Horm Metab Res 2004; 36(8): 564-570
DOI: 10.1055/s-2004-825762
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Novel Resistin Promoter Polymorphisms: Association with Serum Resistin Level in Japanese Obese Individuals

K.  Azuma1 , S.  Oguchi2 , Y.  Matsubara1 , T.  Mamizuka2 , M.  Murata1, 2 , H.  Kikuchi2 , K.  Watanabe2 , F.  Katsukawa3 , H.  Yamazaki3 , A.  Shimada1 , T.  Saruta1
  • 1Department of Internal Mecicine, School of Medicine
  • 2Department of Laboratory Medicine, School of Medicine
  • 3Sports Medicine Research Center, Keio University, Tokyo, Japan
Further Information

Publication History

Received 24 November 2003

Accepted after Revision 1 March 2004

Publication Date:
24 August 2004 (online)

Abstract

Objectives: Resistin, an adipocyte-secreted cytokine recently discovered in mice, has been proposed as a link between obesity and diabetes. We analyzed resistin gene polymorphisms and examined their association with serum resistin level and obesity phenotypes in humans. Subjects and Methods: Sixty young, obese, non-diabetic subjects taking no medication were studied. DNA sequencing and genotyping of identified single nucleotide polymorphisms were performed. Associations between polymorphisms and serum resistin level, BMI, body composition, fat distribution, and several indices of insulin sensitivity were examined. Moreover, single nucleotide polymorphisms in the promoter region were examined for their influence on resistin gene transcriptional activity using luciferase reporter vectors. Results: Ten non-coding single nucleotide polymorphisms were found. The -638G>A, -420C>G, and -358G>A polymorphisms in the promoter region showed marked linkage disequilibrium with each other, and were associated with serum resistin level; however, there was no association between these polymorphisms and parameters related to adiposity or insulin resistance. The results of luciferase assay revealed that -638G>A together with the -420C>G polymorphism influenced resistin gene transcriptional activity. Conclusion: We found that variability in the serum resistin level might be related to polymorphic variants of the promoter region of the gene.

