Effects of uridine on nesfatin-1, orexin-A and leptin levels

Yıl 2023, Cilt: 10 Sayı: 3, 479 - 484, 01.09.2023

Ayşen Çakır , Nevzat Kahveci

https://doi.org/10.52880/sagakaderg.1330855

Öz

Aim: Due to the rapidly increasing obesity problem, studies on molecules and pathways that control food intake are becoming important. Uridine, the main pyrimidine nucleoside in the human circulation, has been shown to be a dynamically regulated mediator of hunger and food intake (1). Nesftatin-1, which suppresses food intake (2), and Orexin-A (3) which increases appetite, are important peptides for regulation of nutrition. Leptin is secreted into the circulation from white adipose tissue and transported to the brain, causing a decrease in appetite and body weight (4).
Material and Methods: In this study, 8-12 week-old, Sprague-Dawley male rats were used (n=14). The rats were randomized into 2 groups: saline (Control group, n=7) or uridine (Uridine group, 500mg/kg, n=7) was administered intraperitoneally for 4 days. The animals were weighed daily. After the experiment, blood samples were obtained retro-orbitally and the serum levels of Nesfatin-1, Orexin-A and Leptin were analyzed by ELISA method.
Results and Conclusion: When the results were examined, it was observed that the percentage of body weight change was higher in the Uridine group compared to the Control group. While serum Nesfatin-1 levels decreased, Orexin-A levels increased significantly in the Uridine group compared to the Control group. No significant difference was found in serum Leptin levels. In this study, it was shown that uridine is an important mediator in regulating food intake and body weight, and that it exerts these effects by decreasing the level of Nesfatin-1 from the non-leptin pathway and increasing the level of Orexin-A.
References:
Kaynakça:
1. Hanssen, R., Rigoux, L., Albus, K., Kretschmer, A. C., Edwin Thanarajah, S., Chen, W., Hinze, Y., Giavalisco, P., Steculorum, S. M., Cornely, O. A., Brüning, J. C., & Tittgemeyer, M. (2023). Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Reports Medicine, 4(1). https://doi.org/10.1016/j.xcrm.2022.100897.
2. Oh-I, S., Shimizu, H., Satoh, T., Okada, S., Adachi, S., Inoue, K., Eguchi, H., Yamamoto, M., Imaki, T., Hashimoto, K., Tsuchiya, T., Monden, T., Horiguchi, K., Yamada, M., & Mori, M. (2006). Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature, 443(7112), 709–712. https://doi.org/10.1038/nature05162.
3. De Lecea, L., Kilduff, T. S., Peyron, C., Gao, X. B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., Frankel, W. N., Van Den Pol, A. N., Bloom, F. E., Gautvik, K. M., & Sutcliffe, J. G. (1998). The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United States of America, 95(1), 322–327. https://doi.org/10.1073/pnas.95.1.322.
4. Ahlma, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature, 382(6588), 250–252. https://doi.org/10.1038/382250a0.

