Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

Maja S Engelstoft, Won-Mee Park, Ichiro Sakata, Line V Kristensen, Anna Sofie Husted, Sherri Osborne-Lawrence, Paul K Piper, Angela K Walker, Maria H Pedersen, Mark K Nøhr, Jie Pan, Christopher J Sinz, Paul E Carrington, Taro E Akiyama, Robert M Jones, Cong Tang, Kashan Ahmed, Stefan Offermanns, Kristoffer L Egerod, Jeffrey M Zigman, Thue W Schwartz, Maja S Engelstoft, Won-Mee Park, Ichiro Sakata, Line V Kristensen, Anna Sofie Husted, Sherri Osborne-Lawrence, Paul K Piper, Angela K Walker, Maria H Pedersen, Mark K Nøhr, Jie Pan, Christopher J Sinz, Paul E Carrington, Taro E Akiyama, Robert M Jones, Cong Tang, Kashan Ahmed, Stefan Offermanns, Kristoffer L Egerod, Jeffrey M Zigman, Thue W Schwartz

Abstract

The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.

Keywords: 7TM, seven transmembrane segment; BAC, bacterial artificial chromosome; CCK, cholecystokinin; CFMB, (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butamide; CGRP, calcitonin gene-related peptide; CHBA, 3-chloro-5-hydroxybenzoic acid; Enteroendocrine; G protein signaling; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; GPCR; Ghrelin; Metabolites; PTx, Bordetella pertussis toxin; PYY, peptide YY; Secretion; hrGFP, humanized Renilla reniformis green fluorescent protein.

Figures

Graphical abstract
Graphical abstract
Figure S1
Figure S1
Ex vivo ghrelin secretion. Acyl-ghrelin release from primary gastric mucosal cells treated with acetylcholine, the M4 allosteric agonist vincamine, acetylcholine and vincamine (gray, hatched), dopamine, galanin or isoproterenol. The data has been normalized to the basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is written in brackets in each bar.
Figure S2
Figure S2
Propionate-induced cAMP accumulation. cAMP accumulation assays in HEK293 cells stably transfected with FFAR2 and treated with increasing concentrations of propionate alone (black) or after addition of 20 µM AR19 (gray).
Figure S3
Figure S3
Expression and functional analysis of lipid 7TM receptors in ghrelin cells. (A) qPCR data for 379 7TM receptors examined in FACS-separated hrGFP-positive (Y-axis) and hrGFP-negative (X-axis) gastric mucosal cells from ghrelin-hrGFP mice. Lipid receptors are marked with green. (B) Acyl-ghrelin release from primary gastric mucosal cells treated with a stable prostaglandin I2 analog (PGI2, beraprost), a CB1 agonist (CP 55,940), the GPER agonists genistein and G-1 or isoproterenol. The data has been normalized to the basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is written in brackets in each bar.
Figure S4
Figure S4
Ghrelin-immunoreactivity and tdTomato fluorescence. Ghrelin-immunoreactivity (green) and tdTomato fluorescence (red) within gastric mucosal cells. Co-localization (yellow) is visualized in the merged picture (right).
Figure 1
Figure 1
Expression and functional analysis of 7TM receptors for neurotransmitters and neuropeptides in gastric ghrelin cells. (A–C) qPCR expression data for 379 7TM receptors (gray plus green dots) and three RAMPs (blue dots, C) examined in FACS-separated hrGFP-positive (Y-axis) and hrGFP-negative (X-axis) gastric mucosal cells. (A) Receptors for neurotransmitters, (B) family A neuropeptide receptors, and (C) family B neuropeptide receptors are highlighted with green dots and the receptor gene name indicated for all neuropeptide receptors but only for the enriched and/or highly expressed small molecule neurotransmitter receptors for clarity. The 45°-angled lines refer to the enrichment within ghrelin cells. The gray shaded area is considered as noise level. The orange dashed lines highlight particularly enriched receptors. The expression data for all the receptors and RAMPs are listed in Table S3. The green shaded areas highlight the lack of enriched neurotransmitter (A) and neuropeptide (B) receptors, respectively (i.e. only gray and no green dots in the shaded green areas). (D and E) Acyl-ghrelin/total ghrelin release from primary gastric mucosal cells treated with isoproterenol, (F and H) increasing concentrations of α-CGRP or isoproterenol, (G) or with BIBN 4096 alone (hatched) and before 10 nM of α-CGRP (gray, hatched). The data is normalized to basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is indicated in brackets in each bar.
