診療と新薬・第 53 巻

第 3 号（2016 年 3 月）

73 （237）

VISCERAL FAT-REDUCING EFFECT OF
SUPPLEMENT CONTAINING APPLE POLYPHENOL AND
OLEANOLIC ACID IN HEALTHY JAPANESE― A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY ―Masatomo NAJIMA1), Akinobu MIYATA2), Hirofumi WADA3) and Emiko WADA3)
1) JACTA (Japan Clinical Trial Association)2) Nihonbashi M s Clinic3) GRACEAS Corporation

Abstract
Objectives: The objective of this research was to investigate the effectiveness of daily
ingestion of a CUTTO tablet, which contains apple polyphenol and oleanolic acid on weight
reduction and waist circumference reduction.
Methods: In this randomized, placebo-controlled, double-blind trial, 40 subjects wererandomized. To evaluate this objective, visceral fat area and subcutaneous fat area were
measured as the primary outcome. Weight, BMI, waist circumference and subjective
reporting was also observed as the primary outcome.
Results: 3 subjects were withdrawn due to personal reasons and 8 subjects were excluded
from eﬃcacy analysis due to taking a meal before getting a CT scan and sending in adequate
records. With 29 subjects, the visceral fat area of CUTTO decreased signiﬁcantly comparedwith Placebo after 12 weeks of ingestion. Furthermore, signiﬁcant diﬀerence was observed
between the two groups in weight, BMI and waist circumference after 12 weeks. Moreover,
8 items out of 9 showed significant difference with results from a questionnaire, in theintergroup comparison of 12-week ingestion.
Conclusion: The present results suggest that daily ingestion of CUTTO tablets including
apple polyphenol and oleanolic acid can reduce weight and waist circumference.

1. INTRODUCTION
In present-day Japan, as the society often allows excess
intake of calories and irregular lifestyles, many people
tends to be distressed about their obesity. Obesity is astate of excessive body fat accumulation than a prescribed
level. Visceral fat obesity, the type of obesity that
accumulates excessive fat around internal organs,especially causes high cholesterol and blood sugar level,
and even leads to serious arteriosclerosis at the end1).
Consequently, obesity becomes a major factor of many
diseases including so-called lifestyle diseases , therefore
a prevention and solution of obesity are an expectation ofmany people in common.
An improvement of daily eating and exercise habits is
obviously important for preventing and solving obesity. Itshould be also effective to take the supplement which
utilizes functionality of food ingredients that can modestly
control vital function, in addition to the improvement of
the habits. There are several reports about the foodingredients that may work on sugar and fat metabolism ofbody and prevent obesity2)3).
As the proverb An apple a day keeps the doctor away

says, the contribution of apple to our health has been
focused for a long time. Apple contains ingredients suchas ﬁber, minerals, and polyphenol which are regarded tohave various physiological functionalities, and these
ingredients are thought to contribute to our health 4).
Oleanolic acid, on the other hand, is the triterpene
contained in olive and grape berry skin, and many reports
explain its functions such as antioxidant eﬀect5).
Ingredients such as polyphenol and oleanolic acidreportedly have a function of preventing metabolic
syndrome 6)7), and are considered to be effective forpreventing or solving obesity.
However, although many supplements containing theapple polyphenol are sold in Japan and several reports
emphasizing its function exist8), there are few publishedreports that discuss the eﬀect and safety of the combined
use of both polyphenol and oleanolic acid. In addition,
their function for obesity is also unclear.
In this study, we examined the effect of apple
polyphenol and oleanolic acid for weight reduction andwaist circumference reduction and the safety of the
combined use of them, by adopting a randomized,
placebo-controlled, double-blind study using the74 （238）

診療と新薬・第 53 巻

supplement containing both of these ingredients.

