s Document title

No evidence for involvement of the leptin gene in anorexia nervosa,

bulimia nervosa, underweight or early onset extreme obesity :
Identification of two novel mutations in the coding sequence and a
novel polymorphism in the leptin gene linked upstream region
Auteur(s) / Author(s)
HINNEY A. (1) ; BORNSCHEUER A. (1) ; DEPENBUSCH M. (1) ; MIERKE B.
(1)
; TÖLLE A. (1) ; MIDDEKE K. (1) ; ZIEGLER A. (2) ; ROTH H. (3) ;
GERBER G. (1) ; ZAMZOW K. (2) ; BALLAUFF A. (1) ; HAMANN A. (4) ;
MAYER H. (5) ; SIEGFRIED W. (6) ; LEHMKUHL G. (7) ; POUSTKA F. (8) ;
SCHMIDT M. (9) ; HERMANN H. (10) ; HERPERTZ-DAHLMANN B. (11) ;
FICHTER M. (10) ; REMSCHMIDT H. (1) ; HEBEBRAND J. (1

Résumé / Abstract

Mutations in the leptin gene can result in profound obesity in both rodents and
humans.1-3 In humans, serum leptin levels correlate with body mass index4 (BMI:
kg m-2). However, in patients with anorexia nervosa (AN) leptin levels are lower
than in BMI-matched healthy controls.5 We had previously argued that genes
involved in weight regulation should be considered as candidate genes for AN. 6 To
investigate this hypothesis we screened the coding region of the leptin gene and
part of the leptin gene linked upstream region (LEGLUR) in 49 patients with AN
and 315 children and adolescents with extreme obesity. Two novel mutations in
the coding region (Ser-91-Ser; Glu-126-Gln), each found in a single proband, and a
novel polymorphism in the LEGLUR (position -1387 G/A; frequency of both alleles
approximately 0.50) were identified. Tests for association of LEGLUR
polymorphism alleles were negative by comparing allele frequencies between 115
AN patients, 71 bulimia nervosa patients, 315 extremely obese children and
adolescents, 141 healthy underweights and 50 controls that were not selected for
body weight. Tests for transmission disequilibrium were also negative. Hence, an
influence of variations in the leptin gene on eating disorders or extreme early
onset obesity could not be detected.
A Polymorphism in the Leptin Promoter Region (-2548 G/A) Influences Gene
Expression and Adipose Tissue Secretion of Leptin
 

J.  Hoffstedt 1, P.  Eriksson 2, S.  Mottagui-Tabar 3, P.  Arner 1

1
Department of Medicine at Huddinge University Hospital, Stockholm, Sweden
2
King Gustaf V Research Institute, Stockholm, Sweden
3
Center for Genomic Research, Karolinska Institutet, Stockholm, Sweden
Abstract

There is a large inter-individual variation in circulating leptin concentrations at

each level of body fat content. The reason for this is unknown. We investigated
whether a polymorphism in the promoter region of the leptin gene (-2548G/A)
influences gene transcription and leptin expression in 39 non-obese female
subjects. Eleven subjects were homozygous for the AA genotype, 18 were
heterozygous (GA) and 10 carried the GG genotype. AA subjects had higher levels
of serum leptin than did GA/GG subjects (14.5 ± 2.1 vs. 9.7 ± 0.9 ng/ml, p = 0.02).
Adipose tissue leptin secretion rate in AA subjects was twice as high as in GA/GG
subjects: 1158 ± 288 vs. 626 ± 84 ng/2 h/107 cells (p = 0.02). These differences
were also statistically significant with leptin levels adjusted for body mass index (p
= 0.03 - 0.04). Adipose tissue leptin mRNA levels were 60 % higher in AA subjects,
as compared to GA/GG subjects, 74 ± 10 vs. 46 ± 4 amol/µg RNA (p = 0.01). EMSA
revealed that nuclear extracts derived from both U937 cells and human
adipocytes form a protein-DNA complex with the leptin -2548G/A polymorphic
site and bind with higher affinity to the -2548A-site. In conclusion, a common
polymorphism in the promoter of the human leptin gene (-2548G/A) influences
leptin expression, possibly at the transcriptional level, and therefore also adipose
secretion levels of the hormone.
Obesity and polycystic ovary syndrome: association with androgens, leptin and
its genotypes

Posted online on May 26, 2010. (doi:10.3109/09513590.2010.487586)

