TNF-α Gene Expression in Subcutaneous Adipose Tissue Associated with HOMA in Asian Indian Postmenopausal Women

Abstract

The present study determines the fat depot-specific expression of leptin and TNF-α and its association with biochemical parameters in postmenopausal women. A total of 108 postmenopausal women were recruited prospectively; 54 were with metabolic syndrome (cases) and 54 were without metabolic syndrome (controls). Leptin and TNF-α mRNA expression in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were done by Real Time-RT PCR. In cases, the mean (±SD) serum estrogen was significantly lower (41.33±24.90 vs. 23.95±14.45, p<0.001) while leptin (12.85±4.51 vs. 10.34±3.89, p=0.002) and TNF-α (13.81±7.13 vs. 8.00±4.38, p<0.001) were significantly higher as compared to controls. Further, the mean relative VAT mRNA expression of both leptin (0.33±0.29 vs. 0.05±0.09, p<0.001) and TNF-α (0.32±0.31 vs. 0.13±0.09, p<0.001) and expression of SAT leptin (4.91±4.01 vs. 0.50±0.92, p<0.001) also lowered significantly in cases as compared to controls. Further, the relative VAT expression of both leptin (r=−0.32, p<0.001) and TNF-α (r=−0.23, p<0.01) showed significant and negative correlation with glucose; expression of SAT leptin showed significant and positive correlation with HDL (r=0.20, p<0.05) and serum estrogen (r=0.30, p<0.01) while negative correlation with glucose (r=−0.26, p<0.01) and serum TNF-α (r=−0.29, p<0.01); and expression of SAT TNF-α showed significant and positive correlation with insulin (r=0.21, p<0.05) and HOMA (r=0.20, p<0.05). In conclusion, the VAT and SAT leptin mRNA expressions may have a modulatory role in metabolic syndrome.

Key words

adipokines - metabolic syndrome - adipose tissue - hyperinsulinemia - leptin - obesity - postmenopause

