Research Article


DOI :10.26650/IstanbulJPharm.2021.933139   IUP :10.26650/IstanbulJPharm.2021.933139    Full Text (PDF)

The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir

Fatma AkarCeren GüneyHamdi Barbaros ÖzerMehmet Bilgehan PektaşHalit Buğra KocaAytaç KocabaşGökhan Sadi

Background and Aims: The dietary high-fructose intake might be a risk factor for several metabolic diseases. Kefir, a fermented milk product, has been proposed to have beneficial health effects. In this study, we aimed to investigate the effects of fructose consumption and kefir supplementation on the lipogenesis-related genes including angiopoietin-like protein 8 (angptl8), phosphoinositide 3-kinase (pi3k), mammalian target of rapamycin (mtor), and peroxisome proliferator-activated receptor γ (pparγ) as well as inflammatory factors in the adipose tissue to provide new mechanistic insights into lipogenesis. Methods: Fructose was given to the rats as a 20% solution in drinking water for 15 weeks. Kefir was administered by gastric gavage once a day during the final six weeks. Results: There was an upregulation of angptl8 mRNA expression in adipose tissue of rats given fructose. However, expressions of pi3k, mtor, and pparγ mRNAs were impaired in the adipose tissue. The increased interleukin (IL)-1β levels, but decreased IL-10, were also measured. There was no change in expressions of sirtuin1 (sirt1) and nuclear factor erythroid 2-related factor 2 (nrf2). Kefir supplementation suppressed expression of angptl8, but increased pi3k and mtor in the adipose tissue of high-fructose-fed rats. Conclusion: Activation of gene expression of angptl8, together with the suppression of pi3k, mtor, and pparγ, showed that there was an inverse association between these lipogenic genes in the adipose tissue of rats fed with high-fructose. Kefir supplementation has modulatory effects on fructose-induced changes except for pparγ expression. These findings showed that dietary fructose and kefir might reciprocally affect the lipogenesis-related genes in the adipose tissue.


