The Relationship between Serum Zonulin Level and Clinical and Laboratory Parameters of Childhood Obesity

Objective: To investigate the relationship between zonulin levels and clinical and laboratory parameters of childhood obesity. Methods: The study included obese children with a body mass index (BMI) >95th percentile and healthy children who were of similar age and gender distribution. Clinical (BMI, waist circumferences, mid-arm circumference, triceps skinfold, percentage of body fat, systolic blood pressure, diastolic blood pressure) and biochemical (glucose, insulin, lipid levels, thyroid function tests, cortisol, zonulin and leptin levels) parameters were measured. Results: A total of 43 obese subjects (23 males, mean age: 11.1±3.1 years) and 37 healthy subjects (18 males, mean age: 11.5±3.5 years) were included in this study. Obese children had significantly higher insulin, homeostasis model assessment of insulin resistance, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), zonulin and leptin levels than healthy children (p0.05). Comparison of the obese children with and without insulin resistance showed no statistically significant differences for zonulin levels (p>0.05). Zonulin levels were found to negatively correlate with HDL-C and positively correlate with leptin levels, after adjusting for age and BMI. Conclusion: To the best of our knowledge, this is the first study investigating the relationship between circulating zonulin level (as a marker of intestinal permeability) and insulin resistance and leptin (as markers of metabolic disturbances associated with obesity) in childhood obesity. The results showed that zonulin was significantly higher in obese children when compared to healthy children, a finding indicating a potential role of zonulin in the etiopathogenesis of obesity and related disturbances.

Kaynakça

1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-781. Epub 2014 May 29

2. Dali-Youcef N, Mecili M, Ricci R, Andres E. Metabolic inflammation: connecting obesity and insulin resistance. Ann Med 2013;45:242-253. Epub 2012 Jul 26

3. Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernandez-Real JM. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLoS One 2012;7:37160. Epub 2012 May 18

4. Pacifico L, Bonci E, Marandola L, Romaggioli S, Bascetta S, Chiesa C. Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:17107-17114.

5. Zhang D, Zhang L, Zheng Y, Yue F, Russell RD, Zeng Y. Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients. Diabetes Res Clin Pract 2014;106:312-318. Epub 2014 Sep 6

6. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763-770.

7. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-295.

8. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 2002:1-190.

9. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976;51:170-179.

10. Rosner B, Prineas RJ, Loggie JM, Daniels SR. Blood pressure nomograms for children and adolescents, by height, sex, and age, in the United States. J Pediatr 1993;123:871-886.

11. Valerio G, Licenziati MR, Iannuzzi A, Franzese A, Siani P, Riccardi G, Rubba P. Insulin resistance and impaired glucose tolerance in obese children and adolescents from Southern Italy. Nutr Metab Cardiovasc Dis 2006;16:279-284. Epub 2006 Mar 20

12. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemiainduced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470-1481. Epub 2008 Feb 27

13. Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091-1103. Epub 2009 Feb 24

14. Ferraris RP, Casirola DM, Vinnakota RR. Dietary carbohydrate enhances intestinal sugar transport in diabetic mice. Diabetes 1993;42:1579- 1587.

15. Ferraris RP, Vinnakota RR. Intestinal nutrient transport in genetically obese mice. Am J Clin Nutr 1995;62:540-546.

16. Gummesson A, Carlsson LM, Storlien LH, Backhed F, Lundin P, Löfgren L, Stenlöf K, Lam YY, Fagerberg B, Carlsson B. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity (Silver Spring) 2011;19:2280-2282.

17. Wapenaar MC, Monsuur AJ, van Bodegraven AA, Weersma RK, Bevova MR, Linskens RK, Howdle P, Holmes G, Mulder CJ, Dijkstra G, van Heel DA, Wijmenga C. Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis. Gut 2008;57:463-467. Epub 2007 Nov 7

18. Fasano A. Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin. Ann N Y Acad Sci 2000;915:214-222.

19. Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 2000;113:4435-4440.

20. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Hostbacterial mutualism in the human intestine. Science 2005;307:1915- 1920.

21. de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 2010;299:440-448. Epub 2010 May 27

22. El Asmar R, Panigrahi P, Bamford P, Berti I, Not T, Coppa GV, Catassi C, Fasano A. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology 2002;123:1607-1615.

23. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev 2011;91:151-175.

24. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008;135:194-204. Epub 2008 Mar 21

25. Deng Y, Scherer PE. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann N Y Acad Sci 2010;1212:1-19.

26. Brock M, Trenkmann M, Gay RE, Gay S, Speich R, Huber LC. MicroRNA- 18a enhances the interleukin-6-mediated production of the acutephase proteins fibrinogen and haptoglobin in human hepatocytes. J Biol Chem 2011;286:40142-40150. Epub 2011 Sep 27

27. Zak-Golab A, Kocelak P, Aptekorz M, Zientara M, Juszczyk L, Martirosian G, Chudek J, Olszanecka-Glinianowicz M. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects. Int J Endocrinol 2013;2013:674106. Epub 2013 Jul 18

28. Goff DC Jr, D’Agostino RB Jr, Haffner SM, Otvos JD. Insulin resistance and adiposity influence lipoprotein size and subclass concentrations. Results from the Insulin Resistance Atherosclerosis Study. Metabolism 2005;54:264-270.

29. Catli G, Anik A, Tuhan HÜ, Kume T, Bober E, Abaci A. The relation of leptin and soluble leptin receptor levels with metabolic and clinical parameters in obese and healthy children. Peptides 2014;56:72-76. Epub 2014 Apr 2

30. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-419.

31. Fasano A. Surprises from celiac disease. Sci Am 2009;301:54-61.

Kaynak Göster