Synergistic Modulation of Inflammatory but Not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1

Obesity (Silver Spring). 2017 Aug;25(8):1410-1420. doi: 10.1002/oby.21900. Epub 2017 Jun 26.

Abstract

Objective: The purpose of the study was to explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of obesity induced by a high-fat diet (HFD).

Methods: C57BL/6J wild-type, Cx3cr1-/- , Ccr2-/- , and Cx3cr1-/- Ccr2-/- double-knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12 weeks of age.

Results: All groups gained weight at a similar rate and developed a similar degree of adiposity, hyperglycemia, glucose intolerance, and impairment of insulin sensitivity in response to HFD. As expected, the circulating monocyte count was decreased in Ccr2-/- and Cx3cr1-/- Ccr2-/- mice but not in Cx3cr1-/- mice. Flow cytometric analysis of perigonadal adipose tissue of male, but not female, mice revealed trends to lower CD11c+MGL1- M1-like macrophages and higher CD11c-MGL1+ M2-like macrophages as a percentage of CD45+F4/80+CD11b+ macrophages in Cx3cr1-/- Ccr2-/- mice versus wild-type mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes.

Conclusions: Although CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence the metabolic effects of a 45% HFD-induced obesity in these model conditions.

MeSH terms

  • Animals
  • Body Composition
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / metabolism*
  • Diet, High-Fat / adverse effects*
  • Female
  • Glucose Intolerance / etiology
  • Glucose Intolerance / genetics
  • Inflammation
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / etiology
  • Obesity / genetics
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*
  • Weight Gain*

Substances

  • CX3C Chemokine Receptor 1
  • Ccr2 protein, mouse
  • Cx3cr1 protein, mouse
  • Insulin
  • Receptors, CCR2