PDF View

References

  • Abu-Farha, M., Abubaker, J., Al-Khairi, I., Cherian, P., Noronha, F., Kavalakatt, S., ... Elkum, N. (2016). Circulating angiopoietin-like protein 8 (betatrophin) association with HsCRP and metabolic syndrome. Cardiovascular Diabetology, 15(1), 25. google scholar
  • Abu-Farha, M., Abubaker, J., Al-Khairi, I., Cherian, P., Noronha, F., Hu, F. B., ... Elkum, N. (2015). Higher plasma betatrophin/ANGPTL8 level in Type 2 Diabetes subjects does not correlate with blood glucose or insulin resistance. Scientific Reports, 5(1), 1-8. google scholar
  • Akar, F., Uludağ, O., Aydın, A., Aytekin, Y. A., Elbeg, S., Tuzcu, M., & Sahin, K. (2012). High-fructose corn syrup causes vascular dysfunction associated with metabolic disturbance in rats: pro-tective effect of resveratrol. Food and Chemical Toxicology, 50(6), 2135-2141. google scholar
  • Akar, F., Sumlu, E., Alçığır, M. E., Bostancı, A., & Sadi, G. (2021). Po-tential mechanistic pathways underlying intestinal and hepatic effects of kefir in high-fructose-fed rats. Food Research Internation-al, 143, 110287. https://doi.org/10.1016/j.foodres.2021.110287 google scholar
  • Barroso, E., Rodrfguez-Rodrfguez, R., Chacon, M. R., Maymo-Masip, E., Ferrer, L., Salvado, L., ... Vazquez-Carrera, M. (2015). PPARp/ö ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1852(5), 1049-1058. google scholar
  • Bastard, J. P., Maachi, M., Lagathu, C., Kim, M. J., Caron, M., Vidal, H., ... Feve, B. (2006). Recent advances in the relationship between obesity, inflammation, and insulin resistance. European Cytokine Network, 17(1), 4-12. google scholar
  • Brown, M. S., & Goldstein, J. L. (2008). Selective versus total insulin resistance: a pathogenic paradox. Cell Metabolism, 7(2), 95-96. google scholar
  • Carbone, C., Piro, G., Merz, V., Simionato, F., Santoro, R., Zecchetto, C., Tortora, G., & Melisi, D. (2018). Angiopoietin-Like Proteins in Angiogenesis, Inflammation and Cancer. International Journal of Molecular Sciences, 19(2), 431. google scholar
  • Chen, C. C., Susanto, H., Chuang, W. H., Liu, T. Y., & Wang, C. H. (2016). Higher serum betatrophin level in type 2 diabetes sub-jects is associated with urinary albumin excretion and renal func-tion. Cardiovascular Diabetology, 15(1), 1-9. google scholar
  • Chen, H. L., Tsai, T. C., Tsai, Y. C., Liao, J. W., Yen, C. C., & Chen, C. M. (2016). Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modula-tion of inflammation and the JAK2 signaling pathway. Nutrition & Diabetes, 6(12), e237-e237. google scholar
  • Choi, J. W., Kang, H. W., Lim, W. C., Kim, M. K., Lee, I. Y., & Cho, H. Y. (2017). Kefir prevented excess fat accumulation in diet-induced obese mice. Bioscience, Biotechnology, and Biochemistry, 81(5), 958-965. google scholar
  • Fu, Z., Berhane, F., Fite, A., Seyoum, B., Abou-Samra, A. B., & Zhang, R. (2014). Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Scientific Reports, 4(1), 1-5. google scholar
  • Gao, J., Ding, G., Li, Q., Gong, L., Huang, J., & Sang, Y. (2019). Tibet kefir milk decreases fat deposition by regulating the gut micro-biota and gene expression of Lpl and Angptl4 in high fat diet-fed rats. Food Research International, 121, 278-287. google scholar
  • Garcfa-Monzdn, C., Petrov, P D., Rey, E., Maranon, P, del Pozo-Maroto, E., Guzman, C., ... Miquilena-Colina, M. E. (2018). Angio-poietin-like protein 8 is a novel vitamin d receptor target gene involved in nonalcoholic fatty liver pathogenesis. The American Journal of Pathology, 188(12), 2800-2810. google scholar
  • Han, C., Wei, S., He, F., Liu, D., Wan, H., Liu, H., ... Xu, F. (2015). The regulation of lipid deposition by insulin in goose liver cells is mediated by the PI3K-AKT-mTOR signaling pathway. PloS One, 10(5), e0098759. google scholar
  • Hannou, S. A., Haslam, D. E., McKeown, N. M., & Herman, M. A. (2018). Fructose metabolism and metabolic disease. The Journal of Clinical Investigation, 128(2), 545-555. google scholar
  • He, W., Barak, Y., Hevener, A., Olson, P., Liao, D., Le, J., ... Evans, R. M. (2003). Adipose-specific peroxisome proliferator-activated recep-tor y knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences, 100(26), 15712-15717. google scholar
  • Hu, H., Sun, W., Yu, S., Hong, X., Qian, W., Tang, B., ... Zhou, L. (2014). Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients. Diabetes Care, 37(10), 2718-2722. google scholar
