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Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity.

Gutierrez DA, Kennedy A, Orr JS, Anderson EK, Webb CD, Gerrald WK, Hasty AH - Diabetes (2011)

Bottom Line: Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed.Gene expression and histological analysis of the CD11b(lo)F4/80(lo) cells indicated that they are a unique undifferentiated monocytic inflammatory population.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee, USA.

ABSTRACT

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(lo)F4/80(lo) and CD11b(hi)F4/80(hi)) accumulated in the adipose tissue of CCR2(-/-) and BM-CCR2(-/-) mice after 6 and 12 weeks of HFD feeding, whereas only the CD11b(hi)F4/80(hi) population was detected in the CCR2(+/+) and BM-CCR2(+/+) controls. After 20 weeks of HFD feeding, the CD11b(lo)F4/80(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(lo)F4/80(lo) cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11b(lo)F4/80(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.

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CD11bloF4/80lo cells accumulate in global CCR2−/− mice. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2+/+ mice after 6 weeks (A), 12 weeks (B), and 20 weeks (C) on an HFD. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2−/− mice after 6 weeks (D), 12 weeks (E), and 20 weeks (F) on an HFD (n = 4 biological replicates).
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Figure 4: CD11bloF4/80lo cells accumulate in global CCR2−/− mice. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2+/+ mice after 6 weeks (A), 12 weeks (B), and 20 weeks (C) on an HFD. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2−/− mice after 6 weeks (D), 12 weeks (E), and 20 weeks (F) on an HFD (n = 4 biological replicates).

Mentions: Similar to the analysis of the BM-CCR2−/− model, analysis of the SVCs of the CCR2−/− mice showed that CD11bloF4/80lo cells aberrantly accumulate in the adipose tissue of global CCR2−/− mice with similar kinetics. The cells accumulated in the adipose tissue of CCR2−/− mice after 6 or 12 weeks of HFD feeding (Fig. 4D and E), whereas no discrete population was found in the CCR2+/+ controls (Fig. 4A and B). Additionally, after 20 weeks of HFD feeding, the CD11bloF4/80lo cells were no longer found in the adipose tissue of CCR2−/− mice (Fig. 4F). Note that there is downward shift of the double-positive populations in both the CCR2+/+ and CCR2−/− mice after 20 weeks of HFD feeding (Fig. 4C and F). Identical flow conditions were used as in the earlier time points. Therefore, we hypothesize that the difference may be due to the excess lipid interference with signal detection; nonetheless, only one population of CD11b+F4/80+ cells was found in both genetic models at this time point. Global CCR2−/− mice were used for subsequent characterization of the CD11bloF4/80lo cells.


Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity.

Gutierrez DA, Kennedy A, Orr JS, Anderson EK, Webb CD, Gerrald WK, Hasty AH - Diabetes (2011)

CD11bloF4/80lo cells accumulate in global CCR2−/− mice. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2+/+ mice after 6 weeks (A), 12 weeks (B), and 20 weeks (C) on an HFD. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2−/− mice after 6 weeks (D), 12 weeks (E), and 20 weeks (F) on an HFD (n = 4 biological replicates).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198070&req=5

Figure 4: CD11bloF4/80lo cells accumulate in global CCR2−/− mice. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2+/+ mice after 6 weeks (A), 12 weeks (B), and 20 weeks (C) on an HFD. Representative contour plots of F4/80 vs. CD11b expression in SVCs from CCR2−/− mice after 6 weeks (D), 12 weeks (E), and 20 weeks (F) on an HFD (n = 4 biological replicates).
Mentions: Similar to the analysis of the BM-CCR2−/− model, analysis of the SVCs of the CCR2−/− mice showed that CD11bloF4/80lo cells aberrantly accumulate in the adipose tissue of global CCR2−/− mice with similar kinetics. The cells accumulated in the adipose tissue of CCR2−/− mice after 6 or 12 weeks of HFD feeding (Fig. 4D and E), whereas no discrete population was found in the CCR2+/+ controls (Fig. 4A and B). Additionally, after 20 weeks of HFD feeding, the CD11bloF4/80lo cells were no longer found in the adipose tissue of CCR2−/− mice (Fig. 4F). Note that there is downward shift of the double-positive populations in both the CCR2+/+ and CCR2−/− mice after 20 weeks of HFD feeding (Fig. 4C and F). Identical flow conditions were used as in the earlier time points. Therefore, we hypothesize that the difference may be due to the excess lipid interference with signal detection; nonetheless, only one population of CD11b+F4/80+ cells was found in both genetic models at this time point. Global CCR2−/− mice were used for subsequent characterization of the CD11bloF4/80lo cells.

Bottom Line: Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed.Gene expression and histological analysis of the CD11b(lo)F4/80(lo) cells indicated that they are a unique undifferentiated monocytic inflammatory population.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee, USA.

ABSTRACT

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(lo)F4/80(lo) and CD11b(hi)F4/80(hi)) accumulated in the adipose tissue of CCR2(-/-) and BM-CCR2(-/-) mice after 6 and 12 weeks of HFD feeding, whereas only the CD11b(hi)F4/80(hi) population was detected in the CCR2(+/+) and BM-CCR2(+/+) controls. After 20 weeks of HFD feeding, the CD11b(lo)F4/80(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(lo)F4/80(lo) cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11b(lo)F4/80(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.

Show MeSH
Related in: MedlinePlus