Öz

Çoğu canlı organizmanın, davranış, fizyoloji ve metabolizmanın iç döngülerinde ritmi koru-yan sirkadiyen saatleri vardır ve bu da organizmaların dünyanın 24 saatlik dönüşünü tahmin etmelerine olanak tanır. Memelilerde, metabolik sistemlerin sirkadiyen entegrasyonu, ışık ve karanlık döngüleri boyunca enerji toplanmasını ve kullanımını optimize eder. Sirkadiyen ritimlerin bozulması obezite ve obeziteye bağlı bozukluklar gibi metabolik işlev bozuklukla-rına yol açabilir. Obezitenin arkasındaki moleküler ve hormonal mekanizma çoğunlukla hi-potalamustaki mRNA ifadeleri ve leptin ve melatonin hormonlarının seviyeleriyle ilişkilidir. Obezite ve ilgili bozukluklarda kronobiyotik bir hormon olan melatonin, leptin ile çapraz etkileşime girerek enerji metabolizması, vücut yağı ve üreme gibi fizyolojik işlevleri düzen-ler. Leptin hormonu hipotalamustaki Nöropeptid Y/Agouti İlgili Peptid (NPY/AgRP) genle-rini inhibe ederek tokluk sinyali verir ve besin alımı, vücut ağırlığı ve üreme sistemi üzerin-de etkilerini gösterir. Bu derlemede obezitenin arkasındaki moleküler ve hormonal meka-nizmalar tartışılmıştır.

Melatonin - leptin interaction and obesity-related genes

Abstract

Most living organisms have circadian clocks which maintain rhythm in internal cycles of behavior, physiology, and metabolism, allowing them to anticipate the earth's 24-hour rota-tion. In mammals, circadian integration of metabolic systems optimizes energy gathering and usage across the light and dark cycles. Disruption of circadian rhythms may lead to metabolic dysfunctions such as obesity and obesity-related disorders. The molecular and hormonal mechanism behind obesity is mostly related to mRNA expressions in hypothala-mus, and leptin, and melatonin hormone levels. In obesity and related disorders, the chron-obiotic hormone melatonin regulates physiological functions such as energy metabolism, body fat, and reproduction by cross-interacting with leptin. Leptin signals satiety by inhibit-ing Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP genes in hypothalamus and exerts its effects on food intake, body weight, and the reproductive system. In this review, the mo-lecular and hormonal mechanisms behind obesity were discussed.

Keywords

• Agouti-Related Protein (AgRP)
• Endocrine
• Gene Expression
• Neuropeptide Y (NPY)
• Suprachiasmatic Nuclei (SCN)

References

1. 1. Al-Hussaniy, H.A., Alburghaif, A.H. & Naji, M.A. 2021. Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions. Journal of Medicine and Life, 14(5): 600-605. https://doi.org/10.25122/jml-2021-0153
2. 2. Balkan, E.İ. & Gündüz, B. 2023. Adult Male Syrian Hamsters (Mesocricetus auratus) Exhibit Daily Oscillations in Their Serum Levels of Melatonin and Leptin As Well As in the Expression of the GnRH, GnIH, and Kisspeptin Genes. Türk Tarım ve Doğa Bilimleri Dergisi, 10(1): 68-75. https://doi.org/10.30910/turkjans.1196793
3. 3. Baltaci, A.K. & Mogulkoc, R. 2007. Pinealectomy and melatonin administration in rats: their effects on plasma leptin levels and relationship with zinc. Acta Biologica Hungarica, 58: 335-343. https://doi.org/10.1556/ABiol.58.2007.4.1
4. 4. Barger, J.L., Walford, R.L. & Weindruch, R. 2003. The retardation of aging by caloric restriction: its significance in the transgenic era. Experimental Gerontology, 38(11-12): 1343-1351. https://doi.org/10.1016/j.exger.2003.10.017
5. 5. Bray, M.S. & Young, M.E. 2012. Chronobiological effects on obesity. Current Obesity Reports, 1: 9-15. https://doi.org/ 10.1007/s13679-011-0005-4
6. 6. Cano, P., Jiménez-Ortega, V., Larrad, A., Toso, C.F.R., Cardinali, D.P. & Esquifino, A.I. 2008. Effect of a high-fat diet on 24-h pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid-stimulating hormone and glucose, and pineal melatonin content, in rats. Endocrine, 33: 118-125. https://doi.org/10.1007/s12020-008-9066-x
7. 7. Challet, E., Caldelas, I., Graff, C. & Pévet, P. 2003. Synchronization of the molecular clockwork by light-and food-related cues in mammals. Biological Chemistry, 384(5):711-9. http://doi.org/10.1515/BC.2003.079
8. 8. Charlot, A., Hutt, F., Sabatier, E. & Zoll, J. 2021. Beneficial effects of early time-restricted feeding on metabolic diseases: importance of aligning food habits with the circadian clock. Nutrients, 13(5): 1405. https://doi.org/10.3390/nu13051405

