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An anorexic lipid mediator regulated by feeding

Nature volume 414, pages 209–212 (2001)Cite this article

Abstract

Oleylethanolamide (OEA) is a natural analogue of the endogenous cannabinoid anandamide. Like anandamide, OEA is produced in cells in a stimulus-dependent manner and is rapidly eliminated by enzymatic hydrolysis, suggesting a function in cellular signalling1. However, OEA does not activate cannabinoid receptors and its biological functions are still unknown2. Here we show that, in rats, food deprivation markedly reduces OEA biosynthesis in the small intestine. Administration of OEA causes a potent and persistent decrease in food intake and gain in body mass. This anorexic effect is behaviourally selective and is associated with the discrete activation of brain regions (the paraventricular hypothalamic nucleus and the nucleus of the solitary tract) involved in the control of satiety. OEA does not affect food intake when injected into the brain ventricles, and its anorexic actions are prevented when peripheral sensory fibres are removed by treatment with capsaicin. These results indicate that OEA is a lipid mediator involved in the peripheral regulation of feeding.

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Figure 1: OEA suppresses food intake in rats deprived of food for 24 h.
Figure 2: Effects of subchronic OEA administration on food intake and body mass.
Figure 3: Role of peripheral sensory fibres in OEA-induced hypophagia.
Figure 4: OEA increases c-fos mRNA expression in brain regions associated with feeding behaviour.
Figure 5: Feeding regulates OEA biosynthesis in small intestine.

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References

  1. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).

    Article  ADS  CAS  Google Scholar 

  2. Piomelli, D., Beltramo, M., Giuffrida, A. & Stella, N. Endogenous cannabinoid signaling. Neurobiol. Dis. 5, 462–473 (1998).

    Article  CAS  Google Scholar 

  3. Bachur, N. R., Masek, K., Melmon, K. L. & Udenfriend, S. Fatty acid amides of ethanolamine in mammalian tissues. J. Biol. Chem. 240, 1019–1024 (1965).

    Article  CAS  Google Scholar 

  4. Schmid, H. H., Schmid, P. C. & Natarajan, V. The N-acylation-phosphodiesterase pathway and cell signalling. Chem. Phys. Lipids 80, 133–142 (1996).

    Article  CAS  Google Scholar 

  5. Chapman, K. D. Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection. Chem. Phys. Lipids 108, 221–229 (2000).

    Article  CAS  Google Scholar 

  6. Giuffrida, A. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci. 2, 358–363 (1999).

    Article  CAS  Google Scholar 

  7. Berdyshev, E. V., Schmid, P. C., Dong, Z. & Schmid, H. H. Stress-induced generation of N-acylethanolamines in mouse epidermal JB6 P+ cells. Biochem. J. 346, 369–374 (2000).

    Article  CAS  Google Scholar 

  8. Cadas, H., Gaillet, S., Beltramo, M., Venance, L. & Piomelli, D. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J. Neurosci. 16, 3934–3942 (1996).

    Article  CAS  Google Scholar 

  9. Cadas, H., di Tomaso, E. & Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17, 1226–1242 (1997).

    Article  CAS  Google Scholar 

  10. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).

    Article  CAS  Google Scholar 

  11. Schmid, P. C., Zuzarte-Augustin, M. L. & Schmid, H. H. Properties of rat liver N-acylethanolamine amidohydrolase. J. Biol. Chem. 260, 14145–14149 (1985).

    Article  CAS  Google Scholar 

  12. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996).

    Article  ADS  CAS  Google Scholar 

  13. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  ADS  CAS  Google Scholar 

  14. Williams, C. M. & Kirkham, T. C. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology 143, 315–317 (1999).

    Article  CAS  Google Scholar 

  15. Khanolkar, A. D. & Makriyannis, A. Structure–activity relationships of anandamide, an endogenous cannabinoid ligand. Life Sci. 65, 607–616 (1999).

    Article  CAS  Google Scholar 

  16. Pertwee, R. G. Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Exp. Opin. Invest. Drugs 9, 1553–1571 (2000).

    Article  CAS  Google Scholar 

  17. Kaneko, H., Kaunitz, J. & Tache, Y. Vagal mechanisms underlying gastric protection induced by chemical activation of raphe pallidus in rats. Am. J. Physiol. 275, G1056–G1062 (1998).

    CAS  Google Scholar 

  18. MacLean, D. B. Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat. Regul. Pept. 11, 321–333 (1985).

    Article  CAS  Google Scholar 

  19. Lee, M. D., Aloyo, V. J., Fluharty, S. J. & Simansky, K. J. Infusion of the serotonin1B (5-HT1B) agonist CP-93,129 into the parabrachial nucleus potently and selectively reduces food intake in rats. Psychopharmacology 136, 304–307 (1998).

