Skip to main content
SpringerLink
Log in

Neuroendocrine and metabolic aspects of narcolepsy

Neuroendokrine und metabolische Aspekte der Narkolepsie

  • Reviews
  • Published:
Somnologie Aims and scope Submit manuscript

Summary

Human narcolepsy is characterized by excessive daytime sleepiness and various pathological manifestations of REM sleep. The disorder has a strong HLA-associated genetic background. Against this background, unknown causes induce in the majority of cases an almost complete stop in the production of orexins (hypocretins) within the hypothalamus in early adulthood. These peptides interact with various neurotransmitter systems involved in the regulation of sleep; in addition, they are also linked to numerous networks regulating appetite, weight and metabolism. As a consequence, narcolepsy is not only characterized by typical disturbances of sleep and wakefulness, but also by endocrine and metabolic abnormalities. These include obesity and reduced circulating leptin levels. The respective data are summarized in this paper and the underlying causes discussed.

Zusammenfassung

Neben erhöhter Tagesmüdigkeit sind REM Schlaf-assoziierte Symptome charakteristisch für die Narkolepsie. Die Erkrankung hat einen HLA-assozierten genetischen Hintergrund, auf dem es aus bisher ungeklärten Grüden in der Adoleszenz oder im frühen Erwachsenenalter zumindest beim überweigenden Teil der Patienten zu einem vollständigen Versagen der Produktion von Orexinen (Hypocretinen) im Hypothalamus kommt. Diese Peptide interagieren mit verschiedenen für die Schlafregulation wichtigen Neurotransmittersystemen. Darüber hinaus aber sind sie auch in eine Reihe zentralnervöser Netzwerke eingebunden, die an der Regulation von Appetit. Gewicht und Metabolismus beteiligt sind. Deshalb ist es nicht verwunderlich, dass sich bei Narkolepsiepatienten neben den typischen schlafassoziierten Symptomen auch endokrine und metabolische Auffälligkeiten finden. Diese Auffälligkeiten, zu denen Adipositas und verminderte Leptinspiegel gehören, werden in der vorliegenden Arbeit dargestellt und ihre Ursachen diskutiert.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Adam JA, Menheere PP, van Dielen FM, Soeters PB, Buurman WA, Greve JW: Decreased plasma orexin-A levels in obese individuals. Int J Obes Relat Metab Disord 26 (2): 274–276. 2002.

    Article  CAS  PubMed  Google Scholar 

  2. Aldrich MS: Diagnostic aspects of narcolepsy, Neurology 50 (2, Suppl 1): S2-S7, 1998.

    Article  CAS  PubMed  Google Scholar 

  3. Arihara Z, Takahashi K, Murakami O, Totsune K Sone M, Satoh M, Ito S, Mouri T: Immunoreactive orexin-A in human plasma. Peptides 22 (1): 139–142, 2001.

    Article  CAS  PubMed  Google Scholar 

  4. Bell I: Diet histories in narcolepsy. In: Guilleminault C, Dement W, Passouant P: Narcolepsy, Spectrum, New York, pp 221–227, 1976.

    Google Scholar 

  5. Blum WF: Leptin—the voice of the adipose tissue. Hormone Research 48(Suppl 4): 2–8, 1997.

    Article  CAS  PubMed  Google Scholar 

  6. Bray GA, Greenway FL: Current and potential drugs for treatment of obesity Endocr Rev 20 (6): 805–875, 1999.

    Article  CAS  PubMed  Google Scholar 

  7. Carlander B, Eliaou JF, Billiard M: Autoimmune hypothesis in narcolepsy. Neurophysiol Clin 23(1): 15–22, 1993.

    Article  CAS  PubMed  Google Scholar 

  8. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, et al.: Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98 (4): 437–451, 1999.

    Article  CAS  PubMed  Google Scholar 

  9. Dalal MA, Schuld A, Hacck M, Uhr M, Geisler P, Eisensehr I, Noachtar S, Pollmächer T: Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology 56 (12): 1749–1751, 2001

    Article  CAS  PubMed  Google Scholar 

  10. Dalal MA, Schuld A, Haack M, Uhr, M, Geisler P, Eisensehr I, Noachtar S, Pollmächer T: Corrections to: Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology 58(2): 334, 2002.

    Google Scholar 

  11. Dalal MA, Schuld A, Pollmächer T: Undetectable CSF level of orexin A (hypocretin-1) in a HLA-DR2 negative patient with narcolepsy-cataplexy. J Sleep Res: 2002, in press.

  12. Fredrikson S, Carlander B, Billiard M, Link H: CSF immune variables in patients with narcolepsy. Acta Neurol Scand 81 (3): 253–254, 1990.

    Article  CAS  PubMed  Google Scholar 

  13. Gencik M, Dahmen N, Wieczorek S, Kasten M, Bierbrauer J, Anghelescu I, Szegedi A, Menezes SA, Epplen JT: A preproorexin gene polymorphism is associated with narcolepsy. Neurology 56(1): 115–117, 2001.

