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The agouti-related protein and body fatness in humans

Abstract

OBJECTIVE: The objective of this study was to examine the impact of a single nucleotide polymorphism (SNP) (−38C>T) in the promoter of the human agouti-related protein (hAgRP) gene on promoter affinity for transcription factors (TFs) and its possible association with body composition phenotypes.

DESIGN: Electrophoretic mobility shift assays for the functional studies and association analyses for the population studies.

SUBJECTS AND METHODS: Nuclear extracts were isolated from the mouse hypothalamus cell line GT1-7 and subjected to binding assays using oligonucleotide probes corresponding to the −38C>T region and an antibody for the E12/E47 TFs. Individuals (n?=?259) from the HERITAGE Family Study were genotyped for the −38C>T SNP and used in the association studies.

RESULTS: Electrophoretic mobility shift and supershift assays confirmed binding of the E12/E47 TF to the −38C>T site in a genotype-dependent manner. The T allele was found exclusively in the black subjects while the genotype with the higher binding affinity, CC, was significantly associated with high BMI, fat mass, and percent body fat in the black subjects of the HERITAGE Family Study.

CONCLUSIONS: The E12/E47 TF could play a role in the regulation of hAgRP expression while the population studies suggest that the TT genotype of the −38C>T SNP could play a protective role against the development of obesity in the black population of the HERITAGE Family Study.

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References

  1. Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, Abusnana S, Goldstone AP, Russell SH, Stanley SA, Smith DM, Yagaloff K, Ghatel MA, Bloom SR . A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 1998; 139: 4428–4431.

    Article  CAS  Google Scholar 

  2. Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van Der Ploeg LH, Woods SC, Seeley RJ . Long-term orexigenic effects of AgRP-(83–132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol Regul Integr Comp Physiol 2000; 279: R47–R52.

    Article  CAS  Google Scholar 

  3. Rosenfeld RD, Zeni L, Welcher AA, Narhi LO, Hale C, Marasco J, Delaney J, Gleason T, Philo JS, Katta V, Hui J, Baumgartner J, Graham M, Stark KL, Karbon W . Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. Biochemistry 1998; 37: 1641–1652.

    Article  Google Scholar 

  4. Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL . Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 1997; 17: 273–274.

    Article  CAS  Google Scholar 

  5. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS . Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278: 135–138.

    Article  CAS  Google Scholar 

  6. Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R, Stark KL . Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997; 11: 593–602.

    Article  CAS  Google Scholar 

  7. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG . Central nervous system control of food intake. Nature 2000; 404: 661–671.

    Article  CAS  Google Scholar 

  8. Ste Marie L, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD . A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 2000; 97: 12339–12344.

    Article  CAS  Google Scholar 

  9. Butler AA, Marks DL, Fan W, Kuhn CM, Bartolome M, Cone RD . Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 2001; 4: 605–611.

    Article  CAS  Google Scholar 

  10. Vink T, Hinney A, van Elburg AA, van Goozen SH, Sandkuijl LA, Sinke RJ, Herpertz-Dahlmann BM, Hebebrand J, Remschmidt H, van Engeland H, Adan RA . Association between an agouti-related protein gene polymorphism and anorexia nervosa. Mol Psychiatry 2001; 6: 325–328.

    Article  CAS  Google Scholar 

  11. Katsuki A, Sumida Y, Gabazza EC et al. Plasma levels of agouti-related protein are increased in obese men. J Clin Endocrinol Metab 2001; 86: 1921–1924.

    Article  CAS  Google Scholar 

  12. Shen CP, Wu KK, Shearman LP, Camacho R, Tota MR, Fong TM, Van Der Ploeg LH . Plasma agouti-related protein level: a possible correlation with fasted and fed states in humans and rats. J Neuroendocrinol 2002; 14: 607–610.

    Article  CAS  Google Scholar 

  13. Brown AM, Mayfield DK, Volaufova J, Argyropoulos G . The gene structure and minimal promoter of the human agouti related protein. Gene 2001; 277: 231–238.

    Article  CAS  Google Scholar 

  14. Mayfield DK, Brown AM, Page GP, Garvey WT, Shriver MD, Argyropoulos G . A role for the agouti related protein promoter in obesity and type 2 diabetes. Biochem Biophys Res Commun 2001; 287: 568–573.

    Article  CAS  Google Scholar 

  15. Wetsel WC, Eraly SA, Whyte DB, Mellon PL . Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons. Endocrinology 1993; 132: 2360–2370.

    Article  CAS  Google Scholar 

  16. Dignam JD, Lebovitz RM, Roeder RG . Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 1983; 11: 1475–1489.

    Article  CAS  Google Scholar 

  17. Bouchard C, Leon AS, Rao DC, Skinner JS, Wilmore JH, Gagnon J . The HERITAGE family study. Aims, design, and measurement protocol. Med Sci Sports Exerc 1995; 27: 721–729.

