Air pollution-mediated susceptibility to inflammation and insulin resistance: Influence of CCR2 pathways in mice

Cuiqing Liu, Xiaohua Xu, Yuntao Bai, Tse Yao Wang, Xiaoquan Rao, Aixia Wang, Lixian Sun, Zhekang Ying, Liubov Gushchina, Andrei Maiseyeu, Masako Morishita, Qinghua Sun, Jack R. Harkema, Sanjay Rajagopalan

Research output: Contribution to journalArticle

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Abstract

Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5- mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2-/- male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2-/- mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2-/- mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalEnvironmental health perspectives
Volume122
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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CCR2 Receptors
Air Pollution
Insulin Resistance
Inflammation
Intra-Abdominal Fat
Glucose
Lipid Metabolism
Liver
Skeletal Muscle
Myography
AMP-Activated Protein Kinases
Euthanasia
High Fat Diet
p38 Mitogen-Activated Protein Kinases
Blood Vessels
Adipose Tissue
Epidemiologic Studies
Flow Cytometry
Fatty Acids
Spleen

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

Cite this

Air pollution-mediated susceptibility to inflammation and insulin resistance : Influence of CCR2 pathways in mice. / Liu, Cuiqing; Xu, Xiaohua; Bai, Yuntao; Wang, Tse Yao; Rao, Xiaoquan; Wang, Aixia; Sun, Lixian; Ying, Zhekang; Gushchina, Liubov; Maiseyeu, Andrei; Morishita, Masako; Sun, Qinghua; Harkema, Jack R.; Rajagopalan, Sanjay.

In: Environmental health perspectives, Vol. 122, No. 1, 01.01.2014, p. 17-26.

Research output: Contribution to journalArticle

Liu, C, Xu, X, Bai, Y, Wang, TY, Rao, X, Wang, A, Sun, L, Ying, Z, Gushchina, L, Maiseyeu, A, Morishita, M, Sun, Q, Harkema, JR & Rajagopalan, S 2014, 'Air pollution-mediated susceptibility to inflammation and insulin resistance: Influence of CCR2 pathways in mice', Environmental health perspectives, vol. 122, no. 1, pp. 17-26. https://doi.org/10.1289/ehp.1306841
Liu, Cuiqing ; Xu, Xiaohua ; Bai, Yuntao ; Wang, Tse Yao ; Rao, Xiaoquan ; Wang, Aixia ; Sun, Lixian ; Ying, Zhekang ; Gushchina, Liubov ; Maiseyeu, Andrei ; Morishita, Masako ; Sun, Qinghua ; Harkema, Jack R. ; Rajagopalan, Sanjay. / Air pollution-mediated susceptibility to inflammation and insulin resistance : Influence of CCR2 pathways in mice. In: Environmental health perspectives. 2014 ; Vol. 122, No. 1. pp. 17-26.
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T1 - Air pollution-mediated susceptibility to inflammation and insulin resistance

T2 - Influence of CCR2 pathways in mice

AU - Liu, Cuiqing

AU - Xu, Xiaohua

AU - Bai, Yuntao

AU - Wang, Tse Yao

AU - Rao, Xiaoquan

AU - Wang, Aixia

AU - Sun, Lixian

AU - Ying, Zhekang

AU - Gushchina, Liubov

AU - Maiseyeu, Andrei

AU - Morishita, Masako

AU - Sun, Qinghua

AU - Harkema, Jack R.

AU - Rajagopalan, Sanjay

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5- mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2-/- male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2-/- mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2-/- mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR.

AB - Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5- mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2-/- male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2-/- mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2-/- mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR.

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