Nutrient-sensing components of the mouse stomach and the gastric ghrelin cell
Maria Nunez-Salces
Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Search for more papers by this authorHui Li
Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Search for more papers by this authorChristine Feinle-Bisset
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Search for more papers by this authorRichard L. Young
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Intestinal Nutrient Sensing Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Search for more papers by this authorCorresponding Author
Amanda J. Page
Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Correspondence
Amanda J. Page, Vagal Afferent Research Group, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Email: [email protected]
Search for more papers by this authorMaria Nunez-Salces
Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Search for more papers by this authorHui Li
Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Search for more papers by this authorChristine Feinle-Bisset
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Search for more papers by this authorRichard L. Young
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Intestinal Nutrient Sensing Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Search for more papers by this authorCorresponding Author
Amanda J. Page
Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Correspondence
Amanda J. Page, Vagal Afferent Research Group, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Email: [email protected]
Search for more papers by this authorFunding information
Maria Nunez-Salces was supported by an Adelaide Scholarship International (ASI) and a CRE in Translating Nutritional Science into Good Health Scholarship, Christine Feinle-Bisset by a National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (grant 1103020, 2016-2021).
Abstract
Background
The ability of the gut to detect nutrients is critical to the regulation of gut hormone secretion, food intake, and postprandial blood glucose control. Ingested nutrients are detected by specific gut chemosensors. However, knowledge of these chemosensors has primarily been derived from the intestine, while available information on gastric chemosensors is limited. This study aimed to investigate the nutrient-sensing repertoire of the mouse stomach with particular emphasis on ghrelin cells.
Methods
Quantitative RT-PCR was used to determine mRNA levels of nutrient chemosensors (protein: G protein–coupled receptor 93 [GPR93], calcium-sensing receptor [CaSR], metabotropic glutamate receptor type 4 [mGluR4]; fatty acids: CD36, FFAR2&4; sweet/umami taste: T1R3), taste transduction components (TRPM5, GNAT2&3), and ghrelin and ghrelin-processing enzymes (PC1/3, ghrelin O-acyltransferase [GOAT]) in the gastric corpus and antrum of adult male C57BL/6 mice. Immunohistochemistry was performed to assess protein expression of chemosensors (GPR93, T1R3, CD36, and FFAR4) and their co-localization with ghrelin.
Key Results
Most nutrient chemosensors had higher mRNA levels in the antrum compared to the corpus, except for CD36, GNAT2, ghrelin, and GOAT. Similar regional distribution was observed at the protein level. At least 60% of ghrelin-positive cells expressed T1R3 and FFAR4, and over 80% expressed GPR93 and CD36.
Conclusions and Inferences
The cellular mechanisms for the detection of nutrients are expressed in a region-specific manner in the mouse stomach and gastric ghrelin cells. These gastric nutrient chemosensors may play a role modulating gastrointestinal responses, such as the inhibition of ghrelin secretion following food intake.
CONFLICT OF INTEREST
The authors have no conflict of interest.
Supporting Information
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Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Steinert RE, Beglinger C. Nutrient sensing in the gut: interactions between chemosensory cells, visceral afferents and the secretion of satiation peptides. Physiol Behav. 2011; 105(1): 62-70.
- 2Depoortere I. Taste receptors of the gut: emerging roles in health and disease. Gut. 2014; 63(1): 179-190.
- 3Rasoamanana R, Darcel N, Fromentin G, Tome D. Nutrient sensing and signalling by the gut. Proc Nutr Soc. 2012; 71(4): 446-455.
- 4Symonds EL, Peiris M, Page AJ, et al. Mechanisms of activation of mouse and human enteroendocrine cells by nutrients. Gut. 2015; 64(4): 618-626.
- 5Sun EW, de Fontgalland D, Rabbitt P, et al. Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine. Diabetes. 2017; 66(8): 2144-2149.
- 6Alamshah A, Spreckley E, Norton M, et al. L-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents. Int J Obes. 2017; 41(11): 1693-1701.
- 7Young RL, Sutherland K, Pezos N, et al. Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes. Gut. 2009; 58(3): 337-346.
