Animal models

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

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.

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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

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.

Correspondence to Troy L. Merry.

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The authors declare no conflict of interest.

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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

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