2. METHOD
2.1. Trial Design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from GRACEAS
Corporation (Tokyo) at two centers (KUROSUHOSPITAL, Tokyo and JACTA, Tokyo).
The study period was 12 weeks, from July 28 th toOctober 23th, 2015.
This study was conducted in accordance with the
ethical principles of the declaration of Helsinki. The study
protocol was approved by the Institutional Review Boardof LLP. Pharmaceutical Law Wisdoms (Tokyo). Written
informed consent was obtained from all Subjects.
The allocation of the test product to the subjects was
carried out by the person in charge of allocation.
The allocation list was sealed and strictly controlled ina safe deposit box of JACTA until the end of the study.
2.2. Subject
Healthy subjects participated in the present study.
All of the subjects in this study were public volunteers
who had enrolled in the monitor bank of Rabbits-coco(Tokyo), Stephens& Associates, Inc. (Tokyo) and Miyao
Co., LTD. (Tokyo).
2.2.1. Inclusion Criteria(1) Healthy female aged between 20 and 59 years;
2.2.2. Exclusion criteria(1) Individuals with BMI > 30 and diagnosed unhealthy;(2) Individuals undergoing treatment of weight reduction;(3) Individuals taking medication, including herbal
medicines;(4) Individuals judged to be unsuitable to participate in
the trial by the doctor conducting present study.
2.2.3. Eﬃcacy eligibility
With respect to the analysis of efficacy, we set thefollowing criteria of exclusion:(1)Participants who consumed a meal in the morning justbefore getting a CT scan(2)Participants who consumed less than 80% of the
expected dose;(3)Participants who do not take adequate records;(4)Participants who fell under the exclusion criteria after
enrolment;(5)Participants who had justiﬁable reason for exclusion.
2.3. Randomization
Recruited subjects were 71 persons. Subjects who
fulﬁlled eligibility criteria were 40 persons. The inclusion
was judged by the principle investigator.
All subjects were sequentially assigned based on arandom number table to one of the masked products andrandomized to group T (Test sample: 20) and group P(Placebo: 20). The allocation was pre-assigned on thebasis of randomized numbers.
2.4. Description of test foods and blinding
The test food, CUTTO and placebo were prepared by

第 3 号（2016 年 3 月）

GRACEAS Corporation. The amount of daily intake is 2
tablets (1 tablet contains 300mg, therefore 2 tablets
contain 600mg). The compositions of CUTTO were apple
polyphenol, oleanolic acid, etc., while Placebo wasconsisted of Comprecel, Pineapple ﬁber, etc. Both tablets
were indistinguishable in shape, color or taste. Tablets
were managed by the identiﬁcation symbol. All involved
were blinded.
2.5. Experimental procedures
2.5.1. Experimental protocol
Subjects consumed 2 tablets of the supplement with hotor cold water every day for 12 weeks. Subjects were
instructed as follows: to take the assigned foods as
indicated; to maintain their usual lifestyles and habits; toavoid excessive amounts of food, drink, or alcohol; tomaintain a daily record of lifestyle factors such as all thefood items or number of steps they took for the day
during the test period; and to send the diary to the study
coordinator every Friday (or Thursday night) by mobile
email.
2.5.2. Outcome
The objective of this study is to verify the weight
reduction and waist circumference reduction effect ofingesting food containing apple polyphenol with oreanolicacid. To evaluate this objective, visceral fat area andsubcutaneous fat area were measured as the primary
outcome.
This measurement was the result of CT images by
Bright Speed (GE Healthcare, Tokyo). Several CT
images around the umbilicus were obtained and single
scan images at the precise point of the umbilicus wereused for analysis. The visceral fat area and subcutaneous
fat area were calculated from CT images using Power
View Fat software (Vigoment Software Corp., Tokyo).
Weight, BMI, waist circumference and subjective
reporting was also observed as the primary outcome.
Height, body weight and BMI were scaled by AD-6228AP(A&D Company, Limited, Tokyo). Waist circumference,at the umbilical level, was measured using a non-elastic
anthropometric tape measure.
The questionnaire covered: bowel movement,sensitivity to cold, clothing size variation, dryness ofskin, fatigue, mood, rate of activity, sleeping quality andfeeling lighter. The score of the answer is between 1 and
9. Score 5 is deﬁned as the average status.
Blood biochemical and urine parameters were recorded
to evaluate the safety of CUTTO as the secondary
outcome. These assessments were conducted upon entry
into the study (pre-intervention) and after 12 weeks(post-intervention).
To evaluate the safety of the test foods, adverse eventswere collected by means of a written questionnaireduring the study.
According to the schedule shown Table 1, we
measured parameters on eﬃcacy and safety.

