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Animal Models

The Iberian pig fed with high-fat diet: a model of renal disease in obesity and metabolic syndrome

International Journal of Obesity volume 44, pages 457–465 (2020)Cite this article

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Abstract

Background

The pathogenesis of renal disease in the context of overweight/obesity, metabolic syndrome, and insulin resistance is not completely understood. This may be due to the lack of a definitive animal model of disease, which limits our understanding of obesity-induced renal damage. We evaluated the changes in renal histology and lipid deposits induced by obesity in a model of insulin resistance: the Iberian swine fed with fat-enriched food.

Methods

Twenty-eight female sows were randomized to standard (SD) or high-fat diet (HFD: 6.8% of saturated fat) for 100 days. Weight, adiposity, analytics, oral glucose tolerance tests, and measured renal function were determined. Renal histology and lipid deposits in renal tissue were analyzed.

Results

Animals on HFD developed obesity, hypertension, high levels of LDL cholesterol, triglycerides, insulin resistance, and glomerular hyperfiltration. No animal developed overt diabetes. Animals on HFD showed “diabetoid changes”, including mesangial expansion [21.40% ± 4 vs.13.20% ± 4.0, p < 0.0001], nodular glomerulosclerosis [7.40% ± 7, 0.75 vs. 2.40% ± 4.7, p = 0.02], and glomerulomegaly (18% vs. 10%, p = 0.010) than those on SD. Tubular atrophy, interstitial fibrosis, inflammation, arteriolar hyalinosis, or fibrointimal thickening were mild and similar between groups. Triglyceride content in renal tissue was higher in animals on HFD than in SD (15.4% ± 0.5 vs. 12.7% ± 0.7; p < 0.01).

Conclusions

Iberian pigs fed with fat-enriched food showed diabetoid changes and glomerulomegaly as observed in obese humans making this model suitable to study obesity-induced renal disease.

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References

  1. http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed January 2018.

  2. https://www.idf.org/e-library/consensus-statements/60-idfconsensus-worldwide-definitionof-the-metabolic-syndrome.

  3. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2005;48:1684–99.

    Article  CAS  Google Scholar 

  4. Thomas G, Sehgal AR, Kashyap SR, Srinivas TR, Kirwan JP, Navaneethan SD. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2011;6:2364–73.

    Article  Google Scholar 

  5. Hsu Cy, Mc Culloch ChE, Iribarren C, Darbinian J, Go AS. Body mass index and risk for end-stage renal disease. Ann Intern Med. 2006;144:21–8.

    Article  Google Scholar 

  6. Hashimoto Y, Tanaka M, Okada H, Senmaru T, Hamaguchi M, Asano M, et al. Metabolically healthy obesity and risk of incident CKD. Clin J Am Soc Nephrol. 2015;10:578–83.

    Article  CAS  Google Scholar 

  7. Stefansson V, Schei J, Solbu MD, Jenssen T, Melsom T, Eriksen B. Metabolic syndrome but not obesity measures are risk factors for accelerated age-related glomerular filtration rate decline in the general population. Kidney Int. 2018;93:1183–90

  8. Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol. 2005;16:2134–40.

    Article  Google Scholar 

  9. Alexander MP, Patel TV, Farag YM, Florez A, Rennke A, Singh AK. Kidney pathological changes in metabolic syndrome: a cross-sectional study. Am J Kidney Dis. 2009;53:751–9.

    Article  CAS  Google Scholar 

  10. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 2001;59:1498–509.

    Article  CAS  Google Scholar 

  11. D’Agati VD, Chagnac A, de Vries AP, Lev M, Porrini E, Herman-Edelstein M, et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol. 2016;12:453–71.

    Article  Google Scholar 

  12. Deji N, Kume S, Araki S, Soumura M, Sugimoto T, Isshiki K, et al. Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am J Physiol Renal Physiol. 2009;296:F118–26.

    Article  CAS  Google Scholar 

  13. Kume S, Uzu T, Araki S, Sugimoto T, Isshiki K, Chin-Kanasaki M, et al. Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol. 2007;18:2715–23.