- 8Martin AM, Lumsden AL, Young RL, Jessup CF, Spencer NJ, Keating DJ. The nutrient-sensing repertoires of mouse enterochromaffin cells differ between duodenum and colon. Neurogastroenterol Motil. 2017; 29(6). e13046
- 9Kreuch D, Keating DJ, Wu T, Horowitz M, Rayner CK, Young RL. Gut mechanisms linking intestinal sweet sensing to glycemic control. Front Endocrinol. 2018; 9: 741.
- 10Jang H-J, Kokrashvili Z, Theodorakis MJ, et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci USA. 2007; 104(38): 15069-15074.
- 11Kokrashvili Z, Mosinger B, Margolskee RF. T1R3 and α-gustducin in gut regulate secretion of glucagon-like peptide-1. Ann N Y Acad Sci. 2009; 1170(1): 91-94.
- 12Liu D, Liman ER. Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. Proc Natl Acad Sci USA. 2003; 100(25): 15160-15165.
- 13Steinert RE, Gerspach AC, Gutmann H, Asarian L, Drewe J, Beglinger C. The functional involvement of gut-expressed sweet taste receptors in glucose-stimulated secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Clin Nutr. 2011; 30(4): 524-532.
- 14Moran AW, Al-Rammahi M, Zhang C, Bravo D, Calsamiglia S, Shirazi-Beechey SP. Sweet taste receptor expression in ruminant intestine and its activation by artificial sweeteners to regulate glucose absorption. J Dairy Sci. 2014; 97(8): 4955-4972.
- 15Choi S, Lee M, Shiu AL, Yo SJ, Aponte GW. Identification of a protein hydrolysate responsive G protein-coupled receptor in enterocytes. Am J Physiol Gastrointest Liver Physiol. 2007; 292(1): G98-G112.
- 16Choi S, Lee M, Shiu AL, Yo SJ, Halldén G, Aponte GW. GPR93 activation by protein hydrolysate induces CCK transcription and secretion in STC-1 cells. Am J Physiol Gastrointest Liver Physiol. 2007; 292(5): G1366-G1375.
- 17Diakogiannaki E, Pais R, Tolhurst G, et al. Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor. Diabetologia. 2013; 56(12): 2688-2696.
- 18Liou AP, Sei Y, Zhao X, et al. The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. Am J Physiol Gastrointest Liver Physiol. 2011; 300(4): G538-G546.
- 19Yasumatsu K, Ogiwara Y, Takai S, et al. Umami taste in mice uses multiple receptors and transduction pathways. J Physiol. 2012; 590(5): 1155-1170.
- 20San Gabriel A, Uneyama H. Amino acid sensing in the gastrointestinal tract. Amino Acids. 2013; 45(3): 451-461.
- 21He W, Yasumatsu K, Varadarajan V, et al. Umami taste responses are mediated by alpha-transducin and alpha-gustducin. J Neurosci. 2004; 24(35): 7674-7680.
- 22Pais R, Gribble FM, Reimann F. Signalling pathways involved in the detection of peptones by murine small intestinal enteroendocrine L-cells. Peptides. 2016; 77: 9-15.
- 23Mace OJ, Schindler M, Patel S. The regulation of K- and L-cell activity by GLUT2 and the calcium-sensing receptor CasR in rat small intestine. J Physiol. 2012; 590(12): 2917-2936.
- 24Feng J, Petersen CD, Coy DH, et al. Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion. Proc Natl Acad Sci USA. 2010; 107(41): 17791-17796.
- 25Daly K, Al-Rammahi M, Moran A, Marcello M, Ninomiya Y, Shirazi-Beechey SP. Sensing of amino acids by the gut-expressed taste receptor T1R1-T1R3 stimulates CCK secretion. Am J Physiol Gastrointest Liver Physiol. 2013; 304(3): G271-G282.
- 26Sivaprakasam S, Gurav A, Paschall AV, et al. An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis. 2016; 5:e238.
- 27Hirasawa A, Tsumaya K, Awaji T, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005; 11(1): 90-94.
- 28Keast RS, Costanzo A. Is fat the sixth taste primary? Evidence and implications. Flavour. 2015; 4(1): 5.
10.1186/2044-7248-4-5 Google Scholar
- 29Liu D, Archer N, Duesing K, Hannan G, Keast R. Mechanism of fat taste perception: association with diet and obesity. Prog Lipid Res. 2016; 63: 41-49.
- 30Widmayer P, Partsch V, Pospiech J, Kusumakshi S, Boehm U, Breer H. Distinct cell types with the bitter receptor Tas2r126 in different compartments of the stomach. Front Physiol. 2020; 11:32.