診療と新薬・第 53 巻

Table 1Item

Term

第 3 号（2016 年 3 月）

75 （239）

Schedule for the study.
Screening

Informed consent●

Selection and/or allocation
Abdominal fat level
Anthropometric measurements
Subjective reporting
Biochemical analysis of the blood
Urine analysis
Ingestion of test foods
Log●

Pre Trial Test

Test period (12 w)

●
●
●
●
●

●
●
●
●
●
←―――――――→←―――――――→● : Implementation↔ : Daily practice during the test period

Recruited (n ＝ 71)

Excluded (n ＝ 31)

Randomized (n ＝ 40)

CUTTO (n ＝ 20)

Placebo (n ＝ 20)

Withdraw (n ＝ 1)
〔personal reason〕

Withdraw (n ＝ 2)
〔personal reason〕

Full analysis set
CUTTO (n ＝ 19)

Placebo (n ＝ 18)

Excluded from eﬃcacy
analysis (n ＝ 5)
〔taking meal before CT
inadequate record〕

Excluded from eﬃcacy
analysis (n ＝ 3)
〔taking meal before CT
inadequate record〕

Pre protocol set
CUTTO (n ＝ 16)

Fig. 1

Placebo (n ＝ 13)

Flow diagram of subject disposition

2.6. Data Analysis
All analyses were performed on the on-treatment
population in the study. The Par protocol set principal
was adopted in the present study and no sample size
design was used. Data were expressed as mean ± SD.

For the Abdominal fat level, anthropometricmeasurements and biochemical analyses of blood andurine, changes from the baseline in the same group wereassessed using the paired t-test. Student's t-test was used
for intergroup comparisons of changes from the baseline.

76 （240）

診療と新薬・第 53 巻

第 3 号（2016 年 3 月）

Table 2 Subject demographics
Item＊

Table 3Item

Visceral fat area

Subcutaneous fat area

Weight

BMI

Waist circumference

Unit

CUTTO

Placebo

Subjects*

−

16

13

Age
BMI

years
kg/m2

48.5±6.8
26.5±2.044.9±8.0
25.7±2.3

Number of subjects
mean ± SD

Changes in abdominal fat areas, weight, BMI and waist circumference

Unit

Time
points

CUTTO group (n=16)

Placebo group (n=13)

Between-groupdiﬀerence(P-value)cm2

Baseline
Week 12
Change93.9±51.1
87.9±40.8− 6.0±17.6

88.5±42.2
95.7±42.7 †7.2±12.9

0.033 #

Baseline
Week 12
Change216.3±67.5
208.3±63.3*− 8.0±14.3

237.6±55.0
230.2±57.6− 7.4±17.0

0.919

Baseline
Week 12
Change64.3±6.6
61.6±6.6 **− 2.7±0.8

62.7±6.1
63.4±6.1 *0.7±0.9＜ 0.001 ##Baseline
Week 12
Change26.5±2.025.3±2.0 **− 1.1±0.3

25.7±2.325.8±2.1
0.1±0.4＜ 0.001 ##Baseline
Week 12
Change89.3±7.6
86.7±7.3 **− 2.6±0.6

89.2±8.989.1±8.6− 0.1±0.8＜ 0.001 ##

cm2

kg

Kg/m2

cm

ValuesValues are expressed as the mean ± SD.
†

p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.

#p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerence in change from baseline.

For subjective reporting, changes from baseline in thesame group were assessed using Wilcoxon signed-rank
test. The Mann-Whitney U test was used for intergroupcomparisons of changes from the baseline. Student's
t-test was used to compare subject backgrounds between
groups. Statistical analyses were performed using Statcel
3 (Yanai, 2011). The results were considered signiﬁcantat the <5% level in the two-sided test.

