Journal Article

Adipose Tissue Exosome-Like Vesicles Mediate Activation of Macrophage-Induced Insulin Resistance

Robert W. Hardy, Yuelong Liu, Cunren Liu, Dongmei Sun, Sue Michalek, Zhong-bin Deng, Timothy Garvey, Xiaoyu Xiang, William E. Grizzle, Ronald Clements, Jim Mobley, Anton Poliakov, Jianhua Wang, Spandan V. Shah, Shuangqin Zhang, Huang-Ge Zhang, Xiaoying Zhuang

2009

Overview

Adipose Tissue Exosome-Like Vesicles Mediate Activation of Macrophage-Induced Insulin Resistance Zhong-bin Deng 1 , Anton Poliakov 2 , Robert W. Hardy 3 , Ronald Clements 4 , Cunren Liu 1 , Yuelong Liu 1 , Jianhua Wang 1 , Xiaoyu Xiang 1 , Shuangqin Zhang 1 , Xiaoying Zhuang 1 , Spandan V. Shah 1 , Dongmei Sun 1 , Sue Michalek 5 , William E. Grizzle 3 , Timothy Garvey 4 , Jim Mobley 2 and Huang-Ge Zhang 1 , 6 1 Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 2 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; 3 Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Albama; 4 Department of Nutrition, University of Alabama at Birmingham, Birmingham, Alabama; 5 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama; 6 Birmingham Veterans Administration Medical Center, Birmingham, Alabama. Corresponding author: Huang-Ge Zhang, huang-ge.zhang{at}ccc.uab.edu . Abstract OBJECTIVE We sought to determine whether exosome-like vesicles (ELVs) released from adipose tissue play a role in activation of macrophages and subsequent development of insulin resistance in a mouse model. RESEARCH DESIGN AND METHODS ELVs released from adipose tissue were purified by sucrose gradient centrifugation and labeled with green fluorescent dye and then intravenously injected into B6 ob/ob mice (obese model) or B6 mice fed a high-fat diet. The effects of injected ELVs on the activation of macrophages were determined through analysis of activation markers by fluorescence-activated cell sorter and induction of inflammatory cytokines using an ELISA. Glucose tolerance and insulin tolerance were also evaluated. Similarly, B6 mice with different gene knockouts including TLR2, TLR4, MyD88, and Toll-interleukin-1 receptor (TIR) domain–containing adaptor protein inducing interferon-β (TRIF) were also used for testing their responses to the injected ELVs. RESULTS ELVs are taken up by peripheral blood monocytes, which then differentiate into activated macrophages with increased secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Injection of obELVs into wild-type C57BL/6 mice results in the development of insulin resistance. When the obELVs were intravenously injected into TLR4 knockout B6 mice, the levels of glucose intolerance and insulin resistance were much lower. RBP4 is enriched in the obELVs. Bone marrow–derived macrophages preincubated with recombinant RBP4 led to attenuation of obELV-mediated induction of IL-6 and TNF-α. CONCLUSIONS ELVs released by adipose tissue can act as a mode of communication between adipose tissues and macrophages. The obELV-mediated induction of TNF-α and IL-6 in macrophages and insulin resistance requires the TLR4/TRIF pathway. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received February 13, 2009. Accepted July 27, 2009. © 2009 American Diabetes Association

• Publisher: American Diabetes Association
• Subject: Adipose Tissue - cytology / Adipose Tissue - physiology / Animals / Biological and medical sciences / Body fat / Bone marrow / Bone Marrow Cells - cytology / Bone Marrow Cells - physiology / Cell Communication - physiology / Cell Differentiation / Communication / Cytokines / Diabetes / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Exosomes - drug effects / Exosomes - physiology / Exosomes - ultrastructure / Glucose / Glucose - metabolism / Glucose Tolerance Test / Inflammation / Insulin - pharmacology / Insulin resistance / Insulin Resistance - physiology / Laboratories / Leukocytes / Macrophage Activation - physiology / Macrophages - physiology / Male / Medical sciences / Methods / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Obese / Microscopy, Electron / Monocytes - cytology / Monocytes - physiology / Obesity / Original / Proteins / Recombinant Proteins - pharmacology / Research design / Retinol-Binding Proteins, Plasma - genetics / Toll-Like Receptor 4 - deficiency / Toll-Like Receptor 4 - genetics / Tumor necrosis factor-TNF