    Article  CAS  Google Scholar 

  14. Wei P, Lane PH, Lane JT, Padanilam BJ, Sansom SC. Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes. Diabetologia. 2004;47:1541–9.

    Article  CAS  Google Scholar 

  15. Jiang T, Wang Z, Proctor G, Moskowitz S, Liebman SE, Rogers T, et al. Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. J Biol Chem. 2005;280:32317–25.

    Article  CAS  Google Scholar 

  16. Dominguez J, Wu P, Packer CS, Temm C, Kelly KJ. Lipotoxic and inflammatory phenotypes in rats with uncontrolled metabolic syndrome and nephropathy. Am J Physiol Renal Physiol. 2007;293:F670–9.

    Article  CAS  Google Scholar 

  17. Henegar JR, Bigler SA, Henegar LK, Tyagi SC, Hall JE. Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol. 2001;12:1211–7.

    CAS  PubMed  Google Scholar 

  18. Bloor ID, Sebert SP, Mahajan RP, Symonds ME. The influence of sex on early stage markers of kidney dysfunction in response to juvenile obesity. Hypertension. 2012;60:991–7.

    Article  CAS  Google Scholar 

  19. Yokota SD, Benyajati S, Dantzler WH. Comparative aspects of glomerular filtration in vertebrates. Ren Physiol. 1985;8:193–221. PMID: 3906795

    CAS  PubMed  Google Scholar 

  20. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10:1093–5. PMID: 8378254

    Article  CAS  Google Scholar 

  21. Sachs DH. The pig as a potential xenograft donor. Vet Immunol Immunopathol. 1994;43:185–91. Review.

    Article  CAS  Google Scholar 

  22. Tumbleson ME, Schook LB. In Advances in swine in biomedical research. Tumbleson ME, Schook LB, editors. Vol. 1. New York, USA: Plenum Press. p. 1–4.

  23. Torres-Rovira L., Astiz S., Caro A., Lopez-Bote C., Ovilo C., Pallares P., et al. Diet-Induced SwineModel with obesity/leptin resistance for the study of metabolic syndrome and type 2 diabetes. Sci World J. 2012; p. 8. 510149.

  24. https://www.nc3rs.org.uk/the-3rs

  25. Luis-Lima S, García-Contreras C, Vázquez-Gómez M, Astiz S, Carrara F, Gaspari F, et al. A simple method to measure renal function in swine by the plasma clearance of iohexol. Int J Mol Sci. 2018;19:pii: E232 https://doi.org/10.3390/ijms19010232

    Article  CAS  Google Scholar 

  26. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55:713–23.

    Article  CAS  Google Scholar 

  27. Barbero A, Astiz S, Lopez-Bote CJ, Perez-Solana ML, Ayuso M, Garcia-Real I, et al. Maternal malnutrition and offspring sex determine juvenile obesity and metabolic disorders in a swine model of leptin resistance. PLoS One. 2013;8:e78424 https://doi.org/10.1371/journal.pone.0078424. eCollection 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nieto R, Miranda A, Garcia M, Aguilera J. The effect of dietary protein content and feeding level on the rate of protein deposition and energy utilization in growing Iberian pigs from15 to 50 kg body weight. Br J Nutr. 2002;88(no. 1):39–49.

    Article  CAS  Google Scholar 

  29. Ovilo C, Fernandez A, Noguera JL, Barragán C, Letón R, Rodríguez C, et al. Fine mapping of porcine chromosome 6 QTL and LEPR effects on body composition in multiple generations of an Iberian by Landrace intercross. Genet Res. 2005;85(no. 1):57–67.

    Article  CAS  Google Scholar 

  30. Muñoz G, Ovilo C, Silio L, Tomas A, Noguera J, Rodriguez M. Single- and joint-population analyses of two experimental pig crosses to confirm quantitative trait loci on Sus scrofa chromosome 6 and leptin receptor effects on fatness and growth traits. J Anim Sci. 2009;87(2):459–68.

    Article  Google Scholar 

  31. Spurlock ME, Gabler NK. The development of porcine models of obesity and the metabolic syndrome. J Nutr. 2008;138(2):397–402.