Figure 2
Figure 2
Expression of 7TM receptors for metabolites in gastric ghrelin cells and functional analysis of FFAR4 in ghrelin secretion in vitro, ex vivo and in vivo. (A) qPCR data for 379 7TM receptors examined in FACS-separated hrGFP-positive (Y-axis) and hrGFP-negative (X-axis) gastric mucosal cells. Receptors for nutrients and dietary metabolites are highlighted with green dots. (B) Inositol triphosphate accumulation in COS7 cells transiently transfected with either FFAR4 (black, solid), FFAR1 (gray, solid), FFAR4 together with Gα∆6qi4myr (black, dotted) or FFAR1 together with Gα∆6qi4myr (gray, dotted) and treated with increasing concentrations of the FFAR4 specific agonist compound B normalized to the maximum compound B-induced FFAR4 activation. (C) Acyl-ghrelin release from primary gastric mucosal cells from wild type or (D) FFAR4 deficient mice treated with increasing concentrations of compound B or 10 µM isoproterenol normalized to the basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is indicated in brackets in each bar. (E) Acyl-ghrelin release from primary gastric mucosal cells treated with 1 µM of compound B or 10 µM of isoproterenol alone, or after addition of pertussis toxin (PTx, hatched) normalized to the basal secretion of ghrelin from vehicle-treated cells with and without PTx treatment, respectively (the PTx treatment did not affect ghrelin secretion from vehicle-treated cells (−PTx: 648±86 pg/ml, +PTx: 607±66 pg/ml)), and shown as means±SEM. Number of repeated experiments is indicated in brackets in each bar. (F) Total-ghrelin concentrations in plasma from mice orally dosed with increasing concentrations of compound B after an overnight fast. (G) Total-ghrelin concentrations in plasma from wild type mice (white) or FFAR4 deficient mice (black) after an overnight fast (basal) and two hours after an oral triglyceride load (120 min).
Figure 3
Figure 3
Functional analysis of FFAR2, FFAR3 and GPR81 in ghrelin secretion ex vivo. (A) Immunohistochemistry with antibodies against mRFP (red) and ghrelin (green) on gastric tissue from mice expressing mRFP from either the FFAR2 promoter (top) or the FFAR3 promoter (bottom) (see text for details). The scale bars in the merged pictures correspond to 25 µm. (B) Acyl-ghrelin release from primary gastric mucosal cells treated with various concentrations of acetate, (C) propionate, (D) CFMB, (E) AR420626, (F) propionate alone and after addition of 20 µM AR19 (hatched), (J) lactate, (L) CHBA, (M) succinate or 10 µM isoproterenol normalized to the basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is written in brackets in each bar. (D, E, and F inserts) cAMP accumulation in HEK293 cells stably transfected with either FFAR2 (black) or FFAR3 (red) and treated with increasing concentrations of CMFB, AR420626, or propionate alone or after addition of 20 µM AR19 (gray). FFAR2-transfected cells treated with propionate and AR19 are shown in Figure S4. (H) Acyl-ghrelin release from primary gastric mucosal from wild type mice (gray), FFAR2 deficient mice (black), or (I) FFAR3 deficient mice (black) treated with 1 mM propionate, 10 mM lactate or 10 µM isoproterenol normalized to the basal secretion of ghrelin from vehicle-treated cells from wild type or knockout mice, respectively, and shown as means±SEM. (G) Acyl-ghrelin release from primary gastric mucosal cells treated with 1 mM propionate, 10 mM lactate or 10 µM isoproterenol alone or after addition of PTx (hatched) normalized to the basal secretion of ghrelin from vehicle-treated cells with and without PTx treatment, respectively (PTx did not affect basal ghrelin secretion – see legend of Figure 2), and shown as means±SEM. Number of repeated experiments is written in brackets in each bar. (K) Total-ghrelin release from primary gastric mucosal cells treated with 10 mM lactate and normalized to the basal secretion of total-ghrelin from vehicle-treated cells.
Figure 4
Figure 4
Functional analysis of CaSR in ghrelin secretion ex vivo. (A) Acyl-ghrelin release from primary gastric mucosal cells treated with various concentrations of R-568, (B) CaCl2, 10 µM isoproterenol, or (C) R-568 alone, 4 mM CaCl2 alone or R-568 together with 4 mM CaCl2 (gray, hatched). The data has been normalized to the basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is written in brackets in each bar.
Figure 5
Figure 5
Expression and functional analysis of 7TM receptors for peptide hormones in gastric ghrelin cells. (A and D) qPCR data for 379 7TM receptors examined in FACS-separated hrGFP-positive (Y-axis) and hrGFP-negative (X-axis) gastric mucosal cells. Family A receptors for peptide hormones and (D) family B receptors for peptide hormones have been marked with green. (B) Acyl-ghrelin release from primary gastric mucosal cells treated with increasing concentrations of α-MSH, 100 nM PG-901 alone (hatched) or before 1 µM α-MSH, (C) 1 µM vasopressin (AVP), kisspeptin (KP), somatostatin (Sst), 10 µM of the somatostatin antagonist BIM-23627, 1 µM CCK8, PYY3-36, neuromedin C (NMC) (significance tested with Mann–Whitney), (E) increasing concentrations of GIP, (F) secretin, GLP-1 or 10 µM isoproterenol. The data has been normalized to the basal secretion of ghrelin from vehicle-treated cells and shown as means±SEM. Number of repeated experiments is written in brackets in each bar.
