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:

Adipocyte and Cell Biology

Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion

International Journal of Obesity volume 41, pages 645–651 (2017)Cite this article

Subjects

Abstract

Objectives:

To understand the mechanism of white fat expansion in the presence of inflammation, we examined the balance of pro- and anti-inflammatory cytokines in epididymal fat during weight gain in diet-induced obese mice.

Methods:

The pro- and anti-inflammatory cytokines were examined in white fat of diet-induced obese mice and lean mice. The mechanism of gene expression was investigated with a focus on intracellular ATP (iATP). ATP activity was tested in cellular and non-cellular systems in activation of serine kinases (IKKβ, JNK and ERK).

Results:

The pro- (tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), IL-6, monocyte chemoattractant protein 1, interferon gamma and osteopontin) and the anti-inflammatory cytokines (IL-10, IL-1Ra, IL-13, soluble TNF receptor 2, pigment epithelium-derived factor and adiponectin) were increased at the same time during the weight gain. The balance was observed even in the absence of tissue expansion upon feeding in lean and obese mice. The iATP levels were positively associated with the cytokine elevation in the adipose tissue. In macrophages, induction of iATP with lauric acid stimulated the expression. Inhibition of iATP with β-oxidation inhibitor (Etomoxir) or mitochondrial uncoupler (2,4-dinitrophenol, DNP) suppressed the expression. ATP exhibited an activity in the activation of inflammatory kinases (IKKβ, JNK and ERK) in the living cells and cell lysate. The kinase activation was blocked in the cells by ATP inhibition.

Conclusions:

The data suggest that the pro- and anti-inflammatory cytokines are dynamically balanced in the white adipose tissue by iATP.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Olefsky JM, Glass CK . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246.

    Article  CAS  Google Scholar 

  2. Donath MY, Shoelson SE . Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98–107.

    Article  CAS  Google Scholar 

  3. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012; 18: 1407–1412.

    Article  CAS  Google Scholar 

  4. Ye J, McGuinness OP . Inflammation during obesity is not all bad: Evidence from animal and human studies. Am J Physiol Endocrinol Metab 2013; 304: E466–E477.

    Article  CAS  Google Scholar 

  5. Ye J, Keller J . Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging 2010; 2: 361–368.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Wernstedt Asterholm I, Tao C, Morley Thomas S, Wang Qiong A, Delgado-Lopez F, Wang Zhao V et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 2014; 20: 103–118.

    Article  CAS  Google Scholar 

  8. Wang H, Ye J . Regulation of energy balance by inflammation: common theme in physiology and pathology. Rev Endocr Metab Disord 2015; 16: 47–54.

    Article  CAS  Google Scholar 

  9. Lumeng CN, Bodzin JL, Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175–184.

    Article  CAS  Google Scholar 

  10. Wang Y, Wang H, Hegde V, Dubuisson O, Gao Z, Dhurandhar NV et al. Interplay of pro- and anti-inflammatory cytokines to determine lipid accretion in adipocytes. Int J Obes (Lond) 2013; 37: 1490–1498.

    Article  CAS  Google Scholar 

  11. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 2008; 7: 485–495.

    Article  CAS  Google Scholar 

  12. Qiu Y, Nguyen Khoa D, Odegaard Justin I, Cui X, Tian X, Locksley Richard M 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. Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 2015; 519: 242–246.

    Article  CAS  Google Scholar 

  14. Ye J, Gao Z, Yin J, He H . Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293: E1118–E1128.

    Article  CAS  Google Scholar 

  15. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S et al. HIF 1 alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009; 29: 4467–4483.

    Article  CAS  Google Scholar 

  16. Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 2006; 124: 587–599.

    Article  CAS  Google Scholar 

  17. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006; 313: 1137–1140.

    Article  Google Scholar 

  18. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56: 1761–1772.

    Article  CAS  Google Scholar 

  19. Lee YS, Li P, Huh JY, Hwang IJ, Lu M, Kim JI et al. Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 2011; 60: 2474–2483.

    Article  CAS  Google Scholar 

  20. Ham J, Rees DA . The adenosine a2b receptor: its role in inflammation. Endocr Metab Immune Disord Drug Targets 2008; 8: 244–254.

    Article  CAS  Google Scholar 

  21. Vitiello L, Gorini S, Rosano G, la Sala A . Immunoregulation through extracellular nucleotides. Blood 2012; 120: 511–518.

    Article  CAS  Google Scholar 

  22. Sun S, Xia S, Ji Y, Kersten S, Qi L . The ATP-P2X7 signaling axis is dispensable for obesity-associated inflammasome activation in adipose tissue. Diabetes 2012; 61: 1471–1478.

    Article  CAS  Google Scholar 

  23. Zhang Y, Zhao Z, Ke B, Wan L, Wang H, Ye J . Induction of posttranslational modifications of mitochondrial proteins by ATP contributes to negative regulation of mitochondrial function. PLoS One 2016; 11: e0150454.

    Article  Google Scholar 

  24. Cacicedo JM, Yagihashi N, Keaney Jr JF, Ruderman NB, Ido Y . AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun 2004; 324: 1204–1209.

    Article  CAS  Google Scholar 

  25. Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab 2009; 296: E955–E964.

    Article  CAS  Google Scholar 

  26. Gao Z, Wang Z, Zhang X, Butler AA, Zuberi A, Gawronska-Kozak B et al. Inactivation of PKC{theta} leads to increased susceptibility to obesity and dietary insulin resistance in mice. Am J Physiol Endocrinol Metab 2007; 292: E84–E91.

    Article  CAS  Google Scholar 

  27. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447: 1116–1120.

    Article  CAS  Google Scholar 

  28. Yin J, Gao Z, He Q, Ye J . Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab 2009; 296: E333–E342.

    Article  CAS  Google Scholar 

  29. Hoesel B, Schmid JA . The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grant R56 DK068036-11 (JY), the National Natural Science Foundation of China (grant number 81370915), Program for Innovative Research Team (in Science and Technology) in University of Henan Province (grant number 15IRTSTHN025) and CNRU (NIH 1P30-DK072476) center grant to the genomic core. The qRT-PCR assay was performed in core facility supported by NIH grant (2P30DK072476). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

JHL, YZ, ZZ, XZ and XY, conducted the experiments. HW and JY designed the study and prepared the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA

    J H Lee, Z Zhao, X Ye & J Ye

  2. Department of Gynaecology and Obstetrics, Third hospital, Beijing University, Beijing, China

    Y Zhang

  3. Central Laboratory, Shanghai Sixth People’s Hospital East, Shanghai, China

    X Zhang

  4. Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine in Henan Province, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China

    H Wang

Authors
  1. J H Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Ye.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, J., Zhang, Y., Zhao, Z. et al. Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion. Int J Obes 41, 645–651 (2017). https://doi.org/10.1038/ijo.2017.3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2017.3

This article is cited by

Search

Advanced search

Quick links