    Article  CAS  Google Scholar 

  32. Gonzalez-Bulnes A, Astiz S, Vazquez-Gomez M, Garcia-Contreras C. Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models A. EuPA Open Proteomics. 2016;10:50–55.

    Article  CAS  Google Scholar 

  33. Koopmans SJ, Schuurman T. Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: from food intake to metabolic disease. Eur J Pharmacol. 2015;759:231–9.

    Article  CAS  Google Scholar 

  34. Kasiske BL, Crosson JT. Renal disease in patients with massive. Arch Intern Med. 1986;146:1105–9.

    Article  CAS  Google Scholar 

  35. Griffin K, Kramer H, Bidani A. Adverse renal consequences of obesity. Am J Physiol Renal Physiol. 2008;294:F685–F696.

    Article  CAS  Google Scholar 

  36. Palatini P, et al. Glomerular hyperfiltration predicts the development of microalbuminuria in stage 1 hypertension. Kidney Int. 2006;70:578–84.

    Article  CAS  Google Scholar 

  37. Wiseman M, Saunders A, Keen H, Viberti F. Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes. N Engl J Med. 1985;312:617–21.

    Article  CAS  Google Scholar 

  38. Sarafidis P, Ruilope L. Insulin resistance, hyperinsulinemia, and renal injury. Am J Nephrol. 2006;26:232–44.

    Article  Google Scholar 

  39. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons. Am J Physiol. 1981;241:F85–93.

    CAS  Google Scholar 

  40. Chagnac A, Weinstein T, Korzets A, Ramadan E, Hirsch J, Gafter U. Glomerular hemodynamics in severe obesity. Am J Physiol Renal Physiol. 2000;278:F817–22.

    Article  CAS  Google Scholar 

  41. Kriz W, Lemley KV. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol. 2015;26:258–69.

    Article  Google Scholar 

  42. Berfield AK, Andress DL, Abrass CK. IGF-1-induced lipid accumulation impairs mesangial cell migration and contractile function. Kidney Int. 2002;62:1229–37.

    Article  CAS  Google Scholar 

  43. Singh AK, Gudehithlu KP, Pegoraro AA, Singh GK, Basheerudin K, Robey RB, et al. Vascular factors altered in glucose-treated mesangial cells and diabetic glomeruli. Changes in vascular factors impair endothelial cell growth and matrix. Lab. Invest. 2004;84:597–606.

    Article  CAS  Google Scholar 

  44. de Vries AP, Ruggenenti P, Ruan XZ, Praga M, Cruzado JM, Bajema IM, et al. ERA-EDTA Working Group Diabesity. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol. 2014;2:417–26.

    Article  Google Scholar 

  45. Bobulescu I, Lotan Y, Zhan J, Rosenthal T, Rogers J, Adams-Huet B, et al. Triglycerides in the human kidney cortex: relationship with body size. PLoS ONE 9: e101285.

  46. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97:2859–65.

    Article  CAS  Google Scholar 

  47. Poudyal H, Brown L. Stearoyl-CoA desaturase: a vital checkpoint in the development and progression of obesity. Endocr Metab Immune Disord Drug Targets. 2011;11:217–31.

    Article  CAS  Google Scholar 

  48. Arany I, Clark J, Reed D, Juncos L, Dixit M. The role of p66shc in renal toxicity of oleic acid. Am J Nephrol. 2013; 38. https://doi.org/10.1159/000354357

  49. Martínez-García C, Izquierdo-Lahuerta A, Vivas Y, Velasco I, Yeo T-K, Chen S, et al. Renal lipotoxicity-associated inflammation and insulin resistance affects actin cytoskeleton organization in podocytes. PLoS One. 2015;10:e0142291 https://doi.org/10.1371/journal.pone.0142291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sieber J, Jehle A. Free fatty acids and their metabolism affect function and survival of podocytes. Front Endocrinol. 2014; 5:186.

  51. Caligiuri SP, Blydt-Hansen T, Love K, Grégoire M, Taylor CG, Zahradka P, et al. Evidence for the use of glomerulomegaly as a surrogate marker of glomerular damage and for alpha-linolenic acid-rich oils in the treatment of early obesity-related glomerulopathy in a diet-induced rodent model of obesity. Appl Physiol Nutr Metab. 2014;39:951–9.