    Article  CAS  Google Scholar 

  20. Schwartz, M. W., Woods, S. C., Porte, D. J., Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    Article  CAS  Google Scholar 

  21. Curran, T., Gordon, M. B., Rubino, K. L. & Sambucetti, L. C. Isolation and characterization of the c-fos (rat) cDNA and analysis of post-translational modification in vitro. Oncogene 2, 79–84 (1987).

    CAS  Google Scholar 

  22. Ritter, R. C., Covasa, M. & Matson, C. A. Cholecystokinin: proofs and prospects for involvement in control of food intake and body weight. Neuropeptides 33, 387–399 (1999).

    Article  CAS  Google Scholar 

  23. Giuffrida, A. & Piomelli, D. in Lipid Second Messengers (eds Laychock, S. G. & Rubin, R. P.) 113–133 (CRC, Boca Raton, 1998).

    Google Scholar 

  24. Désarnaud, F., Cadas, H. & Piomelli, D. Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J. Biol. Chem. 270, 6030–6035 (1995).

    Article  Google Scholar 

  25. Giuffrida, A., Rodríguez de Fonseca, F. & Piomelli, D. Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry. Anal. Biochem. 280, 87–93 (2000).

    Article  CAS  Google Scholar 

  26. Navarro, M. et al. Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport 8, 491–496 (1997).

    Article  CAS  Google Scholar 

  27. Navarro, M. et al. Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake. J. Neurochem. 67, 1982–1991 (1996).

    Article  CAS  Google Scholar 

  28. Guthrie, K. M., Anderson, A. J., Leon, M. & Gall, C. Odor-induced increases in c-fos mRNA expression reveal an anatomical “unit” for odor processing in olfactory bulb. Proc. Natl Acad. Sci. USA 90, 3329–3333 (1993).

    Article  ADS  CAS  Google Scholar 

  29. Lauterborn, J. C., Isackson, P. J., Montalvo, R. & Gall, C. M. In situ hybridization localization of choline acetyltransferase mRNA in adult rat brain and spinal cord. Brain Res. Mol. Brain Res. 17, 59–69 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Schwartz for comments; R. Carrera and A. M. Basso for help with initial experiments; T. Dinh, M. Guzmán and C. Sánchez for reading the manuscript critically; M. A. Gorriti, J. Muñoz, F. Désarnaud, M. A. Villanúa and Y. Xie for help with experiments; and F. Valiño for editorial assistance. This research was supported by grants from the National Institute of Drug Abuse (to D.P.) and from the National Institute of Mental Health (to C.G.). Additional support was from the Comunidad de Madrid, Del Amo Program and Plan Nacional sobre Drogas (to F.R.F. and M.N.). F.R.F. is a research fellow of the Jaime del Amo Program, Complutense University.

Author information

Author notes

  1. F. Nava

    Present address: Department of Neuroscience ‘B. B. Brodie’, University of Cagliari, Cagliari, Italy

  2. E. Murillo-Rodríguez

    Present address: Department of Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico

Authors and Affiliations

  1. Department of Psychobiology, Complutense University, Madrid, 28233, Spain

    F. Rodríguez de Fonseca, M. Navarro, R. Gómez & L. Escuredo

  2. Fundación Hospital Carlos Haya, Málaga, 29010, Spain

    F. Rodríguez de Fonseca

  3. Department of Pharmacology,

    F. Nava, J. Fu, E. Murillo-Rodríguez, A. Giuffrida, J. LoVerme, S. Gaetani, S. Kathuria & D. Piomelli

  4. Department of Anatomy and Neurobiology, University of California, Irvine, 92697, California, USA

    C. Gall

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Corresponding author

Correspondence to D. Piomelli.

Supplementary information

Supplementary Figure 1

(GIF 11.8 KB)

Behavioral specificity of OEA-induced hypophagia. Effects of i.p. vehicle (V) or OEA (5 or 20 mg per kg) on: a, rectal temperature; b, latency to jump in the hot plate test for analgesia; c, percent time spent in open arms in the elevated plus maze test for anxiety; d, cumulative water intake; e, number of operant responses for food. Asterisk, P < 0.05; two asterisks, P < 0.01, n = 8-12 per group.

Supplementary Table 2. Effects of OEA on blood chemistry.
Full size table
Supplementary Table 3. Effects of intracerebroventricular OEA on food intake.
Full size table

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Rodríguez de Fonseca, F., Navarro, M., Gómez, R. et al. An anorexic lipid mediator regulated by feeding. Nature 414, 209–212 (2001). https://doi.org/10.1038/35102582

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