Effects of insulin signaling on mouse taste cell proliferation

Autoři: Shingo Takai aff001;  Yu Watanabe aff001;  Keisuke Sanematsu aff001;  Ryusuke Yoshida aff004;  Robert F. Margolskee aff002;  Peihua Jiang aff002;  Ikiru Atsuta aff003;  Kiyoshi Koyano aff003;  Yuzo Ninomiya aff002;  Noriatsu Shigemura aff001
Působiště autorů: Section of Oral Neuroscience, Faculty of Dental Science, Kyushu University, Fukuoka, Japan aff001;  Monell Chemical Senses Center, Philadelphia, PA, United States of America aff002;  Section of Removable Prosthodontics, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan aff003;  Department of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan aff004;  Division of Sensory Physiology, Research and Development Center for Five-Sense Devices Taste and Odor Sensing, Kyushu University, Fukuoka, Japan aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225190


Expression of insulin and its receptor (IR) in rodent taste cells has been proposed, but exactly which types of taste cells express IR and the function of insulin signaling in taste organ have yet to be determined. In this study, we analyzed expression of IR mRNA and protein in mouse taste bud cells in vivo and explored its function ex vivo in organoids, using RT-PCR, immunohistochemistry, and quantitative PCR. In mouse taste tissue, IR was expressed broadly in taste buds, including in type II and III taste cells. With using 3-D taste bud organoids, we found insulin in the culture medium significantly decreased the number of taste cell and mRNA expression levels of many taste cell genes, including nucleoside triphosphate diphosphohydrolase-2 (NTPDase2), Tas1R3 (T1R3), gustducin, carbonic anhydrase 4 (CA4), glucose transporter-8 (GLUT8), and sodium-glucose cotransporter-1 (SGLT1) in a concentration-dependent manner. Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) signaling, diminished insulin’s effects and increase taste cell generation. Altogether, circulating insulin might be an important regulator of taste cell growth and/or proliferation via activation of the mTOR pathway.

Klíčová slova:

Cell differentiation – Gene expression – Insulin – Insulin signaling – Organoids – Stem cells – Taste – Taste buds


1. Suzuki Y, Takeda M, Sakakura Y, Suzuki N. Distinct Expression Pattern of Insulin-Like Growth Factor Family in Rodent Taste Buds. J Comp Neurol. 2005;482: 74–84. doi: 10.1002/cne.20379 15612015

2. Doyle ME, Fiori JL, Gonzalez Mariscal I, Liu Q-R, Goodstein E, Yang H, et al. Insulin Is Transcribed and Translated in Mammalian Taste Bud Cells. Endocrinology. 2018;159: 3331–3339. doi: 10.1210/en.2018-00534 30060183

3. Zhang C, Cotter M, Lawton A, Oakley B, Wong L, Zeng Q. Keratin 18 is associated with a subset of older taste cells in the rat. Differentiation. Wiley/Blackwell (10.1111); 1995;59: 155–162. doi: 10.1046/j.1432-0436.1995.5930155.x 7589899

4. Heck GL, Mierson S, DeSimone JA. Salt taste transduction occurs through an amiloride-sensitive sodium transport pathway. Science. 1984;223: 403–5. Available: http://www.ncbi.nlm.nih.gov/pubmed/6691151 doi: 10.1126/science.6691151 6691151

5. Baquero AF, Gilbertson TA. Insulin activates epithelial sodium channel (ENaC) via phosphoinositide 3-kinase in mammalian taste receptor cells. Am J Physiol Physiol. 2011;300: C860–C871. doi: 10.1152/ajpcell.00318.2010 21106690

6. Vandenbeuch A, Clapp TR, Kinnamon SC. Amiloride-sensitive channels in type I fungiform taste cells in mouse. BMC Neurosci. 2008;9: 1. doi: 10.1186/1471-2202-9-1 18171468

7. Yoon M-S. The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients. Multidisciplinary Digital Publishing Institute (MDPI); 2017;9. doi: 10.3390/nu9111176 29077002

8. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011;23: 744–755. doi: 10.1016/j.ceb.2011.09.003 21963299

9. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. Am J Physiol Metab. 2009;296: E592–E602. doi: 10.1152/ajpendo.90645.2008 18765678

10. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10: 307–318. doi: 10.1038/nrm2672 19339977

11. Zoncu R, Efeyan A, Sabatini DM. MTOR: From growth signal integration to cancer, diabetes and ageing. Nature Reviews Molecular Cell Biology. 2011. doi: 10.1038/nrm3025 21157483

12. Liu Z, Kim W, Chen Z, Shin Y-K, Carlson OD, Fiori JL, et al. Insulin and Glucagon Regulate Pancreatic α-Cell Proliferation. Vella A, editor. PLoS One. Public Library of Science; 2011;6: e16096. doi: 10.1371/journal.pone.0016096 21283589

13. Beidler LM, Smallman RL. Renewal of cells within taste buds. J Cell Biol. Rockefeller University Press; 1965;27: 263–72. doi: 10.1083/jcb.27.2.263 5884625

14. Hamamichi R, Asano-Miyoshi M, Emori Y. Taste bud contains both short-lived and long-lived cell populations. Neuroscience. 2006;141: 2129–2138. doi: 10.1016/j.neuroscience.2006.05.061 16843606

