Abstract 16039: CX3CR1 And CCR2 Synergistically Modulate Inflammatory but Not Metabolic Effects of High-fat Feeding
Introduction: Obesity is associated with a systemic inflammatory reaction that has been associated with the development of type 2 diabetes and atherosclerosis. Substantial evidence points towards the C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) as important modulators of metabolic and inflammatory phenotypes in high fat diet (HFD)-induced obesity, but the synergistic effects of dual targeting of CX3CR1 and CCR2 have not been studied.
Hypothesis: CX3CR1 and CCR2 exert synergistic effects in HFD-induced obesity.
Methods: C57BL/6J wild type mice (WT), Cx3cr1-/-, Ccr2-/- and Cx3cr1-/-Ccr2-/- double knockout mice were fed a 45% HFD (D124551, Research Diets), which is known to promote hypertriglyceridemia and insulin resistance, for up to 6 months starting at 12-wks old (n=10-16 male mice per group).
Results: WT, Cx3cr1-/-, Ccr2-/-, and Cx3cr1-/-Ccr2-/- gained weight at a similar rate and developed similar degrees of adiposity and hyperglycemia in response to 45% HFD. All groups demonstrated progressive impairment in glucose tolerance, insulin sensitivity (by Insulin Tolerance Test), and glucose-evoked insulin secretion. A complete blood cell count with differential suggested reduced monocyte count in Ccr2-/- (22.2 ± 10.1 % of WT, mean±SEM, P<0.05) and Cx3cr1-/-Ccr2-/- (10.6 ± 1.9% of WT, P<0.05), but not in Cx3cr1-/- (82.8 ± 16.3 % of WT, P=0.45), consistent with the impaired monocytosis due to Ccr2 deficiency. FACS analysis showed that in stromal vascular cells from epididymal adipose, % of CD45(+)F4/80(+)CD11c(+)MGL1(-) M1-like macrophage was lower while CD45(+)F4/80(+)MGL1(+)CD11c(-) M2-like macrophage was higher in the Cx3cr1-/-Ccr2-/- mice vs. WT mice. In contrast, a single knockout of Cx3cr1 or Ccr2 did not affect macrophage phenotypic switching.
Conclusion: A single knockout or double knockout of Cx3cr1 and Ccr2 did not affect weight gain, glucose levels and insulin sensitivity in response to HFD. However, the Cx3cr1-/-Ccr2-/- but not the single knockout of Cx3cr1 or Ccr2 mice, showed reduced adipose macrophage activation. The results indicate that CX3CR1 and CCR2 synergistically modulate inflammatory but not metabolic effects of HFD.
Author Disclosures: H. Zhang: None. C.C. Hinkle: None. S. O’Neill: None. J. Caughey: None. E. Lynch: None. G. Lynch: None. R. Shah: None. R.S. Ahima: None. M.P. Reilly: None.
- © 2015 by American Heart Association, Inc.