title: Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes.
abstract: BACKGROUND
  Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development.
  
  
  METHODS
  KKay mice, a genetically susceptible model of Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4-8 weeks via a versatile aerosol concentrator and exposure system, or administered intra-cerebroventricular with either IKKβ inhibitor (IMD-0354) or TNFα antibody (infliximab) for 4-5 weeks simultaneously with PM2.5 exposure. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen, visceral adipose tissue and hypothalamus were collected to measure inflammatory cells using flow cytometry. Standard immunohistochemical methods and quantitative PCR were used to assess targets of interest.
  
  
  RESULTS
  PM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor [IMD-0354, n = 8 for each group)], but not TNFα blockade with infliximab [(n = 6 for each group], improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchange ratio and heat generation) and reduced peripheral inflammation in response to PM2.5.
  
  
  CONCLUSIONS
  Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Liu
authors.forename: Laura K
authors.initials: LK
authors.lastname: Fonken
authors.forename: Aixia
authors.initials: A
authors.lastname: Wang
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Bai
authors.forename: Tse-Yao
authors.initials: TY
authors.lastname: Wang
authors.forename: Santosh
authors.initials: S
authors.lastname: Maurya
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Ko
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.forename: Timothy
authors.initials: T
authors.lastname: Dvonch
authors.forename: Masako
authors.initials: M
authors.lastname: Morishita
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brook
authors.forename: Jack
authors.initials: J
authors.lastname: Harkema
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Nelson
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D000069285:Infliximab; D019570:Inhalation Exposure / Q000009:adverse effects; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010101:Oxygen Consumption / Q000187:drug effects; D052638:Particulate Matter / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D022722:Thermogenesis / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D001549:Benzamides; D001786:Blood Glucose; D007328:Insulin; D015850:Interleukin-6; D052638:Particulate Matter; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D000069285:Infliximab; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse