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 inflamma...
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| Format: | Article |
| Language: | English |
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BMC
2014-10-01
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| Series: | Particle and Fibre Toxicology |
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| Online Access: | https://doi.org/10.1186/s12989-014-0053-5 |
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| author | Cuiqing Liu Laura K Fonken Aixia Wang Andrei Maiseyeu Yuntao Bai Tse-Yao Wang Santosh Maurya Yi-An Ko Muthu Periasamy Timothy Dvonch Masako Morishita Robert D Brook Jack Harkema Zhekang Ying Bhramar Mukherjee Qinghua Sun Randy J Nelson Sanjay Rajagopalan |
| author_facet | Cuiqing Liu Laura K Fonken Aixia Wang Andrei Maiseyeu Yuntao Bai Tse-Yao Wang Santosh Maurya Yi-An Ko Muthu Periasamy Timothy Dvonch Masako Morishita Robert D Brook Jack Harkema Zhekang Ying Bhramar Mukherjee Qinghua Sun Randy J Nelson Sanjay Rajagopalan |
| author_sort | Cuiqing Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d36eaed32ab64f6fa6e0c2042d00be8b |
| institution | Kabale University |
| issn | 1743-8977 |
| language | English |
| publishDate | 2014-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Particle and Fibre Toxicology |
| spelling | doaj-art-d36eaed32ab64f6fa6e0c2042d00be8b2025-08-20T03:48:15ZengBMCParticle and Fibre Toxicology1743-89772014-10-0111111610.1186/s12989-014-0053-5Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetesCuiqing Liu0Laura K Fonken1Aixia Wang2Andrei Maiseyeu3Yuntao Bai4Tse-Yao Wang5Santosh Maurya6Yi-An Ko7Muthu Periasamy8Timothy Dvonch9Masako Morishita10Robert D Brook11Jack Harkema12Zhekang Ying13Bhramar Mukherjee14Qinghua Sun15Randy J Nelson16Sanjay Rajagopalan17Department of Physiology, Hangzhou Normal UniversityWexner Medical Center, The Ohio State UniversityWexner Medical Center, The Ohio State UniversityDivision of Cardiovascular Medicine, University of MarylandWexner Medical Center, The Ohio State UniversityWexner Medical Center, The Ohio State UniversityWexner Medical Center, The Ohio State UniversityDepartment of Biostatistics, University of MichiganWexner Medical Center, The Ohio State UniversityDepartment of Environmental Health Sciences, University of MichiganDepartment of Environmental Health Sciences, University of MichiganDepartment of Environmental Health Sciences, University of MichiganCenter for Integrative Toxicology, Michigan State UniversityDivision of Cardiovascular Medicine, University of MarylandDepartment of Biostatistics, University of MichiganWexner Medical Center, The Ohio State UniversityWexner Medical Center, The Ohio State UniversityDivision of Cardiovascular Medicine, University of MarylandAbstract 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.https://doi.org/10.1186/s12989-014-0053-5DiabetesParticulate matterHypothalamusInflammationIKKβ |
| spellingShingle | Cuiqing Liu Laura K Fonken Aixia Wang Andrei Maiseyeu Yuntao Bai Tse-Yao Wang Santosh Maurya Yi-An Ko Muthu Periasamy Timothy Dvonch Masako Morishita Robert D Brook Jack Harkema Zhekang Ying Bhramar Mukherjee Qinghua Sun Randy J Nelson Sanjay Rajagopalan Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes Particle and Fibre Toxicology Diabetes Particulate matter Hypothalamus Inflammation IKKβ |
| title | Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes |
| title_full | Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes |
| title_fullStr | Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes |
| title_full_unstemmed | Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes |
| title_short | Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes |
| title_sort | central ikkβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type ii diabetes |
| topic | Diabetes Particulate matter Hypothalamus Inflammation IKKβ |
| url | https://doi.org/10.1186/s12989-014-0053-5 |
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