Inflammatory Mechanisms in Obesity-induced Insulin Resistance

ISSN 1007-7626 CN 11-3870 / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2012 8 28 8 692 ~ 699 1 * 2 1 041000 2 475004 2 R589 2 Inflammatory Mechanisms in Obesity-induced Insulin Resistance YANG Yong-Qing 1 * YANG Ming-Qing 2 1 College of Life Sciences Shanxi Normal University Linfen 2 Yellow River Conservancy Technical Institute Kaifeng 041000 Shanxi China 475004 Henan China Abstract Obesity induces chronic metabolic disorders such as type 2 diabetes dyslipidaemia hypertension and nonalcoholic fatty liver which endanger human health Insulin resistance IR is common observed in these diseases It has been demonstrated that the development of IR is associated with a mild state of chronic systemic inflammation with the activation of several inflammatory pathways and insulin signal transduction defects This review discusses the recent advancement of connections among obesity inflammation and IR It might provide valuable information for the understanding of inflammatory mechanisms in obesity induces insulin resistance and help to develop new therapeutic approaches for obesity-related diseases Key words obesity adipose tissue inflammation insulin resistance 2 1 2012-03-19 2012-04-23 β No 30972091 No ZR09005 * Tel 0357-3010121 E-mail yyqing71@ 163 com Received March 19 2012 Accepted April 23 2012 Supported by National Natural Science Foundation of China No 30972091 Program for Top Young Academic Leaders of Higher Learning Institutions of Shanxi Natural Science Foundation of Shanxi Normal University No ZR09005 and Scientific Research Startup Foundation of Shanxi Normal University for Ph D Program free fatty acids FFAs 2 3 * Corresponding author Tel 0357-3010121 E-mail yyqing71@ 163 com

8 693 1 1 1 1 4 5 4 2 2 1 fat body 1 insulin receptor substrate IRS 4 5 IRS 6 IRS-1-6 8 IRS 1 8 IRS-1 2 1 9 protein tyrosine phosphatase-1b PTP1B IRS-1 2 10 IRS-1 2 SOCS suppressor of cytokine signaling 6 9 10 TNFα tumor necrosis factor alpha IL interleukin -6 IL-1β IRS-1 JNK IKKβ 2 2 AP-1 activator IRS-1 protein-1 NFκB TNFα IL-6 IL-1β IRS-1 JNK IKKβ PKC ERK1 /2 S6K1 IL-8 7 11 Fig 1 1 2 SOCS IRS-1 2 2 1 JNK JNK mitogen activated protein kinase MAPK 2

694 28 Fig 1 Inflammatory signaling interferes with insulin-receptor signaling by serine / threonine phosphorylation of IRS-1 IRS-1 interacts with the juxtamembrane domain of the IR which phosphorylates the IRS proteins Tyrosine phosphorylated IRS proteins leads to activation of several downstream effectors of the insulin Ins signaling However obesity-related stimuli such as TNF-α IL-6 IL-1β resistin FFAs and cellular stress activate inflammatory kinases that phosphorylate the IRS proteins on Ser / Thr residues leading to impairment of insulin response and insulin resistance 11 JNK IRS-1 18 1 JNK1 IRS-1 IKKβ IRS-1 JNK2 JNK1 17-19 12 JNK 2 2 4 PKC PKC db / db leptin PKC-θ PKC-δ 13 JNK FFAs 2 2 2 ERK1 /2 ERK1 /2 MAPK A IRS-1 20 PKC-θ JNK IKKβ 21 ERK1 /2 IRS-1 PKC-θ SOCS-3 IRS-1 22 PKC 9 14 ERK p62 ERK1 /2 2 2 5 S6K1 S6K1 ribosomal protein S6 kinase 1 15 db / db ERK1 IRS-1 / PI3K / Akt / mtor 16 ERK1 /2 8 2 2 3 IKKβ IKKβ S6K1 IRS-1 23 24 S6K1 IKKβ IRS-1 17 IKKβ 25

8 695 I interleukin-1 receptor I IL-1R I 3 39 IL-1α IL-1β FFAs 3 1 4 IL-8 IL-18 IL-8 3 1 TNFα IL-6 IL-1α IL-1β JNK heat shock protein Hsp 60 IKKβ ERK1 /2 PKC S6K1 7 26 3 1 1 TNFα TNFα 1 TNFα IL-6 IL-8 1 TNFα 42 3 IRS-1 9 10 28-30 TNFα 3 2 27 TNFα 3T3-L1 IKKβ JNK ERK1 /2 S6K1 IRS-1 SOCS- 3 2 1 resistin PTP1B IL- 6 IL-8 IL-1β 10 SOCS-3 IRS-1 IRS-1 43 3 1 2 IL-6 IL-6 44 35% IL-6 IRS-1 45 31 IL-6 TNFα 43 32 IL-6 JNK 3 2 2 adiponectin ERK1 /2 IRS-1 2 SOCS IRS-1 PTP1B TNFα IL-6 IRS-1 33 46 IL-6 47 3 1 3 IL-1 IL-1α and IL-1β IRS-2 IL-1α 3T3-L1 ERK1 /2 48 IRS-1 IRS-1 SOCS3 34 35 3 2 3 leptin ob IL-1α 36 IL-1β 50 IL-1β IL-6 JAK 2 26 Janus kinase -STAT3 signal transducers and IL-1β 3T3-L1 activators of transcription 3 SOCS3 ERK1 /2 IRS-1 IRS-1 50 IRS-1 mrna 14 37 38 IL-1 40 IL-18 3T3-L1 ERK1 /2 41 IL-8 IL-18 Hsp60 ERK1 /2 JNK p38 IKKβ 49 ERK IRS-1

696 28 50 51 3 5 52 reactive oxygen species ROS 3 3 FFAs JNK IKKβ IRS-1 FFAs 1 61 FFAs JNK TNFα IL-6 53 FFAs 60 JNK PKCθ IKKβ IRS-1 ER 21 53 FFAs Toll-like receptor TLR 4 TNFα IL-6 IL-1β NADPH JNK IKKβ inducible nitric oxide synthase inos 54 TLR4 FFAs FFAs TLR4 ROS 60 62 63 55 TLR4 ROS 60 64 FFAs PPARγ LXRα FFAs 4 1 3 4 endoplasmic activating transcription factor 6 IRE-1 PERK JNK References IKKβ IRS-1 ATF6 ER 56 ER IRE-1 PERK ATF6 XBP-1 X-box binding protein- 1 57 ER 58 J FFAs ER 1 56 59 ER 875S-883S oxidative stress 60 ROS 1 62 ROS FFAs reticulum ER ER 1 ER IKKβ JNK1 /2 ERK1 /2 PKCθ S6K1 IRS-1 ER PTP1B UPR unfolded protein response IRS-1 ER UPR 3 IRE-1 inositolrequiring enzyme-1 PERK PKR- like endoplasmic-reticulum kinase ATF6 1 Hotamisligil G S Nature 2006 444 7121 860-867 Inflammation and metabolic disorders J 2 García-Escobar E Rodríguez-Pacheco F Haro-Mora JJ et al Effect of insulin analogues on 3T3-l1 adipogenesis and lipolysis J Eur J Clin Invest 2011 41 9 979-986 3 Stienstra R van Diepen J A Tack C J et al Inflammasome is a central player in the induction of obesity and insulin resistance Proc Natl Acad Sci U S A 2011 108 37 15324-15329 4 Roth J Szulc A L Danoff A Energy evolution and human diseases an overview J Am J Clin Nutr 2011 93 4

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