Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes.
Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes.
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中枢 IKKbeta 抑制可预防空气污染介导的外周炎症和 II 型糖尿病的加重。
DOI：
10.1186/s12989-014-0053-5
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发表时间：
2014-10-30
影响因子：
10
通讯作者：
Rajagopalan S
中科院分区：
文献类型：
--
作者：
Liu C;Fonken LK;Wang A;Maiseyeu A;Bai Y;Wang TY;Maurya S;Ko YA;Periasamy M;Dvonch T;Morishita M;Brook RD;Harkema J;Ying Z;Mukherjee B;Sun Q;Nelson RJ;Rajagopalan S
先前的实验和流行病学数据支持暴露于细微环境颗粒物（空气动力学直径<2.5 μm，PM2.5）与胰岛素抵抗/II型糖尿病（II型DM）之间的联系。我们研究了下丘脑炎症在PM2.5介导的糖尿病发展中的作用。将II型DM的遗传易感模型KKay小鼠通过多功能气溶胶浓缩器和暴露系统分配到浓缩PM2.5或过滤空气（FA）中4-8周，或在PM2.5暴露的同时脑室内给予IKKβ抑制剂（IMD-0354）或TNFα抗体（英夫利西单抗）4-5周。评估葡萄糖耐量、胰岛素敏感性、耗氧量和产热率。在安乐死时，收集血液、脾脏、内脏脂肪组织和下丘脑以使用流式细胞术测量炎性细胞。标准免疫组织化学方法和定量PCR用于评估目标。PM2.5暴露可导致高血糖和胰岛素抵抗，并伴有下丘脑IL-6、TNFα和IKKβ mRNA表达和小胶质细胞/星形胶质细胞反应性增加。通过脑室内给予IKKβ抑制剂靶向NFκB通路[IMD-0354，每组n = 8]，而不是用英夫利西单抗阻断TNFα [（每组n = 6]]，改善了葡萄糖耐量、胰岛素敏感性、纠正了能量稳态（O2消耗、CO2产生、呼吸交换率和产热），并减少了对PM2.5的外周炎症反应。IKKβ的中枢抑制可预防PM2.5介导的外周炎症和II型糖尿病的加重。这些结果为空气污染如何介导胰岛素抵抗和II型糖尿病的易感性提供了新的见解。
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. 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. 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. 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.
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影响因子：
10
作者：
Liu C;Bai Y;Xu X;Sun L;Wang A;Wang TY;Maurya SK;Periasamy M;Morishita M;Harkema J;Ying Z;Sun Q;Rajagopalan S
通讯作者：
Rajagopalan S
影响因子：
7.7
作者：
Lumeng, Carey N.;DeYoung, Stephanie M.;Saltiel, Alan R.
通讯作者：
Saltiel, Alan R.
DOI：
10.3109/10253890.2011.607524
发表时间：
2012-03-01
影响因子：
2.3
作者：
Julio-Pieper, Marcela;O'Mahony, Cliona M.;Cryan, John F.
通讯作者：
Cryan, John F.
影响因子：
168.9
作者：
Lim, Stephen S.;Vos, Theo;Flaxman, Abraham D.;Danaei, Goodarz;Shibuya, Kenji;Adair-Rohani, Heather;Amann, Markus;Anderson, H. Ross;Andrews, Kathryn G.;Aryee, Martin;Atkinson, Charles;Bacchus, Loraine J.;Bahalim, Adil N.;Balakrishnan, Kalpana;Balmes, John;Barker-Collo, Suzanne;Baxter, Amanda;Bell, Michelle L.;Blore, Jed D.;Blyth, Fiona;Bonner, Carissa;Borges, Guilherme;Bourne, Rupert;Boussinesq, Michel;Brauer, Michael;Brooks, Peter;Bruce, Nigel G.;Brunekreef, Bert;Bryan-Hancock, Claire;Bucello, Chiara;Buchbinder, Rachelle;Bull, Fiona;Burnett, Richard T.;Byers, Tim E.;Calabria, Bianca;Carapetis, Jonathan;Carnahan, Emily;Chafe, Zoe;Charlson, Fiona;Chen, Honglei;Chen, Jian Shen;Cheng, Andrew Tai-Ann;Child, Jennifer Christine;Cohen, Aaron;Colson, K. Ellicott;Cowie, Benjamin C.;Darby, Sarah;Darling, Susan;Davis, Adrian;Degenhardt, Louisa;Dentener, Frank;Des Jarlais, Don