9. 9. Chehab, F.F., Lim, M.E. & Lu, R. 1996. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics, 12(3): 318-320. https://doi.org/10.1038/ng0396-318
10. 10. Chen, Y., Essner, R.A., Kosar, S., Miller, O.H., Lin, Y.C., Mesgarzadeh, S. & Knight, Z. A. 2019. Sustained NPY signaling enables AgRP neurons to drive feeding. Elife, 8, e46348. https://doi.org/10.7554/eLife.46348
11. 11. Coleman, D.L. 1973. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia, 9(4): 294-298.
12. 12. Coleman, D.L. 2010. A historical perspective on leptin. Nature Medicine, 16(10): 1097-1099. https://doi.org/10.1038/nm1010-1097
13. 13. Coupé, B., Grit, I., Darmaun, D. & Parnet, P. 2009. The timing of “catch-up growth” affects metabolism and appetite regulation in male rats born with intrauterine growth restriction. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 297(3): R813-R824. https://doi.org/10.1152/ajpregu.00201.2009
14. 14. Cunningham, M.,J., Clifton, D.K. & Steiner, R.A. 1999. Leptin’s role on the reproductive axis: perspectives and mechanisms. Biology of Reproduction 60(2): 216-222. https://doi.org/10.1095/biolreprod60.2.216
15. 15. O'Brien, P., Hinder, L.M., Callaghan, B.C. & Feldman, E.L. 2017. Neurological consequences of obesity. The Lancet Neurology, 16(6): 465-477. https://doi.org/10.1016/S1474-4422(17)30084-4
16. 16. Froy, O. 2007. The relationship between nutrition and circadian rhythms in mammals. Frontiers in Neuroendocrinology, 28(2-3): 61-71. https://doi.org/10.1016/j.yfrne.2007.03.001
17. 17. Frühbeck, G., Jebb, S.A. & Prentice, A.M. 1998. Leptin: physiology and pathophysiology. Clinical Physiology, 18(5): 399-419. https://doi.org/10.1046/j.1365-2281.1998.00129.x
18. 18. Galgani, J.E., Ryan, D.H. & Ravussin, E. 2010. Effect of capsinoids on energy metabolism in human subjects. British Journal of Nutrition, 103(1): 38-42. https://doi.org/10.1017/S0007114509991358
19. 19. Gündüz, B. & Hasanoğlu, N. 2016. Molecular evaluation of obesity-related hypothalamic NPY and AgRP gene expressions in melatonin injected and pinealectomized Syrian hamsters (Mesocricetus auratus) housed in short and long photoperio, pp. 98. Paper presented at the 41st Federation of European Physiological Congress, June 29-July 1, Paris, France.
20. 20. Gündüz, B. 2002. Daily rhythm in serum melatonin and leptin levels in the Syrian hamster (Mesocricetus auratus). Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 132(2): 393-401. https://doi.org/10.1016/S1095-6433(02)00041-7
21. 21. Gündüz, B. & Karakaş, A. 2001. Effects of photoperiod and melatonin infusions on body weight in pinealectomized juvenile siberian hamsters (Phodopus Sungorus). Turkish Journal of Biology, 25(3): 301-321.
22. 22. Harter, C.J., Kavanagh, G.S. & Smith, J.T. 2018. The role of kisspeptin neurons in reproduction and metabolism. Journal of Endocrinology, 238(3): R173-R183. https://doi.org/10.1530/JOE-18-0108
23. 23. Hepler, C., Weidemann, B.J., Waldeck, N.J., Marcheva, B., Cedernaes, J., Thorne, A.K., Kobayashi, Y., Newman, M.V., Gao, P., Shao, M., Ramsey, K.M., Gupta, R.K. & Bass, J. 2022. Time-restricted feeding mitigates obesity through adipocyte thermogenesis. Science, 378(6617): 276-284.6. https://doi.org/10.1126/science.abl8007
24. 24. Hill, J.W., Elmquist, J.K. & Elias, C.F. 2008. Hypothalamic pathways linking energy balance and reproduction. American Journal of Physiology-Endocrinology and Metabolism, 294(5): E827-E832. https://doi.org/10.1152/ajpendo.00670.2007