Figure 6
Figure 6
Expression of orphan family A 7TM receptors in ghrelin cells. qPCR data for 379 7TM receptors examined in FACS-separated hrGFP-positive (Y-axis) and hrGFP-negative (X-axis) gastric mucosal cells. Orphan receptors from family A are marked with red. Receptors labeled with names are stably expressed and more than fivefold enriched in ghrelin cells.
Figure 7
Figure 7
Expression of Gα subunits and pertussis toxin in ghrelin cells. (A) Relative mRNA expression of 13 Gα subunits examined in FACS-separated hrGFP-positive (Y-axis) and hrGFP-negative (X-axis) gastric mucosal cells. Cyclophilin was used as a reference gene. Gα subunits with a mean CT value above 35 in either of the cell pools have been left out, but can be seen in Table S4. (B) Relative mRNA expression of the PTx catalytic S1 subunit within ghrelin cells (hrGFP+) and non-ghrelin cells (hrGFP−) in the four different genotypes (gCre−/PTx−, gCre+/PTx−, gCre−/PTx+, and gCre+/PTx+). (C) Levels of plasma acyl-ghrelin in 6-wk-old and 14-wk-old ad lib-fed male in the four different genotypes (gCre−/PTx−, gCre+/PTx−, gCre−/PTx+, and gCre+/PTx+). The data is shown as means±SEM.
Figure 8
Figure 8
Overview of 7TM receptors involved in the control of ghrelin secretion directly at the ghrelin cell level. (A) Overview of expression of 7TM receptors involved in control of hormone secretion in FACS-separated ghrelin-hrGFP positive cells (Y-axis) versus expression in ghelin-hrGFP negative cells (X-axis) isolated from gastric mucosa (see Figure 1 and text for details). Receptors stimulating ghrelin secretion are marked in green, receptors inhibiting ghrelin release are marked in red, receptors functionally tested without effect on ghrelin secretion are marked in black and receptors not tested functionally are marked in gray. (B) Schematic overview of the 7TM receptors judged to be either stimulating (in green to the right) or inhibiting (red or orange to the left and top) ghrelin secretion directly on the ghrelin cell. The main signaling pathway (Gαs or Gαi) employed by each of the receptors in the ghrelin cell is indicated inside the receptor in black. No Gαq-coupled receptor effectively stimulating ghrelin secretion was identified but some receptors are known to be able to signal through Gαq and stimulate secretion in other cell systems (indicated in orange). Main endogenous ligands are indicated for each receptor.

References

    1. Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.
    1. Kumar J., Chuang J.C., Na E.S., Kuperman A., Gillman A.G., Mukherjee S. Differential effects of chronic social stress and fluoxetine on meal patterns in mice. Appetite. 2013;64:81–88.
    1. Verhulst P.J., Depoortere I. Ghrelin's second life: from appetite stimulator to glucose regulator. World Journal of Gastroenterology. 2012;18(25):3183–3195.
    1. Kirchner H., Heppner K.M., Tschop M.H. The role of ghrelin in the control of energy balance. Handbook of Experimental Pharmacology. 2012;209:161–184.
    1. Tschop M., Smiley D.L., Heiman M.L. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–913.
    1. Cummings D.E., Purnell J.Q., Frayo R.S., Schmidova K., Wisse B.E., Weigle D.S. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50(8):1714–1719.
    1. Date Y., Kojima M., Hosoda H., Sawaguchi A., Mondal M.S., Suganuma T. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141(11):4255–4261.
    1. Williams D.L., Cummings D.E., Grill H.J., Kaplan J.M. Meal-related ghrelin suppression requires postgastric feedback. Endocrinology. 2003;144(7):2765–2767.
    1. Overduin J., Frayo R.S., Grill H.J., Kaplan J.M., Cummings D.E. Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology. 2005;146(2):845–850.
    1. Foster-Schubert K.E., Overduin J., Prudom C.E., Liu J., Callahan H.S., Gaylinn B.D. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. Journal of Clinical Endocrinology and Metabolism. 2008;93(5):1971–1979.
    1. Sakata I., Park W.M., Walker A.K., Piper P.K., Chuang J.C., Osborne-Lawrence S. Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells. American Journal of Physiology – Endocrinology and Metabolism. 2012;302(10):E1300–E1310.
    1. Gagnon J., Anini Y. Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture. Endocrinology. 2012;153(8):3646–3656.
    1. Lippl F., Kircher F., Erdmann J., Allescher H.D., Schusdziarra V. Effect of GIP, GLP-1, insulin and gastrin on ghrelin release in the isolated rat stomach. Regulatory Peptides. 2004;119(1–2):93–98.
