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

OBJECTIVE: 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 high fat diet (HFD)-induced obesity. METHODS: C57BL/6J wild type (WT), 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 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(−/−), but not in Cx3cr1(−/−) Mice. Flow cytometric analysis of perigonadal adipose 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 vs. WT mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes. CONCLUSION: Although CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence metabolic effects of 45% HFD-induced obesity in these model conditions.