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: Yasuhiro Uchida, Kyosuke Takeshita, Koji Yamamoto, Ryosuke Kikuchi, Takayuki Nakayama, Mieko Nomura, Xian Wu Cheng, Kensuke Egashira, Tadashi Matsushita, Hideo Nakamura, Toyoaki Murohara
• Journal: Diabetes (Diabetes) Vol. 61 Issue 6 Pg. 1552-61 (Jun 2012) ISSN: 1939-327X [Electronic] United States
• PMID: 22396205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Blood Glucose
• Chemokine CCL2
• Cytokines
• Glucose Transporter Type 4
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Plasminogen Activator Inhibitor 1

Topics

• Adipose Tissue (metabolism)
• Animals
• Antibodies, Neutralizing
• Blood Glucose (metabolism)
• Chemokine CCL2 (metabolism)
• Cytokines (blood)
• Glucose Tolerance Test
• Glucose Transporter Type 4 (metabolism)
• Inflammation (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance (physiology)
• Male
• Mice
• Monocytes (metabolism)
• Plasminogen Activator Inhibitor 1 (metabolism)
• Stress, Physiological (physiology)