    Article  CAS  PubMed  Google Scholar 

  14. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T: Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia and obesity. Neuron 30: 345–354, 2001.

    Article  CAS  PubMed  Google Scholar 

  15. Hebebrand J, Himmelmann GW, Heseker H, Schafer H, Remschmidt H: Use of percentiles for the body mass index in anorexia nervosa: diagnostic, epidemiological, and therapeutic considerations. Int J Eat Disord 19(4): 359–369, 1996.

    Article  CAS  PubMed  Google Scholar 

  16. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, et al.: Recombinant leptin for weight loss in obese and lean adults—a randomized, controlled, dose-escalation trial. JAMA 282 (16): 1568–1575, 1999.

    Article  CAS  PubMed  Google Scholar 

  17. Higuchi S, Usui A, Murasaki M, Matsushita S, Nishioka N, Yoshino A, Matsui T, Muraoka H, Ishizuka Y, Kanba S, Sakurai T: Plasma orexin-A is lower in patients with narcolepsy. Neurosci Lett 318 (2): 61–64, 2002.

    Article  CAS  PubMed  Google Scholar 

  18. Hinze-Selch D, Wetter TC, Zhang Y, Lu HC, Albert ED, Mullington J, Wekerle H, Holsboer F, Pollmächer T: In vivo and in vitro immune variables in patients with narcolepsy and HLA-DR2 matched controls. Neurology 50 (4): 1149–1152, 1998.

    Article  CAS  PubMed  Google Scholar 

  19. Hinze-Selch D, Schuld A, Kraus T, Kühn M, Uhr M, Haack M, Pollmächer T: Effects of antidepressants on weight and on the plasma levels of leptin, TNF-alpha and soluble TNF receptors: a longitudinal study in patients treated with amitriptyline or paroxetine. Neuropsychopharmacology 23 (1): 13–19, 2000.

    Article  CAS  PubMed  Google Scholar 

  20. Hungs M, Mignot E: Pathophysiological and clinical aspects of narcolepsy: a disorder associated with hypocretin abnormalities. Comnologie 4: 111–116, 2000.

    Article  Google Scholar 

  21. Kanbayashi T, Inoue Y, Chiba S, Aizawa R, Saito Y, Tsukamoto H, Fujii Y, Nishino S, Shimizu T: CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 11: 91–93, 2002.

    Article  PubMed  Google Scholar 

  22. Kaufmann C, Schuld A, Pollmächer T, Auer D: Reduced cortical gray matter in narcolepsy—preliminary findings with voxel-based morphometry. Neurophy 58 (12): 1852–1855. 2002.

    Google Scholar 

  23. Kilduff TS, Peyron C: The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23 (8): 359–365, 2000.

    Article  CAS  PubMed  Google Scholar 

  24. Kirchgesser AL, Lui M: Orexin synthesis and response in the gut. Neuron 24 (4): 941–951, 1999.

    Article  Google Scholar 

  25. Kok SW, Meinders AE, Overeem S, Lammers GJ, Roelfsema F, Frölich M, Pijl H: Reduction of plasma leptin levels and loss of its circadian rhythmicity in hypocretin (orexin)-deficient narcoleptic humans. J Clin Endocrinol Metab 87 (2): 805–809. 2002.

    Article  CAS  PubMed  Google Scholar 

  26. Komaki G, Matsumoto Y, Nishikata H, Kawai K, Nozaki T, Takii M, Sogawa H, Kubo C: Orexin-A and leptin change inversely in fasting non-obese subjects. Eur J Endocrinol 144 (6): 645–651, 2001.

    Article  CAS  PubMed  Google Scholar 

  27. Kopelman PG: Obesity as a medical problem. Nature 404 (6778): 635–643, 2000.

    CAS  PubMed  Google Scholar 

  28. Krahn LE, Moore WR, Altchuler SI: Narcolepsy and obesity: remission of severe cataplexy with sibutramine. Sleep Medicine 2(1): 63–65, 2001.

    Article  PubMed  Google Scholar 

  29. Lammers GJ, Pijl H, Iestra J, Langius JA, Buunk G, Meinders AE: Spontaneous food choice in narcolepsy. Sleep 19 (1): 75–76, 1996.

    CAS  PubMed  Google Scholar 

  30. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E: The sleep disorder canine narcolepsy is caused by a mutation in the hypocetin (orexin) receptor 2 gene. Cell 98 (3): 365–376, 1999.

    Article  CAS  PubMed  Google Scholar 

  31. Lopez M, Seoane L, Senaris RM, Dieguez C: Prepro-orexin mRNA levels in the rat hypothalamus, and orexin receptors mRNA levels in the rat hypothalamus and adrenal gland are not influenced by the thyroid status. Neurosci Lett 300 (3): 171–175, 2001.

