Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women

Abstract

OBJECTIVE: Leptin is an adipocyte-secreted hormone involved in body weight regulation, acting through the leptin receptor, localised centrally in the hypothalamus as well as peripherally, amongst others on adipose tissue. The aim of this study was to evaluate whether polymorphisms in the leptin receptor (LEPR) gene were related to obesity and body fat distribution phenotypes, such as waist and hip circumferences and the amount of visceral and subcutaneous fat.

METHODS: Three known LEPR polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, were typed on genomic DNA of 280 overweight and obese women (body mass index (BMI)>25), aged 18–60 y. General linear model (GLM) analyses were performed in 198 pre- and 82 postmenopausal women, adjusting the data for age and menopausal state, plus fat mass for the fat distribution phenotypes.

RESULTS: No associations were found between the LEPR polymorphisms and BMI or fat mass. In postmenopausal women, carriers of the Asn656 allele had increased hip circumference (P=0.03), total abdominal fat (P=0.03) and subcutaneous fat (P=0.04) measured by CT scan. Total abdominal fat was also higher in Gln223Gln homozygotes (P=0.04). Also in postmenopausal women, leptin levels were higher in Lys109Lys homozygotes (P=0.02).

CONCLUSION: In conclusion, polymorphisms in the leptin receptor gene are associated with levels of abdominal fat in postmenopausal overweight women. Since body fat distribution variables were adjusted for fat mass, these results suggest that DNA sequence variations in the leptin receptor gene play a role in fat topography and may be involved in the predisposition to abdominal obesity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue Nature 1994 372: 425–431.

    Article  CAS  Google Scholar 

  2. Lönnqvist F, Arner P, Nordfors L, Schalling M . Overexpression of the obese (ob) gene in adipose tissue of human obese subjects Nature Med 1995 1: 950–953.

    Article  Google Scholar 

  3. 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 New Engl J Med 1996 334: 292–295.

    Article  CAS  Google Scholar 

  4. Lee G-H, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM . Abnormal splicing of the leptin receptor in diabetic mice Nature 1996 379: 632–635.

    Article  CAS  Google Scholar 

  5. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP . Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice Cell 1996 84: 491–495.

    Article  CAS  Google Scholar 

  6. Chua SC, Chung WK, Wu-Peng XS, Zhang Y, Liu S-M, Tartaglia L, Leibel RL . Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor Science 1996 271: 994–996.

    Article  CAS  Google Scholar 

  7. Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim MH, Skoda RC . Defective STAT signaling by the leptin receptor in diabetic mice Proc Natl Acad Sci USA 1996 93: 6231–6235.

    Article  CAS  Google Scholar 

  8. Walder K, Lewandowski P, Morton G, Sanigorski A, de Silva A, Zimmet P, Collier GR . Leptin resistance in a polygenic, hyperleptinemic animal model of obesity and NIDDM: Psammomys obesus Int J Obes Relat Metab Disord 1999 23: 83–89.

    Article  CAS  Google Scholar 

  9. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI . Identification and expression cloning of a leptin receptor, OB-R Cell 1995 83: 1263–1271.

    Article  CAS  Google Scholar 

  10. Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF . The hypothalamic leptin receptor in humans; identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations Diabetes 1996 19: 992–994.

    Article  Google Scholar 

  11. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG . Identification of targets of leptin action in rat hypothalamus J Clin Invest 1996 98: 1101–1106.

    Article  CAS  Google Scholar 

  12. Cohen B, Novick D, Rubinstein M . Modulation of insulin activities by leptin Science 1996 274: 1185–1188.

    Article  CAS  Google Scholar 

  13. Kieffer TJ, Heller RS, Habener JF . Leptin receptors expressed on pancreatic β-cells Biochem Biophys Res Commun 1996 224: 522–527.

    Article  CAS  Google Scholar 

  14. Emilsson V, Liu Y-L, Cawthorne MA, Morton NM, Davenport M . Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion Diabetes 1997 46: 313–316.