  • Huang, X., Liu, G., Guo, J., & Su, Z. (2018). The PI3K/AKT pathway in obesity and type 2 diabetes. International Journal of Biological Sciences, 14(11), 1483. google scholar
  • Izumi, R., Kusakabe, T., Noguchi, M., Iwakura, H., Tanaka, T., Miyaza-wa, T., ... Nakao, K. (2018). CRISPR/Cas9-mediated Angptl8 knock-out suppresses plasma triglyceride concentrations and adiposity in rats. Journal of Lipid Research, 59(9), 1575-1585. google scholar
  • Janssen, A. W., Katiraei, S., Bartosinska, B., Eberhard, D., van Dijk, K. W., & Kersten, S. (2018). Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota. Diabeto-logia, 61(6), 1447-1458. google scholar
  • Jensen, T., Abdelmalek, M. F., Sullivan, S., Nadeau, K. J., Green, M., Roncal, C., ... Tolan, D. R. (2018). Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. Journal of Hepatol-ogy, 68(5), 1063-1075. google scholar
  • Kim, D. H., Jeong, D., Kim, H., & Seo, K. H. (2019). Modern perspec-tives on the health benefits of kefir in next generation sequenc-ing era: Improvement of the host gut microbiota. Critical Reviews in Food Science and Nutrition, 59(11), 1782-1793. google scholar
  • Korkmaz, O. A., Sumlu, E., Koca, H. B., Pektas, M. B., Kocabas, A., Sadi, G., & Akar, F. (2019a). Effects of Lactobacillus plantarum and Lactobacil-lus helveticus on renal insulin signaling, inflammatory markers, and glucose transporters in high-fructose-fed rats. Medicina, 55(5), 207. google scholar
  • Korkmaz, O. A., Sadi, G., Kocabaş, A., Yıldırım, O. G., Sumlu, E., Koca, H. B., ... Akar F. (2019b). Lactobacillus helveticus and Lactobacil-lus plantarum modulate renal antioxidant status in a rat model of fructose-induced metabolic syndrome. Archives of Biological Sciences, 71 (2), 265-273. google scholar
  • Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274-293. google scholar
  • Lee, Y. H., Lee, S. G., Lee, C. J., Kim, S. H., Song, Y. M., Yoon, M. R., ... Lee, H. C. (2016). Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: animal and human studies. Sci-entific Reports, 6(1), 1-12. google scholar
  • Li, H., Yu, L., & Zhao, C. (2019). Dioscin attenuates high-fat diet-in-duced insulin resistance of adipose tissue through the IRS-1/PI3K/ Akt signaling pathway. Molecular Medicine Reports, 19(2), 1230-1237. google scholar
  • Li, S., Brown, M. S., & Goldstein, J. L. (2010). Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proceedings of the National Academy of Sciences, 107(8), 3441-3446. google scholar
  • Ma, X., Lin, L., Yue, J., Pradhan, G., Qin, G., Minze, L. J., ... Sun, Y. (2013). Ghrelin receptor regulates HFCS-induced adipose inflam-mation and insulin resistance. Nutrition & Diabetes, 3(12), e99-e99. Nakamura, F., Ishida, Y., Sawada, D., Ashida, N., Sugawara, T., Sakai, M., ... Fujiwara, S. (2016). Fragmented lactic Acid bacterial cells activate peroxisome proliferator-activated receptors and amelio-rate Dyslipidemia in obese mice. Journal of Agricultural and Food Chemistry, 64(12), 2549-2559. google scholar
  • Nidhina Haridas, P A., Soronen, J., Sadevirta, S., Mysore, R., Quaglia-rini, F., Pasternack, A., ... Fischer-Posovszky, P. (2015). Regulation of angiopoietin-like proteins (ANGPTLs) 3 and 8 by insulin. The Jour-nal of Clinical Endocrinology & Metabolism, 100(10), E1299-E1307. google scholar
  • Okada, T., Kawano, Y., Sakakibara, T., Hazeki, O., & Ui, M. (1994). Es-sential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. Journal of Biological Chemis-try, 269(5), 3568-3573. google scholar
  • Oldoni, F., Cheng, H., Banfi, S., Gusarova, V., Cohen, J. C., & Hobbs, H. H. (2020). ANGPTL8 has both endocrine and autocrine effects on substrate utilization. JCI Insight, 5(17). google scholar
  • Pektas, M. B., Sadi, G., & Akar, F. (2015). Long-term dietary fruc-tose causes gender-different metabolic and vascular dysfunction in rats: modulatory effects of resveratrol. Cellular Physiology and Biochemistry, 37(4), 1407-1420. google scholar
  • Pektas, M. B., Koca, H. B., Sadi, G., & Akar, F. (2016). Dietary fruc-tose activates insulin signaling and inflammation in adipose tis-sue: Modulatory role of resveratrol. BioMed Research International, 2016(8014252), 1-10. google scholar
  • Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boer-winkle, E., ... Hobbs, H. H. (2012). Atypical angiopoietin-like protein that regulates ANGPTL3. Proceedings of the National Academy of Sciences, 109(48), 19751-19756. google scholar
