Reciprocal Modulation of Sweet Taste by Leptin and Endocannabinoids

  • Mayu Niki
  • Masafumi Jyotaki
  • Ryusuke Yoshida
  • Yuzo NinomiyaEmail author
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 52)


Sweet taste perception is important for animals to detect carbohydrate source of calories and has a critical role in the nutritional status of animals. Recent studies demonstrated that sweet taste responses can be modulated by leptin and endocannabinoids [anandamide (N-arachidonoylethanolamine) and 2-arachidonoyl glycerol]. Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor, Ob-Rb. Leptin is shown to selectively suppress sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. In marked contrast, endocannabinoids are orexigenic mediators that act via CB1 receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. In the peripheral taste system, endocannabinoids also oppose the action of leptin and enhance sweet taste sensitivities in wild-type mice but not in mice genetically lacking CB1 receptors. These findings indicate that leptin and endocannabinoids not only regulate food intake via central nervous systems but also may modulate palatability of foods by altering peripheral sweet taste responses via their cognate receptors.


Taste Receptor Sweet Taste Taste Cell Taste Quality Taste Stimulus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by Grant-in-Aids 18109013, 1807704 (Y.N.) for Scientific Research from Japan Society for the Promotion of Science.


  1. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252. doi: 10.1038/382250a0 PubMedCrossRefGoogle Scholar
  2. Barrenetxe J, Villaro AC, Guembe L, Pascual I, Munoz-Navas M, Barber A, Lostao MP (2002) Distribution of the long leptin receptor isoform in brush border, basolateral membrane, and cytoplasm of enterocytes. Gut 50:797–802. doi: 10.1136/gut.50.6.797 PubMedCrossRefGoogle Scholar
  3. Boden G, Chen X, Mozzoli M, Ryan I (1996) Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 81:3419–3423PubMedCrossRefGoogle Scholar
  4. Caicedo A, Kim KN, Roper SD (2002) Individual mouse taste cells respond to multiple chemical stimuli. J Physiol 544:501–509. doi: 10.1113/jphysiol.2002.027862 PubMedCrossRefGoogle Scholar
  5. Chandrashekar J, Kuhn C, Oka Y, Yarmolinsky DA, Hummler E, Ryba NJ, Zuker CS (2010) The cells and peripheral representation of sodium taste in mice. Nature 464:297–301. doi: 10.1038/nature08783 PubMedCrossRefGoogle Scholar
  6. Chaudhari N, Landin AM, Roper SD (2000) A metabotropic glutamate receptor variant functions as a taste receptor. Nat Neurosci 3:113–119. doi: 10.1038/72053 PubMedCrossRefGoogle Scholar
  7. Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thöne-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431. doi: 10.1172/JCI17725 PubMedGoogle Scholar
  8. DeFazio RA, Dvoryanchikov G, Maruyama Y, Kim JW, Pereira E, Roper SD, Chaudhari N (2006) Separate populations of receptor cells and presynaptic cells in mouse taste buds. J Neurosci 26:3971–3980. doi: 10.1523/JNEUROSCI.0515-06.2006 PubMedCrossRefGoogle Scholar
  9. Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825. doi: 10.1038/35071088 PubMedCrossRefGoogle Scholar
  10. Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310:1495–1499. doi: 10.1126/science.1118435 PubMedCrossRefGoogle Scholar
  11. Flier JS (2004) Obesity wars: molecular progress confronts an expanding epidemic. Cell 116:337–350. doi: 10.1016/S0092-8674(03)01081-X PubMedCrossRefGoogle Scholar
