2. Academic Validation
  3. The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice

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

Affiliations

  • 1 Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. t.merry@auckland.ac.nz.
  • 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. t.merry@auckland.ac.nz.
  • 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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