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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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IRΔmyel-mice are protected against obesity-induced insulin resistance.(A) Fasted blood glucose concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 33–36 mice per genotype on HFD.) (B) Fasted serum insulin concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 10 mice per genotype on HFD.) (C) Glucose Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 6–13 mice per genotype and diet.) (D) Insulin Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 4–11 mice per genotype and diet.) (E) Hepatic glucose production (HGP) of male, HFD-fed control- and IRΔmyel-mice before (basal) and during (steady state) euglycemic, hyperinsulinemic clamp analysis. (n = 12 mice per genotype.) (F) Relative expression of G6Pase and Pck1 mRNA in livers of fasted control- and IRΔmyel-mice fed HFD (n = 6 mice per genotype.) (G) Tissue-specific glucose uptake rate (GUR) of male, HFD-fed control- and IRΔmyel-mice under steady state conditions. (WAT = white adipose tissue; SM = skeletal muscle; n = 10 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; ***p≤0.001.)
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pgen-1000938-g002: IRΔmyel-mice are protected against obesity-induced insulin resistance.(A) Fasted blood glucose concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 33–36 mice per genotype on HFD.) (B) Fasted serum insulin concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 10 mice per genotype on HFD.) (C) Glucose Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 6–13 mice per genotype and diet.) (D) Insulin Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 4–11 mice per genotype and diet.) (E) Hepatic glucose production (HGP) of male, HFD-fed control- and IRΔmyel-mice before (basal) and during (steady state) euglycemic, hyperinsulinemic clamp analysis. (n = 12 mice per genotype.) (F) Relative expression of G6Pase and Pck1 mRNA in livers of fasted control- and IRΔmyel-mice fed HFD (n = 6 mice per genotype.) (G) Tissue-specific glucose uptake rate (GUR) of male, HFD-fed control- and IRΔmyel-mice under steady state conditions. (WAT = white adipose tissue; SM = skeletal muscle; n = 10 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; ***p≤0.001.)

Mentions: To address the role of myeloid cell insulin action on whole body glucose metabolism, we next determined blood glucose and serum insulin concentrations in control- and IRΔmyel-mice. Both parameters were indistinguishable between genotypes under NCD (Figure 2A and 2B). As expected, on HFD, control-mice developed significantly increased blood glucose and serum insulin concentrations suggestive of insulin resistance (Figure 2A and 2B). Glucose and insulin levels did also rise in obese IRΔmyel-mice, but strikingly, this increase was significantly blunted in these mice lacking insulin receptors in myeloid cells (Figure 2A and 2B).


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)

IRΔmyel-mice are protected against obesity-induced insulin resistance.(A) Fasted blood glucose concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 33–36 mice per genotype on HFD.) (B) Fasted serum insulin concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 10 mice per genotype on HFD.) (C) Glucose Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 6–13 mice per genotype and diet.) (D) Insulin Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 4–11 mice per genotype and diet.) (E) Hepatic glucose production (HGP) of male, HFD-fed control- and IRΔmyel-mice before (basal) and during (steady state) euglycemic, hyperinsulinemic clamp analysis. (n = 12 mice per genotype.) (F) Relative expression of G6Pase and Pck1 mRNA in livers of fasted control- and IRΔmyel-mice fed HFD (n = 6 mice per genotype.) (G) Tissue-specific glucose uptake rate (GUR) of male, HFD-fed control- and IRΔmyel-mice under steady state conditions. (WAT = white adipose tissue; SM = skeletal muscle; n = 10 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; ***p≤0.001.)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2865520&req=5

pgen-1000938-g002: IRΔmyel-mice are protected against obesity-induced insulin resistance.(A) Fasted blood glucose concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 33–36 mice per genotype on HFD.) (B) Fasted serum insulin concentrations of male control- and IRΔmyel-mice fed either NCD or HFD. (n = 6–7 mice per genotype on NCD; n = 10 mice per genotype on HFD.) (C) Glucose Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 6–13 mice per genotype and diet.) (D) Insulin Tolerance Tests were performed with male control- and IRΔmyel-mice fed NCD or HFD. (n = 4–11 mice per genotype and diet.) (E) Hepatic glucose production (HGP) of male, HFD-fed control- and IRΔmyel-mice before (basal) and during (steady state) euglycemic, hyperinsulinemic clamp analysis. (n = 12 mice per genotype.) (F) Relative expression of G6Pase and Pck1 mRNA in livers of fasted control- and IRΔmyel-mice fed HFD (n = 6 mice per genotype.) (G) Tissue-specific glucose uptake rate (GUR) of male, HFD-fed control- and IRΔmyel-mice under steady state conditions. (WAT = white adipose tissue; SM = skeletal muscle; n = 10 mice per genotype.) (Results are means ± SEM; white bars represent controls and black bars represent IRΔmyel-mice; *p≤0.05; **p≤0.01; ***p≤0.001.)
Mentions: To address the role of myeloid cell insulin action on whole body glucose metabolism, we next determined blood glucose and serum insulin concentrations in control- and IRΔmyel-mice. Both parameters were indistinguishable between genotypes under NCD (Figure 2A and 2B). As expected, on HFD, control-mice developed significantly increased blood glucose and serum insulin concentrations suggestive of insulin resistance (Figure 2A and 2B). Glucose and insulin levels did also rise in obese IRΔmyel-mice, but strikingly, this increase was significantly blunted in these mice lacking insulin receptors in myeloid cells (Figure 2A and 2B).

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