3. RESULT
3.1. Participant Demographics
From all of 71 applicants, 31 were eliminated according to
exdusion criteria. The 40 subjects were randomly
assigned to an intervention group and made a start withingestion. 3 were withdrawn due to personal reasons andthe remaining 37 subjects completed the study. Out of 37
subjects, 8 revealed to fall under the exclusion criteria
for evaluation of efficacy as described in Efficacy
eligibility (2.2.3). 5 subjects consumed a meal in themorning just before getting a CT scan (2.2.3. (1)). 3

subjects did not send adequate records (2.2.3. (2).)
Thus, data obtained with 29 subjects were used for the
analysis of efficacy (Fig. 1). There were no significant
differences in the mean age or BMI between groups(Table 2).
3.2. Abdominal fat level
Table 3 shows changes in abdominal fat areas. For thechange, visceral fat area of the CUTTO group decreased
significantly compared with the Placebo group after 12
weeks of ingestion.
3.3. Weight, BMI and waist circumference
Table 3 shows the results of test analyses. After 12
weeks of ingestion, the CUTTO group showed asignificant difference in weight, BMI and waist
circumference, whereas the Placebo group showed nosigniﬁcant diﬀerence. Furthermore, signiﬁcant diﬀerence
was observed between the two groups of the change in all
three criteria after 12 weeks of ingestion.
3.4. Questionnaire analyses
The results of questionnaire analyses are shown in Table

診療と新薬・第 53 巻

第 3 号（2016 年 3 月）

77 （241）

Table 4 Results of questionnaire analyses

Item

ScoresTime

Between-groupdiﬀerencepoints

CUTTO group (n=16)

Placebo group (n=13)

Bowel movement

Baseline
Week 12
Change5.0±0.0
6.3±1.3 **1.3±1.3

5.0±0.0
4.8±0.9− 0.2±0.90.003 ##

Sensitivity to cold

Baseline
Week 12
Change5.0±0.0
6.1±1.3 **1.1±1.3

5.0±0.0
5.0±0.7
0.0±0.7

0.003 ##

Clothing size
variation

Baseline
Week 12
Change5.0±0.0
5.6±0.9 *0.6±0.9

5.0±0.0
5.2±0.6
0.2±0.6

0.203

Dryness of skin

Baseline
Week 12
Change5.0±0.0
6.5±1.3 **1.5±1.3

5.0±0.0
5.0±0.6
0.0±0.6＜ 0.001 ##Fatigue

Baseline
Week 12
Change5.0±0.0
5.9±0.9 **0.9±0.9

5.0±0.0
5.2±0.6
0.2±0.7

0.027 #

Mood

Baseline
Week 12
Change5.2±0.8
6.3±1.0 **1.1±1.1

5.1±0.3
5.4±0.7 †0.3±0.5

0.034 #

Rate of activity

Baseline
Week 12
Change5.0±0.0
6.4±1.2 **1.4±1.2

5.1±0.3
5.5±1.2
0.5±1.1

0.037 #

Sleeping quality

Baseline
Week 12
Change5.0±0.0
6.6±1.5 **1.6±1.5

5.2±0.6
5.0±1.3− 0.2±1.1

0.002 ##

Feeling lighter

Baseline
Week 12
Change5.0±0.0
5.9±0.9 **0.9±0.9

5.3±0.6
5.1±1.1− 0.2±0.70.001 ##

(P-value)

Scores are expressed as the mean ± SD.
†

p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.

#p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerence in change from baseline.

4 The data of the CUTTO group showed a significant
difference in all nine items of bowel movement ,sensitivity to cold , clothing size variation , drynessof skin , fatigue , mood , rate of activity , sleeping
quality and feeling lighter , whereas in the Placebogroup no item showed difference. Moreover, significant
difference was detected between the two groups of thechange in 9 items excluding clothing size variation after
12 weeks of ingestion.
3.5. Blood and Urine Test
Table 5 and 6 show the blood biochemical and urine
parameters.
With respect to the blood test, a significant difference
was observed in the changes of Total Protein andPotassium of the CUTTO group after 12 weeks ofingestion. However, since the difference was within
range of the baseline and just a shade of diﬀerence, theinvestigator judged it as the range of physiologicalvariation (or clinically safe).
Meanwhile no significant change was depicted in theurine test.
3.6. Adverse Event
No adverse eﬀects were observed after the ingestion offood.

