Vol.3, No.12, 737-741 (2011)
doi:10.4236/health.2011.312122
C
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Health
The influence of adiponectin G276T gene polymorphism
on changes in total and high molecular weight
adiponectin levels by exercise training
Daisuke Ando1,4*, Yo shiyuki Hosaka2, Kohta Suzuki3, Zentaro Yamagata4
1Department of Physical Education, National Defense Academy, Kanagawa, Japan; *Corresponding Author: ando@nda.ac.jp
2Hosaka DM Clinic, Yamanashi, Japan;
3Center for Birth Cohort Studies, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yama-
nashi, Japan;
4Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yama-
nashi, Japan.
Received 18 October 2011; revised 15 November 2011; accepted 24 November 2011.
ABSTRACT
Adiponectin is an adipocyte-secreted hormone
and regulates the metabolism of lipid and glu-
cose. We examined the influence of adiponectin
G276T gene polymorphism on changes in total
or high molecular weight adiponectin levels by
exercise training. A randomized parallel-design
study (n = 53; 40 women and 13 men; age range,
32 - 65 years) was conducted. Participants were
randomly assigned to the exercise (n = 26) or
control (n = 27) group and received exercise
training for 70 min 2 times per week for 12
weeks and exercise advice at the baseline, res-
pectively. Blood sample were obtained before
and after the intervention. The primary outcomes
were changes in total adiponectin and high
molecular weight adiponectin levels. At the
baseline, the participants with and without 276G
allele did not differ with the total and high
molecular weight ad iponectin levels in the entire
study population. No significant difference in
the change in the total and high molecular
weight adiponectin levels between the subjects
with the G276G genotype and 276T allele car-
riers were found. This study provides evidence
that the G276T poly morphism of the ad iponectin
gene is not associated with the magnitude of
the effect of twice-weekly exercise training on
the total and high molecular weight adiponectin
levels.
Keywords: Exercise; High Molecular Weight
Adiponectin; Adipocytokine; Genotype
1. INTRODUCTION
Adiponectin is the most abundantly secreted adi-
pokine [1]. It has been reported to play a role in the de-
velopment of insulin resistance [2], obesity [3], hyper-
lipidemia [4], type 2 diabetes mellitus [5], and cardio-
vascular diseases [6].
Exercise training improves many components of the
metabolic risk factor profile [7]; therefore, it can be
speculated that adiponectin is involved in the regulation
of glucose or lipid metabolism through exercise training.
Previous studies have revealed that the effects of exer-
cise training modify according to the genetic background
[8-10]. It has been shown that the adiponectin gene con-
tains a polymorphism at position 276 (G/T). The poly-
morphism is located in intron 2 of the adiponectin gene
[11]. The adiponectin G276T gene polymorphism has
been shown to be associated with type 2 diabetes, insulin
resistance, and serum adiponectin levels [11,12]. Fur-
thermore, Huang et al. showed that the G276T poly-
morphism of the adiponectin gene affects of the magni-
tude of the effects of exercise training on the circulating
total adiponectin levels [13]. However, the influence of
adiponectin gene polymorphism on the change in circu-
lating adiponectin level by ex ercise training has no t been
well documented.
Additionally, adiponectin circulates in blood in mul-
timeric isoforms. Previous studies on multimer forma-
tion in blood have demonstrated that high molecular
weight (HMW) adiponectin is the active form of proteins
[14,15]. To date, the effects of gene polymorphism on
exercise-training-induced changes in the HMW adi-
ponectin levels is still unclear. Thus, we examined the
effects of adiponectin G276T gene polymorphism on the
changes in total or HMW adiponectin levels by twice-
D. Ando et al. / Health 3 (2011) 737-741
Copyright © 2011 SciRes. Openly accessible at http:// www.scirp.org/journal/HEALTH/
738
weekly exercise training.
2. METHODS
2.1. Stud y Population
We randomly assigned 53 Japanese people (36 women
and 17 men) to exercise and control groups using a par-
allel-design study, which was performed at the fitness
club. Based on the checkup data, we included women
and men aged from 30 to 70 years with a glycosylated
hemoglobin level of 5.5% - 6.4% or plasma glucose
level of 110 - 125 mg/dl. The study was approved by the
Ethical Review Committee, Faculty of Medicine, Uni-
versity of Yamanashi. All the participants p rovided writ-
ten informed consent.
