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

  • Int J Obes (Lond). 2020 Jan;44(1):245-253. doi: 10.1038/s41366-019-0355-7.
Troy L Merry  1  2 ,  Anna E S Brooks  3  4 ,  Stewart W Masson  5 ,  Shannon E Adams  5 ,  Jagdish K Jaiswal  6 ,  Stephen M F Jamieson  3  6  7 ,  Peter R Shepherd  3  8
Affiliations
  • 1. Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. [email protected].
  • 2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. [email protected].
  • 3. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
  • 4. School of Biological Sciences, University of Auckland, Auckland, New Zealand.
  • 5. Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
  • 6. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
  • 7. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
  • 8. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
PMID: 30926949 DOI: 10.1038/s41366-019-0355-7
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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