4. DISCUSSION
We conducted a randomized, placebo-controlled, doubleblind study for examining the efficacy of a supplement
containing apple polyphenol and oreanolic acid. The
objective of this study is to verify the weight reduction

78 （242）

診療と新薬・第 53 巻

Table 5Item

Unit

第 3 号（2016 年 3 月）

Changes in biochemical blood test
ValuesStd. Value

Timepoints

CUTTO group (n=19)

Placebo group (n=18)

7.0 ± 0.4
7.2 ± 0.4 *0.1 ± 0.2

7.3 ± 0.3
7.1 ± 0.3 *− 0.1 ± 0.2 ##Total Protein

mg/dL

6.7-8.3

Baseline
Week 12
ChangeAlbuming/dl

3.8-5.2

Baseline
Week 12
Change4.2 ± 0.3
4.3 ± 0.2
0.0 ± 0.2

4.3 ± 0.2
4.2 ± 0.3
0.0 ± 0.2

A/G

ratio

1.1-2.0

Baseline
Week 12
Change1.51 ± 0.24
1.49 ± 0.22
− 0.01 ± 0.14

1.46 ± 0.17
1.48 ± 0.19
0.03 ± 0.12

AST (GOT)

U/L

10-40

Baseline
Week 12
Change20.1 ± 8.3
20.7 ± 9.4
0.6 ± 2.6

16.8 ± 3.7
17.1 ± 4.0
0.3 ± 2.7

ALT (GPT)

U/L

5-45

Baseline
Week 12
Change17.2 ± 11.0
18.5 ± 12.4
1.4 ± 5.3

13.5 ± 5.0
13.6 ± 5.2
0.1 ± 4.5

LD (LDH)U/L

120-240

Baseline
Week 12
Change196.6 ± 33.1
205.3 ± 30.4 †8.6 ± 18.0

191.1 ± 24.9
191.1 ± 29.8
0.0 ± 13.5

Total Bilirubin

U/L

0.2-1.2

Baseline
Week 12
Change0.68 ± 0.18
0.69 ± 0.18
0.01 ± 0.14

0.64 ± 0.16
0.65 ± 0.16
0.01 ± 0.18

ALP

U/L

100-325

Baseline
Week 12
Change195.1 ± 72.7
197.6 ± 67.1
2.5 ± 19.6

178.4 ± 52.3
174.4 ± 49.0
− 4.0 ± 15.0

γ-GT (γ GTP)

U/L

30 andunder

Baseline
Week 12
Change24.7 ± 17.9
31.1 ± 37.1
6.4 ± 25.1

18.8 ± 6.2
20.3 ± 9.4
1.5 ± 6.1

CK (CPK)

