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.
Leptin, a hormone primarily secreted by the adipocytes, was identified in 1994,1 and has been shown to play an important role in body weight regulation. In humans, leptin (LEP) gene expression is increased in adipose tissue of obese subjects2 and blood leptin levels are higher in most of these individuals.3 A strong correlation is found between leptin concentrations and total body fat.3 Therefore, a state of leptin resistance has been proposed as a potential mechanism for the development of human obesity, in analogy with the insulin resistance seen in type 2 diabetes. A single-gene mutation animal model providing support for this notion is the db/db mouse, in which a genetic defect in the leptin receptor causes leptin resistance and leads to a phenotype similar to the ob/ob mouse, characterised by obesity and insulin resistance, but with high levels of circulating leptin.4,5,6,7 Moreover, leptin resistance has recently been described in a polygenic rodent model, Psammomys obesus.8
The leptin receptor (LEPR) is expressed primarily in the brain, mainly in the choroid plexus and hypothalamic regions such as arcuate nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus and mediolateral hypothalamus,4,9,10,11 but is also widely distributed in peripheral tissues including lung, kidneys, spleen, testes, uterus, lymph nodes, liver, pancreas and adipocytes.4,7,9,12,13,14
Three sisters with LEPR deficiency were recently shown to be characterised by severe early-onset obesity with several metabolic disturbances.15 This is, however, a very rare condition and in most obese humans, no such mutation can be found.10,16 In contrast, several common polymorphisms of the LEPR gene have been uncovered.10,16,17,18,19,20 None of them seems to have a major effect on obesity.10,16,18,20,21,22,23 In the Québec Family Study, significant linkages were observed between LEPR markers and several adiposity and body composition variables, the strongest result being observed between Gln223Arg and fat mass.24 LEPR markers have also been associated with obesity-related phenotypes in Pima Indians,17 in Danish subjects25 and in French Caucasians.21
We have typed three LEPR polymorphisms, all three located in the extracellular binding domain of the receptor, in overweight and obese women, to evaluate whether these gene variants are associated with weight, body composition and fat distribution. The DNA sequence variants resulted in two non-conservative changes (changes in charge): glutamine to arginine at codon 223 (Gln223Arg) in exon 6 as reported previously10 and lysine to asparagine at codon 656 (Lys656Asn) in exon 14; and a conservative change: lysine to arginine at codon 109 (Lys109Arg) in exon 4, both as described earlier.19
Subjects were 280 Caucasian women visiting the outpatient obesity clinic at the University Hospital of Antwerp, who were overweight (25 ≤body mass index (BMI)<30 kg/m2) or obese (BMI≥30 kg/m2). Most subjects were sedentary. Patients with known diabetes were excluded from the study. Subjects defined as being diabetic or with impaired glucose tolerance, based on fasting and 2 h post-glucose load glucose levels using the WHO-criteria,26 were also excluded. Other exclusion criteria were pregnancy, the use of antidepressants or medication known to influence glucose tolerance, appetite or metabolic rate, kidney or liver disease, and specific endocrine diseases such as Cushing's disease or hypothyroidism (TSH-levels above 4 µU/l). All subjects were clinically examined by a physician and shown to be in general good health. The study protocol was approved by the Ethical Committee of the University Hospital Antwerp and subjects gave informed consent.
