Influence of Sex Hormones on Adiponectin Expression in Human Adipocytes

Abstract

Adiponectin is an adipokine with profound antidiabetic and antiatherogenic effects. Circulating adiponectin concentrations are higher in women than in men. In order to study the molecular aspects of this sex-specific dimorphism, we examined the expression of adiponectin in human fat cells under the influence of sex hormones, using SGBS cells as an in vitro model. Androgen and estradiol receptor 1 and 2 (AR, ESR1, ESR2) mRNA expression increased dramatically during adipogenic differentiation. Stimulation with human male and female serum led to a downregulation of adiponectin expression, with male serum exerting significantly stronger inhibitory properties than female serum (p<0.05). Increasing concentrations of testosterone or estradiol influenced neither adiponectin mRNA expression and secretion nor intracellular protein expression of high-, middle-, and low-molecular-weight (HMW, MMW, LMW) adiponectin multimers. These data have been verified in in vitro–differentiated primary human adipocytes. We conclude that although human adipocytes express AR, ESR1, and ESR2 and respond to testosterone treatment with a decrease in leptin expression, expression and secretion of adiponectin is unaffected by sex steroids. We hypothesize, therefore, the existence of a serum factor that is differently regulated by sex steroids and subsequently causes the sex dimorphism in circulating adiponectin levels.

adipocyte - testosterone - estradiol - gene expression

References

• 1 Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue – an update.  Horm Metab Res. 2007;  39 314-321
• 2 Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ, Burrell MA. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation.  Am J Physiol Endocrinol Metab. 2001;  280 E827-E847
• 3 Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 1996;  271 10697-10703
• 4 Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).  Biochem Biophys Res Commun. 1996;  221 286-289
• 5 Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
• 6 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
• 7 Gil-Campos M, Canete RR, Gil A. Adiponectin, the missing link in insulin resistance and obesity.  Clin Nutr. 2004;  23 963-974
• 8 Goldstein BJ, Scalia R. Adiponectin: A novel adipokine linking adipocytes and vascular function.  J Clin Endocrinol Metab. 2004;  89 2563-2568
• 9 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
• 10 Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, Matsuda M, Kondo H, Furuyama N, Kihara S, Nakamura T, Tochino Y, Funahashi T, Matsuzawa Y. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein.  Diabetes. 2002;  51 2734-2741
• 11 Bottner A, Kratzsch J, Muller G, Kapellen TM, Bluher S, Keller E, Bluher M, Kiess W. Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels.  J Clin Endocrinol Metab. 2004;  89 4053-4061
• 12 Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W, Heinze E, Teller W, Hauner H. Contribution of androgens to the gender difference in leptin production in obese children and adolescents.  J Clin Invest. 1997;  100 808-813
• 13 Korner A, Wabitsch M, Seidel B, Fischer-Posovszky P, Berthold A, Stumvoll M, Bluher M, Kratzsch J, Kiess W. Adiponectin expression in humans is dependent on differentiation of adipocytes and down-regulated by humoral serum components of high molecular weight.  Biochem Biophys Res Commun. 2005;  337 540-550
• 14 Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E, Debatin KM, Hauner H. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation.  Int J Obes Relat Metab Disord. 2001;  25 8-15
• 15 Hauner H, Skurk T, Wabitsch M. Cultures of human adipose precursor cells.  Methods Mol Biol. 2001;  155 239-247
• 16 Fischer-Posovszky P, Hebestreit H, Hofmann AK, Strauss G, Moller P, Debatin KM, Wabitsch M. Role of CD95-mediated adipocyte loss in autoimmune lipodystrophy.  J Clin Endocrinol Metab. 2006;  91 1129-1135
• 17 Xu A, Chan KW, Hoo RL, Wang Y, Tan KC, Zhang J, Chen B, Lam MC, Tse C, Cooper GJ, Lam KS. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes.  J Biol Chem. 2005;  280 18073-18080
• 18 Singh R, Artaza JN, Taylor WE, Braga M, Yuan X, Gonzalez-Cadavid NF, Bhasin S. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors.  Endocrinology. 2006;  147 141-154
• 19 Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.  J Clin Invest. 2006;  116 1784-1792
• 20 Lanfranco F, Zitzmann M, Simoni M, Nieschlag E. Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy.  Clin Endocrinol (Oxf). 2004;  60 500-507
• 21 Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids.  Am J Physiol. 1998;  274 C1645-C1652
• 22 Xu X, Pergola G De, Bjorntorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells.  Endocrinology. 1990;  126 1229-1234
• 23 Pergola G De, Xu XF, Yang SM, Giorgino R, Bjorntorp P. Up-regulation of androgen receptor binding in male rat fat pad adipose precursor cells exposed to testosterone: study in a whole cell assay system.  J Steroid Biochem Mol Biol. 1990;  37 553-558
• 24 Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3 H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway.  Endocrinology. 2003;  144 5081-5088
• 25 Ramirez ME, MacMurry MP, Wiebke GA, Felten KJ, Ren K, Meikle AW, Iverius PH. Evidence for sex steroid inhibition of lipoprotein lipase in men: comparison of abdominal and femoral adipose tissue.  Metabolism. 1997;  46 179-185
• 26 Fischer-Posovszky P, Tornqvist H, Debatin KM, Wabitsch M. Inhibition of death-receptor mediated apoptosis in human adipocytes by the insulin-like growth factor I (IGF-I)/IGF-I receptor autocrine circuit.  Endocrinology. 2004;  145 1849-1859
• 27 Simon MF, Daviaud D, Pradere JP, Gres S, Guigne C, Wabitsch M, Chun J, Valet P, Saulnier-Blache JS. Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor gamma2.  J Biol Chem. 2005;  280 14656-14662
• 28 Newell FS, Su H, Tornqvist H, Whitehead JP, Prins JB, Hutley LJ. Characterization of the transcriptional and functional effects of fibroblast growth factor-1 on human preadipocyte differentiation.  Faseb J. 2006;  20 2615-2617
• 29 Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ. Pioglitazone increases secretion of high-molecular-weight adiponectin from adipocytes.  Am J Physiol Endocrinol Metab. 2006;  291 E1100-E1105
• 30 Gui Y, Silha JV, Murphy LJ. Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse.  Obes Res. 2004;  12 1481-1491
• 31 Hector J, Schwarzloh B, Goehring J, Strate TG, Hess UF, Deuretzbacher G, Hansen-Algenstaedt N, Beil FU, Algenstaedt P. TNF-alpha alters visfatin and adiponectin levels in human fat.  Horm Metab Res. 2007;  39 250-255
• 32 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2002;  290 1084-1089
• 33 Wang B, Jenkins JR, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-alpha.  Am J Physiol Endocrinol Metab. 2005;  288 E731-E740
• 34 Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Chambaut-Guerin AM, Klein J, Paschke R. Interleukin-6 is a positive regulator of tumor necrosis factor alpha-induced adipose-related protein in 3T3-L1 adipocytes.  FEBS Lett. 2004;  560 153-157
• 35 Fasshauer M, Klein J, Kralisch S, Klier M, Lossner U, Bluher M, Paschke R. Growth hormone is a positive regulator of adiponectin receptor 2 in 3T3-L1 adipocytes.  FEBS Lett. 2004;  558 27-32
• 36 Gebert CA, Park SH, Waxman DJ. Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation.  Mol Endocrinol. 1997;  11 400-414
• 37 Waxman DJ, Ram PA, Park SH, Choi HK. Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein. Proposed role as an intracellular regulator of male-specific liver gene transcription.  J Biol Chem. 1995;  270 13262-13270

Correspondence