2.2. Intervention
Exercise group: The subjects exercised at the fitness
club two times per week for 12 weeks. Each exercise
session lasted <70 min and included a 5-min warm up,
40-min resistance exercise, 20-min aerobic exercise, and
5-min cool down. A minimum of two days elapsed be-
tween two consecutive training sessions. 1) Resistance
exercise: the resistance exercise program consisted of
four exercises using resistance exercise machines (chest
press, pull downs, knee extension, and knee flexion) for
3 sets of 7 - 15 repetitions and 4 exercises using free
weights (leg lunges, heel raises, sit ups, and back exten-
sions) for 3 sets of 10 - 20 repetitions. The training in-
tensities using resistance exercise machines were 60% -
80% of the baseline one repetition maximum (1-RM).
Initial training loads were 60% of baseline 1-RM and
were increased to 80% of baseline 1-RM by the end of
the study. 2) Aerobic exercise: the subjects exercised on
a bicycle ergometer for 20 min per session. The training
intensity was adjusted to maintain a constant heart rate
between 60% and 75% heart rate reserve, which was
calculated using the following formula: (maximum heart
rate – resting heart rate) × 0.6 – 0.75 + resting heart rate.
The maximal heart rate for each subject was calculated
as 220 minus the age of the subject. The dietary intake
was not restricted throughout the trial period in both the
groups.
Control group: Participants in the control group were
given individual advice on the way to undertake home-
based resistance exercise to be performed for about 30
min at the baseline.
2.3. Outcome Measures
We assessed the outcome measures at the baseline and
those at 12 weeks. Biochemical measurements were col-
lected in the fasting state. Twelve-week blood collection
was performed 48 - 72 h after the last exercise session to
eliminate the effect of the last acute bout of exercise on
all the blood parameters. The outcome measures were
carried out in a blinded fashion .
Serum samples for total adiponectin and HMW adi-
ponectin levels were stored at –80˚C until assayed. The
total serum adiponectin concentrations were measured
by sandwich ELISA, (Otsuka Pharmaceuticals, Tokyo,
Japan), as described previously [3]. Serum HMW adi-
ponectin was measured by means of a novel sandwich
ELISA using a monoclonal antibody to human HMW
adiponectin, as described previously [16]. This sandwich
ELISA, essentially measuring only HMW adiponectin in
the serum, is now available as a kit from Fujirebio (To-
kyo, Japan).
2.4. Genotyping
Genomic DNA was extracted from the entire blood
with a FlexiGene DNA Kit (Q IAGEN, Hild en, Germany)
according to the manufacturer’s protocol. Genotyping of
the G276T polymorphism of adiponectin gene was per-
formed with the polymerase chain reaction–restriction
fragment length polymorphism [17]. The sequences of
the primers were 5’-GGC CTC TTT CAT CAC AGA
CC-3’ (forward primer) and 5’-AGA TGC AGC AAA
GCC AAA GT-3’ (reverse primer). The PCR amplifica-
tions were carried out in 20-µl reaction volumes con-
taining 0.2 mM of dNTP, 1.5 mM of magnesium chlo-
ride, 0.5 U of Taq polymerase (Takara, Tokyo, Japan), 50
ng of genomic DNA, and 0.2 µM of each of the primers.
After the initial denaturation at 95˚C for 5 min, 35 cycles
of PCR were done for 60 s at 95˚C, for 45 s at 58˚C, and
for 45 s at 72˚C, with a final extension at 72˚C for 5 min.
The PCR product of 196 bp fragment was digested with
10 units of PctI (Sib Enzyme Ltd., Novosibirsk, Russia)
in a reaction mixture of 10 µl for 8 h at 37˚C. The di-
gested PCR products were applied to the electrophoresis
of 2% agarose gel and visualized by ethidium bromide.
2.5. Statistical Analysis
All the analyses followed an intention-to-treat princi-
ple using all randomized participants and assuming no
change from the baseline for those with missing data. To
compare the continuous variables between the groups in
baseline, the one-way ANOVA was used. The data after
intervention was analyzed by two-way ANOVA (inter-
vention × genotype). The significance level was estab-
lished at P < 0.05. The results are expressed as mean
standard deviation (SD) or mean mean standard error
(SE). All the analyses were performed using SPSS 17.0
for W i ndows.
