Adipositas und muskuläre Insulinresistenz: Charakterisierung von Mediatoren der Insulinresistenz mit Hilfe eines Co-Kultursystems
Zusammenfassung der Projektergebnisse
Adipose tissue is known to release a host of molecules, the so-called adipokines that exert a regulatory function on other tissues including muscle, liver and the vascular wall. Upon hypertrophy and inflammation of adipose tissue, these adipokines may exert a negative crosstalk and induce insulin resistance in skeletal muscle. Adiponectin may play an important role for muscle insulin sensitivity, and this project followed the hypothesis that the autocrine action of adiponectin on adipocytes may control adipokine release and thus prevent muscle insulin resistance. Human skeletal muscle cells were co-cultured with human fat cells in the presence or absence of adiponectin to analyse its capacity to restore normal insulin action. Only under these conditions adiponectin was able to prevent muscle insulin resistance. Secretome analysis of adipocytes indicated that the release of at least eight different cytokines was diminished in response to adiponectin. We therefore suggest that adiponectin operates as a key regulator of adipocyte secretory function. This autocrine action may prevent the induction of skeletal muscle insulin resistance and may partly explain the antidiabetes action of this hormone. When testing several cytokine candidates we found that MCP-1 alone impaired insulin signaling in skeletal muscle cells at doses similar to its physiological plasma concentrations. In contrast, IL-6 and IL-8 were effective at very high concentrations only. In addition, MCP-1 significantly reduced insulin-stimulated glucose uptake in the myocytes. PCR-analysis demonstrated the presence of chemokine CXC motif receptors. Our data show that human skeletal muscle cells are highly sensitive toward MCP-1, which impairs insulin signaling and glucose uptake. MCP-1 may represent a molecular link in the negative crosstalk between adipose tissue and skeletal muscle. Insulin resistance in muscle cells induced by adipocyte-derived factors was paralleled by enhanced production of ROS, ceramide, and downregulation of myogenic transcription factors. Regeneration of myotubes restored insulin signaling, but downregulation of myogenin and the release of IL-6 and IL-8 could not be restored. We therefore propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells. A deeper analysis of this process may help to discover muscular targets for the treatment of type 2 diabetes. The results of this project highlight the key role of adipocyte secretory function and the regulation by adiponectin. The high sensitivity of skeletal muscle toward MCP-1 sheds a new light on this cytokine and future clinical studies will be needed to address this novel target.
Projektbezogene Publikationen (Auswahl)
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Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors. Diabetes. 2005 Jul;54(7):2003-11
Dietze-Schroeder D, Sell H, Uhlig M, Koenen M, Eckel J
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Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AlCAR, and troglitazone. Biochem Biophys Res Commun. 2006 May 12;343(3):700-6
Sell H, Dietze-Schroeder D, Eckardt K, Eckel J
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Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle. Endocrinology. 2006 May;147(5):2458-67
Sell H, Dietze-Schroeder D, Kaiser U, Eckel J
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Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility. Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E1070-7
Sell H, Eckardt K, Taube A. Tews D, Gurgui M, Van Echten-Deckert G, Eckel J