25. 25. İnan, P. & Gündüz, B. 2024. Variation of NPY and AGRP MRNA expression in Syrian hamsters according to feeding times. Sigma Journal of Engineering and Natural Sciences, 42(5): 1336-1343. https://doi.org/10.14744/sigma.2023.00072
26. 26. Jais, A. & Brüning, J.C. 2017. Hypothalamic inflammation in obesity and metabolic disease. The Journal of Clinical Investigation, 127(1): 24-32. https://doi.org/10.1172/JCI88878
27. 27. Jamshed, H., Beyl, R.A., Della Manna, D.L., Yang, E.S., Ravussin, E. & Peterson, C.M. 2019. Early time-restricted feeding improves 24-hour glucose levels and affects markers of the circadian clock, aging, and autophagy in humans. Nutrients, 11(6): 1234. https://doi.org/10.3390/nu11061234
28. 28. Kalra, S.P., Dube, M.G., Pu, S., Xu, B., Horvath, T.L. & Kalra, P.S. 1999. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocrine Reviews, 20(1): 68-100. https://doi.org/10.1210/edrv.20.1.0357
29. 29. Karakaş, A. & Gündüz, B. 2006. Suprachiasmatic nuclei may regulate the rhythm of leptin hormone release in Syrian hamsters (Mesocricetus auratus). Chronobiology International, 23(1-2): 225-236. https://doi.org/10.1080/07420520500545821
30. 30. Karakaş, A., Çamsarı, Ç., Erdinç, S. & Gündüz, B. 2005. Effects of photoperiod and food availability on growth, leptin, sexual maturation and maintenance in the Mongolian gerbils (Meriones unguiculatus). Zoological Science, 22(6): 665-670. https://doi.org/10.2108/zsj.22.665
31. 31. Karakaş, A., Serin, E. & Gündüz, B. 2006. Food restriction affects locomotor activity in Mongolian gerbils (Meriones unguiculatus). Turkish Journal of Biology, 30(1): 23-28.
32. 32. Kennedy, G.C. 1953. The role of depot fat in the hypothalamic control of food intake in the rat. Proceedings of the Royal Society of London. Series B-Biological Sciences, 140(901): 578-592. https://doi.org/10.1098/rspb.1953.0009
33. 33. Krashes, M.J., Koda, S., Ye, C., Rogan, S.C., Adams, A.C., Cusher, D.S., Maratos-Flier, E., Roth, B. L. & Lowell, B. B. 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. The Journal of Clinical Investigation, 121(4): 1424-1428. https://doi.org/10.1172/JC146229
34. 34. Li, A.J., Wiater, M.F., Oostrom, M.T., Smith, B.R., Wang, Q., Dinh, T.T., Roberts, B.L., Jansen, H.T. & Ritter, S. 2012. Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 302(11): R1313-R1326. https://doi.org/10.1152/ajpregu.00086.2012
35. 35. Li, Q., Rao, A., Pereira, A., Clarke, I.J. & Smith, J.T. 2011. Kisspeptin cells in the ovine arcuate nucleus express prolactin receptor but not melatonin receptor. Journal of Neuroendocrinology, 23(10): 871-882. https://doi.org/10.1111/j.1365-2826.2011.02195.x
36. 36. Lim, K., Zimanyi, M.A. & Black, M.J. 2006. Effect of maternal protein restriction in rats on cardiac fibrosis and capillarization in adulthood. Pediatric Research, 60(1): 83-87. https://doi.org/10.1203/01.pdr.0000220361.08181.c3
37. 37. Marcheva, B., Ramsey, K.M., Peek, C.B., Affinati, A., Maury, E. & Bass, J. 2013. Circadian clocks and metabolism. Circadian Clocks, 127-155. https://doi.org/10.1007/978-3-642-25950-0_6
38. 38. Martin-Gronert, M.S. & Ozanne, S.E. 2006. Maternal nutrition during pregnancy and health of the offspring. Biochemical Society Transactions, 34:779-882. https://doi.org/10.1042/BST0340779