All measurements were performed in the morning with the patients in a fasting state. Height was measured to the nearest 0.5 cm, body weight was measured with a digital scale to the nearest 0.1 kg; BMI was calculated as weight (in kg) over height (in m)2. Waist circumference was measured at mid-level between the lower rib margin and the iliac crest, and hip circumference at the level of the trochanter major. The waist-to-hip ratio (WHR) was calculated from these two circumference values. Fat mass (in kg), percentage body fat and fat free mass (in kg) were assessed by bio-impedance (using a BIA-101, RJL Systems, Detroit) as described by Lukaski27 and calculated with the formula of Deurenberg.28 A computerised tomography (CT) scan was performed at the L4-L5 level to determine visceral, subcutaneous and total abdominal fat areas, according to the technique described by Van der Kooy et al.29
A fasting blood sample was drawn to measure leptin levels in 80 subjects. A serum sample was frozen and stored at −80°C until analysis in batch. Serum leptin levels were measured using a radioimmunoassay, as described previously.30
Genomic DNA was extracted from whole blood by a method adapted from Miller et al.31 Human leucocyte nuclei were precipitated, washed and lysed in SDS and pronase (Boehringer Mannheim). Proteins were precipitated by addition of a saturated NaCl solution, and DNA was subsequently precipitated with ethanol and dissolved in a Tris-EDTA solution (pH 7.5). The three restriction fragment length polymorphisms (RFLPs) used have been described elsewhere.10,19 Polymerase chain reaction (PCR) was performed using 100 ng of genomic DNA, 300 nM of each primer, 200 µM dNTPs and 0.5 U Taq polymerase in PCR buffer (Pharmacia Biotech, Baie d'Urfé, Canada) in a total volume of 20 µl. PCR consisted of one cycle of denaturation for 3 min at 95°C, annealing for 1 min at 55°C, and extension for 1 min at 72°C, followed by 40 cycles at 95°C for 30 s, annealing at 55°C for 30 s and extension at 72°C for 30 s, and a final extension at 72°C for 10 min (GeneAmp 9600 Thermocycler, Perkin Elmer, Foster City, CA, USA). PCR products were digested overnight at 37°C with 5 U of HaeIII, MspI or BstUI restriction enzymes (New England Biolabs, Mississauga, Canada) for the Lys109Arg, Glu223Arg and Lys656Asn polymorphisms, respectively, and DNA fragments were separated on 3% agarose gel electrophoresis.
The normality of the phenotypic distribution was verified for each variable individually, and phenotypes that were not distributed normally were log-transformed, in order to normalise them. A GLM (general linear model) procedure was used to test for differences between the different genotypes at each polymorphism, and results were considered significant if P<0.05. Analyses were performed on phenotypes adjusted for age, menopausal state and fat mass as covariates in the model, except for BMI, fat mass and fat-free mass which were only adjusted for age and menopausal state. Subjects were divided in two groups according to menopausal state: 198 women were premenopausal and 82 postmenopausal. If no clinical data on menopausal state were available, subjects were defined as postmenopausal when age was above 55, or when follicle stimulating hormone (FSH)≥15 U/L (n=3). The interaction between menopausal state and genotype was tested with an interaction term in the model. When this interaction term was significant (P<0.05), the analyses were repeated for pre- and postmenopausal women separately. Since frequencies of the homozygotes for the variant alleles were low in each subgroup, analyses were performed by carrier status, ie carriers of the rare allele (heterozygotes plus homozygotes together) were compared to the noncarriers.
Nine phenotypes were tested for three markers, for a total of 27 tests performed. The Bonferroni-corrected α-level for multiple testing would thus be 0.0019. However, if we apply this correction very strictly the risk of type II error will be increased, and thereby valuable information may be lost. Since the purpose of this study is to explore possible associations between LEPR gene variants and obesity phenotypes, we have chosen to report all results with unadjusted P-values, and take the issue into consideration in the interpretation of the results.
All statistical analyses were performed with the SAS statistical software package (version 6.12). Linkage disequilibrium among the alleles of the three LEPR polymorphisms was tested with the EH program (Columbia University, NY).32
The mean age of the subjects was 39±11 (mean±s.d.) y (range 18–60 y). Anthropometric and metabolic characteristics are shown in Table 1. All women were overweight or obese, with a mean BMI of 34.8±5.4, and a range from 25.9 to 53.6 kg/m2. Pre- and postmenopausal women did not differ in body weight, but postmenopausal women had more visceral fat and a larger waist circumference. Metabolic abnormalities which are known to be associated with abdominal fat were also significantly higher in postmenopausal women.
Genotype and allele frequencies
The genotype and allele frequencies for the three LEPR polymorphisms are presented in Table 2. The genotypes at each of the three markers were in Hardy–Weinberg equilibrium.
The three polymorphisms were in linkage disequilibrium (P<0.001). All 10 subjects who were homozygotes for the Asn variant allele at the Lys656Asn polymorphism were also homozygotes for the wild-type allele at the two other polymorphisms; subjects homozygous for the Arg allele at the Lys109Arg polymorphism were all homozygotes for the Lys allele at the Lys656Asn polymorphism; homozygotes for the Gln allele at the Gln223Arg polymorphism were either homozygotes or heterozygotes for the Lys allele of the Lys109Arg polymorphism, but none of them was homozygote for the variant allele.
