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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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The obesity-associated systemic pro-inflammatory state is reduced in IRΔmyel-mice.(A) Serum TNF-α concentration in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 12 mice per genotype on NCD; n = 21 mice per genotype on HFD.) (B) Percentage of serum high molecular weight (HMW) from total adiponectin in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 10–12 mice per genotype and diet.) (C) In vitro phosphorylation of c-Jun (p-c-Jun) in skeletal muscle (SM) and liver lysates from male, HFD-fed control- and IRΔmyel-mice. Total JNK input was used as loading control. (representative western blot shown). (D) Densitometrical analysis of phospho-c-Jun vs total JNK. (AU = arbitrary units; SM = skeletal muscle; n = 6 mice per genotype.) (E) Relative expression of F4/80, TNF-α and IL-6 mRNA in skeletal muscle (SM) and liver of male, HFD-fed control- and IRΔmyel-mice. (n = 6 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; n.s. = not significant.)
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pgen-1000938-g003: The obesity-associated systemic pro-inflammatory state is reduced in IRΔmyel-mice.(A) Serum TNF-α concentration in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 12 mice per genotype on NCD; n = 21 mice per genotype on HFD.) (B) Percentage of serum high molecular weight (HMW) from total adiponectin in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 10–12 mice per genotype and diet.) (C) In vitro phosphorylation of c-Jun (p-c-Jun) in skeletal muscle (SM) and liver lysates from male, HFD-fed control- and IRΔmyel-mice. Total JNK input was used as loading control. (representative western blot shown). (D) Densitometrical analysis of phospho-c-Jun vs total JNK. (AU = arbitrary units; SM = skeletal muscle; n = 6 mice per genotype.) (E) Relative expression of F4/80, TNF-α and IL-6 mRNA in skeletal muscle (SM) and liver of male, HFD-fed control- and IRΔmyel-mice. (n = 6 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; n.s. = not significant.)

Mentions: As insulin resistance in response to obesity and high fat feeding has been demonstrated to arise from increased concentrations of local and circulating pro-inflammatory cytokines [21] and from a reduction of circulating adiponectin concentrations [22], [23], we determined these parameters in control- and IRΔmyel-mice. Exposure of control-mice to HFD induced a marked increase of serum TNF-α concentrations compared to animals fed NCD. Strikingly, this obesity-induced increase in TNF-α was completely blunted in IRΔmyel-mice (Figure 3A). Moreover, while high fat feeding significantly reduced the portion of high molecular weight (HMW) adiponectin of total serum adiponectin in control animals, this diet-induced reduction was not observed in IRΔmyel-mice (Figure 3B).


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)

The obesity-associated systemic pro-inflammatory state is reduced in IRΔmyel-mice.(A) Serum TNF-α concentration in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 12 mice per genotype on NCD; n = 21 mice per genotype on HFD.) (B) Percentage of serum high molecular weight (HMW) from total adiponectin in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 10–12 mice per genotype and diet.) (C) In vitro phosphorylation of c-Jun (p-c-Jun) in skeletal muscle (SM) and liver lysates from male, HFD-fed control- and IRΔmyel-mice. Total JNK input was used as loading control. (representative western blot shown). (D) Densitometrical analysis of phospho-c-Jun vs total JNK. (AU = arbitrary units; SM = skeletal muscle; n = 6 mice per genotype.) (E) Relative expression of F4/80, TNF-α and IL-6 mRNA in skeletal muscle (SM) and liver of male, HFD-fed control- and IRΔmyel-mice. (n = 6 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; n.s. = not significant.)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2865520&req=5

pgen-1000938-g003: The obesity-associated systemic pro-inflammatory state is reduced in IRΔmyel-mice.(A) Serum TNF-α concentration in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 12 mice per genotype on NCD; n = 21 mice per genotype on HFD.) (B) Percentage of serum high molecular weight (HMW) from total adiponectin in male control- and IRΔmyel-mice fed either NCD or HFD. (n = 10–12 mice per genotype and diet.) (C) In vitro phosphorylation of c-Jun (p-c-Jun) in skeletal muscle (SM) and liver lysates from male, HFD-fed control- and IRΔmyel-mice. Total JNK input was used as loading control. (representative western blot shown). (D) Densitometrical analysis of phospho-c-Jun vs total JNK. (AU = arbitrary units; SM = skeletal muscle; n = 6 mice per genotype.) (E) Relative expression of F4/80, TNF-α and IL-6 mRNA in skeletal muscle (SM) and liver of male, HFD-fed control- and IRΔmyel-mice. (n = 6 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; n.s. = not significant.)
Mentions: As insulin resistance in response to obesity and high fat feeding has been demonstrated to arise from increased concentrations of local and circulating pro-inflammatory cytokines [21] and from a reduction of circulating adiponectin concentrations [22], [23], we determined these parameters in control- and IRΔmyel-mice. Exposure of control-mice to HFD induced a marked increase of serum TNF-α concentrations compared to animals fed NCD. Strikingly, this obesity-induced increase in TNF-α was completely blunted in IRΔmyel-mice (Figure 3A). Moreover, while high fat feeding significantly reduced the portion of high molecular weight (HMW) adiponectin of total serum adiponectin in control animals, this diet-induced reduction was not observed in IRΔmyel-mice (Figure 3B).

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