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Animal Models

Blocking high-fat diet-induced obesity, insulin resistance and fatty liver by overexpression of Il-13 gene in mice

Abstract

Objectives:

The objective of this study was to assess the activity of anti-inflammatory cytokine IL-13 (interleukin-13) in blocking high-fat diet-induced obesity and obesity-associated insulin resistance and liver steatosis.

Methods:

C57BL/6 mice were fed a high-fat diet and received hydrodynamic delivery of plasmids carrying the mouse Il-13 or Gfp (control) gene. IL-13 blood protein levels, food consumption and body weight of mice were continuously monitored for 8 weeks. Fat and lean masses of treated and control animals were determined at the end of the experiment. Serum concentrations of glucose, insulin and lipids were determined, and mRNA levels of macrophage marker genes in adipose tissue and genes involved in energy metabolism were examined using real-time PCR. Glucose tolerance and insulin sensitivity tests were performed to determine glucose homeostasis. Histochemistry and lipid assays were performed to determine the hepatic lipid accumulation.

Results:

Blood concentration of IL-13 was 20 ng ml−1 1 week after gene delivery and declined with time. Overexpression of Il-13 prevented high-fat diet-induced weight gain without affecting food consumption. Mice that underwent Il-13 gene transfer showed regular body weight and normal serum concentrations of glucose and insulin, and less lipid accumulation in the liver. Overexpression of Il-13 blocked macrophage infiltration in adipose tissue and suppressed high-fat diet-induced expression of inflammatory F4/80, Cd68 and Mcp1, and elevated the expression of Ucp1 (uncoupling protein 1 gene) responsible for energy expenditure.

Conclusion:

These results suggest that suppression of diet-induced inflammation by IL-13 is an effective strategy in preventing diet-induced obesity and obesity-associated insulin resistance and fatty liver.

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References

  1. Caprio S, Daniels SR, Drewnowski A, Kaufman FR, Palinkas LA, Rosenbloom AL et al. Influence of race, ethnicity, and culture on childhood obesity: implications for prevention and treatment. Obesity 2008; 16: 2566–2577.

    Article  Google Scholar 

  2. Malik VS, Willett WC, Hu FB . Global obesity: trends, risk factors and policy implications. Nat Rev Endocrinol 2013; 9: 13–27.

    Article  Google Scholar 

  3. Zimmet P, Alberti K, Shaw J . Global and societal implications of the diabetes epidemic. Narure 2001; 414: 728–787.

    Google Scholar 

  4. Sun K, Kusminski CM, Scherer PE . Adipose tissue remodeling and obesity. J Clin Invest 2011; 121: 2094–2101.

    Article  CAS  Google Scholar 

  5. Nishimura S, Manabe I, Nagai R . Adipose tissue inflammation in obesity and metabolic syndrome. Discov Med 2009; 8: 55–60.

    PubMed  Google Scholar 

  6. Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 2009; 58: 2574–2582.

    Article  CAS  Google Scholar 

  7. Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010; 59: 1648–1656.

    Article  CAS  Google Scholar 

  8. Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 2011; 332: 243–247.

    Article  CAS  Google Scholar 

  9. Sica A, Mantovani A . Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787–795.

    Article  CAS  Google Scholar 

  10. Stanya KJ, Jacobi D, Liu S, Bhargava P, Dai L, Gangl MR et al. Direct control of hepatic glucose production by interleukin-13 in mice. J Clin Invest 2013; 123: 261–271.

    Article  CAS  Google Scholar 

  11. Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 2011; 480: 104–108.

    Article  CAS  Google Scholar 

  12. Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 2014; 157: 1292–1308.

    Article  CAS  Google Scholar 

  13. Cardilo-Reis L, Gruber S, Schreier SM, Drechsler M, Papac-Milicevic N, Weber C et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med 2012; 4: 1072–1086.

    Article  CAS  Google Scholar 

  14. Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam KS et al. Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem 2012; 287: 13561–13571.