Associations of LEPR polymorphisms with leptin levels
Leptin levels were measured in 57 pre- and 23 postmenopausal women. No significant differences across genotypes were observed in premenopausal women (Table 3). In the group of postmenopausal women only, an association with the Lys109Arg polymorphism was found (P=0.02), the Lys109Lys homozygotes showing higher leptin levels compared to the Arg carriers (a mean of 20 ng/dl more), despite the fact that the former had a significantly lower BMI (30.8±1.9 compared to 36.6±2.0, P=0.04).
Associations of LEPR polymorphisms with anthropometric variables
No associations were found between any of the three LEPR polymorphisms and body weight, BMI or fat mass (Table 3). A significant association was found for the hip circumference with Lys656Asn (P=0.03), and for total abdominal fat with Gln223Arg (P=0.04).
A significant interaction effect between menopausal state and the Lys109Arg genotype was seen for BMI (P=0.01), and with the Lys656Asn genotype for subcutaneous and total abdominal fat (both P=0.03). These phenotypes were further analysed in pre- and postmenopausal women separately, and significant results were only found in postmenopausal women (Table 4). In this group, a trend (P=0.08) for a somewhat (2.3 kg/m2) higher BMI was seen in Arg109 carriers. Also in postmenopausal women only, significant associations with Lys656Asn were found for the hip circumference (P=0.04), subcutaneous fat (P=0.03) and total abdominal fat (P=0.04), measured by CT-scan and adjusted for variability in fat mass. Carriers of the Asn656 variant allele showed a 3 cm larger hip circumference, and respectively 58 and 59 cm2 larger subcutaneous and total abdominal fat areas than the Lys656Lys homozygotes. An association (P=0.03) was also found between total abdominal fat and Gln223Arg in postmenopausal women, with the Gln223Gln homozygotes having on average 64 cm2 more total abdominal fat than the Arg223 allele carriers. A similar trend was seen for subcutaneous fat (P=0.08).
In this study, we evaluated whether polymorphisms in the LEPR gene were associated with obesity phenotypes, especially with body composition and abdominal fat level, adjusted for total body fat. To this end, three LEPR polymorphisms were typed in a group of overweight and obese women, with a wide range of BMI, in whom extensive anthropometry was performed, including intra-abdominal fat distribution by CT-scan.
The genotype and allele frequencies were comparable to those reported previously in obese as well as in normal-weight Caucasian subjects.18,20,24,33,34 A linkage disequilibrium was observed between the three markers which had been previously reported for Gln223Arg and Lys656Asn,22 but not for Lys109Arg.
Previous reports on these LEPR polymorphisms have not found any association between them and BMI10,20 or percentage of body fat.17 In one study, a small effect on BMI was reported for the Lys656Asn polymorphism, but this was found only in a lean population, and was not observed in obese subjects.20 In Pima indians, three other polymorphisms in the LEPR gene were found to be associated with differences in percentage body fat, but no associations with body fat were found for the LEPR polymorphisms studied here.17 In the Québec Family Study, linkage was observed between Gln223Arg and fat mass, BMI, skinfold measurements and fat-free mass.24 However, no significant associations were found between the three polymorphisms and body composition phenotypes after adjusting for age, sex and height, except for a weak association between fat-free mass and Lys656Asn in obese females.24 In the Heritage Family Study, linkage was observed for Lys109Arg with BMI and fat mass, and an association with BMI and fat mass was reported for the Gln223Arg, but only in Caucasian males (parental generation).33 Preliminary results of a meta-analysis of nine different studies, with a total of 3269 subjects, males and females, showed no significant association of any of these three LEPR genotypes with BMI or waist circumference, after controlling for age and sex.34
In the present study, we also could not find any associations between the LEPR markers and BMI and body fat. However, some trends were observed for body fat distribution phenotypes. Associations between Lys656Asn and hip circumference, total abdominal and subcutaneous fat, and between Gln223Arg and abdominal fat were observed in postmenopausal women. These results were obtained after adjustment for fat mass. It should be noted that waist circumference reflects primarily total abdominal fat, both visceral and subcutaneous, while hip circumference gives an estimate of gluteal subcutaneous fat, but also of muscle mass.