Anahtar Kelimeler

Uridine, Nesfatin-1, Orexin-A, Leptin

Üridinin nesfatin-1, oreksin-A ve leptin seviyeleri üzerine etkileri

Öz

Giriş ve Amaç: Günümüzde hızla artan obezite sorunu nedeniyle gıda alımının kontrolünü sağlayan molekül ve yolaklar ile ilgili araştırmaların önemi giderek artmaktadır. İnsan dolaşımındaki temel pirimidin nükleozidi olan üridinin açlık ve gıda alımının dinamik olarak düzenlenen bir aracısı olduğu gösterilmiştir (1). Gıda alımını baskılayan Nesftatin-1 (2) ve arttıran Oreksin-A (3) beslenmenin düzenlenmesinde önemli iki peptittir. Leptin ise beyaz adipoz dokudan dolaşıma salgılanıp beyne taşınmakta ve iştah ve vücut ağırlığında azalmaya sebep olmaktadır (4).
Gereç ve Yöntem: Çalışmamızda 14 adet 8-12 haftalık Sprague-Dawley cinsi erkek sıçan kullanılmıştır. Randomize olarak 2 gruba ayrılan sıçanlara 4 gün boyunca serum fizyolojik (Kontrol grubu, n=7) veya üridin (Üridin grubu, 500 mg/kg, n=7) intraperitoneal olarak uygulanmıştır. Hayvanlar her gün tartılmıştır ve vücut ağırlıkları not edilmiştir. Deney ardından retro-orbital olarak alınan kan örneklerinden elde edilen serumlardan Nesfatin-1, Oreksin-A ve Leptin seviyeleri ELISA yöntemi ile analiz edilmiştir.
Bulgular ve Sonuç: Sonuçlara bakıldığında Kontrol grubuna göre Üridin grubundaki hayvanların vücut ağırlığı değişim yüzdesinin daha fazla olduğu gözlenmiştir. Kontrol grubuna göre Üridin grubunda serum Nesfatin-1 seviyeleri anlamlı olarak azalırken Oreksin-A seviyeleri anlamlı olarak artmış ancak Leptin seviyelerinde anlamlı bir fark saptanmamıştır. Bu çalışma ile üridinin gıda alımı ve vücut ağırlığını düzenlemede önemli bir aracı olduğu, bu etkileri de leptin dışı yolaktan Nesfatin-1 seviyesini azaltarak ve Oreksin-A seviyesini arttırak yaptığı gösterilmiştir.
Kaynakça:
Kaynakça:
1. Hanssen, R., Rigoux, L., Albus, K., Kretschmer, A. C., Edwin Thanarajah, S., Chen, W., Hinze, Y., Giavalisco, P., Steculorum, S. M., Cornely, O. A., Brüning, J. C., & Tittgemeyer, M. (2023). Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Reports Medicine, 4(1). https://doi.org/10.1016/j.xcrm.2022.100897.
2. Oh-I, S., Shimizu, H., Satoh, T., Okada, S., Adachi, S., Inoue, K., Eguchi, H., Yamamoto, M., Imaki, T., Hashimoto, K., Tsuchiya, T., Monden, T., Horiguchi, K., Yamada, M., & Mori, M. (2006). Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature, 443(7112), 709–712. https://doi.org/10.1038/nature05162.
3. De Lecea, L., Kilduff, T. S., Peyron, C., Gao, X. B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., Frankel, W. N., Van Den Pol, A. N., Bloom, F. E., Gautvik, K. M., & Sutcliffe, J. G. (1998). The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United States of America, 95(1), 322–327. https://doi.org/10.1073/pnas.95.1.322.
4. Ahlma, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature, 382(6588), 250–252. https://doi.org/10.1038/382250a0.

