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Endocrinology. 2010 Mar;151(3):971-9. doi: 10.1210/en.2009-0926. Epub 2010 Jan 7.

An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice.

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1
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

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.

PMID:
20056828
DOI:
10.1210/en.2009-0926
[Indexed for MEDLINE]

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