  12. Friedman JM (2004) Modern science versus the stigma of obesity. Nat Med 10:563–569. doi: 10.1038/nm0604-563 PubMedCrossRefGoogle Scholar
  13. Heck GL, Mierson S, DeSimone JA (1984) Salt taste transduction occurs through an amiloride-sensitive sodium transport pathway. Science 223:403–405PubMedCrossRefGoogle Scholar
  14. Herness S, Zhao FL, Lu SG, Kaya N, Shen T (2002) Expression and physiological actions of cholecystokinin in rat taste receptor cells. J Neurosci 22:10018–10029PubMedGoogle Scholar
  15. Higgs S, Williams CM, Kirkham TC (2003) Cannabinoid influences on palatability: microstructural analysis of sucrose drinking after delta(9)-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716. Psychopharmacology (Berl) 165:370–377. doi: 10.1007/s00213-002-1263-3 Google Scholar
  16. Hisatsune C, Yasumatsu K, Takahashi-Iwanaga H, Ogawa N, Kuroda Y, Yoshida R, Ninomiya Y, Mikoshiba K (2007) Abnormal taste perception in mice lacking the type 3 inositol 1,4, 5-trisphosphate receptor. J Biol Chem 282:37225–37231. doi: 10.1074/jbc.M705641200 PubMedCrossRefGoogle Scholar
  17. Horio N, Jyotaki M, Yoshida R, Sanematsu K, Shigemura N, Ninomiya Y (2010) New frontiers in gut nutrient sensor research: nutrient sensors in the gastrointestinal tract: modulation of sweet taste sensitivity by leptin. J Pharmacol Sci 112:8–12. doi: 10.1254/jphs.09R07FM PubMedCrossRefGoogle Scholar
  18. Huang L, Rong M, Kozak JA, Preuss AK, Zhang H, Max M, Margolskee RF (2002) A transient receptor potential channel expressed in taste receptor cells. Nat Neurosci 5:1169–1176. doi: 10.1038/nn952 PubMedCrossRefGoogle Scholar
  19. Huang AL, Chen X, Hoon MA, Chandrashekar J, Guo W, Tränkner D, Ryba NJ, Zuker CS (2006) The cells and logic for mammalian sour taste detection. Nature 442:934–938. doi: 10.1038/nature05084 PubMedCrossRefGoogle Scholar
  20. Huang YJ, Maruyama Y, Dvoryanchikov G, Pereira E, Chaudhari N, Roper SD (2007) The role of pannexin 1 hemichannels in ATP release and cell–cell communication in mouse taste buds. Proc Natl Acad Sci U S A 104:6436–6441. doi: 10.1073/pnas.0611280104 PubMedCrossRefGoogle Scholar
  21. Huang YA, Maruyama Y, Stimac R, Roper SD (2008) Presynaptic (Type III) cells in mouse taste buds sense sour (acid) taste. J Physiol 586:2903–2912. doi: 10.1113/jphysiol.2008.151233 PubMedCrossRefGoogle Scholar
  22. Ishimaru Y, Inada H, Kubota M, Zhuang H, Tominaga M, Matsunami H (2006) Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci U S A 103:12569–12574. doi: 10.1073/pnas.0602702103 PubMedCrossRefGoogle Scholar
  23. Jamshidi N, Taylor DA (2001) Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 134:1151–1154. doi:10.1038/sj.bjp. 0704379PubMedCrossRefGoogle Scholar
  24. Jang HJ, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim BJ, Zhou J, Kim HH, Xu X, Chan SL, Juhaszova M, Bernier M, Mosinger B, Margolskee RF, Egan JM (2007) Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci U S A 104:15069–15074. doi: 10.1073/pnas.0706890104 PubMedCrossRefGoogle Scholar
  25. Jarrett MM, Limebeer CL, Parker LA (2005) Effect of delta9-tetrahydrocannabinol on sucrose palatability as measured by the taste reactivity test. Physiol Behav 86:475–479. doi: 10.1016/j.physbeh.2005.08.033 PubMedCrossRefGoogle Scholar
  26. Jyotaki M, Shigemura N, Ninomiya Y (2010) Modulation of sweet taste sensitivity by orexigenic and anorexigenic factors. Endocr J 57:467-475. doi:10.1507/endocrj.K10E-095Google Scholar