    Article  CAS  Google Scholar 

  18. Wilmore JH, Stanforth PR, Domenick MA, Gagnon J, Daw EW, Leon AS, Rao DC, Skinner JS, Bouchard C . Reproducibility of anthropometric and body composition measurements: the HERITAGE Family Study. Int J Obes Relat Metab Disord 1997; 21: 297–303.

    Article  CAS  Google Scholar 

  19. Sun XH, Baltimore D . An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers. Cell 1991; 64: 459–470.

    Article  CAS  Google Scholar 

  20. Petropoulos H, Skerjanc IS . Analysis of the inhibition of MyoD activity by ITF-2B and full-length E12/E47. J Biol Chem 2000; 275: 25095–25101.

    Article  CAS  Google Scholar 

  21. Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, Cano A . A new role for E12/E47 in the repression of E-cadherin expression and epithelial–mesenchymal transitions. J Biol Chem 2001; 276: 27424–27431.

    Article  CAS  Google Scholar 

  22. Quong MW, Romanow WJ, Murre C . E protein function in lymphocyte development. Annu Rev Immunol 2002; 20: 301–322.

    Article  CAS  Google Scholar 

  23. Morton GJ, Schwartz MW . The NPY/AgRP neuron and energy homeostasis. Int J Obes Relat Metab Disord 2001; 25 (Suppl 5): S56–S62.

    Article  CAS  Google Scholar 

  24. German MS, Blanar MA, Nelson C, Moss LG, Rutter WJ . Two related helix–loop–helix proteins participate in separate cell-specific complexes that bind the insulin enhancer. Mol Endocrinol 1991; 5: 292–299.

    Article  CAS  Google Scholar 

  25. Sharma A, Henderson E, Gamer L, Zhuang Y, Stein R . Analysis of the role of E2A-encoded proteins in insulin gene transcription. Mol Endocrinol 1997; 11: 1608–1617.

    Article  CAS  Google Scholar 

  26. Wilmore JH, Despres JP, Stanforth PR, Mandel S, Rice T, Gagnon J, Leon AS, Rao D, Skinner JS, Bouchard C . Alterations in body weight and composition consequent to 20 wk of endurance training: the HERITAGE Family Study. Am J Clin Nutr 1999; 70: 346–352.

    Article  CAS  Google Scholar 

  27. Faith MS, Pietrobelli A, Nunez C, Heo M, Heymsfield SB, Allison DB . Evidence for independent genetic influences on fat mass and body mass index in a pediatric twin sample. Pediatrics 1999; 104: 61–67.

    Article  CAS  Google Scholar 

  28. Heo M, Faith MS, Allison DB . Power and sample size for survival analysis under the Weibull distribution when the whole lifespan is of interest. Mech Ageing Dev 1998; 102: 45–53.

    Article  CAS  Google Scholar 

  29. Allison DB, Zhu SK, Plankey M, Faith MS, Heo M . Differential associations of body mass index and adiposity with all-cause mortality among men in the first and second National Health and Nutrition Examination Surveys (NHANES I and NHANES II) follow-up studies. Int J Obes Relat Metab Disord 2002; 26: 410–416.

    Article  CAS  Google Scholar 

  30. Allison DB, Heshka S, Neale MC, Heymsfield SB . Race effects in the genetics of adolescents' body mass index. Int J Obes Relat Metab Disord 1994; 18: 363–368.

    CAS  PubMed  Google Scholar 

  31. Shannon WD, Province MA, Rao DC . Tree-based recursive partitioning methods for subdividing sibpairs into relatively more homogeneous subgroups. Genet Epidemiol 2001; 20: 293–306.

    Article  CAS  Google Scholar 

  32. Parra EJ, Marcini A, Akey J et al. Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 1998; 63: 1839–1851.

    Article  CAS  Google Scholar 

  33. Parra EJ, Kittles RA, Argyropoulos G, Pfaff CL, Hiester K, Bonilla C, Sylvester N, Parrish-Gause D, Garvey WT, Jin L, McKeigue PM, Kamboh MI, Ferrell RE, Pollitzer WS, Shriver MD . Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina. Am J Phys Anthropol 2001; 114: 18–29.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by a grant from the US Army (DAMD 17-97-2-7013). The HERITAGE Family Study is supported by the NHLBI through Grants HL45670 (to CB), HL47323 (to ASL), HL47317 (to DCR), HL47327 (to JSS), and HL47321 (to JHW). Arthur S Leon is partially supported by the Henry L Taylor endowed Professorship in Exercise Science and Health Enhancement. Claude Bouchard is partially supported by the George A Bray Chair in Nutrition.

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Argyropoulos, G., Rankinen, T., Bai, F. et al. The agouti-related protein and body fatness in humans. Int J Obes 27, 276–280 (2003). https://doi.org/10.1038/sj.ijo.802201

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