Aberrant Accumulation of Undifferentiated Myeloid Cells in the Adipose Tissue of CCR2-Deficient Mice Delays Improvements in Insulin Sensitivity

OBJECTIVE Mice with CCR2 deficiency are protected from insulin resistance but only after long periods of high-fat diet (HFD) feeding, despite the virtual absence of circulating inflammatory monocytes. We performed a time course study in mice with hematopoietic and global CCR2 deficiency to determine adipose tissue–specific mechanisms for the delayed impact of CCR2 deficiency on insulin resistance.

RESEARCH DESIGN AND METHODS Mice with global or hematopoietic CCR2 deficiency (CCR2^−/− and BM-CCR2^−/−, respectively) and wild-type controls (CCR2^+/+ and BM-CCR2^+/+, respectively) were placed on an HFD for 6, 12, and 20 weeks. Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed.

RESULTS Flow cytometry analysis showed that two different populations of F4/80⁺ myeloid cells (CD11b^loF4/80^lo and CD11b^hiF4/80^hi) accumulated in the adipose tissue of CCR2^−/− and BM-CCR2^−/− mice after 6 and 12 weeks of HFD feeding, whereas only the CD11b^hiF4/80^hi population was detected in the CCR2^+/+ and BM-CCR2^+/+ controls. After 20 weeks of HFD feeding, the CD11b^loF4/80^lo cells were no longer present in the adipose tissue of CCR2^−/− mice, and only then were improvements in adipose tissue inflammation detected. Gene expression and histological analysis of the CD11b^loF4/80^lo cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11b^loF4/80^lo cells are transiently found in wild-type mice, but CCR2 deficiency leads to the aberrant accumulation of these cells in adipose tissue.

CONCLUSIONS The discovery of this novel adipose tissue monocytic cell population provides advances toward understanding the pleiotropic role of CCR2 in monocyte/macrophage accumulation and regulation of adipose tissue inflammation.