    Article  CAS  Google Scholar 

  15. Wynn TA . IL-13 effector functions. Annu Rev Immunol 2003; 21: 425–456.

    Article  CAS  Google Scholar 

  16. Kanneganti T-D, Dixit VD . Immunological complications of obesity. Nat Immunol 2012; 13: 707–712.

    Article  CAS  Google Scholar 

  17. Liu F, Song Y, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.

    Article  CAS  Google Scholar 

  18. Zhang G, Budker V, Wolff JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 1999; 10: 1735–1737.

    Article  CAS  Google Scholar 

  19. Watanabe C, Seino Y, Miyahira H, Yamamoto M, Fukami A, Ozaki N et al. Remodeling of hepatic metabolism and hyperaminoacidemia in mice deficient in proglucagon-derived peptides. Diabetes 2012; 61: 74–84.

    Article  CAS  Google Scholar 

  20. Wallace TM, Levy JC, Matthews DR . Use and abuse of HOMA modeling. Diabetes care 2004; 27: 1487–1495.

    Article  Google Scholar 

  21. Folch J, Lees M, Sloane-Stanley G . A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497–509.

    CAS  Google Scholar 

  22. Ye J . Mechanisms of insulin resistance in obesity. Front Med 2013; 7: 14–24.

    Article  Google Scholar 

  23. Alkhouri N, Gornicka A, Berk MP, Thapaliya S, Dixon LJ, Kashyap S et al. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem 2010; 285: 3428–3438.

    Article  CAS  Google Scholar 

  24. Feng B, Jiao P, Nie Y, Kim T, Jun D, van Rooijen N et al. Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice. PLoS One 2011; 6: e24358.

    Article  CAS  Google Scholar 

  25. Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A et al. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 2000; 49: 1367–1373.

    Article  CAS  Google Scholar 

  26. Hou CH, Hung L-M, Huang J-P . Exploring the non-alcoholic fatty liver disease pathogenesis mechanisms in high fat and high fructose diet fed rat (649.3). FASEB J 2014; 28: 3.

    Google Scholar 

  27. Bu L, Gao M, Qu S, Liu D . Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J 2013; 15: 1001–1011.

    Article  CAS  Google Scholar 

  28. Gao M, Zhang C, Ma Y, Bu L, Yan L, Liu D . Hydrodynamic delivery of mIL10 gene protects mice from high-fat diet-induced obesity and glucose intolerance. Mol Ther 2013; 21: 1852–1861.

    Article  CAS  Google Scholar 

  29. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006; 281: 26602–26614.

    Article  CAS  Google Scholar 

  30. Farmer DG, Ke B, Shen XD, Kaldas FM, Gao F, Watson MJ et al. Interleukin-13 protects mouse intestine from ischemia and reperfusion injury through regulation of innate and adaptive immunity. Transplantation 2011; 91: 737–743.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhu C, Zhang A, Huang S, Ding G, Pan X, Chen R . Interleukin-13 inhibits cytokines synthesis by blocking nuclear factor-kappaB and c-Jun N-terminal kinase in human mesangial cells. J Biomed Res 2010; 24: 308–316.

    Article  CAS  Google Scholar 

  32. Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T et al. Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 2007; 100: e47–e57.

    CAS  PubMed  Google Scholar 

  33. Jiang H, Harris MB, Rothman P . IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol 2000; 105: 1063–1070.

    Article  CAS  Google Scholar 

  34. Umeshita-Suyama R, Sugimoto R, Akaiwa M, Arima K, Yu B, Wada M et al. Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation. Int Immunol 2000; 12: 1499–1509.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Miss Ryan Fugett for English editing of the manuscript. This work was supported in part by a grant from NIH (RO1HL098295).

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Correspondence to D Liu.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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Darkhal, P., Gao, M., Ma, Y. et al. Blocking high-fat diet-induced obesity, insulin resistance and fatty liver by overexpression of Il-13 gene in mice. Int J Obes 39, 1292–1299 (2015). https://doi.org/10.1038/ijo.2015.52

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