C.;Devries, Karen;Dherani, Mukesh;Ding, Eric L.;Dorsey, E. Ray;Driscoll, Tim;Edmond, Karen;Ali, Suad Eltahir;Engell, Rebecca E.;Erwin, Patricia J.;Fahimi, Saman;Falder, Gail;Farzadfar, Farshad;Ferrari, Alize;Finucane, Mariel M.;Flaxman, Seth;Fowkes, Francis Gerry R.;Freedman, Greg;Freeman, Michael K.;Gakidou, Emmanuela;Ghosh, Santu;Giovannucci, Edward;Gmel, Gerhard;Graham, Kathryn;Grainger, Rebecca;Grant, Bridget;Gunnell, David;Gutierrez, Hialy R.;Hall, Wayne;Hoek, Hans W.;Hogan, Anthony;Hosgood, H. Dean, III;Hoy, Damian;Hu, Howard;Hubbell, Bryan J.;Hutchings, Sally J.;Ibeanusi, Sydney E.;Jacklyn, Gemma L.;Jasrasaria, Rashmi;Jonas, Jost B.;Kan, Haidong;Kanis, John A.;Kassebaum, Nicholas;Kawakami, Norito;Khang, Young-Ho;Khatibzadeh, Shahab;Khoo, Jon-Paul;Kok, Cindy;Laden, Francine;Lalloo, Ratilal;Lan, Qing;Lathlean, Tim;Leasher, Janet L.;Leigh, James;Li, Yang;Lin, John Kent;Lipshultz, Steven E.;London, Stephanie;Lozano, Rafael;Lu, Yuan;Mak, Joelle;Malekzadeh, Reza;Mallinger, Leslie;Marcenes, Wagner;March, Lyn;Marks, Robin;Martin, Randall;McGale, Paul;McGrath, John;Mehta, Sumi;Mensah, George A.;Merriman, Tony R.;Micha, Renata;Michaud, Catherine;Mishra, Vinod;Hanafiah, Khayriyyah Mohd;Mokdad, Ali A.;Morawska, Lidia;Mozaffarian, Dariush;Murphy, Tasha;Naghavi, Mohsen;Neal, Bruce;Nelson, Paul K.;Miquel Nolla, Joan;Norman, Rosana;Olives, Casey;Omer, Saad B.;Orchard, Jessica;Osborne, Richard;Ostro, Bart;Page, Andrew;Pandey, Kiran D.;Parry, Charles D. H.;Passmore, Erin;Patra, Jayadeep;Pearce, Neil;Pelizzari, Pamela M.;Petzold, Max;Phillips, Michael R.;Pope, Dan;Pope, C. Arden, III;Powles, John;Rao, Mayuree;Razavi, Homie;Rehfuess, Eva A.;Rehm, Juergen T.;Ritz, Beate;Rivara, Frederick P.;Roberts, Thomas;Robinson, Carolyn;Rodriguez-Portales, Jose A.;Romieu, Isabelle;Room, Robin;Rosenfeld, Lisa C.;Roy, Ananya;Rushton, Lesley;Salomon, Joshua A.;Sampson, Uchechukwu;Sanchez-Riera, Lidia;Sanman, Ella;Sapkota, Amir;Seedat, Soraya;Shi, Peilin;Shield, Kevin;Shivakoti, Rupak;Singh, Gitanjali M.;Sleet, David A.;Smith, Emma;Smith, Kirk R.;Stapelberg, Nicolas J. C.;Steenland, Kyle;Stoeckl, Heidi;Stovner, Lars Jacob;Straif, Kurt;Straney, Lahn;Thurston, George D.;Tran, Jimmy H.;Van Dingenen, Rita;van Donkelaar, Aaron;Veerman, J. Lennert;Vijayakumar, Lakshmi;Weintraub, Robert;Weissman, Myrna M.;White, Richard A.;Whiteford, Harvey;Wiersma, Steven T.;Wilkinson, James D.;Williams, Hywel C.;Williams, Warwick;Wilson, Nicholas;Woolf, Anthony D.;Yip, Paul;Zielinski, Jan M.;Lopez, Alan D.;Murray, Christopher J. L.;Ezzati, Majid
通讯作者：
Ezzati, Majid
影响因子：
15.9
作者：
Block, Michelle L.;Calderon-Garciduenas, Lilian
通讯作者：
Calderon-Garciduenas, Lilian