  • Ren, G., Kim, J. Y., & Smas, C. M. (2012). Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. American Journal of Physiology-Endocrinology and Metabolism, 303(3), E334-E351. google scholar
  • Rondinone, C. M., Wang, L. M., Lonnroth, P., Wesslau, C., Pierce, J. H., & Smith, U. (1997). Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-depen-dent diabetes mellitus. Proceedings of the National Academy of Sciences, 94(8), 4171-4175. google scholar
  • Rosa, D. D., Dias, M. M., Grzeskowiak, t. M., Reis, S. A., Conceiçâo, L. L., & Maria do Carmo, G. P. (2017). Milk kefir: nutritional, micro-biological and health benefits. Nutrition Research Reviews, 30(1), 82-96. google scholar
  • Rosa, D. D., Grzeskowiak, t. M., Ferreira, C. L., Fonseca, A. C. M., Reis, S. A., Dias, M. M., ... Machado, A. B. (2016). Kefir reduces insulin resistance and inflammatory cytokine expression in an animal model of metabolic syndrome. Food & Function, 7(8), 3390-3401. google scholar
  • Sakaue, H., Ogawa, W., Matsumoto, M., Kuroda, S., Takata, M., Sugimoto, T., ... Kasuga, M. (1998). Posttranscriptional control of adipocyte differentiation through activation of phosphoinositide 3-kinase. Journal of Biological Chemistry, 273(44), 28945-28952. google scholar
  • Scherer, P. E. (2006). Adipose tissue: from lipid storage compart-ment to endocrine organ. Diabetes, 55(6), 1537-1545. google scholar
  • Schneider, K. S., & Chan, J. Y. (2013). Emerging role of Nrf2 in adi-pocytes and adipose biology. Advances in Nutrition, 4(1), 62-66. google scholar
  • Shan, T., Zhang, P., Jiang, Q., Xiong, Y., Wang, Y., & Kuang, S. (2016). Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice. Diabetolo-gia, 59(9), 1995-2004. google scholar
  • Sumlu, E., Bostancı, A., Sadi, G., Alçığır, M. E., & Akar, F. (2020). Lac-tobacillus plantarum improves lipogenesis and IRS-1/AKT/eNOS signalling pathway in the liver of high-fructose-fed rats. Archives of Physiology and Biochemistry, 1-9. google scholar
  • Wang, D., & Sul, H. S. (1998). Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-ki-nase pathway: involvement of protein kinase B/Akt. Journal of Biological Chemistry, 273(39), 25420-25426. google scholar
  • Wang, H., Lai, Y., Han, C., Liu, A., Fan, C., Wang, H., ... Shan, Z. (2016). The effects of serum ANGPTL8/betatrophin on the risk of devel-oping the metabolic syndrome-a prospective study. Scientific Reports, 6(1), 1-8. google scholar
  • Wang, Y., Quagliarini, F., Gusarova, V., Gromada, J., Valenzuela, D. M., Cohen, J. C., & Hobbs, H. H. (2013). Mice lacking ANGPTL8 (Be-tatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proceedings of the National Acad-emy of Sciences, 110(40), 16109-16114. google scholar
  • Yamauchi, T., Kamon, J., Waki, H., Murakami, K., Motojima, K., Kom-eda, K., ... Kadowaki, T. (2001). The mechanisms by which both het-erozygous peroxisome proliferator-activated receptor y (PPARy) deficiency and PPARy agonist improve insulin resistance. Journal of Biological Chemistry, 276(44), 41245-41254. google scholar
  • Yildirim, O. G., Sumlu, E., Aslan, E., Koca, H. B., Pektas, M. B., Sadi, G., & Akar, F. (2019). High-fructose in drinking water initiates acti-vation of inflammatory cytokines and testicular degeneration in rat. Toxicology Mechanisms and Methods, 29(3), 224-232. google scholar
  • Yoshizaki, T., Milne, J. C., Imamura, T., Schenk, S., Sonoda, N., Ba-bendure, J. L., ... Olefsky, J. M. (2009). SIRT1 exerts anti-inflammato-ry effects and improves insulin sensitivity in adipocytes. Molecular and Cellular Biology, 29(5), 1363-1374. google scholar
  • Zhang, H. H., Huang, J., Düvel, K., Boback, B., Wu, S., Squillace, R. M., ... Manning, B. D. (2009). Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PloS one, 4(7), e6189. google scholar
  • Zhang, R. (2012). Lipasin, a novel nutritionally-regulated liver-en-riched factor that regulates serum triglyceride levels. Biochemical and Biophysical Research Communications, 424(4), 786-792. google scholar
  • Zhang, Y., Guo, X., Yan, W., Chen, Y., Ke, M., Cheng, C., ... Wang, S. (2017). ANGPTL8 negatively regulates NF-kB activation by facili-tating selective autophagic degradation of IKKy. Nature Commu-nications, 8(1), 1-13. google scholar
  • Zubirfa, M. G., Gambaro, S. E., Rey, M. A., Carasi, P., Serradell, M. D. L. Â., & Giovambattista, A. (2017). Deleterious metabolic effects of high fructose intake: the preventive effect of Lactobacillus kefiri administration. Nutrients, 9(5), 470. google scholar