15. Perea-Martinez I, Nagai T, Chaudhari N. Functional cell types in taste buds have distinct longevities. Behrens M, editor. PLoS One. 2013;8: e53399. doi: 10.1371/journal.pone.0053399 23320081

16. Yee KK, Li Y, Redding KM, Iwatsuki K, Margolskee RF, Jiang P. Lgr5-EGFP Marks Taste Bud Stem/Progenitor Cells in Posterior Tongue. Stem Cells. 2013;31: 992–1000. doi: 10.1002/stem.1338 23377989

17. Ren W, Lewandowski BC, Watson J, Aihara E, Iwatsuki K, Bachmanov AA, et al. Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo. Proc Natl Acad Sci. 2014; doi: 10.1073/pnas.1409064111 25368147

18. Zhou Y, Liu H-X, Mistretta CM. Bone morphogenetic proteins and noggin: inhibiting and inducing fungiform taste papilla development. Dev Biol. 2006;297: 198–213. doi: 10.1016/j.ydbio.2006.05.022 16828469

19. Liebl DJ, Mbiene J-P, Parada LF. NT4/5 Mutant Mice Have Deficiency in Gustatory Papillae and Taste Bud Formation. Dev Biol. 1999;213: 378–389. doi: 10.1006/dbio.1999.9385 10479455

20. Petersen CI, Jheon AH, Mostowfi P, Charles C, Ching S, Thirumangalathu S, et al. FGF Signaling Regulates the Number of Posterior Taste Papillae by Controlling Progenitor Field Size. Thesleff I, editor. PLoS Genet. Public Library of Science; 2011;7: e1002098. doi: 10.1371/journal.pgen.1002098 21655085

21. Biggs BT, Tang T, Krimm RF. Insulin-like growth factors are expressed in the taste system, but do not maintain adult taste buds. PLoS One. 2016; doi: 10.1371/journal.pone.0148315 26901525

22. Lu W-J, Mann RK, Nguyen A, Bi T, Silverstein M, Tang JY, et al. Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration. Proc Natl Acad Sci. 2018;115: E200–E209. doi: 10.1073/pnas.1719109115 29279401

23. Iwatsuki K, Liu H-X, Gronder A, Singer MA, Lane TF, Grosschedl R, et al. Wnt signaling interacts with Shh to regulate taste papilla development. Proc Natl Acad Sci. 2007;104: 2253–2258. doi: 10.1073/pnas.0607399104 17284610

24. Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J-I, Obata K, Kaneko T. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003;467: 60–79. doi: 10.1002/cne.10905 14574680

25. Ren W, Aihara E, Lei W, Gheewala N, Uchiyama H, Margolskee RF, et al. Transcriptome analyses of taste organoids reveal multiple pathways involved in taste cell generation. Sci Rep. 2017;7: 4004. doi: 10.1038/s41598-017-04099-5 28638111

26. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29: e45. Available: http://www.ncbi.nlm.nih.gov/pubmed/11328886 doi: 10.1093/nar/29.9.e45 11328886

27. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459: 262–265. doi: 10.1038/nature07935 19329995

28. Schuijers J, Clevers H. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. EMBO J. 2012;31: 2685–2696. doi: 10.1038/emboj.2012.149 22617424

29. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988;37: 1163–1167. doi: 10.2337/diab.37.9.1163 3044882

30. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A. National Academy of Sciences; 2004;101: 13489–94. doi: 10.1073/pnas.0405659101 15342917

31. Wauson EM, Zaganjor E, Lee A-Y, Guerra ML, Ghosh AB, Bookout AL, et al. The G Protein-Coupled Taste Receptor T1R1/T1R3 Regulates mTORC1 and Autophagy. Mol Cell. Cell Press; 2012;47: 851–862. doi: 10.1016/J.MOLCEL.2012.08.001 22959271

32. Morgan-Bathke M, Harris ZI, Arnett DG, Klein RR, Burd R, Ann DK, et al. The rapalogue, CCI-779, improves salivary gland function following radiation. PLoS One. 2014; doi: 10.1371/journal.pone.0113183 25437438

33. Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P. Autophagy: for better or for worse. Cell Res. 2012;22: 43–61. doi: 10.1038/cr.2011.152 21912435

34. Perros P, MacFarlane TW, Counsell C, Frier BM. Altered taste sensation in newly-diagnosed NIDDM. Diabetes Care. American Diabetes Association; 1996;19: 768–70. doi: 10.2337/diacare.19.7.768 8799637

35. Lawson WB, Zeidler A, Rubenstein A. Taste detection and preferences in diabetics and their relatives. Psychosom Med. 1979;41: 219–27. Available: http://www.ncbi.nlm.nih.gov/pubmed/472087 doi: 10.1097/00006842-197905000-00005 472087

36. Gondivkar SM, Indurkar A, Degwekar S, Bhowate R. Evaluation of gustatory function in patients with diabetes mellitus type 2. Oral Surgery, Oral Med Oral Pathol Oral Radiol Endodontology. 2009;108: 876–880. doi: 10.1016/j.tripleo.2009.08.015 19913725

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