Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Adipose tissue-related proteins locally associated with resolution of inflammation in obese mice

International Journal of Obesity volume 38, pages 216–223 (2014)Cite this article

Subjects

Abstract

Objective:

Resolution of low-grade inflammation of white adipose tissue (WAT) is one of the keys for amelioration of obesity-associated metabolic dysfunctions. We focused on the identification of adipokines, which could be involved at the early stages of resolution of WAT inflammation.

Methods and procedure:

Male C57BL/6J mice with obesity induced in response to a 22-week feeding corn oil-based high-fat (cHF) diet were divided into four groups and were fed with, for 2 weeks, control cHF diet or cHF-based diets supplemented with: (i) concentrate of n−3 long-chain polyunsaturated fatty acids, mainly eicosapentaenoic and docosahexaenoic acids (cHF+F); (ii) thiazolidinedione drug rosiglitazone (cHF+TZD); and (iii) both compounds (cHF+F+TZD).

Results:

The short-term combined intervention exerted additive effect in the amelioration of WAT inflammation in obese mice, namely in the epididymal fat, even in the absence of any changes in either adipocyte volume or fat mass. The combined intervention elicited hypolipidaemic effect and induced adiponectin, whereas the responses to single interventions (cHF+F, cHF+TZD) were less pronounced. In addition, analysis in WAT lysates using protein arrays revealed that the levels of a small set of adipose tissue-related proteins, namely macrophage inflammatory protein 1γ, endoglin, vascular cell adhesion molecule 1 and interleukin 1 receptor antagonist, changed in response to the anti-inflammatory interventions and were strongly reduced in the cHF+F+TZD mice. These results were verified using both the analysis of gene expression and enzyme-linked immunosorbent analysis in WAT lysates. In contrast with adiponectin, which showed changing plasma levels in response to dietary interventions, the levels of the above proteins were affected only in WAT.

Conclusions:

We identified several adipose tissue-related proteins, which are locally involved in resolution of low-grade inflammation and remodelling of WAT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Dalmas E, Clement K, Guerre-Millo M . Defining macrophage phenotype and function in adipose tissue. Trends Immunol 2011; 32: 307–314.

    Article  CAS  PubMed  Google Scholar 

  2. Lumeng CN, Saltiel AR . Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121: 2111–2117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sell H, Habich Ch, Eckel J . Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 2012; 8: 709–716.

    Article  CAS  PubMed  Google Scholar 

  4. Recchiuti A, Serhan CN . Pro-resolving lipid mediators (SPMs) and their actions in regulating miRNA in novel resolution circuits in inflammation. Front Immunol 2012; 3: 298.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Huber J, Loffler M, Bilban M, Reimers M, Kadl A, Todoric J et al. Prevention of high-fat diet-induced adipose tissue remodeling in obese diabetic mice by n-3 polyunsaturated fatty acids. Int J Obes (Lond) 2007; 31: 1004–1013.

    Article  CAS  Google Scholar 

  6. Flachs P, Ruhl R, Hensler M, Janovská P, Zouhar P, Kus V et al. Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids. Diabetologia 2011; 10: 2626–2638.

    Article  Google Scholar 

  7. Itariu BK, Zeyda M, Hochbrugger EE, Neuhofer A, Prager G, Schindler K et al. Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. Am J Clin Nutr 2012; 96/5: 1137–1149.

    Article  Google Scholar 

  8. Ruxton CH, Reed SC, Simpson MJ, Millington KJ . The health benefits of omega-3 polyunsaturated fatty acids: a review of the evidence. J Hum Nutr Diet 2007; 17/5: 449–459.

    Google Scholar 

  9. Flachs P, Rossmeisl M, Bryhn M, Kopecky J . Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci 2009; 116: 1–16.

    Article  CAS  Google Scholar 

  10. Flachs P, Horakova O, Brauner P, Rossmeisl M, Pecina P, Franssen-van Hal NL et al. Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat. Diabetologia 2005; 48: 2365–2375.

    Article  CAS  PubMed  Google Scholar 

  11. Kuda O, Jelenik T, Jilkova Z, Flachs P, Rossmeisl M, Hensler M et al. n-3 Fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 2009; 52: 941–951.

    Article  CAS  PubMed  Google Scholar 

  12. Sato A, Kawano H, Notsu T, Ohta M, Nakakuki M, Mizuguchi K et al. Antiobesity effect of eicosapentaenoic acid in high-fat/high-sucrose diet-induced obesity: importance of hepatic lipogenesis. Diabetes 2010; 59: 2495–2504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Belzung F, Raclot T, Groscolas R . Fish oil n-3 fatty acids selectively limit the hypertrophy of abdominal fat depots in growing rats fed high-fat diets. Am J Physiol 1993; 264: R1111–R1118.

