptor Stimulates Gut Satiety Hormones Cholecystokinin and Glucose‐Dependent Insulinotropic Peptide Secretion in Pig Model

Wang

Kang

Yang

et al. 2018

Journal of Food Science

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Nutrients regulate the secretion of gut satiety hormones, which is related to the modulation of food intake and blood glucose levels. Calcium-sensing receptor (CaSR) is involved in regulating gut hormone secretion in response to l-amino acids and multivalent cations. Rodents are often used to investigate the effect of nutrients on these hormonal release. However, results obtained using rodent models are difficult to be applied in humans, we used pigs as a model in this study because their physiology is similar to that of humans. In this study, we investigated whether l-Arginine (l-Arg) could induce gut hormones cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) secretion in the porcine duodenum and if so, whether CaSR mediated l-Arg-regulated gut satiety hormone secretion. Our data showed that treatment with 20 and 50 mM l-Arg induced CCK and GIP secretion compared with 0 mM l-Arg. However, treatment with d-Arg (an inactive isomer) failed to elicit this response. The potency of l-Arg to induce CCK and GIP secretion was enhanced in the presence of extracellular Ca and CaSR agonist cinacalcet. However, the effect of Arg on CCK and GIP secretion was attenuated by blocking CaSR and its downstream signaling molecules adenylate cyclase (AC) and phospholipase C (PLC). Taken all together, pig duodenum provides an appropriate model to explore the effects of l-Arg on the secretion of the satiety-related gut hormones CCK and GIP and the role of CaSR in this effect. Further investigations are needed to verify the effect of l-Arg on food intake and blood glucose in human study. PRACTICAL APPLICATION: l-Arginine is able to modulate cholecystokinin and glucose-dependent insulinotropic peptide secretion through the CaSR in pig model, which has a potential role in regulating food intake and blood glucose levels.

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Section: Misukonissupporting

confidence: 91%

“…In addition, Alamshah et al. () demonstrated that ileal administration of l ‐Phe stimulated GLP‐1 and PYY release and reduced food intake in rats. However, the addition of CaSR inhibitor NPS 2143 attenuated the hormone release and anorectic effect induced by l ‐Phe in rats.…”

Section: Discussionmentioning

confidence: 99%

Sensing of L‐Arginine by Gut‐Expressed Calcium Sensing Receptor Stimulates Gut Satiety Hormones Cholecystokinin and Glucose‐Dependent Insulinotropic Peptide Secretion in Pig Model

Wang

Kang

Yang

et al. 2018

Journal of Food Science

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“…Ex vivo intestinal perfusion demonstrates that the calcium concentration of the environment is essential for robust amino acid-induced GLP-1 secretion [8], which is thought to act via the synergistic stimulation of the calcium-sensing receptor by both calcium and amino acids [10,30]. It has also been demonstrated more recently that the calcium-sensing receptor mediates the effects of amino acids on gut hormone secretion, appetite and food intake in rodents, in vivo [11]. The present study is the first to demonstrate that ingestion of milk minerals rich in calcium further increases whey protein-induced postprandial GLP-1 secretion in humans.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism(s) by which dietary protein stimulates GLP-1 availability is thought to involve direct stimulation by amino acids of the calcium-sensing receptor expressed on L-cells in the intestine [8]. Importantly, it has now been shown across in vitro [9,10], ex vivo [8] and in vivo rodent models [11] that the calcium-sensing receptor regulates gut hormone release and is responsive to physiologically relevant extracellular calcium and amino acid concentrations across fasting to postprandial concentration range. However, to date, no study has demonstrated the synergistic effect of protein and calcium ingestion on GLP-1 availability in humans.…”

Section: Introductionmentioning

confidence: 99%

Co-ingestion of whey protein hydrolysate with milk minerals rich in calcium potently stimulates glucagon-like peptide-1 secretion: an RCT in healthy adults

