Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation

International Journal of Obesity volume 26, pages 1523–1532 (2002)Cite this article

Abstract

OBJECTIVE: Both orexin (ORX)- and melanin-concentrating hormone (MCH) are expressed in different neurons in the lateral hypothalamic area (LH), and are considered to have common effects on stimulating food intake. There are no reports to demonstrate neural interactions between them at the ultrastructural level. We observed these neurons in the LH to evaluate the relationships between them.

DESIGN: We used two different types of double immunostaining to reveal the ultrastructure of both the ORX- and MCH-containing neurons. A preembedding double immunostaining technique was used to study the synaptic relationships between the two kinds of neuron.

RESULTS: The main new findings are as follows: 1) Both ORX- and MCH-containing neurons received other synaptic input and made synaptic input to other neurons; 2) Reciprocal synaptic relationships were observed between the ORX- and MCH-containing neurons.

CONCLUSION: The ORX- and MCH-containing neurons in the lateral hypothalamic area may influence food intake through synapse with each other.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Anand BK, Brobeck JR . Hypothalamic control of food intake in rats and cats Yale J Biol Med 1951 24: 123–146.

    CAS  Google Scholar 

  2. Bernardis LL, Bellinger LL . The lateral hypothalamic area revisited: ingestive behavior Neurosci Biobehav Rev 1996 20: 189–287.

    Article  CAS  Google Scholar 

  3. Luiten PG, ter Horst GJ, Steffens AB . The hypothalamus, intrinsic connections and outflow pathways to the endocrine system in relation to the control of feeding and metabolism Prog Neurobiol 1987 28: 1–54.

    Article  CAS  Google Scholar 

  4. Steinbaum EA, Miller NE . Obesity from eating elicited by daily stimulation of hypothalamus Am J Physiol 1965 208: 1–5.

    Article  CAS  Google Scholar 

  5. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek J, Kanarek R, Maratos-Flier E . A role for melanin-concentrating hormone in the central regulation of feeding behavior Nature 1996 380: 243–247.

    Article  CAS  Google Scholar 

  6. Jezová D, Bartanusz V, Westergren I, Johansson BB, Rivier J, Vale W, Rivier C . Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood–brain barrier Endocrinology 1992 130: 1024–1029.

    Google Scholar 

  7. Rossi M, Choi SJ, O'Shea D, Miyoshi T, Ghatei MA, Bloom SR . Melanin-concentrating hormone acutely stimulats feeding, but chronic administration has no effect on body weight Endocrinology 1997 138: 351–355.

    Article  CAS  Google Scholar 

  8. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JRS, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu W-S, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior Cell 1998 92: 573–585.

    Article  CAS  Google Scholar 

  9. Presse F, Sorokovsky I, Max J-P, Nicolaidis S, Nahon J-L . Melanin-concentrating hormone is a potent anorectic peptide regulated by food deprivation and glucopenia in the rat Neuroscience 1996 71: 735–745.

    Article  CAS  Google Scholar 

  10. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E . Mice lacking melanin-concentrating hormone are hypophagic and lean Nature 1998 396: 670–674.

    Article  CAS  Google Scholar 

  11. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon J-L, Vale W, Sawchenko PE . The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization J Comp Neurol 1992 319: 218–245.

    Article  CAS  Google Scholar 

  12. Chen CT, Dun SL, Kwok EH, Dun NJ, Chang J-K . Orexin A-like immunoreactivity in the rat brain Neurosci Lett 1999 260: 161–164.

    Article  CAS  Google Scholar 

  13. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K . Distribution of orexin neurons in the adult rat brain Brain Res 1999 827: 243–260.

    Article  CAS  Google Scholar 

  14. Naito N, Kawazoe I, Nakai Y, Kawauchi H . Melanin-concentrating hormone-like immunoreactive material in the rat hypothalamus; characterization and subcellular localization Cell Tiss Res 1988 253: 291–295.

    Article  CAS  Google Scholar 

  15. Zhang JH, Sampogna S, Morales FR, Chase MH . Orexin (hypocretin)-like immunoreactivity in the cat hypothalamus: a light and electron microscopic study Sleep 2001 24: 67–76.

    Article  CAS  Google Scholar 

  16. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK . Differential expression of orexin receptors 1 and 2 in the rat brain J Comp Neurol 2001 435: 6–25.

    Article  CAS  Google Scholar 

  17. Saito Y, Cheng M, Leslie FM, Civelli O . Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain J Comp Neurol 2001 435: 26–40.