Madhavi Pusalkar1, Pervin Meherji2, Jyotsna Gokral2, Lalita Savardekar3, Saravanan

Chinnaraj1, Anurupa Maitra1

anurupamaitra@yahoo.co.in

Obesity and hyperandrogenaemia are key features of polycystic ovary syndrome

(PCOS). The aim of this study was to investigate whether leptin and androgens are
associated with obesity in PCOS subjects and identify whether there exist any
genetic alterations in leptin gene in women with PCOS. The results reveal that
leptin levels are elevated in women with PCOS and associate with BMI. However,
irrespective of the obesity status leptin levels are higher in PCOS cases indicating
that increased BMI/obesity may not be the only factor contributing to elevated
levels of leptin. With regard to testosterone and androstenedione, the levels were
increased in obese individuals irrespective of PCOS status. No correlation
between leptin and androstenedione or testosterone was observed in controls
and PCOS subjects. The single-nucleotide polymorphism G19A detected in the
untranslated exon 1 of leptin gene was not associated with PCOS and does not
contribute to elevated levels of leptin. The results overall suggest that androgen
and leptin levels are increased in PCOS and obesity. It demonstrates that obesity
is a confounding factor for hyperandrogenaemia irrespective of their PCOS status.
The study rules out role of obesity status and leptin genotype in increase in leptin
levels observed in PCOS cases.
Polymorphisms of the LEP- and LEPR Gene and Obesity in Patients Using
Antipsychotic Medication

Gregoor, Jochem G. MD; van der Weide, Jan PhD; Mulder, Hans PhD; Cohen,
Dan MD, PhD; van Megen, Harold J.G.M. MD, PhD; Egberts, Antoine C.G. PhD;
Heerdink, Eibert R. PhD

Abstract

Weight gain is one of the most serious adverse effects of atypical antipsychotic
agents. Genetic factors influence the risk of an individual to gain weight. The
objective of our study was to determine whether the LEPR Q223R polymorphism
and the LEP promoter 2548G/A polymorphism are associated with obesity in a
group of male and female patients using atypical antipsychotic drugs. A cross-
sectional study design was used. The study population consisted of 200 patients
aged between 18 and 65 years, diagnosed with a psychotic disorder, all of whom
had been using an atypical antipsychotic for at least 3 months. The primary
outcome measure was the presence of obesity. Determinants were the LEPR
Q223R (rs1137101) polymorphism and the LEP promoter 2548G/A single
nucleotide polymorphism ([SNP] rs7799039). Of the 200 included patients, 61
(31%) were obese. In females, the LEPR 223QR (adjusted odds ratio, 0.11; 95%
confidence interval [CI], 0.02-0.54) and LEPR 223RR (adjusted odds ratio, 0.07;
95% CI, 0.01-0.63) genotypes were associated with a lower risk of obesity. In
males, this association was not found. In females, the average body weight was
13.6 kg more (95% CI, 1.11-26.1) in the LEPR 223QQ group compared with the
LEPR 223RR group. No significant association was found between the LEP
promoter 2548G/A polymorphism and obesity. Taken together, the results of our
study show that the LEPR Q223R polymorphism may be associated with obesity in
women with a psychotic disorder treated with atypical antipsychotic drugs and
stress the importance of stratification for gender when investigating the role of
variations of the LEP- and LEPR genes on the metabolic side effects of
antipsychotic medications.
Mutation Screening and Identification of a Sequence Variation in the
Human OB Gene Coding Region

Robert V. Considine, Eileen L. Considine, Charlene J. Williams, Mark R. Nyce, Peili Zha
a
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jeffers
b
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Biochemistry an
c
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Surgery, Jefferso
Received 5 February 1996. 
Available online 22 April 2002.

Abstract
In the present study mRNA from the subcutaneous adipose tissue of 68 obese
(defined as a body mass index ≥27.3 for men and ≥27.8 for women) and 38 lean
subjects was screened for mutations in the ob gene coding region. No mutations in
the coding region of the human ob gene were detected using Conformation
Sensitive Gel Electrophoresis in 105 subjects. A first base substitution (G to A)
was detected in one individual, which changed a valine to a methionine at position
94. The mRNA of all subjects contained the codon for glutamine-49, ruling out the
possibility of a splice defect occurring during the removal of intron 2. These
observations suggest that defects in the ob gene sequence itself are not the primary
cause of obesity in humans.