    Article  CAS  PubMed  Google Scholar 

  32. Mayer G, Schulz H (Hrsg.): Kompendium Schlafmedizin. IX, Narkolepsie, I. Aufl. ecomed. Landsberg/Lech. Germany, p. IX-2.1, 1997.

  33. Mayer G, Hellmann F, Leonhard E, Mejer-Ewert K: Circadian temperature and activity rhythms in unmedicated narcoleptic patients. Pharmacol Biochem Behav 58 (2): 395–402, 1997.

    Article  CAS  PubMed  Google Scholar 

  34. McGranaghan PA, Piggins HD: Orexin A-like immunoreactivity in the hypothalamus and thalamus of the syrian hamster (Mesocrictus auratus) and siberian hamster (Phodopus sungorus), with special reference to circadian structures, Brain Research 904(2): 234–244, 2001.

    Article  CAS  PubMed  Google Scholar 

  35. Mignot E: Genetic and familial aspects of narcolepsy. Neurology 50 (2 Suppl 1) S16-S22, 1998.

    Article  CAS  PubMed  Google Scholar 

  36. Nishino S, Mignot E: Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 52 (1): 27–78, 1997.

    Article  CAS  PubMed  Google Scholar 

  37. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E: Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355 (9197): 39–40, 2000.

    Article  CAS  PubMed  Google Scholar 

  38. Nishino S, Ripley B, Overeem S, Nevismalova S, Lammers GJ, Vankova J, Okun M, Rogers W, Brooks S, Mignot E: Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 50: 381–388, 2001.

    Article  CAS  PubMed  Google Scholar 

  39. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R., et al.: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6(9): 991–997, 2000.

    Article  CAS  PubMed  Google Scholar 

  40. Pollmächer T, Mullington J, Lauer CJ: REM sleep disinhibition at sleep onset: a comparison between narcolepsy and depression. Biol Psychiatry 42 (8): 713–720, 1997.

    Article  PubMed  Google Scholar 

  41. Sakurai T: Orexins and orexin receptors: implication in feeding behavior. Regul Pept 85 (1): 25–30, 1999.

    Article  CAS  PubMed  Google Scholar 

  42. Schuld A, Hebebrand J, Geller F, Pollmächer T: Increased body-mass index in patients with narcolepsy. Lancet 355 (9211): 1274–1275, 2000.

    Article  CAS  PubMed  Google Scholar 

  43. Schuld A, Blum WF, Uhr M, Haack M, Kraus T, Holsboer F, Pollmächer T: Reduced leptin levels in human narcolepsy. Neuroendocrinology 72 (4): 195–198, 2000.

    Article  CAS  PubMed  Google Scholar 

  44. Schuld A, Beitinger PA, Dalal M, Geller F, Wetter TC, Albert ED, Hebebrand J Pollmächer T: Increased body mass index (BMI) in male narcoleptic patients, but not in HLA-DR2-positive healthy male volunteers. Sleep Medicine: 2002, in press.

  45. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG: Central nervous system control of food intake. Nature 404 (6778): 661–671 2000.

    CAS  PubMed  Google Scholar 

  46. Siegel JM: Narcolepsy: a key role for hypocretins (orexins). Cell 98 (4): 409–412, 1999.

    Article  CAS  PubMed  Google Scholar 

  47. Sinton CM, Fitch TE, Gershenfeld HK: The effects of leptin on REM sleep and slow wave delta in rats are reversed by food deprivation. J Sleep Res 8 (3): 197–203, 1999.

    Article  CAS  PubMed  Google Scholar 

  48. Sugimoto T, Nagake Y, Sugimoto S, Akagi S, Ichikawa H, Nakamura Y, Ogawa N, Makino H: Plasma orexin concentrations in patients on hemodialysis. Nephron, 90 (4): 379–383, 2002.

    Article  PubMed  Google Scholar 

  49. 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 27 (3): 469–474, 2000.

    Article  CAS  PubMed  Google Scholar 

  50. Yamamoto Y, Ueta Y, Date Y, Nakazato, M, Hara Y, Serino R, Nomura, M, Shibuya I, Matsukura S, Yamashita H: Down regulation of the prepro-orexin gene expression in genetically obese mice. Brain Res Mol Brain Res 65(1): 14–22, 1999.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Kraepelinstraße 10, 80804, Munich, Germany

    Mira A. Dalal, Andreas Schuld, Pierre Beitinger, Valerie Bubendorff & Thomas Pollmächer M.D.

Authors
  1. Mira A. Dalal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Schuld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Beitinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valerie Bubendorff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Pollmächer M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Pollmächer M.D..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalal, M.A., Schuld, A., Beitinger, P. et al. Neuroendocrine and metabolic aspects of narcolepsy. Somnologie 6, 95–100 (2002). https://doi.org/10.1046/j.1439-054X.2002.02193.x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1046/j.1439-054X.2002.02193.x

Keywords

Schlüsselwörter

Search

Navigation