title: Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1.
abstract: Stressors contribute to thrombosis and insulin resistance. Since obesity-related adipose inflammation is also involved in these pathological states, we assumed that stress correlates with adipose inflammation. Male mice were subjected to 2-week intermittent restraint stress. Expression of plasma lipids, monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-α, and interleukin-6), adiponectin, heat shock protein 70.1 (HSP70.1), and coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in blood and inguinal white adipose tissue (WAT) was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. To examine effects of MCP-1 blockade, animals were treated with control or neutralizing antibody, or transplanted with control or 7ND (dominant-negative form of MCP-1)-overexpressing adipose-derived stromal cells (ADSCs). Stress increased monocyte accumulation, free fatty acids, proinflammatory cytokine, and HSP70.1 and reduced adiponectin. Adipose stromal cells highly expressed MCP-1. The stress-induced adipose inflammation increased PAI-1 and TF but did not give rise to thrombus formation. Without any changes in GTT, stress worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. Neutralizing antibody and 7ND-ADSCs reversed stress-induced adipose inflammation, procoagulant state, and insulin resistance. Stress evoked adipose inflammation to increase coagulation factors and impair insulin sensitivity through adipose-derived MCP-1.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uchida
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kikuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakayama
authors.forename: Mieko
authors.initials: M
authors.lastname: Nomura
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D057134:Antibodies, Neutralizing; D001786:Blood Glucose / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D001786:Blood Glucose; D018932:Chemokine CCL2; D016207:Cytokines; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D017395:Plasminogen Activator Inhibitor 1