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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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Related in: MedlinePlus

BM-CCR2−/− mice have a modest improvement in glucose tolerance after extended periods of HFD feeding. All GTT (left panels) and ITT (right panels) experiments were performed by injecting mice with dextrose or insulin, at doses described in RESEARCH DESIGN AND METHODS, after a 5-h morning fast. A: GTT after 6 weeks of HFD feeding (mean ± SEM; n = 8–10 mice per group). B: ITT after 6 weeks of HFD feeding (mean ± SEM; n = 4–5 mice per group). C: GTT after 12 weeks of HFD feeding (mean ± SEM; n = 3–5 mice per group). D: ITT after 12 weeks of HFD feeding (mean ± SEM; n = 7–10 mice per group). E: GTT after 20 weeks of HFD feeding (mean ± SEM; n = 8–9 mice per group). F: ITT after 20 weeks on an HFD (mean ± SEM; n = 9 mice per group). *P < 0.05 compared with the BM-CCR2+/+ group at the 15-min time point.
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Figure 1: BM-CCR2−/− mice have a modest improvement in glucose tolerance after extended periods of HFD feeding. All GTT (left panels) and ITT (right panels) experiments were performed by injecting mice with dextrose or insulin, at doses described in RESEARCH DESIGN AND METHODS, after a 5-h morning fast. A: GTT after 6 weeks of HFD feeding (mean ± SEM; n = 8–10 mice per group). B: ITT after 6 weeks of HFD feeding (mean ± SEM; n = 4–5 mice per group). C: GTT after 12 weeks of HFD feeding (mean ± SEM; n = 3–5 mice per group). D: ITT after 12 weeks of HFD feeding (mean ± SEM; n = 7–10 mice per group). E: GTT after 20 weeks of HFD feeding (mean ± SEM; n = 8–9 mice per group). F: ITT after 20 weeks on an HFD (mean ± SEM; n = 9 mice per group). *P < 0.05 compared with the BM-CCR2+/+ group at the 15-min time point.

Mentions: To examine the systemic metabolic effects of CCR2 deficiency, we performed GTTs and ITTs. We found no differences in glucose or insulin tolerance between groups at the 6- or 12-week time points (Fig. 1A–D). However, a modest improvement in glucose tolerance was found in the BM-CCR2−/− mice (P < 0.05), 15 min post-glucose injection, after 20 weeks of HFD feeding (Fig. 1E). Fasting glucose and insulin levels were not different between groups at any time (Table 1). Similar results were obtained in the global CCR2−/− mice, in which differences in glucose tolerance were not observed until after 20 weeks of HFD feeding (Supplementary Fig. 5A–C). The discrepancy in glucose tolerance between the hematopoietic and global CCR2-deficient models can be attributed to the reduced ability of mice undergoing BMT to gain weight (22). On average, BM-CCR2−/− mice weighed <40 g after 20 weeks of HFD feeding, whereas the CCR2−/− weighed >48 g during the same HFD feeding period.


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)

BM-CCR2−/− mice have a modest improvement in glucose tolerance after extended periods of HFD feeding. All GTT (left panels) and ITT (right panels) experiments were performed by injecting mice with dextrose or insulin, at doses described in RESEARCH DESIGN AND METHODS, after a 5-h morning fast. A: GTT after 6 weeks of HFD feeding (mean ± SEM; n = 8–10 mice per group). B: ITT after 6 weeks of HFD feeding (mean ± SEM; n = 4–5 mice per group). C: GTT after 12 weeks of HFD feeding (mean ± SEM; n = 3–5 mice per group). D: ITT after 12 weeks of HFD feeding (mean ± SEM; n = 7–10 mice per group). E: GTT after 20 weeks of HFD feeding (mean ± SEM; n = 8–9 mice per group). F: ITT after 20 weeks on an HFD (mean ± SEM; n = 9 mice per group). *P < 0.05 compared with the BM-CCR2+/+ group at the 15-min time point.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: BM-CCR2−/− mice have a modest improvement in glucose tolerance after extended periods of HFD feeding. All GTT (left panels) and ITT (right panels) experiments were performed by injecting mice with dextrose or insulin, at doses described in RESEARCH DESIGN AND METHODS, after a 5-h morning fast. A: GTT after 6 weeks of HFD feeding (mean ± SEM; n = 8–10 mice per group). B: ITT after 6 weeks of HFD feeding (mean ± SEM; n = 4–5 mice per group). C: GTT after 12 weeks of HFD feeding (mean ± SEM; n = 3–5 mice per group). D: ITT after 12 weeks of HFD feeding (mean ± SEM; n = 7–10 mice per group). E: GTT after 20 weeks of HFD feeding (mean ± SEM; n = 8–9 mice per group). F: ITT after 20 weeks on an HFD (mean ± SEM; n = 9 mice per group). *P < 0.05 compared with the BM-CCR2+/+ group at the 15-min time point.
Mentions: To examine the systemic metabolic effects of CCR2 deficiency, we performed GTTs and ITTs. We found no differences in glucose or insulin tolerance between groups at the 6- or 12-week time points (Fig. 1A–D). However, a modest improvement in glucose tolerance was found in the BM-CCR2−/− mice (P < 0.05), 15 min post-glucose injection, after 20 weeks of HFD feeding (Fig. 1E). Fasting glucose and insulin levels were not different between groups at any time (Table 1). Similar results were obtained in the global CCR2−/− mice, in which differences in glucose tolerance were not observed until after 20 weeks of HFD feeding (Supplementary Fig. 5A–C). The discrepancy in glucose tolerance between the hematopoietic and global CCR2-deficient models can be attributed to the reduced ability of mice undergoing BMT to gain weight (22). On average, BM-CCR2−/− mice weighed <40 g after 20 weeks of HFD feeding, whereas the CCR2−/− weighed >48 g during the same HFD feeding period.

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