title: An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice.
abstract: Chronic inflammation in adipose tissue is thought to be important for the development of insulin resistance in obesity. Furthermore, the level of monocyte chemoattractant protein-1 (MCP-1) is increased not only in adipose tissue but also in the circulation in association with obesity. However, it has remained unclear to what extent the increased circulating level of MCP-1 contributes to insulin resistance. We have now examined the relevance of circulating MCP-1 to the development of insulin resistance in mice. The plasma concentration of MCP-1 was increased chronically or acutely in mice to the level observed in obese animals by chronic subcutaneous infusion of recombinant MCP-1 with an osmotic pump or by acute intravenous infusion of MCP-1 with an infusion pump, respectively. Whole-body metabolic parameters as well as inflammatory changes in adipose tissue were examined. A chronic increase in the circulating level of MCP-1 induced insulin resistance, macrophage infiltration into adipose tissue, and an increase in hepatic triacylglycerol content. An acute increase in the circulating MCP-1 concentration also induced insulin resistance but not macrophage infiltration into adipose tissue. In addition, inhibition of signaling by MCP-1 and its receptor CCR2 by administration of a novel CCR2 antagonist ameliorated insulin resistance in mice fed a high-fat diet without affecting macrophage infiltration into adipose tissue. These data indicate that an increase in the concentration of MCP-1 in the circulation is sufficient to induce systemic insulin resistance irrespective of adipose tissue inflammation.
authors.affiliation: Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Tateya
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tamori
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Hajime
authors.initials: H
authors.lastname: Kanda
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000273:Adipose Tissue / Q000276:immunology; D000818:Animals; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000097:blood*; D004041:Dietary Fats / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology; D007333:Insulin Resistance; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D054390:Receptors, CCR2