    1. Anderwald C., Brabant G., Bernroider E., Horn R., Brehm A., Waldhausl W. Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Diabetes. 2003;52(7):1792–1798.
    1. Flanagan D.E., Evans M.L., Monsod T.P., Rife F., Heptulla R.A., Tamborlane W.V. The influence of insulin on circulating ghrelin. American Journal of Physiology – Endocrinology and Metabolism. 2003;284(2):E313–E316.
    1. Leonetti F., Iacobellis G., Ribaudo M.C., Zappaterreno A., Tiberti C., Iannucci C.V. Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity. Regulatory Peptides. 2004;122(3):179–183.
    1. Saad M.F., Bernaba B., Hwu C.M., Jinagouda S., Fahmi S., Kogosov E. Insulin regulates plasma ghrelin concentration. Journal of Clinical Endocrinology and Metabolism. 2002;87(8):3997–4000.
    1. McCowen K.C., Maykel J.A., Bistrian B.R., Ling P.R. Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic euglycemic conditions in rodents. Journal of Endocrinology. 2002;175(2) (R7-11)
    1. Caixas A., Bashore C., Nash W., Pi-Sunyer F., Laferrere B. Insulin, unlike food intake, does not suppress ghrelin in human subjects. Journal of Clinical Endocrinology and Metabolism. 2002;87(4):1902.
    1. Schaller G., Schmidt A., Pleiner J., Woloszczuk W., Wolzt M., Luger A. Plasma ghrelin concentrations are not regulated by glucose or insulin: a double-blind, placebo-controlled crossover clamp study. Diabetes. 2003;52(1):16–20.
    1. Degen L., Drewe J., Piccoli F., Grani K., Oesch S., Bunea R. Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 2007;292(4):R1391–R1399.
    1. Brennan I.M., Otto B., Feltrin K.L., Meyer J.H., Horowitz M., Feinle-Bisset C. Intravenous CCK-8, but not GLP-1, suppresses ghrelin and stimulates PYY release in healthy men. Peptides. 2007;28(3):607–611.
    1. Rudovich N.N., Nikiforova V.J., Otto B., Pivovarova O., Gogebakan O., Erban A. Metabolomic linkage reveals functional interaction between glucose-dependent insulinotropic polypeptide and ghrelin in humans. American Journal of Physiology – Endocrinology and Metabolism. 2011;301(4):E608–E617.
    1. Hagemann D., Holst J.J., Gethmann A., Banasch M., Schmidt W.E., Meier J.J. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion. Regulatory Peptides. 2007;143(1–3):64–68.
    1. Batterham R.L., Cohen M.A., Ellis S.M., Le Roux C.W., Withers D.J., Frost G.S. Inhibition of food intake in obese subjects by peptide YY3-36. New England Journal of Medicine. 2003;349(10):941–948.
    1. Iwakura H., Ariyasu H., Hosoda H., Yamada G., Hosoda K., Nakao K. Oxytocin and dopamine stimulate ghrelin secretion by the ghrelin-producing cell line, MGN3-1 in vitro. Endocrinology. 2011;152(7):2619–2625.
    1. Shimada M., Date Y., Mondal M.S., Toshinai K., Shimbara T., Fukunaga K. Somatostatin suppresses ghrelin secretion from the rat stomach. Biochemical and Biophysical Research Communications. 2003;302(3):520–525.
    1. de la Cour C.D., Norlen P., Hakanson R. Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: a microdialysis study. Regulatory Peptides. 2007;143(1–3):118–126.
    1. Murakami N., Hayashida T., Kuroiwa T., Nakahara K., Ida T., Mondal M.S. Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats. Journal of Endocrinology. 2002;174(2):283–288.
    1. Ito T., Thidarmyint H., Murata T., Inoue H., Neyra R.M., Kuwayama H. Effects of peripheral administration of PYY3-36 on feed intake and plasma acyl-ghrelin levels in pigs. Journal of Endocrinology. 2006;191(1):113–119.
    1. Gomez G., Englander E.W., Greeley G.H., Jr. Nutrient inhibition of ghrelin secretion in the fasted rat. Regulatory Peptides. 2004;117(1):33–36.
    1. Qader S.S., Salehi A., Hakanson R., Lundquist I., Ekelund M. Long-term infusion of nutrients (total parenteral nutrition) suppresses circulating ghrelin in food-deprived rats. Regulatory Peptides. 2005;131(1–3):82–88.
    1. Zhao T.J., Sakata I., Li R.L., Liang G., Richardson J.A., Brown M.S. Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(36):15868–15873.
    1. Mundinger T.O., Cummings D.E., Taborsky G.J., Jr. Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology. 2006;147(6):2893–2901.
    1. Broglio F., Gottero C., Van Koetsveld P., Prodam F., Destefanis S., Benso A. Acetylcholine regulates ghrelin secretion in humans. Journal of Clinical Endocrinology and Metabolism. 2004;89(5):2429–2433.
