Skip to main content
SpringerLink
Log in

Linkage and Association Studies between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Québec Family Study

  • Original Articles
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

The agouti yellow mouse shows adult onset of moderate obesity and diabetes. A depressed basal lipolytic rate in adipocytes or a decreased adrenergic tone arising from antagonizing α-melanocyte-stimulating hormone (MSH) activation of melanocortin receptors (MCR) could be at the origin of the obesity phenotype.

Materials and Methods

MCR 4 and 5 (MC4R, MC5R) genes were studied in the Québec Family Study. Sequence variations were detected by Southern blot probing of restricted genomic DNA, and mRNA tissue expression was detected by RT-PCR. Subjects with a wide range of weight were used for single-point sib-pair linkage studies (maximum of 289 sibships from 124 nuclear families). Analysis of variance across genotypes in unrelated males (n = 143) and females (n = 156) was also undertaken. Body mass index (BMI), sum of six skinfolds (SF6), fat mass (FM), percent body fat (%FAT), respiratory quotient (RQ), resting metabolic rate (RMR), fasting glucose and insulin, and glucose and insulin area during an oral glucose tolerance test were analyzed.

Results

MC4R showed polymorphism with NcoI, and MC5R, with PstI and PvuII, with a heterozygosity of 0.38, 0.10, and 0.20, respectively. Linkages were observed between MC5R and BMI (p = 0.001), SF6 (p = 0.005), FM (p = 0.001), and RMR (p = 0.002), whereas associations were observed in females between MC5R and BMI (p = 0.003), and between MC4R and FM (p = 0.002) and %FAT (p = 0.004). After correction for multiple tests, these p values are lowered by one tenth. MC4R and MC5R mRNAs have been detected in brain, adipose tissue, and skeletal muscle.

Conclusions

MC4R and MC5R exibit evidence of linkage or association with obesity phenotypes, but this evidence is strongest for MC5R.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bray GA. (1992) Pathophysiology of obesity. Am. J. Clin. Nutr. 55: 488S–494S.

    Article  CAS  PubMed  Google Scholar 

  2. Bouchard C. (1994) Genetics of obesity: Overview and research directions. In: Bouchard C (ed). The Genetics of Obesity. CRC Press, Boca Raton, FL, pp. 223–233.

    Google Scholar 

  3. Chagnon YC, Bouchard C. (1996) The genetics of obesity: Advances from rodent studies. Trends Genet. 12: 441–444.

    Article  CAS  PubMed  Google Scholar 

  4. Herberg L, Coleman DL. (1977) Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 26: 59–99.

    Article  CAS  PubMed  Google Scholar 

  5. Bultman SJ, Michaud EJ, Woychik RP. (1992) Molecular characterization of the mouse agouti locus. Cell 71: 1195–1204.

    Article  CAS  PubMed  Google Scholar 

  6. Klebig ML, Wilkinson JE, Geisler JG, Woychik RP. (1995) Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc. Natl. Acad. Sci. USA 92: 4728–4732.

    Article  CAS  PubMed  Google Scholar 

  7. Mynatt RL, Miltenberger RJ, Klebig ML, Zemel MB, Wilkinson JE, Wilkison WO, Woychik RP. (1997) Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity. Proc. Natl. Acad. Sci. USA 94: 919–922.

    Article  CAS  PubMed  Google Scholar 

  8. Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI, Barsh GS. (1995) Structure and function of ASP, the human homolog of the mouse agouti gene. Hum. Mol. Genet. 4: 223–230.

    Article  CAS  PubMed  Google Scholar 

  9. Kwon HY, Bultman SJ, Löffler C, Chen W-J, Furdon PJ, Powell JG, Usala A-L, Wilkinson W, Hansmann I. (1994) Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc. Natl. Acad. Sci. USA 91: 9760–9764.

    Article  CAS  PubMed  Google Scholar 

  10. Xu W, Reed DR, Ding Y, Price RA. (1995) Absence of linkage between human obesity and the mouse agouti homologous region (20q11.2) or other markers spanning chromosome 20q. Obes. Res. 3: 559–562.

    Article  CAS  PubMed  Google Scholar 

  11. Norman RA, Leibel RL, Chung WK, Power-Kehoe L, Chua SC Jr, Knowler WC, Thompson DB, Bogardus C, Ravussin E. (1996) Absence of linkage of obesity and energy metabolism to markers flanking homologous of rodent obesity genes in Pima Indians. Diabetes 45: 1229–1232.

    Article  CAS  PubMed  Google Scholar 

  12. Zemel MB, Kim JH, Woychik RP, Michaud EJ, Kadwell SH, Patel IR, Wilkinson WO. (1995) Agouti regulation of intracellular calcium: Role in the insulin resistance of viable yellow mice. Proc. Natl. Acad. Sci. USA 92: 4733–4737.

    Article  CAS  PubMed  Google Scholar 

  13. Kim JH, Mynatt RL, Moore JW, Woychik RP, Moustaid N, Zemel MB. (1996) The effects of calcium channel blockade on agoutiinduced obesity. FASEB J. 10: 1646–1652.

    Article  CAS  PubMed  Google Scholar 

  14. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkinson WO, Cone RD. (1994) Agouti protein is an antagonist of the melanocyte-stimulating hormone receptor. Nature 371: 799–802.

    Article  CAS  PubMed  Google Scholar 

  15. Kim JH, Kiefer LL, Woychik RP, Wilkison WO, Truedale AT, Ittoop O, Willard DH, Nichois J, Zemel MB. (1997) Agouti regulation of intracellular calcium: Role of melanocortin receptors. Am. J. Physiol. 272(Endocrinol. Metab. 35): E379–E384.

