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Submitted on July 29, 2005
Accepted on January 17, 2006
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany
* To whom correspondence should be addressed. E-mail: eckel{at}uni-duesseldorf.de.
Adipose tissue is a major secretory and endocrine active organ producing a variety of bioactive proteins which may regulate energy metabolism and insulin sensitivity. In several studies, we could already show that adipocyte-secretory products induce skeletal muscle insulin resistance. However, the precise nature of these factors has remained elusive. Human adipocytes were found to secrete various cytokines including IL-6, IL-8, MIP-1
/
and MCP-1. Among these candidates, MCP-1 alone impaired insulin signaling in skeletal muscle cells at doses similar to its physiological plasma concentrations (200 pg/ml) whereas IL-6, IL-8 and MIP-1 were effective at very high concentrations only. In addition, MCP-1 significantly reduced insulin-stimulated glucose uptake in the myocytes. Expression analysis of chemokine receptors in skeletal muscle cells revealed the presence of CXCR1/2 and CCR1/2/4/5/10. The action of MCP-1 on insulin signaling in skeletal muscle cells occurs via ERK1/2 activation but does not involve activation of the NF-
B pathway. In conclusion, our data show that adipocytes secrete various adipokines that may be involved in the negative crosstalk between adipose tissue and skeletal muscle. Human skeletal muscle cells are highly sensitive toward MCP-1 which impairs insulin signaling and glucose uptake at concentrations even below that found in the circulation. Other cytokines that are released by adipocytes, however, impair insulin action only at supraphysiological concentrations. Therefore, MCP-1 may represent a molecular link in the negative crosstalk between adipose tissue and skeletal muscle assigning a completely novel important role to MCP-1 besides inflammation.
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