D. Ando et al. / Health 3 (2011) 737-741
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739739
3. RESULTS
3.1. Participants
Of the 53 women and men enrolled, 49 underwent fol-
low-up evaluations. One participant in the control group
(one woman) refused final testing for personal reasons;
three participants in the exercise group (one man and
two women) dropped out citing personal o r medical rea-
sons unrelated to the study. We included 53 participants
in the intention-to-treat analysis.
3.2. Effects of Adiponectin Gene
Polymorphism
DNA was available from all the subjects. The G276G
genotype was found in 24 subjects (45.3%), the G276T
genotype was found in 21 subjects (39.6%), and the
T276T genotype was found in 8 subjects (15.0%). In the
exercise group, the G276G genotype was found in 11
subjects (42.3%) and 276T allele was found in 15 sub-
jects (57.7%). In the contro l group, the G276G genotype
was found in 13 subjects (48.2%) and 276T allele was
found in 14 subjects (52.8%). Because the frequency of
the T276T genotype was low, we combined it with the
G276T genotype in all the statistical analyses [13].
At the baseline, the participants with and without
276G allele did not differ with the total and HMW adi-
ponectin levels in the entire study population (data not
shown) or within the exercise group and the control
group (Tabl e 1). No significant difference in the change
in the total and HMW adiponectin levels between the
subjects with the G276G genotype and 276T allele car-
riers of the adiponectin gene were found (Table 2).
4. DISCUSSION
The most important finding in this study is that the
change in the total and HMW adiponectin levels by
twice-weekly exercise training was not associated with
adiponectin G2 76 T gene polym orphi sm.
The beneficial effect of exercise varies for each indi-
vidual and may be affected not only by the environ-
mental conditions but also the genetic background [8].
To date, few reports have investigated the effect of gene
polymorphism on exercise-training-induced changes in
the total adiponectin levels [13,18]. In this study, the
change in the total adiponectin by exercise training was
not modified by the G276T polymorphism of the adi-
ponectin gene. However, in contrast to our results, Huang
et al. showed that the G276T polymorphism of the adi-
ponectin gene was associated with the magnitude of the
effects of exercise training on the circulating total adi-
ponectin levels [13]. The difference of the study design
is suggested as one reason for the discrepancy. The data
of before-after trial is used in the study by Huang et al.
though the data of randomized controlled trial is used in
our study. Moreover, the exercise regimen in the study
by Huang et al. was 5 days/week for 6 months. In con-
trast, the exercise regimen in our study was 2 days/week
for 12 weeks. Differences in the duration or/and fre-
-quency of exercise training could explain these different
results. It would be useful to further investigate whether
the adiponectin allelic variants affect changes in the cir-
culating total ad iponectin levels by the various exercises
Table 1. Subject characteristics at baseline.
Exercise Control
Characteristic G276G genotype (n = 11) 276T genotype (n = 15)G276G genotype (n = 13)276T genotype (n = 14)P value*
Age (yr) 58.6 ± 6.2 53.9 ± 8.3 54.9 ± 7.7 57.4 ± 9.6 0.44
Weight (kg) 56.6 ± 13.0 61.6 ± 11.3 61.1 ± 11.4 53.1 ± 1 0.2 0.18
BMI 22.8 ± 3.1 24.7 ± 3.8 23.6 ± 3.4 22.0 ± 3.7 0.21
Total adiponectin (µg/ml) 10.4 ± 4.0 9.7 ± 3.8 9.5 ± 6.2 12.1 ± 6.3 0.53
HMW adiponecti n (µg/ml) 6.8 ± 4.2 6.5 ± 3.7 5.5 ± 4.3 7.4 ± 4.7 0.70
Note: Values are expressed as means ± SD. Abbreviations: BMI, body mass index; HMW, high-molecula r-weight. *One-way ANOVA.
Table 2. Weight, BMI, total adiponectin, HMW adiponectin levels: change with intervention by adiponectin polymorphism.
