Investigation of the Effects of Ghrelin and Kisspeptin Levels in Liver Tissue of Rats Fed with High Fructose Diet -A Histological Study

Abstract

Purpose: High fructose corn syrup (HFCS) is used commonly in the food industry and has been associated with various diseases including obesity, diabetes and fatty liver. Ghrelin, an orexigenic hormone with widespread receptors in many tissues, exerts various central and peripheral effects. Food intake may reduce its synthesis. Kisspeptin plays a major role in reproductive hormones and its receptors are expressed in tissues with high metabolic activity, such as the liver. This study aims to investigate the effects of HFCS consumption on liver tissue and its relationship with Kisspeptin and Ghrelin levels. Materials and Methods: Fourteen adult male Wistar albino rats, aged eight to ten weeks, were used in this study and divided into two groups; Control and HFCS (n=7). Tumor Necrosis Factor-alpha (TNF-α), Ghrelin, and Kisspeptin levels in the liver tissues of the rats were measured using an immunohistochemical method and subsequently analyzed through histoscoring. Results: Our data revealed a significant increase in Kisspeptin, Caspase 3, and TNF-α levels and a decrease in Ghrelin levels in the HFCS group compared to the Control group. Conclusion: In conclusion, our study demonstrates, for the first time, changes in liver Kisspeptin levels induced by a high fructose diet. Furthermore, the consumption of HFCS in food led to inflammatory activation, tissue damage, and reduced Ghrelin levels.

Keywords

• Apoptosis
• ghrelin
• kisspeptin
• proinflammatory cytokines

Yüksek Fruktozlu Diyetle Beslenen Sıçanların Karaciğer Dokusunda Ghrelin ve Kisspeptin Düzeylerinin Etkilerinin Histolojik Olarak Araştırılması

Abstract

Amaç: Yüksek fruktozlu mısır şurubu(YFMŞ), gıda endüstrisinde yaygın olarak kullanılmakta olup; obezite, diyabet ve yağlı karaciğer hastalığı gibi birçok hastalıkla ilişkilidir. Ghrelin, merkezi ve periferik etkilere sahip birçok dokuda yaygın reseptörlere sahip olmasının yanı sıra oreksijenik bir hormondur. Gıda alınımını azaltabilmektedir. Kisspeptin, üreme hormonlarında önemli bir rol oynamakta ve karaciğer dâhil olmak üzere yüksek metabolik aktiviteye sahip birçok dokuda reseptörü bulunmaktadır. Bu çalışmada YFMŞ tüketiminin karaciğer dokusu üzerindeki etkilerinin ve bunun Kisspeptin ve Ghrelin seviyeleri ile ilişkisinin incelenmesi amaçlanmaktadır. Araçlar ve Yöntem: Çalışmada 8-10 haftalık, 14 adet erişkin Wistar albino erkek sıçan kullanıldı ve 2 gruba ayrıldı (Kontrol, YFMŞ n=7). Sıçanların karaciğer dokularındaki Kaspaz 3, TNF-α, Ghrelin ve Kisspeptin seviyeleri immünohistokimyasal yöntemle ölçüldü ve ardından histoskorlama ile analiz edildi. Bulgular: Verilerimize göre YFMŞ grubunda kontrol grubuna göre Kisspeptin, Kaspase 3, TNF-α düzeylerinde anlamlı artış ve Ghrelin düzeylerinde azalma gözlemlendi. Sonuç: Sonuç olarak, çalışmamızda yüksek fruktozlu diyetin karaciğer Kisspeptin düzeylerinde neden olduğu değişiklikler ilk kez gösterilmiştir. Ayrıca, gıdada YFMŞ kullanımı inflamatuar aktivasyona, doku hasarına ve Ghrelin düzeylerinin düşmesine neden olmuştur.

Keywords

• apoptozis
• ghrelin
• kisspeptin
• proinflamatuvar sitokinler

References

1. 1. Li X, Luan Y, Li Y, et al. The effect of high-fructose corn syrup vs. sucrose on anthropometric and metabolic parameters: A systematic review and meta-analysis. Front Nutr. 2022;9:1013310.
2. 2. Wang X, Zhu L, Li X, Wang X, Hao R, Li J. Effects of high fructose corn syrup on intestinal microbiota structure and obesity in mice. NPJ science of food. 2022;6(1):17.
3. 3. Akalu Y, Molla MD, Dessie G, Ayelign B. Physiological Effect of Ghrelin on Body Systems. Int J Endocrinol. 2020;2020.
4. 4. Müller TD, Nogueiras R, Andermann ML, et al. Ghrelin. Mol Metab. 2015;4(6):437-460.
5. 5. Mills EG, Izzi-Engbeaya C, Abbara A, Comninos AN, Dhillo WS. Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour. Nat Rev Endocrinol. 2021;17(2):97-113.
6. 6. Bowe JE, Hill TG, Hunt KF, et al. A role for placental kisspeptin in β cell adaptation to pregnancy. JCI insight. 2019;4(20):e124540.
7. 7. Izzi-Engbeaya C, Comninos AN, Clarke SA, et al. The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans. Diabetes Obes Metab. 2018;20(12):2800-2810.
8. 8. Velasco I, León S, Barroso A, et al. Gonadal hormone-dependent vs. -independent effects of kisspeptin signaling in the control of body weight and metabolic homeostasis. Metabolism. 2019;98:84-94.

