Expression of Chemokine Receptors in Insulin-resistant Human Skeletal Muscle Cells

Abstract

Adipokines including chemokines are able to induce insulin resistance in human skeletal muscle cells, which may also be relevant for the observed link between obesity and diabetes. This study is aimed to analyze the expression of chemokine CC motif receptors (CCRs) in the insulin-resistant state in human skeletal muscle cells. Differentiated skeletal muscle cells were incubated for 24-72 hours with high concentrations of glucose and insulin (GI) or TNFα. In addition, myocytes were co-stimulated with monocyte chemotactic protein (MCP)-1 or adipocyte-conditioned medium (CM) and TNFα for 24 and 48 hours. Treatment with GI rapidly induced insulin resistance whereas TNFα impaired insulin signaling in a more chronic fashion (48-72 h). CM and MCP-1 also induced insulin resistance that was, however, not increased by co-stimulation with TNFα. Expression of CCR2 was decreased during differentiation but up-regulated in insulin-resistant myocytes after treatment with GI (24-72 h) and TNFα (72 h). Expression of CCR4 and CCR10 was down-regulated after treatment with TNFα, MCP-1, and CM. Our data show that the expression of CCR2, CCR4, and CCR10 is differentially regulated by different insulin resistance-inducing treatments in myotubes. However, we could not find a clear correlation between the level of insulin resistance and CCR expression in myotubes. In conclusion, we propose that upregulation of CCR2 in skeletal muscle does not represent a major step leading to muscle insulin resistance.

Key words

insulin resistance - skeletal muscle - chemokine receptor

References

• 1 Petersen KF, Shulman GI. Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus.  Am J Cardiol. 2002;  90 11-18
• 2 Kahn BB, Flier JS. Obesity and insulin resistance.  J Clin Invest. 2000;  106 473-481
• 3 Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ.  Proc Nutr Soc. 2001;  60 329-339
• 4 Frayn KN. Obesity and metabolic disease: is adipose tissue the culprit?.  Proc Nutr Soc. 2005;  64 7-13
• 5 Sell H, Eckel J, Dietze-Schroeder D. Pathways leading to muscle insulin resistance - The muscle - fat connection.  Arch Physiol Biochem. 2006;  112 105-113
• 6 Dietze D, Koenen M, Rohrig K, Horikoshi H, Hauner H, Eckel J. Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes.  Diabetes. 2002;  51 2369-2376
• 7 Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes.  Mol Cell Endocrinol. 2001;  175 81-92
• 8 Sell H, Dietze-Schroeder D, Kaiser U, Eckel J. Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle.  Endocrinology. 2006;  147 2458-2467
• 9 Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation.  N Engl J Med. 2006;  354 610-621
• 10 Bastard JP, Maachi M, Lagathu C. et al . Recent advances in the relationship between obesity, inflammation, and insulin resistance.  Eur Cytokine Netw. 2006;  17 4-12
• 11 Dietze-Schroeder D, Sell H, Uhlig M, Koenen M, Eckel J. Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors.  Diabetes. 2005;  54 2003-2011
• 12 Huang C, Somwar R, Patel N, Niu W, Torok D, Klip A. Sustained exposure of L6 myotubes to high glucose and insulin decreases insulin-stimulated GLUT4 translocation but upregulates GLUT4 activity.  Diabetes. 2002;  51 2090-2098
• 13 Savage DB, Petersen KF, Shulman GI. Mechanisms of insulin resistance in humans and possible links with inflammation.  Hypertension. 2005;  45 828-833
• 14 Weisberg SP, Hunter D, Huber R. et al . CCR2 modulates inflammatory and metabolic effects of high-fat feeding.  J Clin Invest. 2006;  116 115-124
• 15 De Paepe B, De Bleecker JL. Beta-chemokine receptor expression in idiopathic inflammatory myopathies.  Muscle Nerve. 2005;  31 621-627
• 16 Mine S, Okada Y, Tanikawa T, Kawahara C, Tabata T, Tanaka Y. Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein-1 in patients with diabetes mellitus.  Biochem Biophys Res Commun. 2006;  344 780-785
• 17 Weber C, Draude G, Weber KS, Wubert J, Lorenz RL, Weber PC. Downregulation by tumor necrosis factor-alpha of monocyte CCR2 expression and monocyte chemotactic protein-1-induced transendothelial migration is antagonized by oxidized low-density lipoprotein: A potential mechanism of monocyte retention in atherosclerotic lesions.  Atherosclerosis. 1999;  145 115-123
• 18 Weber KS, Nelson PJ, Grone HJ, Weber C. Expression of CCR2 by endothelial cells: Implications for MCP-1 mediated wound injury repair and In vivo inflammatory activation of endothelium.  Arterioscler Thromb Vasc Biol. 1999;  19 2085-2093
• 19 Yang B, Houlberg K, Millward A, Demaine A. Polymorphisms of chemokine and chemokine receptor genes in Type 1 diabetes mellitus and its complications.  Cytokine. 2004;  26 114-121
• 20 Veillard NR, Braunersreuther V, Arnaud C. et al . Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages.  Atherosclerosis. 2006;  188 51-58
• 21 Ishibashi M, Egashira K, Hiasa K. et al . Antiinflammatory and antiarteriosclerotic effects of pioglitazone.  Hypertension. 2002;  40 687-693
• 22 Steffens S, Veillard NR, Arnaud C. et al . Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.  Nature. 2005;  434 782-786
• 23 Strle K, Broussard SR, McCusker RH. et al . C-Jun N-Terminal Kinase Mediates Tumor Necrosis Factor-{alpha} Suppression of Differentiation in Myoblasts.  Endocrinology. 2006;  147 4363-4373

1 These authors contributed equally to this work.

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