  27. Kawai K, Sugimoto K, Nakashima K, Miura H, Ninomiya Y (2000) Leptin as a modulator of sweet taste sensitivities in mice. Proc Natl Acad Sci U S A 97:11044–11049PubMedCrossRefGoogle Scholar
  28. Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF (1997) Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic β-cells. Diabetes 46:1087–1093PubMedCrossRefGoogle Scholar
  29. Kirkham TC, Williams CM, Fezza F, Di Marzo V (2002) Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550–557. doi:10.1038/sj.bjp. 0704767PubMedCrossRefGoogle Scholar
  30. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635. doi: 10.1038/379632a0 PubMedCrossRefGoogle Scholar
  31. Li X, Staszewski L, Xu H, Durick K, Zoller M, Adler E (2002) Human receptors for sweet and umami taste. Proc Natl Acad Sci U S A 99:4692–4696. doi: 10.1073/pnas.072090199 PubMedCrossRefGoogle Scholar
  32. Mahler SV, Smith KS, Berridge KC (2007) Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances ‘liking’ of a sweet reward. Neuropsychopharmacology 32:2267–2278. doi:10.1038/sj.npp. 1301376PubMedCrossRefGoogle Scholar
  33. Margolskee RF (2002) Molecular mechanisms of bitter and sweet taste transduction. J Biol Chem 277:1–4. doi: 10.1074/jbc.R100054200 PubMedCrossRefGoogle Scholar
  34. Margolskee RF, Dyer J, Kokrashvili Z, Salmon KSH, Ilegems E, Daly K, Maillet EL, Ninomiya Y, Mosinger B, Shirazi-Beechey SP (2007) T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotranspoter 1. Proc Natl Acad Sci U S A 104:15075–15081. doi: 10.1073/pnas.0706678104 PubMedCrossRefGoogle Scholar
  35. Matsunami H, Montmayeur JP, Buck LB (2000) A family of candidate taste receptors in human and mouse. Nature 404:601–604. doi: 10.1038/35007072 PubMedCrossRefGoogle Scholar
  36. Medler KF, Margolskee RF, Kinnamon SC (2003) Electrophysiological characterization of voltage-gated currents in defined taste cell types of mice. J Neurosci 23:2608–2617PubMedGoogle Scholar
  37. Monteleone P, Matias I, Martiadis V, De Petrocellis L, Maj M, Di Marzo V (2005) Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Neuropsychopharmacology 30:1216–1221. doi:10.1038/sj.npp. 1300695PubMedCrossRefGoogle Scholar
  38. Mueller KL, Hoon MA, Erlenbach I, Chandrashekar J, Zuker CS, Ryba NJ (2005) The receptors and coding logic for bitter taste. Nature 434:225–229. doi: 10.1038/nature03352 PubMedCrossRefGoogle Scholar
  39. Nakagawa Y, Nagasawa M, Yamada S, Hara A, Mogami H, Nikolaev VO, Lohse MJ, Shigemura N, Ninomiya Y, Kojima I (2009) Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion. PLoS One 4:e5106. doi: 10.1371/journal.pone.0005106 PubMedCrossRefGoogle Scholar
  40. Nakamura Y, Sanematsu K, Ohta R, Shirosaki S, Koyano K, Nonaka K, Shigemura N, Ninomiya Y (2008) Diurnal variation of human sweet taste recognition thresholds is correlated with plasma leptin level. Diabetes 57:2661–2665. doi: 10.2337/db07-1103 PubMedCrossRefGoogle Scholar
  41. Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS (2001) Mammalian sweet taste receptors. Cell 106:381–390. doi: 10.1016/S0092-8674(01)00451-2 PubMedCrossRefGoogle Scholar
  42. Niijima A (1991) Effects of taste stimulation on the efferent activity of the pancreatic vagus nerve in the rat. Brain Res Bull 26:165–167. doi: 10.1016/0361-9230(91)90202-U PubMedCrossRefGoogle Scholar
  43. Ninomiya Y, Sako N, Imai Y (1995) Enhanced gustatory neural responses to sugars in the diabetic db/db mouse. Am J Physiol 269:R930–937PubMedGoogle Scholar