An association between blood leptin levels and subcutaneous fat distribution was reported previously, a phenomenon that is thought to be related to the higher leptin secretion by subcutaneous fat compared to omental fat.35 In this study, we also find an association of this subcutaneous fat depot with some polymorphisms in the leptin receptor gene, at least in obese postmenopausal women. It is known that leptin receptors are present on adipose tissue, and it was suggested that these could mediate an autocrine or paracrine function of leptin. The association which we found with subcutaneous fat suggests that leptin is not only secreted by these cells, but that it could also affect fat accumulation in these cells acting through the leptin receptor. Moreover, variants of the LEPR gene may predispose to an increased abdominal fat accumulation over time.
We are aware that since our population is limited to overweight and obese subjects, we have restricted the range of BMI and other obesity-related variables. This reduction in range has potentially decreased our ability to identify LEPR variant effects as no comparison could be undertaken between normal-weight and obese women. Nevertheless, the range of BMI is still large in this group of women, with values from 25.5 to 53.6.
Leptin levels have been shown to vary widely for a given degree of adiposity, and it has been proposed that they could partly be modulated by genetic factors. An effect of genetic polymorphisms on leptin levels was shown previously for polymorphisms in LEP, PPARγ, and POMC genes.36,37,38 Previous studies found associations between leptin levels and the LEPR Lys109Arg polymorphism39 or with the Gln223Arg polymorphism,40,41 but none of these was independent of BMI. We find an association between blood leptin levels and the Lys109Arg polymorphism in the LEPR gene in postmenopausal women, with significantly higher leptin levels in the Lys109Lys homozygotes, despite a lower body weight, BMI and fat mass in this subgroup. However, this postmenopausal group of women in whom leptin levels were measured was very small, so that no conclusions can be drawn from this.
When testing for differences between carriers of the rare allele and non carriers instead of comparing all three genotypes, recessive effects will be missed particularly if the number of homozygotes for the rare allele is small. Under the conditions of this study, only additive and dominant effects of the rare alleles are likely to be detected. Because of the limited sample size and especially the number of homozygotes for the less frequently occurring variants, we however had no choice but to perform the analyses as performed.
In addition, it is important to remember that the P-values were not adjusted for multiple testing. Bonferroni adjusted P-levels would have been as low as 0.0019 compared to 0.05. However, we have elected to report differences significant at 0.05 in order to make sure that all potentially useful leads are identified for subsequent studies. This has led us to the observation that LEPR sequence variants may be involved in the predisposition to become abdominally obese.
In conclusion, frequently occuring genetic polymorphisms in the leptin receptor gene are not associated with total adiposity, but seem to be associated mainly with subcutaneous fat accumulation in postmenopausal overweight and obese women when data are adjusted for total body fat level. These observations suggest that mutations in the leptin receptor gene play a role in subcutaneous abdominal fat accumulation in women who have an excess amount of body fat.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cohen B, Novick D, Rubinstein M . Modulation of insulin activities by leptin Science 1996 274: 1185–1188.
Kieffer TJ, Heller RS, Habener JF . Leptin receptors expressed on pancreatic β-cells Biochem Biophys Res Commun 1996 224: 522–527.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ma Z, Gingerich RL, Santiago JV, Klein S, Smith CH, Landt M . Radioimmunoassay of leptin in human plasma Clin Chem 1996 42: 942–946.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
- leptin receptor
- body composition
- abdominal fat distribution
- genetic polymorphisms
Fat mass and obesity-associated (FTO) and leptin receptor (LEPR) gene polymorphisms in Egyptian obese subjects
Archives of Physiology and Biochemistry (2019)
The influence of the rs1137101 genotypes of leptin receptor gene on the demographic and metabolic profile of normal Saudi females and those suffering from polycystic ovarian syndrome
BMC Women's Health (2019)
International Journal of Experimental Pathology (2018)
Obesity phenotype in relation to gene polymorphism among samples of Egyptian children and their mothers
Genes & Diseases (2018)