9. 9. Ventura EE, Davis JN, Goran MI. Sugar content of popular sweetened beverages based on objective laboratory analysis: focus on fructose content. Obesity (Silver Spring, Md). 2011;19(4):868-874.
10. 10. Eser N, Yoldas A, Turk A, Kalaycı Yigin A, Yalcin A, Cicek M. Ameliorative effects of garlic oil on FNDC5 and irisin sensitivity in liver of streptozotocin-induced diabetic rats. J. Pharm. Pharmacol. 2021;73(6):824-834.
11. 11. Kaplan S, Türk A, Aydın H, Erten M, Kırıcı P. Vitamin D improves oxidative stress and histopathological damage in rat ovaries caused by hyperthyroidism. The journal of obstetrics and gynaecology research. 2021;47(10):3551-3560.
12. 12. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. The journal of histochemistry and cytochemistry: official journal of the Histochemistry Society. 1981;29(4):577-580.
13. 13. Moeller SM, Fryhofer SA, Osbahr AJ, 3rd, Robinowitz CB. The effects of high fructose syrup. J Am Coll Nutr. 2009;28(6):619-626.
14. 14. Ma X, Nan F, Liang H, et al. Excessive intake of sugar: An accomplice of inflammation. Front Immunol. 2022;13:988481.
15. 15. Li YC, Hsieh CC. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model. PloS one. 2014;9(5):e97341.
16. 16. Topsakal S, Ozmen O, Ozgocmen M. Effects of alpha-lipoic acid on high fructose induced hepatic pathology. Biotech Histochem. 2019;94(4):271-276.
17. 17. Altintas F, Caliskan S, Ozmen O, Kilic-Toprak E. Swimming exercise restores damaging effects of fructose-enriched diet on the liver in rats. Tissue Cell. 2022;78:101894.
18. 18. Hassan NF, Hassan AH, El-Ansary MR. Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet. Sci Rep. 2022;12(1):20227.
19. 19. Korkmaz OA, Sumlu E, Koca HB, et al. Effects of Lactobacillus Plantarum and Lactobacillus Helveticus on Renal Insulin Signaling, Inflammatory Markers, and Glucose Transporters in High-Fructose-Fed Rats. Medicina (Kaunas, Lithuania). 2019;55(5):207.
20. 20. Sarchielli E, Comeglio P, Squecco R, et al. Tumor Necrosis Factor-α Impairs Kisspeptin Signaling in Human Gonadotropin-Releasing Hormone Primary Neurons. J. Clin. Endocrinol. Metab. 2017;102(1):46-56.
21. 21. Catak Z, Aydin S, Sahin I, Kuloglu T, Aksoy A, Dagli AF. Regulatory neuropeptides (ghrelin, obestatin and nesfatin-1) levels in serum and reproductive tissues of female and male rats with fructose-induced metabolic syndrome. Neuropeptides. 2014;48(3):167-177.
22. 22. Ma X, Lin L, Yue J, et al. Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance. Nutr Diabetes. 2013;3(12):e99.
23. 23. Aygen B, Kucuksu M, Aydin S, Ozercan IH. Effect of enalapril maleate on ghrelin levels in metabolic syndrome in rats. Peptides. 2015;67:39-44.
24. 24. Ma X, Lin L, Yue J, et al. Suppression of Ghrelin Exacerbates HFCS-Induced Adiposity and Insulin Resistance. Int J Mol Sci. 2017;18(6):1172.
25. 25. Fukunaga N, Ribeiro RVP, Bissoondath V, Billia F, Rao V. Ghrelin May Inhibit Inflammatory Response and Apoptosis During Ischemia-Reperfusion Injury. Transplantation proceedings. 2022;54(8):2357-2363.
26. 26. Ramzan F, Khan MA, Ramzan MH. The effect of chronic kisspeptin administration on seminal fructose levels in male mice. Endocrine. 2014;45(1):144-147.
27. 27. Dudek M, Kołodziejski PA, Pruszyńska-Oszmałek E, et al. Effects of high-fat diet-induced obesity and diabetes on Kiss1 and GPR54 expression in the hypothalamic-pituitary-gonadal (HPG) axis and peripheral organs (fat, pancreas and liver) in male rats. Neuropeptides. 2016;56:41-49.
28. 28. Guzman S, Dragan M, Kwon H, et al. Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model. The Journal of clinical investigation. 2022;132(10).
29. 29. Khazali H, Mahmoud F. Changes of plasma concentration and gene expression of ghrelin and leptin in rats receiving kisspeptin and morphine. Vet Res Forum: an international quarterly journal. 2022;13(1):85-90.