Role of Neuropeptide Y and Proopiomelanocortin in Fluoxetine- Induced Anorexia

  • Myung Chang-Seon (College of Pharmacy, Chungnam National University) ;
  • Kim Bom-Taeck (Department of Family Practice and Community Health, Ajou University School of Medicine) ;
  • Choi Si Ho (Department of Pharmacology, BK Project of Medical Science, Yonsei University College of Medicine) ;
  • Song Gyu Yong (College of Pharmacy, Chungnam National University) ;
  • Lee Seok Yong (College of Pharmacy, Sungkyunkwan University) ;
  • Jahng Jeong Won (Department of Pharmacology, BK Project of Medical Science, Yonsei University College of Medicine)
  • Published : 2005.06.01

Abstract

Fluoxetine is an anorexic agent known to reduce food intake and weight gain. However, the molecular mechanism by which fluoxetine induces anorexia has not been well-established. We examined mRNA expression levels of neuropeptide Y (NPY) and proopiomelanocortin (POMC) in the brain regions of rats using RT-PCR and in situ hybridization techniques after 2 weeks of administering fluoxetine daily. Fluoxetine persistently suppressed food intake and weight gain during the experimental period. The pair-fed group confirmed that the reduction in body weight in the fluoxetine treated rats resulted primarily from decreased food intake. RT-PCR analyses showed that mRNA expression levels of both NPY and POMC were markedly reduced by fluoxetine treatment in all parts of the brain examined, including the hypothalamus. POMC mRNA in situ signals were significantly decreased, NPY levels tended to increase in the arcuate nucleus (ARC) of fluoxetine treated rats (compared to the vehicle controls). In the pair-fed group, NPY mRNA levels did not change, but the POMC levels decreased (compared with the vehicle controls). These results reveal that the chronic administration of fluoxetine decreases expression levels in both NPY and POMC in the brain, and suggests that fluoxetine-induced anorexia may not be mediated by changes in the ARC expression of either NPY or POMC. It is possible that a fluoxetine raised level of 5-HT play an inhibitory role in the orectic action caused by a reduced expression of ARC POMC ($\alpha$-MSH).