- 31Janssen S, Laermans J, Verhulst PJ, 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. Proc Natl Acad Sci USA. 2011; 108(5): 2094-2099.
- 32Wang Q, Liszt KI, Deloose E, et al. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut. FASEB J. 2019; 33(4): 4907-4920.
- 33Kojima 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.
- 34Ariyasu H, Takaya K, Tagami T, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab. 2001; 86(10): 4753-4758.
- 35Druce MR, Wren AM, Park AJ, et al. Ghrelin increases food intake in obese as well as lean subjects. Int J Obes. 2005; 29(9): 1130-1136.
- 36Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001; 86(12): 5992.
- 37Masuda Y, Tanaka T, Inomata N, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 2000; 276(3): 905-908.
- 38Levin F, Edholm T, Schmidt PT, et al. Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J Clin Endocrinol Metab. 2006; 91(9): 3296-3302.
- 39Seoane LM, Crujeiras AB, Al-Massadi O, Casanueva FF. Gastric ghrelin in the regulation of appetite and metabolism. In: RG Smith, MO Thorner, eds. Ghrelin in Health and Disease. Totowa, NJ: Humana Press; 2012: 73-89.
10.1007/978-1-61779-903-7_4 Google Scholar
- 40Poher A-L, Tschöp MH, Müller TD. Ghrelin regulation of glucose metabolism. Peptides. 2018; 100: 236-242.
- 41Varela L, Vázquez MJ, Cordido F, et al. Ghrelin and lipid metabolism: key partners in energy balance. J Mol Endocrinol. 2011; 46(2): R43-R63.
- 42Zhu X, Cao Y, Voogd K, Steiner DF. On the processing of proghrelin to ghrelin. J Biol Chem. 2006; 281(50): 38867-38870.
- 43Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008; 132(3): 387-396.
- 44Bednarek MA, Feighner SD, Pong S-S, et al. Structure−function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem. 2000; 43(23): 4370-4376.
- 45Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001; 50(8): 1714-1719.
- 46Williams DL, Grill HJ, Cummings DE, Kaplan JM. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology. 2003; 144(12): 5184-5187.
- 47Mundinger TO, Cummings DE, Taborsky GJ Jr. Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology. 2006; 147(6): 2893-2901.
- 48Zhao TJ, Sakata I, Li RL, et al. Ghrelin secretion stimulated by β1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. Proc Natl Acad Sci USA. 2010; 107(36): 15868-15873.
- 49Flanagan DE, Evans ML, Monsod TP, et al. The influence of insulin on circulating ghrelin. Am J Physiol Endocrinol Metab. 2003; 284(2): E313-E316.
- 50Shimada M, Date Y, Mondal MS, et al. Somatostatin suppresses ghrelin secretion from the rat stomach. Biochem Biophys Res Commun. 2003; 302(3): 520-525.
- 51Brennan IM, Otto B, Feltrin KL, Meyer JH, 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.
- 52Hagemann D, Holst JJ, Gethmann A, Banasch M, Schmidt WE, Meier JJ. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion. Regul Pept. 2007; 143(1–3): 64-68.
- 53Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003; 349(10): 941-948.
- 54Foster-Schubert KE, Overduin J, Prudom CE, et al. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab. 2008; 93(5): 1971-1979.
- 55Monteleone P, Bencivenga R, Longobardi N, Serritella C, Maj M. Differential responses of circulating ghrelin to high-fat or high-carbohydrate meal in healthy women. J Clin Endocrinol Metab. 2003; 88(11): 5510-5514.
- 56Li H, Kentish SJ, Wittert GA, Page AJ. Apelin modulates murine gastric vagal afferent mechanosensitivity. Physiol Behav. 2018; 194: 466-473.
- 57Kentish SJ, Li H, Frisby CL, Page AJ. Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner. Peptides. 2017; 89: 35-41.
- 58Bookout AL, Mangelsdorf DJ. Quantitative real-time PCR protocol for analysis of nuclear receptor signaling pathways. Nucl Recept Signal. 2003; 1:e012.
- 59Lee H, Macpherson LJ, Parada CA, Zuker CS, Ryba NJP. Rewiring the taste system. Nature. 2017; 548(7667): 330-333.