  44. Ninomiya Y, Imoto T, Yatabe A, Kawamura S, Nakashima K, Katsukawa H (1998) Enhanced responses of the chorda tympani nerve to nonsugar sweeteners in the diabetic db/db mouse. Am J Physiol 274:R1324–1330PubMedGoogle Scholar
  45. Ninomiya Y, Shigemura N, Yasumatsu K, Ohta R, Sugimoto K, Nakashima K, Lindemann B (2002) Leptin and sweet taste. Vitam Horm 64:221–248PubMedCrossRefGoogle Scholar
  46. Rehfeld JF (1998) The new biology of gastrointestinal hormones. Physiol Rev 78:1087–1108PubMedGoogle Scholar
  47. Romanov RA, Rogachevskaja OA, Bystrova MF, Jiang P, Margolskee RF, Kolesnikov SS (2007) Afferent neurotransmission mediated by hemichannels in mammalian taste cells. EMBO J 26:657–667. doi: 10.1038/sj.emboj.7601526 PubMedCrossRefGoogle Scholar
  48. Saladin R, Vos DP, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J (1995) Transient increase in obese gene expression after food intake or insulin administration. Nature 377:527–529. doi: 10.1038/377527a0 PubMedCrossRefGoogle Scholar
  49. San Gabriel A, Uneyama H, Yoshie Y, Torii K (2005) Cloning and characterization of a novel mGluR1 variant from vallate papillae that functions as a receptor for l-glutamate stimuli. Chem Senses 30:i25–i26. doi: 10.1093/chemse/bjh095 PubMedCrossRefGoogle Scholar
  50. Sanematsu K, Horio N, Murata Y, Yoshida R, Ohkuri T, Shigemura N, Ninomiya Y (2009) Modulation and transmission of sweet taste information for energy homeostasis. Ann N Y Acad Sci 1170:102–106PubMedCrossRefGoogle Scholar
  51. Schoeller DA, Cella LK, Sinha MK, Caro JF (1997) Entrainment of the diurnal rhythm of plasma leptin to meal timing. J Clin Invest 100:1882–1887. doi: 10.1172/JCI119717 PubMedCrossRefGoogle Scholar
  52. Shen T, Kaya N, Zhao FL, Lu SG, Cao Y, Herness S (2005) Co-expression patterns of the neuropeptides vasoactive intestinal peptide and cholecystokinin with the transduction molecules alpha-gustducin and T1R2 in rat taste receptor cells. Neuroscience 130:229–238. doi: 10.1016/j.neuroscience.2004.09.017 PubMedCrossRefGoogle Scholar
  53. Shigemura N, Miura H, Kusakabe Y, Hino A, Ninomiya Y (2003) Expression of leptin receptor (Ob-R) isoforms and signal transducers and activators of transcription (STATs) mRNAs in the mouse taste buds. Arch Histol Cytol 66:253–260. doi: 10.1679/aohc.66.253 PubMedCrossRefGoogle Scholar
  54. Shigemura N, Ohta R, Kusakabe Y, Miura H, Hino A, Koyano K, Nakashima K, Ninomiya Y (2004) Leptin modulates behavioral responses to sweet substances by influencing peripheral taste structures. Endocrinology 145:839–843. doi: 10.1210/en2003-0602 PubMedCrossRefGoogle Scholar
  55. Shin YK, Martin B, Golden E, Dotson CD, Maudsley S, Kim W, Jang HJ, Mattson MP, Drucker DJ, Egan JM, Munger SD (2008) Modulation of taste sensitivity by GLP-1 signaling. J Neurochem 106:455–463. doi: 10.1111/j.1471-4159.2008.05397.x PubMedCrossRefGoogle Scholar
  56. Sinha MK, Sturis J, Ohannesian J, Magosin S, Stephens T, Heiman ML, Polonsky KS, Caro JF (1996) Ultradian oscillations of leptin secretion in humans. Biochem Biophys Res Commun 228:733–738. doi: 10.1006/bbrc.1996.1724 PubMedCrossRefGoogle Scholar
  57. Stevens DR, Seifert R, Bufe B, Müller F, Kremmer E, Gauss R, Meyerhof W, Kaupp UB, Lindemann B (2001) Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 413:631–635. doi: 10.1038/35098087 PubMedCrossRefGoogle Scholar
  58. Sugiura T, Kobayashi Y, Oka S, Waku K (2002) Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids 66:173–192. doi: 10.1054/plef.2001.0356 PubMedCrossRefGoogle Scholar
