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.

  • Article
  • Published:

Animal models

The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice

International Journal of Obesity volume 44, pages 245–253 (2020)Cite this article

Subjects

Abstract

Background and objectives

Excessive adipose tissue macrophage accumulation in obesity has been implicated in mediating inflammatory responses that impair glucose homeostasis and promote insulin resistance. Colony-stimulating factor 1 (CSF1) controls macrophage differentiation, and here we sought to determine the effect of a CSF1 receptor inhibitor, PLX3397, on adipose tissue macrophage levels and understand the impact on glucose homeostasis in mice.

Methods

A Ten-week-old mice were fed a chow or high-fat diet for 10 weeks and then treated with PLX3397 via oral gavage (50 mg/kg) every second day for 3 weeks, with subsequent monitoring of glucose tolerance, insulin sensitivity and assessment of adipose tissue immune cells.

Results

PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization.

Conclusions

Our results indicate that macrophage infiltration of adipose tissue induced by a high-fat diet may not be the trigger for impairments in whole body glucose homeostasis, and that anti-CSF1 therapies are not likely to be useful as treatments for insulin resistance.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.

    Article  CAS  Google Scholar 

  2. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017;127:1–4.

    Article  Google Scholar 

  3. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    Article  CAS  Google Scholar 

  4. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.

    Article  CAS  Google Scholar 

  5. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.

    Article  CAS  Google Scholar 

  6. Wunderlich FT, Strohle P, Konner AC, Gruber S, Tovar S, Bronneke HS, et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 2010;12:237–49.

    Article  CAS  Google Scholar 

  7. Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC, et al. Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 2006;4:465–74.

    Article  CAS  Google Scholar 

  8. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389:610–4.

    Article  CAS  Google Scholar 

  9. Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 2015;21:403–16.

    Article  CAS  Google Scholar 

  10. Matthews VB, Allen TL, Risis S, Chan MH, Henstridge DC, Watson N, et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia. 2010;53:2431–41.

    Article  CAS  Google Scholar 

  11. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes. 1996;45:881–5.

    Article  Google Scholar 

  12. Dominguez H, Storgaard H, Rask-Madsen C, Steffen Hermann T, Ihlemann N, Baunbjerg Nielsen D, et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res. 2005;42:517–25.

    Article  CAS  Google Scholar 

  13. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes. 2006;55:2688–97.

    Article  CAS  Google Scholar 

  14. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116:115–24.

    Article  CAS  Google Scholar 

  15. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.

    Article  CAS  Google Scholar 

  16. Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes. 2012;61:1680–90.

    Article  CAS  Google Scholar 

  17. Rovida E, Sbarba PD. Colony-stimulating factor-1 receptor in the polarization of macrophages: a target for turning bad to good ones? J Clin Cell Immunol 2015;6. https://doi.org/10.4172/2155-9899.1000379.

  18. Leinonen E, Hurt-Camejo E, Wiklund O, Hulten LM, Hiukka A, Taskinen MR. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis. 2003;166:387–94.

    Article  CAS  Google Scholar 

  19. Lim AK, Ma FY, Nikolic-Paterson DJ, Thomas MC, Hurst LA, Tesch GH. Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice. Diabetologia. 2009;52:1669–79.

    Article  CAS  Google Scholar 

  20. Lyons YA, Pradeep S, Wu SY, Haemmerle M, Hansen JM, Wagner MJ, et al. Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy. Oncotarget. 2017;8:96496–505.

    Article  Google Scholar 

  21. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017;5:53.

    Article  Google Scholar 

  22. Sasmono RT, Williams E. Generation and characterization of MacGreen mice, the Cfs1r-EGFP transgenic mice. Methods Mol Biol. 2012;844:157–76.

    Article  CAS  Google Scholar 

  23. Merry TL, Tran M, Stathopoulos M, Wiede F, Fam BC, Dodd GT, et al. High-fat-fed obese glutathione peroxidase 1-deficient mice exhibit defective insulin secretion but protection from hepatic steatosis and liver damage. Antioxid Redox Signal. 2014;20:2114–29.

    Article  CAS  Google Scholar 

  24. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    Article  CAS  Google Scholar 

  25. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    Article  CAS  Google Scholar 

  26. Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 2008;8:301–9.

    Article  CAS  Google Scholar 

  27. 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;60:2474–83.

    Article  CAS  Google Scholar 

  28. Zhuge F, Ni Y, Nagashimada M, Nagata N, Xu L, Mukaida N, et al. DPP-4 Inhibition by linagliptin attenuates obesity-related inflammation and insulin resistance by regulating M1/M2 macrophage polarization. Diabetes. 2016;65:2966–79.

    Article  CAS  Google Scholar 

  29. Cranford TL, Enos RT, Velazquez KT, McClellan JL, Davis JM, Singh UP, et al. Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain. Int J Obes. 2016;40:844–51.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was funded by the Maurice and Phyllis Paykel Trust, Maurice Wilkins Center for Biodiscovery, and the University of Auckland Faculty Research Development Fund (all to TLM), and TLM is supported by a Rutherford Discovery Fellowship.

Author information

Authors and Affiliations

  1. Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Troy L. Merry, Stewart W. Masson & Shannon E. Adams

  2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand

    Troy L. Merry, Anna E. S. Brooks, Stephen M. F. Jamieson & Peter R. Shepherd

  3. School of Biological Sciences, University of Auckland, Auckland, New Zealand

    Anna E. S. Brooks

  4. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Jagdish K. Jaiswal & Stephen M. F. Jamieson

  5. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Stephen M. F. Jamieson

  6. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Peter R. Shepherd

Authors
  1. Troy L. Merry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna E. S. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stewart W. Masson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shannon E. Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jagdish K. Jaiswal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephen M. F. Jamieson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter R. Shepherd
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PRS and TLM designed the study; AESB, SWM, SEA, JKJ, SMFJ, and TLM performed the experiments; AESB, SMFJ, and TLM analyzed the data; PRS, SMFJ, and TLM wrote the paper; all authors approved the final paper.

Corresponding author

Correspondence to Troy L. Merry.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Merry, T.L., Brooks, A.E.S., Masson, S.W. et al. The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice. Int J Obes 44, 245–253 (2020). https://doi.org/10.1038/s41366-019-0355-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-019-0355-7

This article is cited by

Search

Advanced search

Quick links