Exercise Control
G276G genotype
(n = 11) 276T geno type
(n = 15) G276G genotype
(n = 11) 276T geno type
(n = 15)
Intervention × genotype
Weight (kg) –0.1 ± 0.3 –1.0 ± 0.9 –0.7 ± 0.5 –0.1 ± 0.3 0.24
BMI –0.02 ± 0.13 –0.40 ± 0.37 –0.26 ± 0.18 –0.03 ± 0.11 0.22
Total adiponectin (µg/ml) –0.47 ± 0.94 0.19 ± 0.58 –0.02 ± 0.60 –0.49 ± 0.57 0.40
HMW adiponecti n (µg/ml) –0.30 ± 0 .79 –0.59 ± 0.37 0.05 ± 0.36 –0.17 ± 0.28 0.85
Note: Values are expressed as means ± SE. Abbreviations: BMI, body mass index; HMW, high-molecular-weight. *Two-way ANOVA; P valu e f or In ter actio n in
model.
D. Ando et al. / Health 3 (2011) 737-741
Copyright © 2011 SciRes. Openly accessible at http:// www.scirp.org/journal/HEALTH/
740
training regimen. Additionally, it will be necessary to
examine subject difference in the further studies. Shin et
al. reported that G276T polymorphism of the adiponectin
gene associates with different responses of total adi-
ponectin to mild weight loss in overweight-obese subject
[19]. More recently, Chung et al. indicated that adi-
ponectin genetic variants affects total adiponectin levels
in with impaired fasting glucose or newly diagnosed
type 2 diabetes in response to dietary intervention [20].
However, our study subjects included non-obese indi-
viduals. There is a possibility that a different result is
obtained when the same exercise program to the present
study is executed to the individuals with obesity, im-
paired fasting glucose or type 2 diabetes.
It has been shown that HMW adiponectin strongly
correlates with glucose tolerance as compared to the
total adiponectin [21], and HMW adiponectin has proven
to be more successful than other multimers at reducing
blood glucose levels [22]. In the present study, the
change in the HMW adiponectin by exercise training
was not modified by the G276T polymorphism of the
adiponectin gene. To our knowledge, this is the first
study to show the HMW ad iponectin lev els changes with
exercise training may not be influenced by the G276T
polymorphism of the adiponectin gene. The experimen-
tal study evaluating the effect of adiponectin allelic
variants on the chan ge in the HMW adiponectin levels in
various exercise protocol are needed to more completely
understand the influence of adiponectin allelic variants
on the changes in adiponectin oligomer distribution by
exercise training.
This study has some important limitations. The exer-
cise type in our study was combination of resistance and
aerobic exercise. These two types of exercise produce
different effects and may alter glucose metabolism
through different mechanisms [23]. Further studies are
needed to clarify the effect of exercise type. Second,
several single nucleotide polymorphisms have been
identified in the adiponectin gen e [24]. We did not geno-
type other adiponectin gene polymorphisms. Therefore,
we could not exclude the possibility that interaction of
other polymorphism of the adiponectin gene with the
G276T polymorphism of the adiponectin gene. Further-
more, it has been shown that the fat mass–and obesity-
associated (FTO) gene polymorphism may affect circu-
lating adiponectin levels through the changes in BMI
[25]. Therefore, the genetic variants of other genes may
affect changes in circulating adiponectin levels by exer-
cise training. Finally, our observations and conclusions
are limited by small sample size. Most studies assessing
the effect of genes polymorphism on particular disease
have larger sample size. Thus, our present findings
should be verified in an independent sample.
In conclusion, the present study provides evidence
that the G276T polymorphism of the adiponectin g ene is
not associated with the magnitude of the effect of twice-
weekly exercise training on the total and HMW adi-
ponectin levels.
5. ACKNOWLEDGEMENTS
This study was supported by a Grant-in-Aid (#17390182 to Zentaro
Yamagata; #19700541 to Daisuke Ando) for scientific research from
the Ministry of Education, Culture, Sports, Science and Technology,
Japan. The authors thank Dr. Katsuhiro Koyama for their useful dis-
cussions and Mr. Fuminao Sekiguchi for help in extracting the Ge-
nomic DNA. Gratitude is expressed to the staff at the Fujiyosida city
hall and the Nishikatsura town hall for participant recruitment.
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