    Article  CAS  Google Scholar 

  15. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelin M, Dina C, Chambaz J, Lacorte J-M, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction Nature 1998 392: 398–401.

    Article  Google Scholar 

  16. Rolland V, Clément K, Dugail I, Guy-Grand B, Basdevant A, Froguel P, Lavau M . Leptin receptor gene in a large cohort of massively obese subjects: no indication of the fa/fa rat mutation. Detection of an intronic variant with no association with obesity Obes Res 1998 6: 122–127.

    Article  CAS  Google Scholar 

  17. Thompson DB, Ravussin E, Bennett PH, Bogardus C . Structure and sequence variation at the human leptin receptor gene in lean and obese Pima indians Hum Mol Genet 1997 6: 675–679.

    Article  CAS  Google Scholar 

  18. Echwald SM, Sorensen TD, Sorensen TIA, Tybjaerg-Hansen A, Andersen T, Chung WK, Leibel RL, Pedersen O . Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity Biochem Biophys Res Commun 1997 233: 248–252.

    Article  CAS  Google Scholar 

  19. Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, Sothern M, Udall JN, Kahle B, Leibel RL . Exonic and intronic sequence variation in the human leptin receptor gene Diabetes 1997 46: 1509–1511.

    Article  CAS  Google Scholar 

  20. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeigue PM, Scott J, Aitman TJ . Leptin receptor gene variation and obesity: lack of association in a white British male population Hum Mol Genet 1997 6: 869–876.

    Article  CAS  Google Scholar 

  21. Francke S, Clément K, Dina C, Inoue H, Behn P, Vatin V, Basdevant A, Guy-Grand B, Permutt MA, Froguel P, Hager J . Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families Hum Genet 1997 100: 491–496.

    Article  CAS  Google Scholar 

  22. Silver K, Walston J, Chung WK, Yao F, Parikh VV, Andersen R, Cheskin LJ, Elahi D, Muller D, Leibel RL, Shuldiner AR . The Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate with traits related to obesity Diabetes 1997 46: 1898–1900.

    Article  CAS  Google Scholar 

  23. Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T, Azuma N, Natsui K, Nishimura H, Yoshimasa Y, Nishi S, Thompson DB, Nakao K . Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity Diabetologia 1997 40: 1204–1210.

    Article  CAS  Google Scholar 

  24. Chagnon YC, Chung WK, Pérusse L, Chagnon M, Leibel RL, Bouchard C . Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study Int J Obes Relat Metab Disord 1999 23: 278–286.

    Article  CAS  Google Scholar 

  25. Oksanen L, Kaprio J, Mustajoki P, Kontula K . A common pentanucleotide polymorphism of the 3'-untranslated part of the leptin receptor gene generates a putative stem-loop motif in the mRNA and is associated with serum insulin levels in obese individuals Int J Obes Relat Metab Disord 1998 22: 634–640.

    Article  CAS  Google Scholar 

  26. Alberti KGMM, Zimmet PZ for the WHO Consultation . Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and Classification of Diabetes Mellitus. Provisional report of a WHO consultation Diabetic Med 1998 15: 539–553.

    Article  CAS  Google Scholar 

  27. Lukaski HC, Johnson E, Bolonchuk WW, Lykken GI . Assessment of fat-free mass using bioelectrical measurements of the human body Am J Clin Nutr 1985 41: 810–817.

    Article  CAS  Google Scholar 

  28. Deurenberg P, Weststrate JA, Hautvast JGAJ . Changes in fat-free mass during weight loss measured by bioelectrical impedance and by densitometry Am J Clin Nutr 1989 49: 33–36.

    Article  CAS  Google Scholar 

  29. Van der Kooy K, Seidell JC . Techniques for the measurement of visceral fat: a practical guide Int J Obes Relat Metab Disord 1993 17: 187–196.

    CAS  PubMed  Google Scholar 

  30. Ma Z, Gingerich RL, Santiago JV, Klein S, Smith CH, Landt M . Radioimmunoassay of leptin in human plasma Clin Chem 1996 42: 942–946.