References

  • 1 Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
  • 2 Banerjee R R, Lazar M A. Resistin: molecular history and prognosis.  J Mol Med. 2003;  81 218-226
  • 3 Way J M, Gorgun C Z, Tong Q, Uysal K T, Brown K K, Harrington W W, Oliver W R , Willson T M, Kliewer S A, Hotamisligil G S. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.  J Biol Chem. 2001;  276 25651-26553
  • 4 Rajala M W, Lin Y, Ranalletta M, Yang X M, Qian H, Gingerich R, Barzilai N, Scherer P E. Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue.  Mol Endocrinol. 2002;  16 1920-1930
  • 5 Maebuchi M, Machidori M, Urade R, Ogawa T, Moriyama T. Low resistin level in adipose tissue and serum in high-fat fed mice and genetically obese mice: development of an ELISA system for quantification of resistin.  Arch Biochem Biophys. 2003;  416 164-170
  • 6 Steppan C M, Brown E J, Wright C M, Bhat S, Banerjee R R, Dai C Y, Enders G H, Silberg D G, Wen X, Wu G D, Lazar M A. A family of tissue-specific resistin-like molecules.  Proc Natl Acad Sci USA. 2001;  98 502-506
  • 7 Smith S R, Bai F, Charbonneau C, Janderova L, Argyropoulos G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance.  Diabetes. 2003;  52 1611-1618
  • 8 McTernan C L, McTernan P G, Harte A L, Levick P L, Barnett A H, Kumar S. Resistin, central obesity, and type 2 diabetes.  Lancet. 2002;  359 46-47
  • 9 McTernan P G, McTernan C L, Chetty R, Jenner K, Fisher F M, Lauer M N, Crocker J, Barnett A H, Kumar S. Increased resistin gene and protein expression in human abdominal adipose tissue.  J Clin Endocrinol Metab. 2002;  87 2407-2410
  • 10 Yang R Z, Huang Q, Xu A, McLenithan J C, Eison J A, Shuldiner A R, Alkan S, Gong D W. Comparative studies of resistin expression and phylogenomics in human and mouse.  Biochem Biophys Res Commun. 2003;  310 927-935
  • 11 Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle.  Biochem Biophys Res Commun. 2001;  285 561-564
  • 12 Fain J N, Cheema P S, Bahouth S W, Lloyd H M. Resistin release by human adipose tissue explants in primary culture.  Biochem Biophys Res Commun. 2003;  300 674-678
  • 13 Savage D B, Sewter C P, Klenk E S, Segal D G, Vidal-Puig A, Considine R V, O’Rahilly S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans.  Diabetes. 2001;  50 2199-2202
  • 14 Patel L, Buckels A C, Kinghorn I J, Murdock P R, Holbrook J D, Plumpton C, Macphee C H, Smith S A. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators.  Biochem Biophys Res Commun. 2003;  300 472-476
  • 15 Zhang J, Qin Y, Zheng X, Qiu J, Zou D J. Serum resistin level in essential hypertension patients with different glucose tolerance.  Diabet Med. 2003;  20 828-831
  • 16 Yannakoulia M, Yiannakouris N, Bluher S, Matalas A L, Klimis-Zacas D, Mantzoros C S. Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentration in healthy humans.  J Clin Endocrinol Metab. 2003;  88 1730-1736
  • 17 Silha J V, Krsek M, Skrha J V, Sucharda P, Nyomba B LG, Murphy L J. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlation with insulin resistance.  Eur J Endocrinol. 2003;  149 331-335
  • 18 Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A, Saruta T. Correlation between serum resistin level and adiposity in obese individuals.  Obes Res. 2003;  11 997-1001
  • 19 Yang J, Li M, Wu C Y, Xu Q S, Deng J Y. Reduced resistin levels in patients with type 2 diabetes mellitus.  Zhonghua Yi Xue Za Zhi. 2003;  83 1471-1474
  • 20 Fehmann H C, Heyn J. Plasma resistin levels in patients with type 1 and type 2 diabetes and in healthy controls.  Horm Metab Res. 2002;  34 671-673
  • 21 Furuhashi M, Ura N, Higashiura K, Mrakami H, Shimamoto K. Circulating resistin levels in essential hypertension.  Clin Endocrinol. 2003;  59 507-510
  • 22 Monzillo L U, Hamdy O, Horton E S, Ledbury S, Mullooly C, Jarema C, Porter S, Ovalle K, Moussa A, Mantzoros C S. Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance.  Obes Res. 2003;  11 1048-1054
  • 23 Lee J H, Chan J L, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros C S. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: Cross-sectional and interventional studies in normal, insulin resistant and diabetic subjects.  J Clin Endocrinol Metab. 2003;  88 4848-4856
  • 24 Kielstein J T, Becker B, Graf S, Brabant G, Haller H, Fliser D. Increased resistin blood levels are not associated with insulin resistance in patients with renal disease.  Am J Kidney Dis. 2003;  42 62-66
  • 25 Wang H, Chu W S, Hemphill C, Elbein S C. Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians.  J Clin Endocrinol Metab. 2002;  87 2520-2524
  • 26 Pizzuti A, Argiolas A, di Paola R, Baratta R, Rauseo A, Bozzali M, Vigneri R, Dallapiccola B, Trischitta V, Frittitta L. An ATG repeat in the 3′-untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance.  J Clin Endocrinol Metab. 2002;  88 4403-4406
  • 27 Ma X, Warram J, Trischitta V, Doria A. Genetic variants at the resistin locus and risk of type 2 diabetes in Caucasians.  J Clin Endocrinol Metab. 2002;  87 4407-4410
  • 28 Tan M S, Chang S Y, Chang D M, Tsai J C, Lee Y J. Association of resistin gene 3′-untranslated region + 62G>A polymorphism with type 2 diabetes and hypertension in a Chinese population.  J Clin Endocrinol Metab. 2003;  88 1258-1263
  • 29 Osawa H, Onuma H, Murakami A, Ochi M, Nishimiya T, Kato K, Shimizu I, Fujii Y, Ohashi J, Makino H. Systematic search for single nucleotide polymorphisms in the resistin gene: the absence of evidence for the association of three identified single nucleotide polymorphisms with Japanese type 2 diabetes.  Diabetes. 2002;  51 863-866
  • 30 Sentinelli F, Romeo S, Arca M, Filippi E, Leonetti F, Banchieri M, di Mario U, Baroni M G. Human resistin gene, obesity, and type 2 diabetes: mutation analysis and population study.  Diabetes. 2002;  51 860-862
  • 31 Engert J C, Vohl M C, Williams S M, Lepage P, Loredo-Osti J C, Faith J, Dore C, Renaud Y, Burtt N P, Villeneuve A, Hirschhorn J N, Altshuler D, Groop L C, Despres J P, Gaudet D, Hudson T J. 5′ flanking variants of resistin are associated with obesity.  Diabetes. 2002;  51 1629-1634
  • 32 Urbanek M, Du Y, Silander K, Collins F S, Steppan C M, Strauss J F , Dunaif A, Spielman R S, Legro R S. Variation in resistin gene promoter not associated with polycystic ovary syndrome.  Diabetes. 2003;  52 214-217
  • 33 Yeni-Komshian H, Abbasi F, Carantoni M, Reaven G M. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers.  Diabetes Care. 2000;  23 171-175
  • 34 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
  • 35 Janke J, Engeli S, Gorzelniak K, Luft F C, Sharma A M. Resistin gene expression in human adipocytes is not related to insulin resistance.  Obes Res. 2002;  10 1-5
  • 36 Chakravarti A, Buetow K H, Waber P G, Boehm C D, Kazazian H H. Nonuniform recombination within the human beta-globin gene cluster.  Am J Hum Genet. 1984;  36 1239-1258
  • 37 Humphries S, Temple A, Lane A, Green F, Cooper J. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant.  Thromb Haemost. 1996;  74 567-572

K. Azuma

Division of Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine

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