    PubMed  CAS  Google Scholar 

  16. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385: 165–168.

    Article  CAS  PubMed  Google Scholar 

  17. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141.

    Article  CAS  PubMed  Google Scholar 

  18. Bouchard C. (1996) Genetic epidemiology, association and sib-pair linkage: Results from The Québec Family Study. In: Bray GA, Ryan DH (eds). Molecular and Genetic Aspects of Obesity. Louisiana State University Press, Baton Rouge, pp. 470–481.

    Google Scholar 

  19. Behnke AR, Wilmore JH. (1974) Evaluation and Regulation of Body Build and Composition. Prentice-Hall, Englewood Cliffs, NJ

    Google Scholar 

  20. Siri WE. (1976) The gross composition of the body. Adv. Biol. Med. Phys. 4: 239–280.

    Article  Google Scholar 

  21. Himes JH, Bouchard C. (1989) Validity of anthropometry in classifying youths as obese. Int. J. Obes. 13: 183–193.

    PubMed  CAS  Google Scholar 

  22. Dériaz O, Dionne F, Pérusse L, Tremblay A, Vohl M-C, Côté G, Bouchard C. (1994) DNA variation in the genes of the Na,K-adenosine triphosphatase and its relation with resting metabolic rate, respiratory quotient, and body fat. J. Clin. Invest. 93: 838–843.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Oppert JM, Nadeau A, Tremblay A, Després JP, Thériault G, Dériaz O, Bouchard C. (1995) Plasma glucose, insulin, and glucagon before and after long-term overfeeding in identical twins. Metabolism 44: 96–105.

    Article  CAS  PubMed  Google Scholar 

  24. Desbuquois B, Aurbach GD. (1971) Use of polyethylene glycol to separate free and antibody-bound peptide hormone in radioimmunoassays. J. Clin. Endocrinol. Metab. 37: 732–738.

    Article  Google Scholar 

  25. Richterich R, Dauwalder H. (1971) Determination of plasma glucose concentration by the hexokinase-glucose-6-phosphate-dehydrogenase method (in German). Schweiz. Med. Wochenschr. 101: 601–618.

    Google Scholar 

  26. Sambrook J, Fritsch EF, Maniatis T. (1989) Molecular Cloning. A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 9.16–9.19.

    Google Scholar 

  27. Reed KC, Mann DA. (1985) Rapid transfer of DNA from agarose gels to nylon membranes. Nucl. Acids Res. 13: 7207–7221.

    Article  CAS  PubMed  Google Scholar 

  28. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Waston SJ, DelValle J. (1993) Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268: 15174–15179.

    PubMed  CAS  Google Scholar 

  29. Chhajlani V, Muceniece R, Wikberg JE. (1993) Molecular cloning of a novel human melanocortin receptor. Biochem. Biophys. Res. Commun. 195: 866–873.

    Article  CAS  PubMed  Google Scholar 

  30. Gantz I, Shimoto Y, Konda Y, Miwa H, Dickinson CJ, Yamada T. (1994) Molecular cloning, expression, and characterization of a fifth melanocortin receptor. Biochem. Biophys. Res. Commun. 200: 1214–1220.

    Article  CAS  PubMed  Google Scholar 

  31. S.A.G.E. (1994) Statistical Analysis for Genetic Epidemiology, release 2.2. Computer program package available from the Department of Biometry and Genetics, LSU Medical Center, New Orleans, LA.

    Google Scholar 

  32. Gantz I, Tashiro T, Barcroft C, Konda Y, Shimoto Y, Miwa H, Glover T, Munzert G, Yamada T. (1993) Localization of the genes encoding the melanocortin-2 (adrenocorticotropic hormone) and melanocortin-3 receptors to chromosomes 18pll.2 and 20ql3.2–ql3.3 by fluorescence in situ hybridization. Genomics 18: 166–167.

    Article  CAS  PubMed  Google Scholar 

  33. Boston BA, Cone RD. (1996) Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3-L1 cell line. Endocrinology 137: 2043–2050.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Chowdhary BP, Gustavsson I, Wikberg JE, Chhajlani V. (1995) Localization of the human melanocortin-5 receptor gene (MC5R) to chromosome band 18p11.2 by fluorescence in situ hybridization. Cytogenet. Cell. Genet. 68: 79–81.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge the contribution of Guy Fournier and Lucie Allard as well as Dr. Germain Thériault for the data collection in the Québec Family Study, and François Michaud and Claude Leblanc for the management of the databases. The results of this paper were obtained in part by using the program S.A.G.E., which is supported by a U.S. Public Health Service Resource grant (1P41RR03655) from the National Center for Research Resources. This research was supported by the Medical Research Council of Canada (PG-11811).

Author information

Authors and Affiliations

  1. Physical Activity Sciences Laboratory, Kinesiology, PEPS, Laval University, Ste-Foy, Québec, G1K 7P4, Canada

    Yvon C. Chagnon, Louis Pérusse, Monique Chagnon &  Claude Bouchard

  2. Glaxo Research Institute, Research Triangle Park, North Carolina, USA

    Wen-Ji Chen & William O. Wilkison

  3. Diabetes Research Unit, Laval University Medical Center, Ste-Foy, Québec, Canada

    André Nadeau

Authors
  1. Yvon C. Chagnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen-Ji Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louis Pérusse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monique Chagnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. André Nadeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William O. Wilkison
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claude Bouchard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claude Bouchard.

Additional information

Communicated by D. F. Steiner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chagnon, Y.C., Chen, WJ., Pérusse, L. et al. Linkage and Association Studies between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Québec Family Study. Mol Med 3, 663–673 (1997). https://doi.org/10.1007/BF03401705

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03401705

Keywords

Search

Navigation