    1. Ao Y., Go V.L., Toy N., Li T., Wang Y., Song M.K. Brainstem thyrotropin-releasing hormone regulates food intake through vagal-dependent cholinergic stimulation of ghrelin secretion. Endocrinology. 2006;147(12):6004–6010.
    1. Hosoda H., Kangawa K. The autonomic nervous system regulates gastric ghrelin secretion in rats. Regulatory Peptides. 2008;146(1–3):12–18.
    1. Williams D.L., Grill H.J., Cummings D.E., Kaplan J.M. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology. 2003;144(12):5184–5187.
    1. Engelstoft M.S., Egerod K.L., Holst B., Schwartz T.W. A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metabolism. 2008;8(6):447–449.
    1. Tolhurst G., Reimann F., Gribble F.M. Intestinal sensing of nutrients. Handbook of Experimental Pharmacology. (209) 20122012:309–335. 309–335.
    1. Sakata I., Nakano Y., Osborne-Lawrence S., Rovinsky S.A., Lee C.E., Perello M. Characterization of a novel ghrelin cell reporter mouse. Regulatory Peptides. 2009;155(1–3):91–98.
    1. Nohr M.K., Pedersen M.H., Gille A., Egerod K.L., Engelstoft M.S., Husted A.S. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology. 2013;154(10):3552–3564.
    1. Regard J.B., Kataoka H., Cano D.A., Camerer E., Yin L., Zheng Y.W. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. Journal of Clinical Investigation. 2007;117(12):4034–4043.
    1. Shi, D.F., Song, J., Ma, J., Novack, A., Pham, P., Nashashibi, I., Rabbat, C.J., and Chen, X., 2010. GPR120 receptor agonists and uses thereof. Metabolex, Inc. WO 2010/080537.
    1. Boatman, P.D., Bruce, M.A., Chu, Z.L., and Leonard, J.N., 2006. GPR41 and modulators thereof for the treatment of insulin-related disorders. PCT International Application. p. WO 2006052566.
    1. Hald A., Rono B., Lund L.R., Egerod K.L. LPS counter regulates RNA expression of extracellular proteases and their inhibitors in murine macrophages. Mediators of Inflammation. 2012;2012:157894.
    1. Egerod K.L., Engelstoft M.S., Grunddal K.V., Nohr M.K., Secher A., Sakata I. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology. 2012;153(12):5782–5795.
    1. Kostenis E. Potentiation of GPCR-signaling via membrane targeting of G-protein α subunits. Journal of Receptors and Signal Transduction. 2002;22:267–281.
    1. Gliddon B.L., Nguyen N.V., Gunn P.A., Gleeson P.A., van Driel I.R. Isolation, culture and adenoviral transduction of parietal cells from mouse gastric mucosa. Biomedical Materials. 2008;3(3):034117.
    1. Yanovsky Y., Zigman J.M., Kernder A., Bein A., Sakata I., Osborne-Lawrence S. Proton- and ammonium-sensing by histaminergic neurons controlling wakefulness. Frontiers in Systems Neuroscience. 2012;6:23.
    1. Kumar A., Goel A., Paul S. Re: Urodynamic Testing – is it a useful tool in the management of children with cutaneous stigmata of occult spinal dysraphism?: L. T. Lavallee, M. P. Leonard, C. Dubois and L. A. Guerra. Journal of Urology. 2013;189:678–683. ([190(2): p. 812–3])
    1. Garg M., Singh V., Kumar A., Re Osman. Clinically insignificant residual fragments: an acceptable term in the computed tomography era? Urology. 2013;82(2):496–497.
    1. Reimann F., Habib A.M., Tolhurst G., Parker H.E., Rogers G.J., Gribble F.M. Glucose sensing in L cells: a primary cell study. Cell Metabolism. 2008;8(6):532–539.
    1. Briscoe C.P., Peat A.J., McKeown S.C., Corbett D.F., Goetz A.S., Littleton T.R. Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. British Journal of Pharmacology. 2006;148(5):619–628.
    1. Lee T., Schwandner R., Swaminath G., Weiszmann J., Cardozo M., Greenberg J. Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Molecular Pharmacology. 2008;74(6):1599–1609.
    1. Tolhurst G., Heffron H., Lam Y.S., Parker H.E., Habib A.M., Diakogiannaki E. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012;61(2):364–371.
    1. Goodwin M.L., Harris J.E., Hernandez A., Gladden L.B. Blood lactate measurements and analysis during exercise: a guide for clinicians. Journal of Diabetes Science and Technology. 2007;1(4):558–569.
    1. Dvorak C.A., Liu C., Shelton J., Kuei C., Sutton S.W., Lovenberg T.W. Identification of hydroxybenzoic acids as selective lactate receptor (GPR81) agonists with antilipolytic effects. ACS Medicinal Chemistry Letters. 2012;3(8):637–639.