Citations

Copy and paste a formatted citation or use one of the options to export in your chosen format


EXPORT



APA

Akar, F., Güney, C., Özer, H.B., Pektaş, M.B., Koca, H.B., Kocabaş, A., & Sadi, G. (2021). The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir. İstanbul Journal of Pharmacy, 51(3), 299-306. https://doi.org/10.26650/IstanbulJPharm.2021.933139


AMA

Akar F, Güney C, Özer H B, Pektaş M B, Koca H B, Kocabaş A, Sadi G. The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir. İstanbul Journal of Pharmacy. 2021;51(3):299-306. https://doi.org/10.26650/IstanbulJPharm.2021.933139


ABNT

Akar, F.; Güney, C.; Özer, H.B.; Pektaş, M.B.; Koca, H.B.; Kocabaş, A.; Sadi, G. The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir. İstanbul Journal of Pharmacy, [Publisher Location], v. 51, n. 3, p. 299-306, 2021.


Chicago: Author-Date Style

Akar, Fatma, and Ceren Güney and Hamdi Barbaros Özer and Mehmet Bilgehan Pektaş and Halit Buğra Koca and Aytaç Kocabaş and Gökhan Sadi. 2021. “The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir.” İstanbul Journal of Pharmacy 51, no. 3: 299-306. https://doi.org/10.26650/IstanbulJPharm.2021.933139


Chicago: Humanities Style

Akar, Fatma, and Ceren Güney and Hamdi Barbaros Özer and Mehmet Bilgehan Pektaş and Halit Buğra Koca and Aytaç Kocabaş and Gökhan Sadi. The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir.” İstanbul Journal of Pharmacy 51, no. 3 (Jul. 2024): 299-306. https://doi.org/10.26650/IstanbulJPharm.2021.933139


Harvard: Australian Style

Akar, F & Güney, C & Özer, HB & Pektaş, MB & Koca, HB & Kocabaş, A & Sadi, G 2021, 'The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir', İstanbul Journal of Pharmacy, vol. 51, no. 3, pp. 299-306, viewed 2 Jul. 2024, https://doi.org/10.26650/IstanbulJPharm.2021.933139


Harvard: Author-Date Style

Akar, F. and Güney, C. and Özer, H.B. and Pektaş, M.B. and Koca, H.B. and Kocabaş, A. and Sadi, G. (2021) ‘The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir’, İstanbul Journal of Pharmacy, 51(3), pp. 299-306. https://doi.org/10.26650/IstanbulJPharm.2021.933139 (2 Jul. 2024).


MLA

Akar, Fatma, and Ceren Güney and Hamdi Barbaros Özer and Mehmet Bilgehan Pektaş and Halit Buğra Koca and Aytaç Kocabaş and Gökhan Sadi. The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir.” İstanbul Journal of Pharmacy, vol. 51, no. 3, 2021, pp. 299-306. [Database Container], https://doi.org/10.26650/IstanbulJPharm.2021.933139


Vancouver

Akar F, Güney C, Özer HB, Pektaş MB, Koca HB, Kocabaş A, Sadi G. The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir. İstanbul Journal of Pharmacy [Internet]. 2 Jul. 2024 [cited 2 Jul. 2024];51(3):299-306. Available from: https://doi.org/10.26650/IstanbulJPharm.2021.933139 doi: 10.26650/IstanbulJPharm.2021.933139


ISNAD

Akar, Fatma - Güney, Ceren - Özer, HamdiBarbaros - Pektaş, MehmetBilgehan - Koca, HalitBuğra - Kocabaş, Aytaç - Sadi, Gökhan. The inverse association between ANGPTL8 and PI3K-mTOR- PPARγ expressions in adipose tissue of high-fructose- fed rats: The modulatory effect of kefir”. İstanbul Journal of Pharmacy 51/3 (Jul. 2024): 299-306. https://doi.org/10.26650/IstanbulJPharm.2021.933139



TIMELINE


Submitted05.05.2021
Accepted03.09.2021
Published Online06.12.2021

LICENCE


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


SHARE




Istanbul University Press aims to contribute to the dissemination of ever growing scientific knowledge through publication of high quality scientific journals and books in accordance with the international publishing standards and ethics. Istanbul University Press follows an open access, non-commercial, scholarly publishing.