mg/dL

40-150Baseline
Week 12
Change112.6 ± 76.3
106.3 ± 62.6
− 6.3 ± 55.4

86.8 ± 34.0
74.2 ± 25.5 †− 12.7 ± 29.3

Urea Nitrogen

mg/dL

8-20

Baseline
Week 12
Change12.6 ± 3.0
12.6 ± 3.6
0.0 ± 3.5

12.0 ± 2.9
11.1 ± 3.0− 0.9 ± 2.6

Creatinine

mEq/L

0.47-0.79

Baseline
Week 12
Change0.66 ± 0.12
0.64 ± 0.10 †− 0.02 ± 0.06

0.68 ± 0.08
0.68 ± 0.07
− 0.01 ± 0.05

Sodium

mEq/L

137-147

Baseline
Week 12
Change141.2 ± 1.7
141.3 ± 1.8
0.1 ± 2.2

142.6 ± 2.2
141.7 ± 2.1 *− 0.9 ± 1.6

Chloride

mEq/L

98-108Baseline
Week 12
Change102.2 ± 1.9
102.3 ± 1.6
0.1 ± 1.7

103.3 ± 2.2
102.0 ± 2.7 *− 1.3 ± 2.6 ‡Potassium

mg/dL

3.5-5.0

Baseline
Week 12
Change3.9 ± 0.2
4.0 ± 0.2 **0.2 ± 0.2

4.0 ± 0.3
4.0 ± 0.3
− 0.0 ± 0.3 #Calcium

mg/dL

8.4-10.4

Baseline
Week 12
Change9.4 ± 0.6
9.4 ± 0.6
0.0 ± 0.3

9.3 ± 0.2
9.3 ± 0.3
0.0 ± 0.3

Inorganic Phosphorus

mg/dL

2.5-4.5

Baseline
Week 12
Change3.7 ± 0.4
3.6 ± 0.5
− 0.1 ± 0.4

3.8 ± 0.7
3.8 ± 0.6
0.0 ± 0.4

Total Cholesterol

mg/dL

120-219

Baseline
Week 12
Change214.9 ± 42.2
223.8 ± 48.0 †8.9 ± 20.9

210.7 ± 42.2
210.6 ± 44.0
− 0.1 ± 29.5

Neutral Fat (TG)mg/dL

30-149Baseline
Week 12
Change95.0 ± 55.5
92.4 ± 53.0
− 2.6 ± 28.6

95.9 ± 26.6
94.5 ± 43.7
− 1.4 ± 29.0

Glucosemg/dL

70-109Baseline
Week 12
Change88.7 ± 8.0
87.6 ± 9.3− 1.2 ± 6.6

85.7 ± 6.8
83.2 ± 11.3
− 2.5 ± 8.1

Values are expressed as the mean ± SD.
†
p ＜ 0.1, * p ＜ 0.05, ** p ＜ 0.01 against baseline.
‡p ＜ 0.1, # p ＜ 0.05, ## p ＜ 0.01 between-group diﬀerences in change from baseline.

診療と新薬・第 53 巻

第 3 号（2016 年 3 月）

79 （243）

Table 6 Transition of Urinalysis
Item

Unit

Std. Value

Speciﬁc Gravity

mg/dL

1.0061.030

pH

g/dL

5.0-7.5

ValuesTimepoints

CUTTO group (n ＝ 19)

Placebo group (n ＝ 18)

Baseline
Week 12
Change1.021±0.008
1.019±0.008− 0.002±0.010

1.023±0.008
1.021±0.007− 0.002±0.009

Baseline
Week 12
Change6.3±0.9
6.3±0.9
0.0±1.1

5.9±0.4
6.0±0.7
0.0±0.7

Values are expressed as the mean ± SD.

and waist circumference reduction effect of the
supplement. As the primary outcome, the study showed
the significant differences in visceral fat area, weight,
BMI and waist circumference. In addition, several
categories on the questionnaire conducted to search thesubjective evaluation of the test product showed thesignificant differences, and this result indicates the
improvement of QOL. As the secondary outcome, theobservation of clinical ﬁndings such as medical interview,
blood test and urine test revealed no abnormal changes
had been triggered by the ingestion of the test product.
Main Findings
In this study we examined the changes of abdominal fat
level, weight, BMI and waist circumference of the test
group after 12-week ingestion of the test product,
compared to the Placebo group. As for the abdominal fat
level, the level of the visceral fat area of the test group inparticular showed a signiﬁcant reduction compared to thePlacebo group, and the weight, BMI and waist
circumference of the test group also showed somesigniﬁcant reduction compared to the Placebo. The levelof subcutaneous fat area, on the other hand, both groups
showed the similar tendency of reduction, therefore no
signiﬁcant diﬀerence was observed between them.
In addition, we conducted the questionnaire to search
the subjective evaluation of the test product. The resultof the test group showed the signiﬁcant diﬀerence in all 9
categories, and among them in 8 categories (except thecategory clothing size variation ) the significant
diﬀerence was detected between the two groups. In thePlacebo group, on the other hand, no category showed
the signiﬁcant diﬀerence after 12-week ingestion period.
Among the categories of the questionnaire there is anegative-type question such as fatigue , but overall the
improvement of QOL by the ingestion of the test productwas indicated.
The test product contains apple polyphenol andoreanolic acid. Apple polyphenol is a polyphenol whose
principal ingredients are procyanidins9), and other thanprocyanidins it also contains catechins and chlorogenic
acid 10). These polyphenols have a strong antioxidant
effect, and there are a lot of reports that show the

