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Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance.

Mauer J, Chaurasia B, Plum L, Quast T, Hampel B, Blüher M, Kolanus W, Kahn CR, Brüning JC - PLoS Genet. (2010)

Bottom Line: Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle.Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity.This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany.

ABSTRACT
A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in mice (IR(Deltamyel)-mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance.

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Obese IRΔmyel-mice exhibit reduced macrophage marker and pro-inflammatory gene expression in stromal vascular cells of the adipose tissue.(A) Relative expression of immune cell markers F4/80, CD11c, Gr-1, CD3, CD4, CD8 and Kit mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (B) Relative expression of cytokines and chemokines TNF-α, IL-6, IL-1β, IFNγ, Arg1, CCL2/MCP1, CCL3/MIP1α, CCL5/Rantes and CXCL5 mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (C) Relative mRNA expression of adipocyte-specific genes leptin and adiponectin (adipoq) and stromal vascular cell-specific gene CD34 in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; ***p≤0.001.)
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pgen-1000938-g005: Obese IRΔmyel-mice exhibit reduced macrophage marker and pro-inflammatory gene expression in stromal vascular cells of the adipose tissue.(A) Relative expression of immune cell markers F4/80, CD11c, Gr-1, CD3, CD4, CD8 and Kit mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (B) Relative expression of cytokines and chemokines TNF-α, IL-6, IL-1β, IFNγ, Arg1, CCL2/MCP1, CCL3/MIP1α, CCL5/Rantes and CXCL5 mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (C) Relative mRNA expression of adipocyte-specific genes leptin and adiponectin (adipoq) and stromal vascular cell-specific gene CD34 in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; ***p≤0.001.)

Mentions: Since not only macrophages, but also a variety of other immune cells are highly abundant in the obese adipose tissue and contribute to the development of obesity-induced insulin resistance [12], [13], [24], we assessed mRNA expression of different immune cell markers in the stromal vascular (SV) fraction of WAT from obese control- and IRΔmyel-mice. In control mice, markers for macrophages (F4/80), dendritic cells (CD11c), granulocytes (Gr-1), T-lymphocytes (CD3, CD4, CD8) and mast cells (Kit) were highly enriched in the SV fraction compared to adipocytes (Figure 5A). However, in line with the data on whole WAT, we observed a specific reduction of the macrophage marker F4/80, but not of markers for granulocytes, mast cells, dendritic cells or T-lymphocytes, in the SV fraction of IRΔmyel-mice (Figure 5A).


Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance.

Mauer J, Chaurasia B, Plum L, Quast T, Hampel B, Blüher M, Kolanus W, Kahn CR, Brüning JC - PLoS Genet. (2010)

Obese IRΔmyel-mice exhibit reduced macrophage marker and pro-inflammatory gene expression in stromal vascular cells of the adipose tissue.(A) Relative expression of immune cell markers F4/80, CD11c, Gr-1, CD3, CD4, CD8 and Kit mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (B) Relative expression of cytokines and chemokines TNF-α, IL-6, IL-1β, IFNγ, Arg1, CCL2/MCP1, CCL3/MIP1α, CCL5/Rantes and CXCL5 mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (C) Relative mRNA expression of adipocyte-specific genes leptin and adiponectin (adipoq) and stromal vascular cell-specific gene CD34 in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; ***p≤0.001.)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2865520&req=5

pgen-1000938-g005: Obese IRΔmyel-mice exhibit reduced macrophage marker and pro-inflammatory gene expression in stromal vascular cells of the adipose tissue.(A) Relative expression of immune cell markers F4/80, CD11c, Gr-1, CD3, CD4, CD8 and Kit mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (B) Relative expression of cytokines and chemokines TNF-α, IL-6, IL-1β, IFNγ, Arg1, CCL2/MCP1, CCL3/MIP1α, CCL5/Rantes and CXCL5 mRNA in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (C) Relative mRNA expression of adipocyte-specific genes leptin and adiponectin (adipoq) and stromal vascular cell-specific gene CD34 in adipocytes (A) and stromal vascular (SV) fraction of male control- and IRΔmyel-mice fed HFD. (n = 5 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; ***p≤0.001.)
Mentions: Since not only macrophages, but also a variety of other immune cells are highly abundant in the obese adipose tissue and contribute to the development of obesity-induced insulin resistance [12], [13], [24], we assessed mRNA expression of different immune cell markers in the stromal vascular (SV) fraction of WAT from obese control- and IRΔmyel-mice. In control mice, markers for macrophages (F4/80), dendritic cells (CD11c), granulocytes (Gr-1), T-lymphocytes (CD3, CD4, CD8) and mast cells (Kit) were highly enriched in the SV fraction compared to adipocytes (Figure 5A). However, in line with the data on whole WAT, we observed a specific reduction of the macrophage marker F4/80, but not of markers for granulocytes, mast cells, dendritic cells or T-lymphocytes, in the SV fraction of IRΔmyel-mice (Figure 5A).

Bottom Line: Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle.Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity.This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany.

ABSTRACT
A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in mice (IR(Deltamyel)-mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance.

Show MeSH
Related in: MedlinePlus