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

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 CD11c1+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.