improvement of lipid metabolism 6)8)11) . Also, theprocyanidins, the principal ingredients of apple
polyphenol, are reported to have high-functioning
inhibition of a pancreatic lipase activity 12) . As thepancreatic lipase activity is inhibited, the fatty acidabsorption from the intestine is suppressed. This
contributes to the reduction of the amount of the fatty
acid absorption, and eventually it possibly enables theinhibition of fat accumulation. In addition, it is reported
that apple polyphenol decreases the transcription ofgenes involved in fatty acid synthesis and upregulate theβ(beta)-oxidation of fat13). These facts suggest that apple
polyphenol increases lipolysis and may be eﬀective for the
reduction of fat itself.
On the other hand, oreanolic acid is reported to havefunctionalities of downregulating the genes controlling fat
synthesis and suppressing the production of fatty acid7).
Therefore, it can be said that by ingesting this test
product (CUTTO), both apple polyphenol and oreanolicacid contained in CUTTO functioned as the inhabitation
and/or reduction of fat accumulation, and accomplishedthe weight reduction and waist circumference reductionof the subjects.
Secondary Findings
And in this study, it was observed that based upon clinicalfindings such as blood test and urine test, no abnormalchange was triggered by ingestion of the test product. In
the blood test, signiﬁcant diﬀerence was observed in thechanges of Total protein and Potassium of the CUTTO
group after 12-week ingestion. On the other hand, nodifference was observed with the urine test. In either
case, since the diﬀerence was within a range of baseline
and a shade of diﬀerence, the investigator judged it as therange of physiological variation (or clinically safe).
Therefore, based upon the medical interview, blood test
and urine test, we observed no harmful inﬂuence against
biochemical and/or physiological matters of the subjects
which seem to have causal relationship with CUTTO.
During the study, three subjects were withdrawn due
to personal reasons and eight were revealed to fall underthe exclusion criteria. Among eight, five subjects
consumed meal in the morning just before getting CT

80 （244）

診療と新薬・第 53 巻

scan, whereas three subjects did not send adequate
records. In either case, they were not related to theadverse event caused by the test product.
Therefore, these results indicated the safety of theingestion of the test product (CUTTO) for the 12-weektest period.
General Information
Obesity not only leads to the diseases such as lifestylediseases , but also causes deterioration of the external
appearance and especially for women, it can trigger off
the serious degradation of QOL. In addition, the fact thatJapan is facing the aging society accelerates their pursuitof anti-aging , which is basically aimed at youngerlooking or more-beautiful looking . Apple polyphenol
contained in the test product is regarded as a highly-safe
ingredient and is registered as GRAS (generally
recognized as safe), one of the safety standards of food in
the US. Oreanolic acid, on the other hand, is theingredient can be seen widely throughout nature, such as
in rape or olive leaves. As illustrated so far, these
ingredients have an antioxidant effect in addition to an
improvement of lipid metabolism, therefore they areuseful in preventing allergies or reducing oxidant
stress14)15). For these reasons, it is considered that the
combination of the improvement of daily eating andexercise habits and the ingestion of this test product can
prevent obesity, improve the external appearance andkeep our body in good health.
Limitations
For this study we used the test product (supplement)
containing apple polyphenol and oreanolic acid, and each
ingredient reportedly own the functionality of improving
lipid metabolism 7)11)〜13). Therefore the outcome of thisstudy should be strongly related to these findings.
However, the functional mechanism of these reports ismainly based upon the in-vitro settings or the researchusing rats, and the behavior in the human body is amatter of speculation. In addition, we have not yet
discovered the mutual influences between apple
polyphenol and oreanolic acid. Furthermore, in this study
we did not ﬁnd any signiﬁcant diﬀerences in subcutaneous
fat area, but could not find whether these ingredientswere truly not functional for that area, or the test period
was too short to have certain result and the longer testp e r i od w a s r e q u i r e d t o r e ve a l s o m e s i g n i f i c a n t
differences. Therefore, these points should be further
scrutinized in the future.
Conclusion
In conclusion, we found out that the ingestion of the
supplement (CUTTO) containing apple polyphenol andoreanolic acid for 12 weeks contributed to the weight
reduction and waist circumference reduction. In addition,no safety-related matter occurred during 12-week test
period.