et al. 2019

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Purpose To examine whether calcium type and co-ingestion with protein alter gut hormone availability. Methods Healthy adults aged 26 ± 7 years (mean ± SD) completed three randomized, double-blind, crossover studies. In all studies, arterialized blood was sampled postprandially over 120 min to determine GLP-1, GIP and PYY responses, alongside appetite ratings, energy expenditure and blood pressure. In study 1 (n = 20), three treatments matched for total calcium content (1058 mg) were compared: calcium citrate (CALCITR); milk minerals rich in calcium (MILK MINERALS); and milk minerals rich in calcium plus co-ingestion of 50 g whey protein hydrolysate (MILK MINERALS + PROTEIN). In study 2 (n = 6), 50 g whey protein hydrolysate (PROTEIN) was compared to MILK MINERALS + PROTEIN. In study 3 (n = 6), MILK MINERALS was compared to the vehicle of ingestion (water plus sucralose; CONTROL). Results MILK MINERALS + PROTEIN increased GLP-1 incremental area under the curve (iAUC) by ~ ninefold (43.7 ± 11.1 pmol L −1 120 min; p < 0.001) versus both CALCITR and MILK MINERALS, with no difference detected between CALCITR (6.6 ± 3.7 pmol L −1 120 min) and MILK MINERALS (5.3 ± 3.5 pmol L −1 120 min; p > 0.999). MILK MINERALS + PROTEIN produced a GLP-1 iAUC ~ 25% greater than PROTEIN (p = 0.024; mean difference: 9.1 ± 6.9 pmol L −1 120 min), whereas the difference between MILK MINERALS versus CONTROL was small and nonsignificant (p = 0.098; mean difference: 4.2 ± 5.

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“…Obvious candidate receptors include the other amino acid‐sensing receptors belonging to class C GPCRs such as CaSR and T1R1‐T1R3, which show overlapping tissue expression and L‐amino acid preferences with GPRC6A . In fact, CaSR has recently been demonstrated to mediate the effects of L‐phenylalanine on gut hormone release, which proves that this receptor is capable of inducing GLP‐1 secretion …”

Section: Suggested Physiological Functions Of Gprc6amentioning

confidence: 99%

Pharmacology and physiological function of the orphan GPRC6A receptor

Jørgensen

Bräuner‐Osborne

2020

Basic Clin Pharma Tox

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is characterized by having an unusual long amino-terminal domain (590 amino acids), which includes a Venus flytrap domain and a cysteine-rich domain containing nine conserved cysteine residues, and a 7-transmembrane (7TM) domain containing three extra-and three intracellular loops and an intracellular C-terminal ( Figure 1). 1 The receptor forms homodimers through a large hydrophobic interface and a disulphide bridge in the Venus flytrap domain, and the receptor is N-glycosylated at seven extracellular asparagine residues, which modulates surface expression and function. 2 The amino acids are highlighted in the snakeplot in Figure 1. The receptor is constitutively internalized and suggested to be recycled via the Rab11-slow recycling pathway to ensure a steady pool of receptors in the plasma membrane despite a chronic exposure to the omnipresent L-amino acids and divalent cation agonists. 3 AbstractThe G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) is a G q/11 -coupled receptor widely expressed in human and rodent tissues. The proposed endogenous ligands are L-amino acids, divalent cations, osteocalcin and testosterone. This MiniReview provides an updated overview of the literature including the latest in vitro and in vivo studies. GPRC6A forms homodimers, it undergoes constitutive internalization, and very interestingly, the reason for the intracellular retention of the human receptor has been revealed. Multiple physiological functions of GPRC6A have been suggested based on studies using three different global GPRC6A knockout (KO) mouse models where exon II, exon VI or the full locus has been deleted. The newest studies on the full locus GPRC6A KO model show intact glucose and bone homoeostasis with a minor reduction in serum osteocalcin levels. Unfortunately, the physiological function of the receptor remains elusive due to a general lack of consensus/validation of reported phenotypes of the different KO models, and more research is thus warranted to uncover the physiological function. Recent discoveries of human genetic variants that cause either a premature stop codon or an intracellular retention of the receptor point towards human population studies as the preferred approach to continue studies on the function of GPRC6A. 78 | JØRGENSEN aNd BRÄUNER-OSBORNE How to cite this article: Jørgensen CV, Bräuner-Osborne H. Pharmacology and physiological function of the orphan GPRC6A receptor.

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l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents

Cited by 96 publications

References 49 publications

Sensing of L‐Arginine by Gut‐Expressed Calcium Sensing Receptor Stimulates Gut Satiety Hormones Cholecystokinin and Glucose‐Dependent Insulinotropic Peptide Secretion in Pig Model

Sensing of L‐Arginine by Gut‐Expressed Calcium Sensing Receptor Stimulates Gut Satiety Hormones Cholecystokinin and Glucose‐Dependent Insulinotropic Peptide Secretion in Pig Model

Co-ingestion of whey protein hydrolysate with milk minerals rich in calcium potently stimulates glucagon-like peptide-1 secretion: an RCT in healthy adults

Pharmacology and physiological function of the orphan GPRC6A receptor

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