Keywords

References

  1. Anelli, M., Bizzi, A., Caccia, S., Codegoni, A. M., Fracasso, C., and Garattini, S., Anorectic activity of fluoxetine and norfluoxetine in mice, rats, and guinea-pigs. J. Pharm. Pharmacol., 44, 696-698(1992) https://doi.org/10.1111/j.2042-7158.1992.tb05500.x
  2. Badawy, A. A. B., Morgan, C. J., Bano, S., Buckland, P., and McGuffin, P., Mechanism of enhancement of rat brain serotonin synthesis by acute fluoxetine administration. J. Neurochem., 66, 436-437 (1996) https://doi.org/10.1046/j.1471-4159.1996.66010436.x
  3. Baker, R. A., Herkenham, M., and Brady, L. S., Effects of longterm treatment with antidepressant drugs on proopiomelanocortin and neuropeptide Y mRNA expression in the hypothalamic arcuate nucleus of rats. J. Neuroendocrinol., 8, 337-343 (1996) https://doi.org/10.1046/j.1365-2826.1996.04422.x
  4. Bernardis, L. L. and Bellinger, L. L., The lateral hypothalamic area revisited: ingestive behavior. Neurosci. Biobehav. Rev., 20, 189-287 (1996) https://doi.org/10.1016/0149-7634(95)00015-1
  5. Dryden, S., Frankish, H. M., Wang, Q., and Williams, G., Increased feeding and neuropeptide Y (NPY) but not NPY mRNA levels in the hypothalamus of the rat following central administration of the serotonin synthesis inhibitor p-chlorophenylalanine. Brain Res., 724, 232-237 (1996) https://doi.org/10.1016/0006-8993(96)00329-0
  6. Gutierrez, A., Saracibar, G., Casis, L., Echevarria, E., Rodriguez, V. M., Macarulla, M. T., Abecia, L. C., and Portillo, M. P., Effects of fluoxetine administration on neuropeptide Y and orexins in obese Zucker rat hypothalamus. Obesity Res., 10, 532-539 (2002) https://doi.org/10.1038/oby.2002.72
  7. Hervas, I. and Artigas, F., Regional effects of fluoxetine on extracellular 5-HT in DRN- and MRN-innervated areas of the rat brain. J. Neurochem., 66, S36 (1996)
  8. Jahng, W. W., Houpt, T. A., Joh, T. H., and Son, J. H., Differential expression of monoamine oxidase A, serotonin transporter, tyrosine hydroxylase and norepinephrine transporter mRNA by anorexia mutation and food deprivation. Dev. Brain Res., 107, 241-246 (1998) https://doi.org/10.1016/S0165-3806(98)00013-3
  9. Kim, E. M., Welch, C. C., Grace, M. K., Billington, C. J., and Levine, A. S., Chronic food restriction and acute food deprivation decrease mRNA levels of opioid peptides in arcuate nucleus. Am. J. Physiol., 270(5 Pt 2), R1019-R1024 (1996)
  10. Kim, E.-M., Grace, M. K., O'Hare, E., Billington, C. J., and Levine, A. S., Injection of $\alpha$-MSH, but not $\beta$-endorphin, into the PVN decreases POMC gene expression in the ARC. Neuroreport, 13, 497-500 (2002) https://doi.org/10.1097/00001756-200203250-00028
  11. Kristensen, P., Judge, M. E., Thim, L., Ribel, U., Christjansen, K. N., Wulff, B. S., Clausen, J. T., Jensen, P. B., Madsen, O. D., Vrang, N., Larsen, P. J., and Hastrup, S., Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature, 393, 72-76 (1998) https://doi.org/10.1038/29993
  12. Le Feuvre, R. A., Aisenthal, L., and Rothwell, N. J., Involvement of corticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) and related compounds. Brain Res., 555, 245-250 (1991) https://doi.org/10.1016/0006-8993(91)90348-Y
  13. Leibowitz, S. F., Weiss, G. F., and Suh, J., Medial hypothalamic nuclei mediate serotonin's inhibitory effect on feeding behavior. Pharmacol. Biochem. Behav., 37, 735-742 (1990) https://doi.org/10.1016/0091-3057(90)90556-W
  14. Marsh, D. J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K. A., Fisher, S. L., Burn, P., and Palmiter, R. D., Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nature Genet., 21, 119-122 (1999) https://doi.org/10.1038/5070
  15. Mizuno, T. M., Kleopoulos, S. P., Bergen, H. T., Roberts, J. L., Priest, C. A., and Mobbs, C. V., Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin. Diabetes, 47, 294-297 (1998) https://doi.org/10.2337/diabetes.47.2.294
  16. Muck-Seler, D., Jevric-Causevic, A., and Diksic, M., Influence of fluoxetine on regional serotonin synthesis in the rat brain. J. Neurochem., 67, 2434-2442 (1996) https://doi.org/10.1046/j.1471-4159.1996.67062434.x
  17. Ollmann, M. M., Wilson, B. D., Yang, Y. K., Kerns, J. A., Chen, Y., Gantz, I., and Barsh, G. S., Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science, 278, 135-138 (1997) https://doi.org/10.1126/science.278.5335.135
  18. Paxions, G. and Watson, C., The Rat Brain in Stereotaxic Coordinate. San Diego, CA, Academic Press (1986)
  19. Pollock, J. D. and Rowland, N., Peripherally administered serotonin decreases food intake in rats. Pharmacol. Biochem. Behav., 15, 179-183 (1981) https://doi.org/10.1016/0091-3057(81)90174-X
  20. Rang, H. P., Dale, M. M., Ritter, J. M., and Moore, P. K., Obesity. In Rang, H. P., Dale, M. M., J. M. Ritter, & P. K. Moore (Eds.), Pharmacology (pp. 394-403). Oxford: Churchill Livingstone (2003)
  21. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Williams, S. C., Richardson, J. A., Kozlowski, G. P., Wilson, S., Arch, J. R., Buckingham, R. E., Haynes, A. C., Carr, S. A., Annan, R. S., McNulty, D. E., Liu, W. S., Terrett, J. A., Elshourbagy, N. A., Bergsma, D. J., and Yanagisawa, M., Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92, 573-585 (1998) https://doi.org/10.1016/S0092-8674(00)80949-6
  22. Schwartz, M. W., Seeley, R. J., Woods, S. C., Weigle, D. S., Campfield, L. A., Burn, P., and Baskin, D. G., Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes, 46, 2119-2123 (1997) https://doi.org/10.2337/diabetes.46.12.2119
  23. Weiss, G. F., Rogacki, N., Fueg, A., Buchen, D., Suh, J. S., Wong, D. T., and Leibowitz, S. F., Effect of hypothalamic and peripheral fluoxetine injection on natural patterns of macronutrient intake in the rat. Psychopharmacology, 105, 467-476 (1991) https://doi.org/10.1007/BF02244365
  24. Wolf, G., Neuropeptides responding to leptin. Nutr. Rev., 55, 85-88 (1997) https://doi.org/10.1111/j.1753-4887.1997.tb01602.x
  25. Yaswen, L., Diehl, N., Brennan, M. B., and Hochgeschwender, U., Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med., 5, 1066-1070 (1999) https://doi.org/10.1038/12506