- 60Takai S, Yasumatsu K, Inoue M, et al. Glucagon-like peptide-1 is specifically involved in sweet taste transmission. FASEB J. 2015; 29(6): 2268-2280.
- 61Liu D, Costanzo A, Evans MDM, et al. Expression of the candidate fat taste receptors in human fungiform papillae and the association with fat taste function. Br J Nutr. 2018; 120(1): 64-73.
- 62Himoto T, Tani J, Miyoshi H, et al. Investigation of the factors associated with circulating soluble CD36 levels in patients with HCV-related chronic liver disease. Diabetol Metab Syndr. 2013; 5(1): 51.
- 63Garbacz WG, Lu P, Miller TM, et al. Hepatic overexpression of CD36 improves glycogen homeostasis and attenuates high-fat diet-induced hepatic steatosis and insulin resistance. Mol Cell Biol. 2016; 36(21): 2715-2727.
- 64 Merck. Anti-LPA receptor 5 Antibody (GPR92), ABT114. https://www.merckmillipore.com/AU/en/product/Anti-LPA-receptor-5-Antibody-GPR92,MM_NF-ABT114. Accessed 25 May 2019.
- 65Sakata I, Nakamura K, Yamazaki M, et al. Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides. 2002; 23(3): 531-536.
- 66Khoder G, Al-Yassir F, Al Menhali A, et al. Probiotics upregulate trefoil factors and downregulate pepsinogen in the mouse stomach. Int J Mol Sci. 2019; 20(16): 3901.
- 67Fakhry J, Stebbing MJ, Hunne B, et al. Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus. Cell Tissue Res. 2019; 376(1): 37-49.
- 68Engelstoft MS, Park WM, Sakata I, et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab. 2013; 2(4): 376-392.
- 69Lu X, Zhao X, Feng J, et al. Postprandial inhibition of gastric ghrelin secretion by long-chain fatty acid through GPR120 in isolated gastric ghrelin cells and mice. Am J Physiol Gastrointest Liver Physiol. 2012; 303(3): G367-G376.
- 70Steensels S, Vancleef L, Depoortere I. The sweetener-sensing mechanisms of the ghrelin cell. Nutrients. 2016; 8(12): 795.
- 71Steinert RE, Meyer-Gerspach AC, Beglinger C. The role of the stomach in the control of appetite and the secretion of satiation peptides. Am J Physiol Endocrinol Metab. 2012; 302(6): E666-E673.
- 72Macro JA, Dimaline R, Dockray GJ. Identification and expression of prohormone-converting enzymes in the rat stomach. Am J Physiol. 1996; 270(1): G87-G93.
- 73Rehfeld Jens F, Zhu X, Norrbom C, et al. Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17. Biochem J. 2008; 415(1): 35-43.
- 74Haid D, Widmayer P, Voigt A, Chaudhari N, Boehm U, Breer H. Gustatory sensory cells express a receptor responsive to protein breakdown products (GPR92). Histochem Cell Biol. 2013; 140(2): 137-145.
- 75Rettenberger A, Schulze W, Breer H, Haid D. Analysis of the protein related receptor GPR92 in G-cells. Front Physiol. 2015; 6: 261.
- 76Haid D, Jordan-Biegger C, Widmayer P, Breer H. Receptors responsive to protein breakdown products in G-cells and D-cells of mouse, swine and human. Front Physiol. 2012; 3: 65.
- 77Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell. 2016; 165(3): 535-550.
- 78Adriaenssens A, Lam BY, Billing L, et al. A Transcriptome-Led exploration of molecular mechanisms regulating somatostatin-producing D-cells in the gastric epithelium. Endocrinology. 2015; 156(11): 3924-3936.
- 79Vancleef L, Van Den Broeck T, Thijs T, et al. Chemosensory signalling pathways involved in sensing of amino acids by the ghrelin cell. Sci Rep. 2015; 5:15725.
- 80Hass N, Schwarzenbacher K, Breer H. T1R3 is expressed in brush cells and ghrelin-producing cells of murine stomach. Cell Tissue Res. 2010; 339(3): 493-504.
- 81Vancleef L, Thijs T, Baert F, et al. Obesity impairs oligopeptide/amino acid-induced ghrelin release and smooth muscle contractions in the human proximal stomach. Mol Nutr Food Res. 2018; 62:1700804.