    CAS  Google Scholar 

  31. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988 16: 1215–1216.

    Article  CAS  Google Scholar 

  32. Terwilliger J, Ott J . Linkage disequilibrium between alleles at marker loci In: Handbook of human genetic linkage The Johns Hopkins University Press: Baltimore, MD 1994 188–198.

  33. Chagnon YC, Wilmore JH, Borecki IB, Gagnon J, Pérusse L, Chagnon M, Collier GR, Leon AS, Skinner JS, Rao DC, Bouchard C . Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE Family Study J Clin Endocrinol Metab 2000 85: 29–34.

    CAS  PubMed  Google Scholar 

  34. Heo M, Leibel RL, Boyer BB, Chung WK, Koulu M, Karvonen M, Pesonen U, Rissanen A, Laakso M, Uusitupa M, Chagnon Y, Bouchard C, Donahue PA, Burns T, Shuldiner A, Silver K, Pederson O, Echwald S, Sorensen TIA, Behn P, Permutt MA, Allison DB . A preliminary meta-analysis of the association of LEPR polymorphisms with anthropometric variables. [Abstract.] Obes Res 1999 7: 37S.

    Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. Mammès O, Betoulle D, Aubert R, Giraud V, Tuzet S, Petiet A, Coles-Linhart N, Fumeron F . Novel polymorphisms in the 5'region of the LEP gene. Association with leptin levels and response to low-calorie diet in human obesity Diabetes 1998 47: 487–489.

    Article  Google Scholar 

  37. Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Lebel P, Dallongeville J, Deeb S, Auwerx J, Amouyel P . A genetic polymorphism of the peroxisome proliferator-activated receptor g gene influences plasma leptin levels in obese humans Hum Mol Genet 1998 7: 435–440.

    Article  CAS  Google Scholar 

  38. Hixson JE, Almasy L, Cole S, Birnbaum S, Mitchell BD, Mahaney MC, Stern MP, MacCluer JW, Blangero J, Comuzzie AG . Normal variation in leptin levels is associated with polymorphisms in the Proopiomelanocortin gene, POMC J Clin Endocrinol Metab 1999 84: 3187–3191.

    CAS  PubMed  Google Scholar 

  39. Mammès O, Betoulle D, Aubert R, Fumeron F . Leptin receptor gene polymorphisms in French obese subjects. [Abstract.] Int J Obes Relat Metab Disord 1998 22 (Suppl 3): S117.

    Google Scholar 

  40. Thompson DB, Norman RA, Ravussin E, Knowler WC, Bennett P, Bogardus C . Association of the GLN223ARG polymorphism in the leptin receptor gene with plasma leptin levels, insulin secretion and NIDDM in Pima indians. [Abstract.] Diabetes 1997 46 (Suppl 1): 960.

    Google Scholar 

  41. Blakemore AIF, Lee AJ, Quinton ND, Ross RJM, Eastell R . Association of GLN223ARG polymorphism in the leptin receptor gene with serum leptin levels and BMI in postmenopausal Caucasian women. [Abstract.] Int J Obes Relat Metab Disord 1998 22 (Suppl 3): S40.

    Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the collaboration of Jan Vertommen and co-workers at the Laboratory of Endocrinology (Professor I De Leeuw) at the University of Antwerp for DNA-extraction and handling of the samples, and to Lin Gan, M.D., of the Physical Activity Sciences Laboratory, Laval University, Québec, for his contribution to the DNA studies. The genetic studies of C Bouchard and his colleagues were funded by the Medical Research Council of Canada (PG-11811, MT-13960 and GR-15187). C Bouchard is currently partially supported by the George A Bray Chair in Nutrition.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to LF Van Gaal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wauters, M., Mertens, I., Chagnon, M. et al. Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women. Int J Obes 25, 714–720 (2001). https://doi.org/10.1038/sj.ijo.0801609

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801609

Keywords

This article is cited by

Search

Quick links