    1. Conigrave A.D., Quinn S.J., Brown E.M. l-amino acid sensing by the extracellular Ca2+-sensing receptor. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(9):4814–4819.
    1. Nemeth E.F., Steffey M.E., Fox J. The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism. Pediatric Nephrology. 1996;10(3):275–279.
    1. Feng J., Petersen C.D., Coy D.H., Jiang J.K., Thomas C.J., Pollak M.R. Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(41):17791–17796.
    1. Liou A.P., Sei Y., Zhao X., Feng J., Lu X., Thomas C. The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to l-phenylalanine in acutely isolated intestinal I cells. American Journal of Physiology – Gastrointestinal and Liver Physiology. 2011;300(4):G538–G546.
    1. Mace O.J., Schindler M., Patel S. The regulation of K- and L-cell activity by GLUT2 and the calcium-sensing receptor CasR in rat small intestine. Journal of Physiology. 2012;590(Pt 12):2917–2936.
    1. Grieco P., Han G., Weinberg D., Van der Ploeg L.H., Hruby V.J. Design and synthesis of highly potent and selective melanotropin analogues of SHU9119 modified at position 6. Biochemical and Biophysical Research Communications. 2002;292(4):1075–1080.
    1. Moller C.L., Raun K., Jacobsen M.L., Pedersen T.A., Holst B., Conde-Frieboes K.W. Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved. Molecular and Cellular Endocrinology. 2011;341(1-2):9–17.
    1. Lu X., Zhao X., Feng J., Liou A.P., Anthony S., Pechhold S. Postprandial inhibition of gastric ghrelin secretion by long-chain fatty acid through GPR120 in isolated gastric ghrelin cells and mice. American Journal of Physiology – Gastrointestinal and Liver Physiology. 2012;303(3):G367–G376.
    1. Tulipano G., Soldi D., Bagnasco M., Culler M.D., Taylor J.E., Cocchi D. Characterization of new selective somatostatin receptor subtype-2 (sst2) antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH release in anesthetized male rats after short-term high-dose dexamethasone treatment. Endocrinology. 2002;143(4):1218–1224.
    1. Ignatov A., Lintzel J., Kreienkamp H.J., Schaller H.C. Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway. Biochemical and Biophysical Research Communications. 2003;311(2):329–336.
    1. Maggiolini M., Vivacqua A., Fasanella G., Recchia A.G., Sisci D., Pezzi V. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. Journal of Biological Chemistry. 2004;279(26):27008–27016.
    1. Bologa C.G., Revankar C.M., Young S.M., Edwards B.S., Arterburn J.B., Kiselyov A.S. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nature Chemical Biology. 2006;2(4):207–212.
    1. Zbucki R.L., Sawicki B., Hryniewicz A., Winnicka M.M. Cannabinoids enhance gastric X/A-like cells activity. Folia Histochemica et Cytobiologica. 2008;46(2):219–224.
    1. Madison L.D., Scarlett J.M., Levasseur P., Zhu X., Newcomb K., Batra A. Prostacyclin signaling regulates circulating ghrelin during acute inflammation. Journal of Endocrinology. 2008;196(2):263–273.
    1. Wettschureck N., Offermanns S. Mammalian G proteins and their cell type specific functions. Physiological Reviews. 2005;85(4):1159–1204.
    1. Janssen S., Laermans J., Verhulst P.J., Thijs T., Tack J., Depoortere I. Bitter taste receptors and alpha-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(5):2094–2099.
    1. Huang M.H., Nguyen V., Wu Y., Rastogi S., Lui C.Y., Birnbaum Y. Reducing ischaemia/reperfusion injury through delta-opioid-regulated intrinsic cardiac adrenergic cells: adrenopeptidergic co-signalling. Cardiovascular Research. 2009;84(3):452–460.
    1. Nguyen V.T., Wu Y., Guillory A.N., McConnell B.K., Fujise K., Huang M.H. Delta-opioid augments cardiac contraction through beta-adrenergic and CGRP-receptor co-signaling. Peptides. 2012;33(1):77–82.
    1. Green T., Dockray G.J. Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neuroscience Letters. 1987;76(2):151–156.
    1. Holzer P. Role of visceral afferent neurons in mucosal inflammation and defense. Current Opinion in Pharmacology. 2007;7(6):563–569.
    1. Konturek P.C., Brzozowski T., Walter B., Burnat G., Hess T., Hahn E.G. Ghrelin-induced gastroprotection against ischemia-reperfusion injury involves an activation of sensory afferent nerves and hyperemia mediated by nitric oxide. European Journal of Pharmacology. 2006;536(1–2):171–181.
    1. Sibilia V., Rindi G., Pagani F., Rapetti D., Locatelli V., Torsello A. Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology. 2003;144(1):353–359.
