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DOI: 10.1055/s-0028-1093342
© Georg Thieme Verlag KG Stuttgart · New York
Effect of Conditioned Media from Mature Human Adipocytes on Insulin-stimulated Akt/PKB Phosphorylation in Human Skeletal Muscle Cells: Role of BMI and Fat Cell Size
Publikationsverlauf
received 06.05.2008
accepted 28.08.2008
Publikationsdatum:
27. Oktober 2008 (online)
![](https://www.thieme-connect.de/media/hmr/200903/lookinside/thumbnails/10.1055-s-0028-1093342-1.jpg)
Abstract
Obesity is associated with chronic low-grade inflammation. It is currently hypothesized that products secreted from fat cells not only cause this proinflammatory condition but may also have a direct impact on the development of insulin resistance in skeletal muscle. The aim of this study was to investigate if adipocyte-conditioned media interfere with insulin-stimulated Akt/PKB phosphorylation in in vitro differentiated human skeletal muscle cells. Primary human skeletal muscle cells were exposed to adipocyte-conditioned media from subjects with a wide range of BMI. Insulin-induced phosphorylation of the signaling proteins Akt/PKB and ERK-2 was analyzed using a bead-based fluorescence detection system and was correlated to BMI and fat cell size. Adipocyte-conditioned media reduced insulin-stimulated Akt/PKB phosphorylation in a manner depending on BMI and fat cell volume. This inhibition in serine phosphorylation was comparable to that observed in TNF-α-treated control cultures. Conditioned media from omental adipocytes reduced Akt/PKB phosphorylation moderately to a greater extent compared to media from subcutaneous fat cells from the same donors (p<0.05). Furthermore, there were significant associations between the concentration of selected adipokines and Akt/PKB phosphorylation. These data provide first direct evidence that secreted factors from freshly isolated mature fat cells separated according fat cell size reduce insulin-stimulated Akt/PKB phosphorylation in human skeletal muscle cells and may contribute to the pathogenesis of obesity-associated insulin resistance.
Key words
obesity - insulin resistance - adipokines
References
- 1 Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 1994; 17 961-969
- 2 Wei M, Gaskill SP, Haffner SM, Stern MP. Waist circumference as the best predictor of noninsulin dependent diabetes mellitus (NIDDM) compared to body mass index, waist/hip ratio and other anthropometric measurements in Mexican Americans – a 7-year prospective study. Obes Res. 1997; 5 16-23
- 3 Seidell JC. Obesity, insulin resistance and diabetes – a worldwide epidemic. Br J Nutr. 2000; 83 ((Suppl 1)) S5-S8
- 4 Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989; 321 337-343
- 5 Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001; 50 1612-1617
- 6 Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor α inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA. 1994; 91 4854-4858
- 7 Bastard JP, Maachi M, Nhieu JT van, Jardel C, Bruckert E, Grimaldi A, Robert JJ, Capeau J, Hainque B. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002; 87 2084-2089
- 8 Iwasaki T, Nakajima A, Yoneda M, Terauchi Y. Relationship between the serum concentrations of C-reactive protein and parameters of adiposity and insulin resistance in patients with type 2 diabetes mellitus. Endocr J. 2006; 53 345-356
- 9 Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue – an update. Horm Metab Res. 2007; 39 314-321
- 10 Festa A, D’Agostino Jr R, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000; 102 42-47
- 11 Tsiotra PC, Tsigos C, Yfanti E, Anastasiou E, Vikentiou M, Psarra K, Papasteriades C, Raptis SA. Visfatin, TNF-alpha and IL-6 mRNA expression is increased in mononuclear cells from type 2 diabetic women. Horm Metab Res. 2007; 39 758-763
- 12 Janke J, Engeli S, Gorzelniak K, Feldpausch M, Heintze U, Bohnke J, Wellner M, Herse F, Lassalle P, Luft FC, Sharma AM. Adipose tissue and circulating endothelial cell specific molecule-1 in human obesity. Horm Metab Res. 2006; 38 28-33
- 13 Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000; 43 1498-1506
- 14 Salans LB, Cushman SW, Weismann RE. Studies of human adipose tissue. Adipose cell size and number in nonobese and obese patients. J Clin Invest. 1973; 52 929-941
- 15 Harmelen V van, Skurk T, Röhrig K, Lee YM, Halbleib M, Aprath-Husmann I, Hauner H. Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int J Obes Relat Metab Disord. 2003; 27 889-895
