Stress Augments Insulin Resistance and Prothrombotic State
Role of Visceral Adipose-Derived Monocyte Chemoattractant Protein-1
- Yasuhiro Uchida1,
- Kyosuke Takeshita1,2⇓,
- Koji Yamamoto3,
- Ryosuke Kikuchi1,
- Takayuki Nakayama4,
- Mieko Nomura3,
- Xian Wu Cheng1,
- Kensuke Egashira5,
- Tadashi Matsushita3,
- Hideo Nakamura6 and
- Toyoaki Murohara1
- 1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- 2Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan
- 3Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan
- 4Department of Hematology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- 5Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka, Japan;
- 6Department of Pathology, Nagoya University Hospital, Nagoya, Japan.
- Corresponding author: Kyosuke Takeshita, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0828/-/DC1.
- Received June 20, 2011.
- Accepted February 7, 2012.
- © 2012 by the American Diabetes Association.
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