BESLENME DAVRANIŞI: FARMAKOLOJİK HEDEF MOLEKÜLLER

Öz

Şişmanlık veya zayıflık; enerji harcanması ve besin alımı arasındaki dengenin bozulması sonucunda gelişmektedir. Kalp ve damar hastalıkları ve tip II diyabetin etyolojisinde yer alan obezitenin ve kansere bağlı olarak gelişen ölümlerin en sık nedeni olan anoreksi-kaşeksinin başarılı bir şekilde tedavisi ve enerji dengesinin nasıl düzenlendiğinin iyi bir şekilde bilinmesiyle mümkündür. Enerji dengesinin sürdürülmesi, karşılıklı olarak etkileşen karmaşık ve dinamik bir süreçle sağlanmaktadır. Sindirim sistemi ve yağ dokusu gibi periferal dokulardan ve santral sinir sisteminin çeşitli bölgelerinden gelen uyarıların koordinasyonu ve uygun cevabın oluşturulmasında hipotalamus anahtar rol oynamaktadır. Hipotalamusa gelen uyarılara aracılık eden, dolayısıyla beslenme davranışının oluşmasına katılımı olan leptin, nöropeptid Y, oreksinler, proopiomelanokortin deriveleri, agouti-ilişkili protein (AgRP), kokain ve amfetamin regulated transkript, kolesistokinin, serotonin, noradrenalin, insülin, glukagon, kortikotropin salıverici faktör ve kortikosteroidler, girelin, galanin, galanin benzeri peptid, bombesin ve insandaki homoloğu gastrin salgılatıcı peptit, opiyatlar, kannabinoidler, nörotensin, nitrik oksid gibi çok sayıda nöromedyatör ve hormon ve TNF-α, IL1, IL6, silyar nörotrofik faktör gibi çok çeşitli sitokin tanımlanmıştır. Bu öğelerden her biri iştahın ve/veya enerji metabolizmasının belirleyici molekülleridir. Bu moleküllerin beslenme dışında rol oynadıkları diğer işlevlerin de bilinmesi, bu molekülleri hedef alan yeni ilaçların yan tesir profillerinin öngörülebilmesi açısından ayrıca önem taşımaktadır

Anahtar Kelimeler

• İştah, ilaç, şişmanlık, zayıflık, leptin, nöropeptid Y, sitokin

Feeding Behaviour: Pharmacological Target Molecules

Öz

Obesity and leanness are the results of the imbalance between energy intake and expenditure. Obesity has important roles in the etiology of tip II diabetes mellitus and cardiovascular diseases. On the other hand, anorexia-cachexia is the most frequent cause of cancer related deaths. So, it is important to know how energy balance is regulated so that these preventing or treating diseases can be prevented or treated. Energy homeostasis is maintained by complex and dynamic processes interacting with each other. Hypothalamus plays a key role in coordination and integration of stimuli from peripheral tissuses such as gastrointestinal system and fat tissue and from several regions of central nervous system. It also has important roles in appropriate adaptive response. Many neuromediator and hormons such as leptin, neuropeptide Y, orexins, derivates of proopiomelanocortin, agouti-related protein, cocaine and amphetamine-regulated transcript, cholecystokinin, serotonin, noradrenalin, insulin, glucagon and glucagon like peptide, corticotrophin releasing factor and corticosteroids, ghrelin, galanin and galanin like peptide, bombesin and its homolouge as gastrin releasing peptide in human, opioids, cannabinoids, neurotensin, nitric oxide and several cytokines such as TNF-α, IL1, IL6, ciliary neurotrophic factor mediate stimuli terminating in hypothalamus. So they contribute to feeding behaviour. It is also important to know the other actions of these molecules apart from their roles in feeding when predicting the side effect profiles of new drugs targeting these molecules

Anahtar Kelimeler

• Appetite, obesity, leanness, leptin, neuropeptide Y, cytokine

Kaynakça

1. Parker EM. The Role of central neuropeptide, neurotansmitter and hormonal systems in the regulation of body weight. Neurotransmissions 1999, 15: 3-11. 2. Heymsfield SB, Greenberg AS, Fujioka K et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999, 282: 1568-1575.
2. Chiesi M, Huppertz C, Hofbauer KG. Pharmacotherapy of obesity: targets and perspectives. Trends in Pharmacological Sciences 2001, 22: 247-254.
3. Wilding JPH. Neuropeptides and appetite control. Diabetic Medicine 2002, 19: 519- 627.
4. Sahu A. Karla SP. Neuropeptidergic regulationof feeding behavior, neuropeptide Y. Trends Endocrinol Metab 1993, 4: 217- 224.
5. Van Dijk G. Thelie TE. Glucagon-like peptide-1 (7-36) amide: a central regulator of satiety and interoceptive stres. Neuropeptides 1999, 33: 406-414.
6. Seeley RJ, Blake K, Rushing PA, et al. The role of CNS glucagon-like peptide-1 (7-36) amide receptörs in mediating the viseral illness effectsof lithium chloride. J Neurosci 2000, 20: 616-1621.
7. Batterham RL, Cohen MA, Ellis SM et al. Inhibition of food intake in obese subjects by peptide YY3-36. Engl J Med 2003, 349: 941- 948.
8. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immu nodefiency syndrome. New Engl J Med 1992, 327: 329-337

9. M o l d a w e r L L , C o p e l a r d E M . Proinflammatory cytokines, nutritional support and the cachexia syndrome. Cancer 1997, 79: 1828-1839. 21. Plata-Salaman CR. Immunoregulators in the nervous system. Neuroscience Biobehav. Rev. 1991 15: 185-215.
10. Kokot F, Ficek R. Effects of Neuropeptide Y on Appetite. Mineral and Electrolyte Metabolism 1999, 25: 303-305.
11. Kojima M, Hosoda H, Date Y, et al. Ghreline: discovery of natural endogenous ligand for the growth hormone secretgogue receptor. Trends Endocrinol Metab. 2001, 12: 118-122. 1944.
12. Colombo G, Agabio R, Diaz G et al. Appe-tite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci 1998, 63: 113-117.
13. Morley JE, Flood JF. Evidence that nitric oxide modulates food intake in mice. Life Sci 1991, 49: 707-711.
14. King BM, Smith RL. Hypothalamic obesity after hypohysectomy or adrenalectomy: dependence on corticosterone. Am J Physiol 1985, 249: 522-526.
15. Bender DA. Uptake of tryptophan into the brain: dietary influences on serotoninergic function. Bibl Nutr Dieta 1986, 38: 82-86.
16. Beltowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit 2003, 9: 55-61.
17. Rolfe DFS, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate In mammals. Physiol Rev 1997, 77: 731-758.
18. Agyropoulos G. Effects of mutations to the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation to severe obesity and type 2 diabetes. J Clin İnvest 1998, 102: 1345-1351.
19. Martinez-Botas J. Absence of perilipin results in leanness and reverses obesity In Leprdb/db mice Nat Genet 2000, 26: 474-479.
20. Gundlach AL. Galanin/GALP and galanin receptors: role in central control of feeding, body weight/obesity and reproduction? Eur J Pharmacol 2002, 440: 255-268.