- 16 Weisberg SP, MacCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112 1796-1808
- 17 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112 1821-1830
- 18 Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A. From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes. 2004; 53 1285-1292
- 19 Fronzo RA De, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981; 30 1000-1007
- 20 Dietze D, Koenen M, Röhrig 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
- 21 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
- 22 Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007; 92 1023-1033
- 23 Skurk T, Herder C, Kraft I, Müller-Scholze S, Hauner H, Kolb H. Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology. 2005; 146 1006-1011
- 24 Friedman JE, Ishizuka T, Shao J, Huston L, Highman T, Catalano P. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes. 1999; 48 1807-1814
- 25 Dietze D, Ramrath S, Ritzeler O, Tennagels N, Hauner H, Eckel J. Inhibitor kappaB kinase is involved in the paracrine crosstalk between human fat and muscle cells. Int J Obes Relat Metab Disord. 2004; 28 985-992
- 26 Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000; 21 697-738
- 27 Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L, Lönnqvist F, Arner P. Mapping of early signaling events in tumor necrosis factor-alpha-mediated lipolysis in human fat cells. J Biol Chem. 2002; 277 1085-1091
- 28 Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995; 96 88-98
- 29 Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest. 1997; 100 1166-1173
- 30 Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001; 286 327-334
- 31 Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004; 53 693-700
- 32 Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet. 2002; 360 57-58
- 33 Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003; 52 812-817
- 34 Herder C, Haastert B, Müller-Scholze S, Koenig W, Thorand B, Holle R, Wichmann HE, Scherbaum WA, Martin S, Kolb H. Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes. 2005; 54 ((Suppl 2)) S11-S17
- 35 Hauner H. Secretory factors from human adipose tissue and their functional role. Proc Nutr Soc. 2005; 64 163-169
- 36 Gottschling-Zeller H, Birgel M, Röhrig K, Hauner H. Effect of tumor necrosis factor alpha and transforming growth factor beta 1 on plasminogen activator inhibitor-1 secretion from subcutaneous and omental human fat cells in suspension culture. Metabolism. 2000; 49 666-671
- 37 Phillips DI, Caddy S, Ilic V, Fielding BA, Frayn KN, Borthwick AC, Taylor R. Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. Metabolism. 1996; 45 947-950
- 38 Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB, Storlien LH. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997; 46 983-988
- 39 Sell H, Eckardt K, Taube A, Tews D, Gurgui M, Echten-Deckert G, Eckel J. Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility. Am J Physiol Endocrinol Metab. 2008; 294 E1070-E1077
- 40 Frayn KN, Tan GD, Karpe F. Adipose tissue: a key target for dia-betes pathophysiology and treatment?. Horm Metab Res. 2007; 39 739-742
- 41 Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998; 83 847-850
- 42 Hube F, Birgel M, Lee YM, Hauner H. Expression pattern of tumour necrosis factor receptors in subcutaneous and omental human adipose tissue: role of obesity and non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1999; 29 672-678
- 43 Bruun JM, Lihn AS, Madan AK, Pedersen SB, Schiott KM, Fain JN, Richelsen B. Higher production of IL-8 in visceral vs. subcutaneous adipose tissue. Implication of nonadipose cells in adipose tissue. Am J Physiol Endocrinol Metab. 2004; 286 E8-E13
- 44 Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab. 2005; 90 2282-2289
- 45 Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol Rev. 1994; 74 761-811
- 46 Liu LS, Spelleken M, Röhrig K, Hauner H, Eckel J. Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. Diabetes. 1998; 47 515-522
- 47 Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95 2409-2415
- 48 Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995; 95 2111-2119
- 49 Hube F, Hauner H. The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance?. Horm Metab Res. 1999; 31 626-631
- 50 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
Correspondence
T. SkurkMD
Else Kröner-Fresenius-Centre for Nutritional Medicine
Technische Universität München
Am Forum 5
85350 Freising-Weihenstephan
Germany
Telefon: +49/8161/71 20 01
Fax: +49/8161/71 20 97
eMail: thomas.skurk@wzw.tum.de