  59. Talavera K, Yasumatsu K, Voets T, Droogmans G, Shigemura N, Ninomiya Y, Margolskee RF, Nilius B (2005) Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature 438:1022–1025. doi: 10.1038/nature04248 PubMedCrossRefGoogle Scholar
  60. Teff KL, Mattes RD, Engelman K (1991) Cephalic phase insulin release in normal weight males: verification and reliability. Am J Physiol 261:E430–436PubMedGoogle Scholar
  61. Tomchik SM, Berg S, Kim JW, Chaudhari N, Roper SD (2007) Breadth of tuning and taste coding in mammalian taste buds. J Neurosci 27:10840–10848. doi: 10.1523/JNEUROSCI.1863-07.2007 PubMedCrossRefGoogle Scholar
  62. Toyono T, Seta Y, Kataoka S, Kawano S, Shigemoto R, Toyoshima K (2003) Expression of metabotropic glutamate receptor group I in rat gustatory papillae. Cell Tissue Res 313:29–35. doi: 10.1007/s00441-003-0740-2 PubMedCrossRefGoogle Scholar
  63. Ugawa S, Minami Y, Guo W, Saishin Y, Takatsuji K, Yamamoto T, Tohyama M, Shimada S (1998) Receptor that leaves a sour taste in the mouth. Nature 395:555–556. doi: 10.1038/26882 PubMedCrossRefGoogle Scholar
  64. Wiley JL, Burston JJ, Leggett DC, Alekseeva OO, Razdan RK, Mahadevan A, Martin BR (2005) CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol 145:293–300. doi:10.1038/sj.bjp. 0706157PubMedCrossRefGoogle Scholar
  65. Williams CM, Kirkham TC (1999) Anandamide induces overeating: Mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 143:315–317. doi: 10.1007/s002130050953 CrossRefGoogle Scholar
  66. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682. doi: 10.1126/science.1063545 PubMedCrossRefGoogle Scholar
  67. Wong GT, Gannon KS, Margolskee RF (1996) Transduction of bitter and sweet taste by gustducin. Nature 381:796–800. doi: 10.1038/381796a0 PubMedCrossRefGoogle Scholar
  68. Yoshida R, Ninomiya Y (2010) New insights into the signal transmission from taste cells to gustatory nerve fibers. Int Rev Cell Mol Biol 279:101–134PubMedCrossRefGoogle Scholar
  69. Yoshida R, Shigemura N, Sanematsu K, Yasumatsu K, Ishizuka S, Ninomiya Y (2006) Taste responsiveness of fungiform taste cells with action potentials. J Neurophysiol 96:3088–3095. doi: 10.1152/jn.00409.2006 PubMedCrossRefGoogle Scholar
  70. Yoshida R, Miyauchi A, Yasuo T, Jyotaki M, Murata Y, Yasumatsu K, Shigemura N, Yanagawa Y, Obata K, Ueno H, Margolskee RF, Ninomiya Y (2009) Discrimination of taste qualities among mouse fungiform taste bud cells. J Physiol 587:4425–4439. doi: 10.1113/jphysiol.2009.175075 PubMedCrossRefGoogle Scholar
  71. Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, Shigemura N, Yamamoto T, Margolskee RF, Ninomiya Y (2010) Endocannabinoids selectively enhance sweet taste. Proc Natl Acad Sci U S A 107:935–939. doi: 10.1073/pnas.0912048107 PubMedCrossRefGoogle Scholar
  72. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432. doi: 10.1038/372425a0 PubMedCrossRefGoogle Scholar
  73. Zhao FL, Shen T, Kaya N, Lu SG, Cao Y, Herness S (2005) Expression, physiological action, and coexpression patterns of neuropeptide Y in rat taste-bud cells. Proc Natl Acad Sci U S A 102:11100–11105. doi: 10.1073/pnas.0501988102 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2011

Authors and Affiliations

  • Mayu Niki
    • 1
  • Masafumi Jyotaki
    • 1
  • Ryusuke Yoshida
    • 1
  • Yuzo Ninomiya
    • 1
    Email author
  1. 1.Section of Oral NeuroscienceKyushu University, Graduate School of Dental SciencesFukuokaJapan

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