    Article  CAS  Google Scholar 

  18. Guan J-L, Saotome T, Wang Q-P, Funahashi H, Hori T, Tanaka S, Shioda S . Orexinergic innervation of POMC-containing neurons in the rat arcuate nucleus Neuro Report 2001 12: 547–551.

    CAS  Google Scholar 

  19. Hsu S-M, Raine L, Fanger H . Use of avidin–biotin–peroxidase complex (ABC) in immunoperoxidase techniques. A comparison between ABC and unlabeled antibody (PAP) procedures J Histochem Cytochem 1981 29: 577–580.

    Article  CAS  Google Scholar 

  20. Wang Q-P, Nakai Y . Double preembedding immunostaining for the study by electron microscopy of synaptic relationships between immunocytochemically identified neurons Neurosci Protoc 1996 50: 05–01–13.

    Google Scholar 

  21. Horvath TL, Diano S, van den Pol AN . Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations J Neurosci 1999 19: 1072–1087.

    Article  CAS  Google Scholar 

  22. Horvath TL, Peyron C, Diano S, Ivanov A, Aston Jones G, Kilduff TS, van den Pol AN . Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system J Comp Neurol 1999 415: 145–159.

    Article  CAS  Google Scholar 

  23. de Lecea L, Kilduff T, Peyron C, Gao X-B, Foye PE, Danuelson PE, Fukuhara C, Battenberg ELF, Gautvik VT, Bartlett II FS, Frankel WN, van den Pol AN, Bloom FG, Gautvik KM, Sutcliffe JG . The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity Proc Nalt Acad Sci USA 1998 95: 322–327.

    Article  CAS  Google Scholar 

  24. Broberger C, De Lecea L, Sutcliffe JG, Hökfelt T . Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems J Comp Neurol 1998 402: 460–474.

    Article  CAS  Google Scholar 

  25. Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Ollmann MM, Barsh GS, Sakurai T, Yanagisawa M, Elmquist JK . Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area J Comp Neurol 1998 402: 442–459.

    Article  CAS  Google Scholar 

  26. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS . Neurons containing hypocretin (orexin) project to multiple neuronal systems J Neurosci 1998 18: 9996–10015.

    Article  CAS  Google Scholar 

  27. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR . A selective orexin-1 receptor antagonist reduces food consumption in male and female rats Regul Pept 2000 96: 45–51.

    Article  CAS  Google Scholar 

  28. Ida T, Nakahara K, Kuroiwam T, Fukui K, Nakazato M, Murakami T, Murakami N . Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats Neurosci Lett 2000 293: 119–122.

    Article  CAS  Google Scholar 

  29. Li MD, Parker SL, Kane JK . Regulation of feeding-associated peptides and receptors by nicotine Mol Neurobiol 2000 22: 143–165.

    Article  CAS  Google Scholar 

  30. Niimi M, Sato M, Taminato T . Neuropeptide Y in central control of feeding and interactions with orexin and leptin Endocrine 2001 14: 269–273.

    Article  CAS  Google Scholar 

  31. Xi M-C, Morales FR, Chase MH . Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat Brain Res 2001 901: 259–264.

    Article  CAS  Google Scholar 

  32. Methippara MM, Alam MN, Szymusiak R, McGinty D . Effects of lateral preoptic area application of orexin-A on sleep-wakefulness Neuro Report 2000 11: 3423–3426.

    CAS  Google Scholar 

  33. Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L . Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons J Neurosci 2000 20: 7760–7765.

    Article  CAS  Google Scholar 

  34. Jaszberenyi M, Bujdoso E, Pataki I, Telegdy G . Effects of orexins on the hypothalamic-pituitary-adrenal system J Neuroendocrinol 2000 12: 1174–1178.

    Article  CAS  Google Scholar 

  35. Kuru M, Ueta Y, Serino R, Nakazato M, Yamamoto Y, Shibuya I, Yamashita H . Centrally administrered orexin/hypocretin activates HPA axis in rats Neuro Report 2000 11: 1977–1980.

    CAS  Google Scholar 

  36. Russell SH, Kim MS, Smell CJ, Abbott CR, Morgan DG, Taheri S, Murphy KG, Todd JF, Ghatei MA, Bloom SR . Central administration of orexin A suppresses basal and domperidone stimulated plasma prolactin J Neuroendocrinol 2000 12: 1213–1218.