• References

• 1 Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell 2001; 104: 531-543
• 2 Saltiel AR. You are what you secrete. Nat Med 2001; 7: 887-888
• 3 Matsuzawa Y. Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006; 3: 35-42
• 4 Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327-332
• 5 Sadashiv, Tiwari S, Paul BN, Kumar S, Chandra A, Dhananjai S, Negi MP S. Adiponectin mRNA in adipose tissue and its association with metabolic risk factors in postmenopausal obese women. Hormones (Athens) 2013; 12: 119-276
• 6 Sadashiv, Tiwari S, Paul BN, Kumar S, Chandra A, Dhananjai S, Negi MP S. Over expression of resistin in adipose tissue of the obese induces insulin resistance. World J Diabetes 2012; 3: 135-141
• 7 Trayhurn P. Adipocyte biology. Obes Rev 2007; 8 (Suppl. 01) 41-44
• 8 Cao YL, Wang YX, Wang DF, Meng X, Zhang J. Correlation between omental TNF-alpha protein and plasma PAI-1 in obesity subjects. Int J Cardiol 2008; 128: 399-405
• 9 Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000; 101: 2149-2153
• 10 Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract 2005; 69: 29-35
• 11 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91
• 12 Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM, Lodish HF. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes 2002; 51: 3176-3188
• 13 Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activisceral adipose tissue ion of IKK-beta and NF-kappaB. Nat Med 2005; 11: 183-190
• 14 Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med 2006; 166: 902-908
• 15 Dominguez H, Storgaard H, Rask-Madsen C, Steffen Hermann T, Ihlemann N, Baunbjerg Nielsen D, Spohr C, Kober L, Vaag A, Torp-Pedersen C. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res 2005; 42: 517-525
• 16 Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996; 45: 881-885
• 17 Paquot N, Castillo MJ, Lefèbvre PJ, Scheen AJ. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab 2000; 85: 1316-1319
• 18 Ahima RSCP. Revisiting leptin’s role in obesity and weight loss. J Clin Invest 2008; 118: 2380-2383
• 19 Montague CT, Prins JB, Sanders L, Zhang J, Sewter CP, Digby J, Byrne CD, O’Rahilly S. Depot-related gene expression in human subcutaneous and omental adipocytes. Diabetes 1998; 47: 1384-1391
• 20 Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295
• 21 Vidal H, Auboeuf D, De Vos P, Staels B, Riou JP, Auwerx J, Laville M. The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue. J Clin Invest 1996; 98: 251-255
• 22 Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346: 570-578
• 23 Howard JK, Flier JS. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 2006; 17: 365-371
• 24 Gabrielsson BG, Johansson JM, Lönn M, Jernås M, Olbers T, Peltonen M, Larsson I, Lönn L, Sjöström L, Carlsson B, Carlsson LM. High expression of complement components in omental adipose tissue in obese men. Obes Res 2003; 11: 699-708
• 25 Dusserre E, Moulin P, Vidal H. Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 2000; 1500: 88-96
• 26 Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 2007; 56: 1010-1013
• 27 Winkler G, Kiss S, Keszthelyi L, Sápi Z, Ory I, Salamon F, Kovács M, Vargha P, Szekeres O, Speer G, Karádi I, Sikter M, Kaszás E, Dworak O, Gerö G, Cseh K. Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level. Eur J Endocrinol 2003; 149: 129-135
• 28 Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004; 145: 2273-2282
• 29 Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497
• 30 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 31 Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 1997; 46: 342-347
• 32 Hube F, Lietz U, Igel M, Jensen PB, Tornqvist H, Joost HG, Hauner H. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm Metab Res 1996; 28: 690-693
• 33 Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, Jingami H, Kawada T, Nakao K. Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 1995; 44: 855-858
• 34 You T, Yang R, Lyles MF, Gong D, Nicklas BJ. Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors. Am J Physiol Endocrinol Metab 2005; 288: E741-E747
• 35 Gottschling-Zeller H, Birgel M, Scriba D, Blum WF, Hauner H. Depot-specific release of leptin from subcutaneous and omental adipocytes in suspension culture: effect of tumor necrosis factor-alpha and transforming growth factor-beta1. Eur J Endocrinol 1999; 141: 436-442
• 36 Castracane VD, Kraemer RR, Franken MA, Kraemer GR, Gimpel T. Serum leptin concentration in women: effect of age, obesity, and estrogen administration. Fertil Steril 1998; 70: 472-477
• 37 Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 2006; 55: 978-987
• 38 Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 2013; 34: 309-338
• 39 Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-770
• 40 Münzberg H, Flier JS, Bjørbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 2004; 145: 4880-4889
• 41 Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155-1161
• 42 Hennige AM, Stefan N, Kapp K, Lehmann R, Weigert C, Beck A, Moeschel K, Mushack J, Schleicher E, Häring HU. Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. FASEB J 2006; 20: 1206-1208
• 43 Szanto I, Kahn CR. Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. PNAS 2000; 97: 2355-2360
• 44 Koistinen HA, Bastard JP, Dusserre E, Ebeling P, Zegari N, Andreelli F, Jardel C, Donner M, Meyer L, Moulin P, Hainque B, Riou JP, Laville M, Koivisto VA, Vidal H. Subcutaneous adipose tissue expression of tumour necrosis factor-alpha is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects. Eur J Clin Invest 2000; 30: 302-310
• 45 Gormez S, Demirkan A, Atalar F, Caynak B, Erdim R, Sozer V, Gunay D, Akpinar B, Ozbek U, Buyukdevrim AS. Adipose tissue gene expression of adiponectin, tumor necrosis factor-α and leptin in metabolic syndrome patients with coronary artery disease. Intern Med 2011; 50: 805-810
• 46 Bulló M, Garcia-Lorda P, Salas-Salvadó J. Plasma soluble tumor necrosis factor alpha receptors and leptin levels in normal-weight and obese women: effect of adiposity and diabetes. Eur J Endocrinol 2002; 146: 325-331
• 47 Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997; 82: 4196-4200