    Article  CAS  PubMed  Google Scholar 

  14. Raclot T, Groscolas R, Langin D, Ferre P . Site-specific regulation of gene expression by n-3 polyunsaturated fatty acids in rat white adipose tissues. J Lipid Res 1997; 38/10: 1963–1972.

    Google Scholar 

  15. Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG, Pascoe WS . Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987; 237: 885–888.

    Article  CAS  PubMed  Google Scholar 

  16. Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW, Romanelli AJ et al. N-3 fatty acids preserve insulin sensitivity in vivo in a PPAR{alpha}-dependent manner. Diabetes 2007; 56: 1034–1041.

    Article  CAS  PubMed  Google Scholar 

  17. Jucker BM, Cline GW, Barucci N, Shulman GI . Differential effects of safflower oil versus fish oil feeding on insulin-stimulated glycogen synthesis, glycolysis, and pyruvate dehydrogenase flux in skeletal muscle: a 13C nuclear magnetic resonance study. Diabetes 1999; 48: 134–140.

    Article  CAS  PubMed  Google Scholar 

  18. Kus V, Flachs P, Kuda O, Bardova K, Janovska P, Svobodova M et al. Unmasking differential effects of rosiglitazone and pioglitazone in the combination treatment with n-3 fatty acids in mice fed a high-fat diet. PLoS One 2011; 6: e27126–e27127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Groeger AL, Cipollina C, Cole MP, Woodcock SR, Bonacci G, Rudolph TK et al. Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nat Chem Biol 2010; 6: 433–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T et al. Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes 2005; 54/12: 3358–3370.

    Article  Google Scholar 

  21. Sugii S, Olson P, Sears DD, Saberi M, Atkins AR, Barish GD et al. PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proc Natl Acad Sci USA 2009; 106: 22504–22509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Flachs P, Mohamed-Ali V, Horakova O, Rossmeisl M, Hosseinzadeh-Attar MJ, Hensler M et al. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed high-fat diet. Diabetologia 2006; 49/2: 394–397.

    Article  Google Scholar 

  23. Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S et al. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes 2006; 55: 924–928.

    Article  CAS  PubMed  Google Scholar 

  24. Kim H, Haluzik M, Gavrilova O, Yakar S, Portas J, Sun H et al. Thiazolidinediones improve insulin sensitivity in adipose tissue and reduce the hyperlipidaemia without affecting the hyperglycaemia in a transgenic model of type 2 diabetes. Diabetologia 2004; 47: 2215–2225.

    Article  CAS  PubMed  Google Scholar 

  25. Wang P, Renes J, Bouwman F, Bunschoten A, Mariman E, Keijer J . Absence of an adipogenic effect of rosiglitazone on mature 3T3-L1 adipocytes: increase of lipid catabolism and reduction of adipokine expression. Diabetologia 2007; 50: 654–665.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tilg H, Moschen AR . Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–783.

    Article  CAS  PubMed  Google Scholar 

  27. Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003; 52: 1655–1663.

    Article  CAS  PubMed  Google Scholar 

  28. Maury E, Brichard SM . Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314: 1–16.

    Article  CAS  PubMed  Google Scholar 

  29. Hung J, McQuillan BM, Thompson PL, Beilby JP . Circulating adiponectin levels associate with inflammatory markers, insulin resistance and metabolic syndrome independent of obesity. Int J Obes (Lond) 2008; 32: 772–779.

    Article  CAS  Google Scholar 

  30. Horakova O, Medrikova D, van Schothorst EM, Bunschoten A, Flachs P, Kus V et al. Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice. PLoS One 2012; 7: e43764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ruzickova J, Rossmeisl M, Prazak T, Flachs P, Sponarova J, Veck M et al. Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids 2005; 12: 1177–1185.

    Google Scholar 

  32. Rossmeisl M, Macek JZ, Kuda O, Jelenik T, Medrikova D, Stankova B et al. Metabolic Effects of n-3 PUFA as phospholipids are superior to triglycerides in mice fed a high-fat diet: possible role of endocannabinoids. PLoS One 2012; 7: e38834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Medrikova D, Macek JZ, Bardova K, Janovská P, Rossmeisl M, Kopecky J . Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control. Int J Obes (Lond) 2011; 2: 262–272.

    Google Scholar 

  34. Dietze-Schroeder D, Sell H, Uhlig M, Koenen M, Eckel J . Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors. Diabetes 2005; 54: 2003–2011.