Anahtar Kelimeler

Üridin, Nesfatin-1, Oreksin-A, Leptin

Kaynakça

• Ahlma, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature, 382(6588), 250–252. https://doi.org/10.1038/382250a0
• Alphan, M. (2008). Obezitenin etiyolojisi. Baysal A, Baş M(editörler). Yetişkinlerde Ağırlık Yönetimi, 1. (s:17-34). İstanbul, Ekspress Basımevi.
• Al, N., Çakir, A., Koç, C., Cansev, M., & Alkan, T. (2020). Antioxidative effects of uridine in a neonatal rat model of hyperoxic brain injury. Turkish Journal of Medical Sciences, 50(8), 2059–2066. https://doi.org/10.3906/sag-2002-14
• Aslan, K., Serdar, Z., & Tokullugil, H. A. (2004). Multifonksiyonel hormon: leptin. Uludağ Üniversitesi Tıp Fakültesi Dergisi, 30(2).
• Cansev, M. (2006). Uridine and cytidine in the brain: Their transport and utilization. Brain Research Reviews, 52(2), 389–397. https://doi.org/10.1016/j.brainresrev.2006.05.001
• Cansev, M., Minbay, Z., Goren, B., Yaylagul, E. O., Cetinkaya, M., Koksal, N., & Alkan, T. (2013). Neuroprotective effects of uridine in a rat model of neonatal hypoxic-ischemic encephalopathy. Neuroscience Letters, 542, 65–70. https://doi.org/10.1016/j.neulet.2013.02.035
• Connolly, G. P., & Duley, J. A. (1999). Uridine and its nucleotides: Biological actions, therapeutic potentials. Içinde Trends in Pharmacological Sciences (C. 20, Sayı 5, ss. 218–225). https://doi.org/10.1016/S0165-6147(99)01298-5
• Dai, H., Li, X., He, T., Wang, Y., Wang, Z., Wang, S., Xing, M., Sun, W., & Ding, H. (2013). Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction. Peptides, 46, 167–171. https://doi.org/10.1016/j.peptides.2013.06.006
• Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Sakurai, T., Yanagisawa, M., & Nakazato, M. (1999). Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proceedings of the National Academy of Sciences of the United States of America, 96(2), 748–753. https://doi.org/10.1073/pnas.96.2.748
• De Lecea, L., Kilduff, T. S., Peyron, C., Gao, X. B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., Frankel, W. N., Van Den Pol, A. N., Bloom, F. E., Gautvik, K. M., & Sutcliffe, J. G. (1998). The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United States of America, 95(1), 322–327. https://doi.org/10.1073/pnas.95.1.322
• Deng, Y., Wang, Z. V., Gordillo, R., An, Y., Zhang, C., Liang, Q., Yoshino, J., Cautivo, K. M., De Brabander, J., Elmquist, J. K., Horton, J. D., Hill, J. A., Klein, S., & Scherer, P. E. (2017). An adipo-biliary-uridine axis that regulates energy homeostasis. Science, 355(6330). https://doi.org/10.1126/science.aaf5375
• Deng, Y., Wang, Z. V., Gordillo, R., Zhu, Y., Ali, A., Zhang, C., Wang, X., Shao, M., Zhang, Z., Iyengar, P., Gupta, R. K., Horton, J. D., Hill, J. A., & Scherer, P. E. (2018). Adipocyte Xbp1s overexpression drives uridine production and reduces obesity. Molecular Metabolism, 11, 1–17. https://doi.org/10.1016/j.molmet.2018.02.013
• Digby, J. E., Chen, J., Tang, J. Y., Lehnert, H., Matthews, R. N., & Randeva, H. S. (2006). Orexin receptor expression in human adipose tissue: Effects of orexin-A and orexin-B. Journal of Endocrinology, 191(1), 129–136. https://doi.org/10.1677/joe.1.06886
• Gasser, T., Moyer, J. D., & Handschumacher, R. E. (1981). Novel single-pass exchange of circulating uridine in rat liver. Science, 213(4509), 777–778. https://doi.org/10.1126/science.7256279
• Goumenou, A. G., Matalliotakis, I. M., Koumantakis, G. E., & Panidis, D. K. (2003). The role of leptin in fertility. Içinde European Journal of Obstetrics and Gynecology and Reproductive Biology (C. 106, Sayı 2, ss. 118–124). https://doi.org/10.1016/S0301-2115(02)00359-7
• Hanssen, R., Rigoux, L., Albus, K., Kretschmer, A. C., Edwin Thanarajah, S., Chen, W., Hinze, Y., Giavalisco, P., Steculorum, S. M., Cornely, O. A., Brüning, J. C., & Tittgemeyer, M. (2023). Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Reports Medicine, 4(1). https://doi.org/10.1016/j.xcrm.2022.100897
• Kabalak, T. (2001) Obezite, Metabolik Sendrom. İçinde:Kabalak T, Yılmaz C, Tüzün M(editörler). Endokrinoloji El Kitabı (s:691-700). 2. Baskı. Güven Kitabevi.