- 82Nakagawa Y, Nagasawa M, Mogami H, Lohse M, Ninomiya Y, Kojima I. Multimodal function of the sweet taste receptor expressed in pancreatic beta-cells: generation of diverse patterns of intracellular signals by sweet agonists. Endocr J. 2013; 60(10): 1191-1206.
- 83Masubuchi Y, Nakagawa Y, Ma J, et al. A novel regulatory function of sweet taste-sensing receptor in adipogenic differentiation of 3T3-L1 cells. PLoS One. 2013; 8(1):e54500.
- 84Williams DL, Cummings DE, Grill HJ, Kaplan JM. Meal-related ghrelin suppression requires postgastric feedback. Endocrinology. 2003; 144(7): 2765-2767.
- 85Sakata I, Park WM, Walker AK, et al. Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells. Am J Physiol Endocrinol Metab. 2012; 302(10): E1300-E1310.
- 86Gaillard D, Laugerette F, Darcel N, et al. The gustatory pathway is involved in CD36-mediated orosensory perception of long-chain fatty acids in the mouse. FASEB J. 2008; 22(5): 1458-1468.
- 87Laugerette F, Passilly-Degrace P, Patris B, et al. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. J Clin Invest. 2005; 115(11): 3177-3184.
- 88Drover VA, Nguyen DV, Bastie CC, et al. CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice. J Biol Chem. 2008; 283(19): 13108-13115.
- 89Nassir F, Wilson B, Han X, Gross RW, Abumrad NA. CD36 is important for fatty acid and cholesterol uptake by the proximal but not distal intestine. J Biol Chem. 2007; 282(27): 19493-19501.
- 90Chen M, Yang Y, Braunstein E, Georgeson KE, Harmon CM. Gut expression and regulation of FAT/CD36: possible role in fatty acid transport in rat enterocytes. Am J Physiol Endocrinol Metab. 2001; 281(5): E916-E923.
- 91Mills JC, Syder AJ, Hong CV, Guruge JL, Raaii F, Gordon JI. A molecular profile of the mouse gastric parietal cell with and without exposure to Helicobacter pylori. Proc Natl Acad Sci USA. 2001; 98(24): 13687-13692.
- 92Ohgusu H, Shirouzu K, Nakamura Y, et al. Ghrelin O-acyltransferase (GOAT) has a preference for n-hexanoyl-CoA over n-octanoyl-CoA as an acyl donor. Biochem Biophys Res Commun. 2009; 386(1): 153-158.
- 93Ikenoya C, Takemi S, Kaminoda A, et al. Beta-oxidation in ghrelin-producing cells is important for ghrelin acyl-modification. Sci Rep. 2018; 8(1):9176.
- 94Egerod KL, Engelstoft MS, Lund ML, et al. Transcriptional and functional characterization of the G protein-coupled receptor repertoire of gastric somatostatin cells. Endocrinology. 2015; 156(11): 3909-3923.
- 95Janssen S, Laermans J, Iwakura H, Tack J, Depoortere I. Sensing of fatty acids for octanoylation of ghrelin involves a gustatory G-protein. PLoS One. 2012; 7(6):e40168.
- 96Gong Z, Yoshimura M, Aizawa S, et al. G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro. Am J Physiol Endocrinol Metab. 2014; 306(1): E28-E35.
- 97Hunne B, Stebbing MJ, McQuade RM, Furness JB. Distributions and relationships of chemically defined enteroendocrine cells in the rat gastric mucosa. Cell Tissue Res. 2019; 378(1): 33-48.
- 98Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000; 407(6806): 908-913.
- 99Theander-Carrillo C, Wiedmer P, Cettour-Rose P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 2006; 116(7): 1983-1993.
- 100Perez-Tilve D, Heppner K, Kirchner H, et al. Ghrelin-induced adiposity is independent of orexigenic effects. FASEB J. 2011; 25(8): 2814-2822.
- 101Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab. 2001; 86(10): 5083-5086.
- 102Reimer MK, Pacini G, Ahren B. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology. 2003; 144(3): 916-921.
- 103Salehi A, Dornonville de la Cour C, Hakanson R, Lundquist I. Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regul Pept. 2004; 118(3): 143-150.
- 104Murray CD, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut. 2005; 54(12): 1693-1698.
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