    1. Zaki M., Coudron P.E., McCuen R.W., Harrington L., Chu S., Schubert M.L. H. pylori acutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion. American Journal of Physiology – Gastrointestinal and Liver Physiology. 2013;304(8):G715–G722.
    1. Erdmann J., Lippl F., Schusdziarra V. Differential effect of protein and fat on plasma ghrelin levels in man. Regulatory Peptides. 2003;116(1–3):101–107.
    1. Tannous dit El Khoury D., Obeid O., Azar S.T., Hwalla N. Variations in postprandial ghrelin status following ingestion of high-carbohydrate, high-fat, and high-protein meals in males. Annals of Nutrition and Metabolism. 2006;50(3):260–269.
    1. Gormsen L.C., Gjedsted J., Gjedde S., Vestergaard E.T., Christiansen J.S., Jorgensen J.O. Free fatty acids decrease circulating ghrelin concentrations in humans. European Journal of Endocrinology. 2006;154(5):667–673.
    1. Gormsen L.C., Nielsen C., Gjedsted J., Gjedde S., Vestergaard E.T., Christiansen J.S. Effects of free fatty acids, growth hormone and growth hormone receptor blockade on serum ghrelin levels in humans. Clinical Endocrinology (Oxford) 2007;66(5):641–645.
    1. Karpe F., Dickmann J.R., Frayn K.N. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60(10):2441–2449.
    1. Sommer F., Backhed F. The gut microbiota – masters of host development and physiology. Nature Reviews Microbiology. 2013;11(4):227–238.
    1. Muir J.G., Lu Z.X., Young G.P., Cameron-Smith D., Collier G.R., O'Dea K. Resistant starch in the diet increases breath hydrogen and serum acetate in human subjects. American Journal of Clinical Nutrition. 1995;61(4):792–799.
    1. Peters S.G., Pomare E.W., Fisher C.A. Portal and peripheral blood short chain fatty acid concentrations after caecal lactulose instillation at surgery. Gut. 1992;33(9):1249–1252.
    1. Tarini J., Wolever T.M. The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Applied Physiology, Nutrition, and Metabolism. 2010;35(1):9–16.
    1. Vitaglione P., Lumaga R.B., Stanzione A., Scalfi L., Fogliano V. beta-Glucan-enriched bread reduces energy intake and modifies plasma ghrelin and peptide YY concentrations in the short term. Appetite. 2009;53(3):338–344.
    1. Gruendel S., Garcia A.L., Otto B., Mueller C., Steiniger J., Weickert M.O. Carob pulp preparation rich in insoluble dietary fiber and polyphenols enhances lipid oxidation and lowers postprandial acylated ghrelin in humans. Journal of Nutrition. 2006;136(6):1533–1538.
    1. Lundquist F., Tygstrup N., Winkler K., Mellemgaard K., Munck-Petersen S. Ethanol metabolism and production of free acetate in the human liver. Journal of Clinical Investigation. 1962;41:955–961.
    1. Szulc M., Mikolajczak P.L., Geppert B., Wachowiak R., Dyr W., Bobkiewicz-Kozlowska T. Ethanol affects acylated and total ghrelin levels in peripheral blood of alcohol-dependent rats. Addiction Biology. 2013;(6):689–701.
    1. Nilsson N.E., Kotarsky K., Owman C., Olde B. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochemical and Biophysical Research Communications. 2003;303(4):1047–1052.
    1. Theil P.K., Jorgensen H., Serena A., Hendrickson J., Bach Knudsen K.E. Products deriving from microbial fermentation are linked to insulinaemic response in pigs fed breads prepared from whole-wheat grain and wheat and rye ingredients. British Journal of Nutrition. 2011;105(3):373–383.
    1. Bach Knudsen K.E., Jorgensen H., Canibe N. Quantification of the absorption of nutrients derived from carbohydrate assimilation: model experiment with catheterised pigs fed on wheat- or oat-based rolls. British Journal of Nutrition. 2000;84(4):449–458.
    1. Windmueller H.G., Spaeth A.E. Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate, and aspartate. Journal of Biological Chemistry. 1980;255(1):107–112.
    1. Vaugelade P., Posho L., Darcy-Vrillon B., Bernard F., Morel M.T., Duee P.H. Intestinal oxygen uptake and glucose metabolism during nutrient absorption in the pig. Proceedings of the Society for Experimental Biology and Medicine. 1994;207(3):309–316.
    1. Fleming S.E., Zambell K.L., Fitch M.D. Glucose and glutamine provide similar proportions of energy to mucosal cells of rat small intestine. American Journal of Physiology. 1997;273(4 Pt 1):G968–G978.
    1. Ahmed K., Tunaru S., Tang C., Muller M., Gille A., Sassmann A. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metabolism. 2010;11(4):311–319.
