title: Air pollution-mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Physiology, Hangzhou Normal University, Hangzhou, China.
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Liu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Bai
authors.forename: Tse-Yao
authors.initials: TY
authors.lastname: Wang
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.forename: Aixia
authors.initials: A
authors.lastname: Wang
authors.forename: Lixian
authors.initials: L
authors.lastname: Sun
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Liubov
authors.initials: L
authors.lastname: Gushchina
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.forename: Masako
authors.initials: M
authors.lastname: Morishita
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000397:Air Pollution / Q000009:adverse effects*; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1
chemical_list: D004041:Dietary Fats; D054390:Receptors, CCR2; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1