第 3 号（2016 年 3 月）

CONFLICT OF INTEREST
Hirofumi Wada and Emiko Wada are directors of GRACEAS Corporation.
All remaining authors have declared no conﬂicts of interest.

REFERENCES
1) Tanabe M, Okajima T. Diagnosis and Treatment of Obesity. IRYO.
2009; 63(7), p. 421-6
2) Kawada T. Food Function Study of Obesity and Fat Energy
Metabolism ( JSNFS Award for Excellence in Research (2013)).
Nippon Eiyo Shokuryo Gakkaishi. 2014; 67(3), p. 119-25
3) Saito M. Energy Expenditure by Brown Adipose Tissue and its
Activation by Food Substances. KAGAKU TO SEIBUTSU. 2012;50(1), p. 23-9
4) Shoji T. Application of Apple polyphenols for Food Ingredient. Nippon
Shokuhin Kagaku Kaishi. 2006; 53(3), p. 159-64
5) Assimopoulou AN, Zlatanos SN, Papageorgiou VP. Antioxidant
activity of natural resins and bioactive triterpenes in oil substrates.
Food Chem. 2005; 92(4), p. 721-7
6) Ohta Y, Funayama M, Seino H, et al. Apple Polypheonol Improves
Lipid Metabolism and Insulin Independence in Obese Rats. Nippon
Shokuhin Kagaku Kogaku Kaishi. 2007; 54(6), p. 287-94
7) Wan Q, Lu H, Liu X, et al. The study of oleanolic acid on the estrodiol
production and the fat production of mouse preadipocyte 3T3-L1 invitro . Hum Cell. 2015; 28(1), p. 5-13
8) Tenore GC, Calabrese G, Stiuso P, et al. Effects of Annurca apple
polyphenols on lipid metabolism in HepG2 cell lines: A source ofnutraceuticals potentially indicated for the metabolic syndrome. FoodRes Int. 2014; 63(part B), p. 252-7
9) Ohnishi-Kameyama M, Yanagida A, Kanda T, et al. Identiﬁcation of
catechin oligomers from apple (Malus pumila cv. Fuji) in matrixassisted laser desorption/ionization time-of-ﬂight mass spectrometry
and fast-atom bombardment mass spectrometry. Rapid Commun Mass
Spectrom. 1997; 11(1), p. 31-6.
10) Kanda T, Akiyama H, Yanagida A, et al. Inhibitory effects of apple
polyphenol on induced histamine release from RBL-2H3 cells and rat
mast cells. Biosci Biotechnol Biochem. 1998; 62(7), p. 1284-9.
11) Murase T, Nagasawa A, Suzuki J, et.al. Beneficial effects of tea
catechins on diet-induced obesity: stimulation of lipid catabolism in theliver. Int J Obes Relat Metab Disord. 2002; 26(11), p. 1459-64.
12) Sugiyama H, Akazome Y, Shoji T, et al. Oligomeric procyanidins inapple polyphenol are main active components for inhibition of
pancreatic lipase and triglyceride absorption. J Agric Food Chem.
2007; 55(11), p. 4604-9
13) Ohta Y, Sami M, Kanda T, et.al. Gene Expression Analysis of theAnti-obesity Eﬀect by Apple Polyphenols in Rats Fed a High Fat Dietor a Normal Diet. J. Oleo Sci. 2006; 55(6), p. 305-14
14) Nadaoka I. Project Bio Development of the apple polyphenol
combination food aiming at contribution to healthy longevity. seibutsukogaku kaishi. 2015; 93(9), p. 558-9
15) Cho SO, Ban JY, Kim JY, et al. Aralia cordata Protects Against
Amyloid β Protein (25‒35)‒Induced Neurotoxicity in Cultured
Neurons and Has Antidementia Activities in Mice. J Pharmacol Sci.
2009; 111(1), p. 22-32.