39. 39. McArthur, A.J., Gillette, M.U. & Prosser, R.A. 1991. Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Research, 565(1): 158-161. https://doi.org/10.1016/0006-8993(91)91748-P
40. 40. McMillen, I.C., Adam, C.L. & Mühlhäusler, B.S. 2005. Early origins of obesity: programming the appetite regulatory system. The Journal of Physiology, 565(1): 9-17. https://doi.org/10.1113/jphysiol.2004.081992
41. 41. McMillen, I.C., MacLaughlin, S.M., Muhlhausler, B.S., Gentili, S., Duffield, J.L. & Morrison, J.L. 2008. Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition. Basic & Clinical Pharmacology & Toxicology, 102(2): 82-89. https://doi.org/10.1111/j.1742-7843.2007.00188.x
42. 42. Meli, R., Pacilio, M., Raso, G.M., Esposito, E., Coppola, A., Nasti, A., Di Carlo, C., Nappi C. & Di Carlo, R. 2004. Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats. Endocrinology, 145(7): 3115-3121. https://doi.org/10.1210/en.2004-0129
43. 43. Mercer, J.G., Hoggard, N., Williams, L.M., Lawrence, C.B., Hannah, L.T. & Trayhurn, P. 1996. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Letters, 387(2-3): 113-116. https://doi.org/10.1016/0014-5793(96)00473-5
44. 44. Mohawk, J.A., Green, C.B. & Takahashi, J.S. 2012. Central and peripheral circadian clocks in mammals. Annual Review of Neuroscience, 35(1): 445-462. https://doi.org/10.1146/annurev-neuro-060909-153128
45. 45. Morgan, P.J., Ross, A.W., Mercer, J.G. & Barrett, P. 2003. Circadian and Seasonal Rhythms-Photoperiodic programming of body weight through the neuroendocrine hypothalamus. Journal of Endocrinology, 177(1): 27-34. https://doi.org/0022-0795/03/0177-027
46. 46. Nelson, W. & Halberg, F. 1986. Meal-timing, circadian rhythms and life span of mice. The Journal of Nutrition, 116(11): 2244-2253. https://doi.org/10.1093/jn/116.11.2244
47. 47. Nieminen, P., Mustonen, A.M., Asikainen, J. & Hyvärinen, H. 2002. Seasonal weight regulation of the raccoon dog (Nyctereutes procyonoides): interactions between melatonin, leptin, ghrelin, and growth hormone. Journal of Biological Rhythms, 17(2): 155-163. https://doi.org/10.1177/074873040201700206
48. 48. Oosterman, J.E., Kalsbeek, A., La Fleur, S.E. & Belsham, D.D. 2015. Impact of nutrients on circadian rhythmicity. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 308(5): R337-R350. https://doi.org/10.1152/ajpregu.00322.2014
49. 49. Prunet-Marcassus, B., Desbazeille, M., Bros, A., Louche, K., Delagrange, P., Renard, P., Casteilla, L. & Pénicaud, L. 2003. Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity. Endocrinology, 144(12): 5347-5352. https://doi.org/10.1210/en.2003-0693
50. 50. Qi, Y., Lee, N.J., Ip, C.K., Enriquez, R., Tasan, R., Zhang, L. & Herzog, H. 2022. NPY derived from AGRP neurons controls feeding via Y1 and energy expenditure and food foraging behaviour via Y2 signalling. Molecular Metabolism, 59: 101455. https://doi.org/10.1016/j.molmet.2022.101455
51. 51. Rasmussen, D.D., Boldt, B.M., Wilkinson, C., Yellon, S.M. & Matsumoto, A.M. 1999. Daily melatonin administration at middle age suppresses male rate visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology, 140(2): 1009-1012. https://doi.org/10.1210/endo.140.2.6674
52. 52. Reiter, R. 1974. Circannual reproductive rhythms in mammals related to photoperiod and pineal function: a review. Chronobiologia, 1(4):365-395