    Article  CAS  PubMed  Google Scholar 

  35. Baumruk F, Flachs P, Horakova M, Floryk D, Kopecky J . Transgenic UCP1 in white adipocytes modulates mitochondrial membrane potential. FEBS Lett 1999; 444: 206–210.

    Article  CAS  PubMed  Google Scholar 

  36. 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  PubMed  PubMed Central  Google Scholar 

  37. Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H . Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 2004; 323: 630–635.

    Article  CAS  PubMed  Google Scholar 

  38. Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA . Possible new role for NF-kappaB in the resolution of inflammation. Nat Med 2001; 7: 1291–1297.

    Article  CAS  PubMed  Google Scholar 

  39. Kim CS, Kawada T, Yoo H, Kwon BS, Yu R . Macrophage inflammatory protein-related protein-2, a novel CC chemokine, can regulate preadipocyte migration and adipocyte differentiation. FEBS Lett 2003; 548: 125–130.

    Article  CAS  PubMed  Google Scholar 

  40. Nunez V, Alameda D, Rico D, Mota R, Gonzalo P, Cedenilla M et al. Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression. Proc Natl Acad Sci USA 2010; 107: 10626–10631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Surmi BK, Webb CD, Ristau AC, Hasty AH . Absence of macrophage inflammatory protein-1{alpha} does not impact macrophage accumulation in adipose tissue of diet-induced obese mice. Am J Physiol Endocrinol Metab 2010; 299/3: E437–E445.

    Article  Google Scholar 

  42. Hung SC, Chang CF, Ma HL, Chen TH, Low-Tone HL . Gene expression profiles of early adipogenesis in human mesenchymal stem cells. Gene 2004; 340: 141–150.

    Article  CAS  PubMed  Google Scholar 

  43. Shockley KR, Rosen CJ, Churchill GA, Lecka-Czernik B . PPARgamma2 regulates a molecular signature of marrow mesenchymal stem cells. PPAR Res 2007; 2007: 81219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Xu F, Burk D, Gao Z, Yin J, Zhang X, Weng J et al. Angiogenic deficiency and adipose tissue dysfunction are associated with macrophage malfunction in SIRT1−/− mice. Endocrinology 2012; 153: 1706–1716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goldberg RB . Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab 2009; 94: 3171–3182.

    Article  CAS  PubMed  Google Scholar 

  46. Bosanska L, Michalsky D, Lacinova Z, Dostalova I, Bartlova M, Haluzikova D et al. The influence of obesity and different fat depots on adipose tissue gene expression and protein levels of cell adhesion molecules. Physiol Res 2010; 59: 79–88.

    CAS  PubMed  Google Scholar 

  47. Meier CA, Bobbioni E, Gabay C, Assimacopoulos-Jeannet F, Golay A, Dayer JM . IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J Clin Endocrinol Metab 2002; 87/3: 1184–1188.

    Article  Google Scholar 

  48. Cartier A, Bergeron J, Poirier P, Almeras N, Tremblay A, Lemieux I et al. Increased plasma interleukin-1 receptor antagonist levels in men with visceral obesity. Ann Med 2009; 41: 471–478.

    Article  CAS  PubMed  Google Scholar 

  49. Juge-Aubry CE, Somm E, Giusti V, Pernin A, Chicheportiche R, Verdumo C et al. Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes 2003; 52: 1104–1110.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our work was supported by the EU FP7 project DIABAT (HEALTH-F2-2011-278373), by the Ministry of Health of the Czech Republic (NT13763-4), RVO: 67985823, the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, the Deutsche Forschungsgemeinschaft (SE 1922/2-1), the Commission of the European Communities (Collaborative Project ADAPT, contract number HEALTH-F2-2008-201100) and EU COST Action BM0602, and by EPAX AS (Aalesund, Norway).

Author information

Author notes

  1. D Medrikova

    Present address: 4Current address: Joint Research Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Center for Molecular Biology (ZMBH) University of Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.,

  2. Z M Jilkova and M Hensler: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic v.v.i., Prague, Czech Republic

    Z M Jilkova, M Hensler, D Medrikova, P Janovska, O Horakova, M Rossmeisl, P Flachs & J Kopecky

  2. Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, Düsseldorf, Germany

    H Sell & J Eckel

Authors
  1. Z M Jilkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Hensler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Medrikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Janovska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O Horakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Rossmeisl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Flachs
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Sell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Eckel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Kopecky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Kopecky.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jilkova, Z., Hensler, M., Medrikova, D. et al. Adipose tissue-related proteins locally associated with resolution of inflammation in obese mice. Int J Obes 38, 216–223 (2014). https://doi.org/10.1038/ijo.2013.108

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.108

Keywords

This article is cited by

Search

Advanced search

Quick links