    Article  CAS  Google Scholar 

  37. Russell SH, Smell CJ, Dakin CL, Abbott CR, Morgan DG, Ghatei MA, Bloom SR . The central effects of orexin-A in the hypothalamic–pituitary–adrenal axis in vivo and in vitro in male rats J Neuroendocrinol 2001 13: 561–566.

    Article  CAS  Google Scholar 

  38. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM . Reduced number of hypocretin neurons in human narcolepsy Neuron 2000 27: 469–474.

    Article  CAS  Google Scholar 

  39. van den Pol AN . Narcolepsy: a neurodegenerative disease of the hypocretin system? Neuron 2000 27: 415–418.

    Article  CAS  Google Scholar 

  40. Yoshimichi G, Yoshimatsu H, Masaki T, Sakata T . Orexin-A regulates body temperature in coordination with arousal status Exp Biol Med (Maywood) 2001 226: 468–476.

    Article  CAS  Google Scholar 

  41. Kiyashchenko LI, Mileykovskiy BY, Lai YY, Siegel JM . Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and pontine inhibitory area J Neurophysiol 2001 85: 2008–2016.

    Article  CAS  Google Scholar 

  42. Bingham S, Davey PT, Babbs AJ, Irving EA, Sammons MJ, Wyles M, Jeffrey P, Cutler L, Riba I, Johns A, Porter RA, Upton N, Hunter AJ, Parsons AA . Orexin-A, an hypothalamic peptide with analgesic properties Pain 2001 92: 81–90.

    Article  CAS  Google Scholar 

  43. Gonzalez MI, Kalia V, Hole DR, Wilson CA . α-Melanocyte-stimulating hormone (α-MSH) and melanin-concentrating hormone (MCH) modify monoaminergic levels in the preoptic area of the rat Peptides 1997 18: 387–392.

    Article  CAS  Google Scholar 

  44. Tsukamura H, Thompson RC, Tsukahara S, Ohkura S, Maekawa F, Moriyama R, Niwa Y, Foster DJ, Maeda K . Intracerebroventricular administration of melanin-concentrating hormone suppresses pulsatile luteinizing hormone release in the female rat J Neuroendocrinol 2000 12: 529–534.

    Article  CAS  Google Scholar 

  45. Chiocchio SR, Gallardo MG, Louzan P, Gutnisky V, Tramezzani JH . Melanin-concentrating hormone stimulates the release of luteinizing hormone-releasing hormone and gonadotropins in the female rat acting at both median eminence and pituitary levels Biol Reprod 2001 64: 1466–1472.

    Article  CAS  Google Scholar 

  46. Gilchriest BJ, Tipping DJ, Hake L, Levy A, Baker BI . Differences in arginine vasotocin gene transcripts and cortisol secretion in trout with high or low endogenous melanin-concentrating hormone secretion J Neuroendocrinol 2001 13: 407–411.

    Article  CAS  Google Scholar 

  47. Gilham ID, Baker BI . Evidence for the participation of a melanin-concentrating hormone in physiological colour change in the eel J Endocrinol 1984 102: 237–243.

    Article  CAS  Google Scholar 

  48. Baker BI, Eberle AN, Baumann JB, Siegrist W, Girard J . Effect of melanin concentrating hormone on pigment and adrenal cells in vitro Peptides 1985 6: 1125–1130.

    Article  CAS  Google Scholar 

  49. Oshima N, Kasukawa H, Fujii R, Wilkes BC, Hruby VJ, Castrucci AM, Hadley ME . Melanin concentrating hormone (MCH) effects on teleost (Chrysiptera cyanea) melanophores J Exp Zool 1985 235: 175–180.

    Article  CAS  Google Scholar 

  50. van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB . Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin J Neurosci 1998 18: 7962–7971.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by grants from the High-Technology Research Center project and the Ministry of Education, Science, Sports and Culture of Japan (to SS). We also express our thanks to Drs Vaughan and Vale (The Salk Institute, California).

Author information

Authors and Affiliations

  1. Department of Anatomy, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan

    J-L Guan, K Uehara, S Lu, Q-P Wang, H Funahashi & S Shioda

  2. Institute of Basic Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

    T Sakurai

  3. Department of Molecular Genetics, Howard Hughes Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA

    M Yanagizawa

  4. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Japan

    S Shioda

Authors
  1. J-L Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Uehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Q-P Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Funahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Sakurai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Yanagizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Shioda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Shioda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guan, JL., Uehara, K., Lu, S. et al. Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation. Int J Obes 26, 1523–1532 (2002). https://doi.org/10.1038/sj.ijo.0802155

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802155

Keywords

This article is cited by

Search

Advanced search

Quick links