53. 53. Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P. & Baskin, D.G. 1996. Identification of targets of leptin action in rat hypothalamus. The Journal of Clinical Investigation, 98(5): 1101-1106. https://doi.org/10.1172/JCI118891
54. 54. Schwartz, M.W., Woods, S.C., Porte Jr, D., Seeley, R.J. & Baskin, D.G. 2000. Central nervous system control of food intake. Nature, 404(6778), 661-671. hat Ovid: Schwartz: Nature, Volume 404(6778): 661-671. https://doi.org/10.1038/35007534
55. 55. Selmaoui, B., Oguine, A. & Thibault, L. 2001. Food access schedule and diet composition alter rhythmicity of serum melatonin and pineal NAT activity. Physiology & Behavior, 74(4-5): 449-455. https://doi.org/10.1016/S0031-9384(01)00592-3
56. 56. Shochat, T. 2012. Impact of lifestyle and technology developments on sleep. Nature and Science of Sleep, 19-31. https://doi.org/10.2147/NSS.S18891
57. 57. Smith, J.T., Clifton, D.K. & Steiner, R.A. 2006. Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling. Reproduction, 131(4): 623-630. https://doi.org/10.1530/rep.1.00368
58. 58. Stetson, M.H., Elliott, J.A. & Menaker, M. 1975. Photoperiodic regulation of hamster testis: circadian sensitivity to the effects of light. Biology of Reproduction, 13(3): 329-339. https://doi.org/10.1095/biolreprod13.3.329
59. 59. Tacad, D.K., Tovar, A.P., Richardson, C.E., Horn, W.F., Krishnan, G.P., Keim, N.L. & Krishnan, S. 2022. Satiety associated with calorie restriction and time-restricted feeding: peripheral hormones. Advances in Nutrition, 13(3):792-820. https://doi.org/10.1093/advances/nmac014
60. 60. Varela, L., Stutz, B., Song, J.E., Kim, J.G., Liu, Z.W., Gao, X.B. & Horvath, T.L. 2021. Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward autoactivation loop in mice. The Journal of Clinical Investigation, 131(10):e144239. https://doi.org/10.1172/JCI144239
61. 61. Wade, G.N., Schneider, J.E. & Li, H.Y. 1996. Control of fertility by metabolic cues. American Journal of Physiology-Endocrinology and Metabolism, 270(1): E1-E19. https://doi.org/10.1152/ajpendo.1996.270.1.E1
62. 62. Weindruch, R. & Sohal, R.S. 1997. Caloric intake and aging. New England Journal of Medicine, 337(14): 986-994. https://doi.org/10.1056/NEJM199710023371407
63. 63. Wolden-Hansen, T., Mitton, D.R., McCants, R.L., Yellon, S.M., Wilkinson, C.W., Matsumoto, A.M. & Rasmussen, D.D. 2000. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology, 141(2): 487-497. https://doi.org/10.1210/endo.141.2.7311
64. 64. WHO (World Health Organization). 2021. Obesity and overweight. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. (Date accessed: 10.06.2022).
65. 65. Zalatan, F., Krause, J.A. & Blask, D.E. 2001. Inhibition of isoproterenol-induced lipolysis in rat inguinal adipocytes in vitro by physiological melatonin via a receptor-mediated mechanism. Endocrinology, 142(9): 3783-3790. https://doi.org/10.1210/endo.142.9.8378
66. 66. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. & Friedman, J. M. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature (London) 372: 425–432. https://doi.org/10.1038/372425a0
67. 67. Zieba, D.A., Klocek, B., Williams, G.L., Romanowicz, K., Boliglowa, L. & Wozniak, M. 2007. In vitro evidence that leptin suppresses melatonin secretion during long days and stimulates its secretion during short days in seasonal breeding ewes. Domestic Animal Endocrinology, 33(3): 358-365. https://doi.org/10.1016/j.domaniend.2006.06.004