• Khezri, M. K., Turkkan, A., Koc, C., Salman, B., Levent, P., Cakir, A., Kafa, I. M., Cansev, M., & Bekar, A. (2021). Anti-Apoptotic and Anti-Oxidant Effects of Systemic Uridine Treatment in an Experimental Model of Sciatic Nerve Injury. Turkish neurosurgery, 31(3), 373–378. https://doi.org/10.5137/1019-5149.JTN.31127-20.3
• Lubkin, M., & Stricker-Krongrad, A. (1998). Independent feeding and metabolic actions of orexins in mice. Biochemical and Biophysical Research Communications, 253(2), 241–245. https://doi.org/10.1006/bbrc.1998.9750
• Moran, O., & Phillip, M. (2003). Leptin: Obesity, diabetes and other peripheral effects - A review. Içinde Pediatric Diabetes (C. 4, Sayı 2, ss. 101–109). https://doi.org/10.1034/j.1399-5448.2003.00017.x
• Oh-I, S., Shimizu, H., Satoh, T., Okada, S., Adachi, S., Inoue, K., Eguchi, H., Yamamoto, M., Imaki, T., Hashimoto, K., Tsuchiya, T., Monden, T., Horiguchi, K., Yamada, M., & Mori, M. (2006). Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature, 443(7112), 709–712. https://doi.org/10.1038/nature05162
• Pan, W., Hsuchou, H., & Kastin, A. J. (2007). Nesfatin-1 crosses the blood-brain barrier without saturation. Peptides, 28(11), 2223–2228. https://doi.org/10.1016/j.peptides.2007.09.005
• Rodgers, R. J., Tschöp, M. H., & Wilding, J. P. H. (2012). Anti-obesity drugs: Past, present and future. Içinde DMM Disease Models and Mechanisms (C. 5, Sayı 5, ss. 621–626). https://doi.org/10.1242/dmm.009621
• 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. S., Buckingham, R. E., Haynes, A. C., Carr, S. A., Annan, R. S., McNulty, D. E., Liu, W. S., Terrett, J. A., Elshourbagy, N. A., … Yanagisawa, M. (1998). Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92(4), 573–585. https://doi.org/10.1016/S0092-8674(00)80949-6
• Shimizu, H., Oh-I, S., Hashimoto, K., Nakata, M., Yamamoto, S., Yoshida, N., Eguchi, H., Kato, I., Inoue, K., Satoh, T., Okada, S., Yamada, M., Yada, T., & Mori, M. (2009). Peripheral administration of nesfatin-1 reduces food intake in mice: The leptin-independent mechanism. Endocrinology, 150(2), 662–671. https://doi.org/10.1210/en.2008-0598
• Steculorum, S. M., Paeger, L., Bremser, S., Evers, N., Hinze, Y., Idzko, M., Kloppenburg, P., & Brüning, J. C. (2015). Hypothalamic UDP Increases in Obesity and Promotes Feeding via P2Y6-Dependent Activation of AgRP Neurons. Cell, 162(6), 1404–1417. https://doi.org/10.1016/j.cell.2015.08.032
• Stengel, A., Goebel, M., Wang, L., Rivier, J., Kobelt, P., Mönnikes, H., Lambrecht, N. W. G., & Taché, Y. (2009). Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: Differential role of corticotropin-releasing factor2 receptor. Endocrinology, 150(11), 4911–4919. https://doi.org/10.1210/en.2009-0578
• Urasaki, Y., Pizzorno, G., & Le, T. T. (2016). Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice. PLoS ONE, 11(1). https://doi.org/10.1371/journal.pone.0146994
• Urasaki, Y., Pizzorno, G., & Le, T. T. (2014). Uridine affects liver protein glycosylation, insulin signaling, and heme biosynthesis. PLoS One. 2014 Jun 11;9(6):e99728. doi: 10.1371/journal.pone.0099728. PMID: 24918436; PMCID: PMC4053524.
• Willie, J. T., Chemelli, R. M., Sinton, C. M., & Yanagisawa, M. (2001). To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Içinde Annual Review of Neuroscience (C. 24, ss. 429–458). https://doi.org/10.1146/annurev.neuro.24.1.429
• Yamamoto, T., Koyama, H., Kurajoh, M., Shoji, T., Tsutsumi, Z., & Moriwaki, Y. (2011). Biochemistry of uridine in plasma. Içinde Clinica Chimica Acta (C. 412, Sayılar 19–20, ss. 1712–1724). https://doi.org/10.1016/j.cca.2011.06.006
• Yosten, G. L. C., & Samson, W. K. (2009). Nesfatin-1 exerts cardiovascular actions in brain: Possible interaction with the central melanocortin system. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 297(2). https://doi.org/10.1152/ajpregu.90867.2008
• 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, 372(6505), 425–432. https://doi.org/10.1038/372425a0
• Zhang, Y., Guo, S., Xie, C., & Fang, J. (2020). Uridine Metabolism and Its Role in Glucose, Lipid, and Amino Acid Homeostasis. Içinde BioMed Research International (C. 2020). https://doi.org/10.1155/2020/7091718
• Zhu, Y., Yamanaka, A., Kunii, K., Tsujino, N., Goto, K., & Sakurai, T. (2002). Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive pathways. Physiology and Behavior, 77(2–3), 251–257. https://doi.org/10.1016/S0031-9384(02)00843-0