    1. Broom D.R., Stensel D.J., Bishop N.C., Burns S.F., Miyashita M. Exercise-induced suppression of acylated ghrelin in humans. Journal of Applied Physiology. 2007;102(6):2165–2171.
    1. Broom D.R., Batterham R.L., King J.A., Stensel D.J. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 2009;296(1):R29–R35.
    1. Shiiya T., Ueno H., Toshinai K., Kawagoe T., Naito S., Tobina T. Significant lowering of plasma ghrelin but not des-acyl ghrelin in response to acute exercise in men. Endocrine Journal. 2011;58(5):335–342.
    1. Balaguera-Cortes L., Wallman K.E., Fairchild T.J., Guelfi K.J. Energy intake and appetite-related hormones following acute aerobic and resistance exercise. Applied Physiology, Nutrition, and Metabolism. 2011;36(6):958–966.
    1. Chaiban J.T., Bitar F.F., Azar S.T. Effect of chronic hypoxia on leptin, insulin, adiponectin, and ghrelin. Metabolism. 2008;57(8):1019–1022.
    1. Wasse L.K., Sunderland C., King J.A., Batterham R.L., Stensel D.J. Influence of rest and exercise at a simulated altitude of 4,000 m on appetite, energy intake, and plasma concentrations of acylated ghrelin and peptide YY. Journal of Applied Physiology. 2012;112(4):552–559.
    1. Brown E.M., Pollak M., Hebert S.C. Sensing of extracellular Ca2+ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca(2+)-sensing receptor. American Journal of Kidney Diseases. 1995;25(3):506–513.
    1. Reimann F., Tolhurst G., Gribble F.M. G-protein-coupled receptors in intestinal chemosensation. Cell Metabolism. 2012;15(4):421–431.
    1. Davey A.E., Leach K., Valant C., Conigrave A.D., Sexton P.M., Christopoulos A. Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology. 2012;153(3):1232–1241.
    1. Rey O., Young S.H., Yuan J., Slice L., Rozengurt E. Amino acid-stimulated Ca2+ oscillations produced by the Ca2+-sensing receptor are mediated by a phospholipase C/inositol 1,4,5-trisphosphate-independent pathway that requires G12, Rho, filamin-A, and the actin cytoskeleton. Journal of Biological Chemistry. 2005;280(24):22875–22882.
    1. Makita N., Sato J., Manaka K., Shoji Y., Oishi A., Hashimoto M. An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(13):5443–5448.
    1. Saffouri B., Weir G., Bitar K., Makhlouf G. Stimulation of gastrin secretion from the perfused rat stomach by somatostatin antiserum. Life Science. 1979;25(20):1749–1753.
    1. Bauer B., Wex T., Kuester D., Meyer T., Malfertheiner P. Differential expression of human beta defensin 2 and 3 in gastric mucosa of Helicobacter pylori-infected individuals. Helicobacter. 2013;18(1):6–12.
    1. Takahashi H., Kurose Y., Suzuki Y., Kojima M., Yamaguchi T., Yoshida Y. Changes in blood pancreatic polypeptide and ghrelin concentrations in response to feeding in sheep. Journal of Animal Science. 2010;88(6):2103–2107.
    1. Gagnon J., Anini Y. Glucagon stimulates ghrelin secretion through the activation of MAPK and EPAC and potentiates the effect of norepinephrine. Endocrinology. 2013;154(2):666–674.
    1. Hirasawa A., Tsumaya K., Awaji T., Katsuma S., Adachi T., Yamada M. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nature Medicine. 2005;11(1):90–94.
    1. Zigman J.M., Westermark G.T., LaMendola J., Steiner D.F. Expression of cone transducin, Gz alpha, and other G-protein alpha-subunit messenger ribonucleic acids in pancreatic islets. Endocrinology. 1994;135(1):31–37.
    1. Wang Y., Park S., Bajpayee N.S., Nagaoka Y., Boulay G., Birnbaumer L. Augmented glucose-induced insulin release in mice lacking G(o2), but not G(o1) or G(i) proteins. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(4):1693–1698.
    1. Kimple M.E., Joseph J.W., Bailey C.L., Fueger P.T., Hendry I.A., Newgard C.B. Galphaz negatively regulates insulin secretion and glucose clearance. Journal of Biological Chemistry. 2008;283(8):4560–4567.
    1. Lizarzaburu M., Turcotte S., Du X., Duquette J., Fu A., Houze J. Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus. Bioorganic & Medicinal Chemistry Letters. 2012;22(18):5942–5947.
    1. Ku G.M., Pappalardo Z., Luo C.C., German M.S., McManus M.T. An siRNA screen in pancreatic beta cells reveals a role for Gpr27 in insulin production. PLoS Genetics. 2012;8(1):e1002449.
    1. Meyer R.C., Giddens M.M., Schaefer S.A., Hall R.A. GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(23):9529–9534.

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