    Article  CAS  Google Scholar 

  52. Li Z, Woollard JR, Wang S, Korsmo MJ, Ebrahimi B, Grande JP, et al. Increased glomerular filtration rate in early metabolic syndrome is associated with renal adiposity and microvascular proliferation. Am J Physiol Renal Physiol. 2011;301:F1078–87.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the INIA farm staff for their assistance with animal care and handling. CGC, MVG, SA, and AGB are members of the EU COST-Action BM1308 “Sharing Advances on Large Animal Models (SALAAM)”. The authors would like to acknowledge the DIABESITY working group of the ERA-EDTA. the IMBRAIN (CIBICAN) project (FP7-RE6-POT- 2012-CT2012-31637-IMBRAIN) funded under the 7th Framework Program (capacities); the Instituto de Salud Carlos III (ISCIII) for the following grants: PI13/00342, PI, PI16/01814, the REDINREN RD16/0009 and PI10/02428; funding from the IRSIN (Instituto Reina Sofia de Investigacion), FEDER funds, SLL is a research fellow supported by the Instituto de Salud Carlos III (Grants for Río Hortega specialized healthcare post training contracts), ISCIII CM15/00214, Spain; EP is a Researcher of the Ramón y Cajal Program of the ISCIII. EP and AGB are the guarantors of the study.

Funding

The IMBRAIN (CIBICAN) project (FP7-RE6-POT-2012-CT2012-31637-IMBRAIN) 329 funded under the 7th Framework Program (capacities); the Instituto de Salud Carlos 330 III (ISCIII) for the following grants: PI13/00342, PI, PI16/01814, the REDINREN RD16/0009 and PI10/02428; funding from the IRSIN (Instituto Reina Sofia de Investigacion), FEDER funds, SLL is a research fellow supported by the Instituto de Salud Carlos III (Grants for Río Hortega specialized healthcare post training contracts), ISCIII CM15/00214, Spain; EP is a Researcher of the Ramón y Cajal Program of the ISCIII.

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Author notes

  1. These authors contributed equally: Rosa Rodríguez Rodríguez, Antonio González-Bulnes

Authors and Affiliations

  1. Pathology Department, Hospital Universitario de Canarias, Tenerife, Spain

    Rosa Rodríguez Rodríguez & Eduardo Salido-Ruiz

  2. University of La Laguna, Santa Cruz de Tenerife, Spain

    Rosa Rodríguez Rodríguez, Ana Elena Rodriguez-Rodriguez, Eduardo Salido-Ruiz & Esteban Porrini

  3. Comparative Physiology Group, SGIT-INIA, Madrid, Spain

    Antonio González-Bulnes, Consolacion Garcia-Contreras, Susana Astiz, Marta Vazquez-Gomez, Jose Luis Pesantez & Beatriz Isabel

  4. Faculty of Veterinary, Universidad Complutense de Madrid, Madrid, Spain

    Antonio González-Bulnes

  5. Instituto Tecnologías Biomédicas (ITB), Tenerife, Spain

    Eduardo Salido-Ruiz, Sergio Luis-Lima & Esteban Porrini

  6. Microsvet, Micros Veterinaria, León, Spain

    Jorge González

  7. Nephrology Department, Research Unit Hospital Universitario de Canarias, Tenerife, Spain

    Javier Donate Correa, Sergio Luis-Lima & Esteban Porrini

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  1. Rosa Rodríguez Rodríguez
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Contributions

AGB and EP had the idea of the study; RRR and JG performed the histological analysis, CGC, MVG, JLP, and BI helped in the performance of the study, AERR, ESR, and JDC helped in the histological evaluation, SLL performed the plasma clearance of iohexol.

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Correspondence to Esteban Porrini.

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Rodríguez, R.R., González-Bulnes, A., Garcia-Contreras, C. et al. The Iberian pig fed with high-fat diet: a model of renal disease in obesity and metabolic syndrome. Int J Obes 44, 457–465 (2020). https://doi.org/10.1038/s41366-019-0434-9

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