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Functional Foods in Health and Disease 2014; 4(6):276-284 Page 276 of 284
Research Article Open Access
Efficacy and safety of Citrus sudachi peel in obese adults:
A randomized, double-blind, pilot study
Masashi Akaike1, Ken-ichi Aihara2, Hiroaki Yanagawa3, Takashi Iwase4, Sumiko
Yoshida2, Chiho Sato3, Tomoka Saijo3, Hiroaki Mikasa5, Yoshizaki Kashiwada6,
Yoshihisa Takaishi6, Koichiro Tsuchiya7, Toshiaki Tamaki8, Toshio Matsumoto2,
Masataka Sata4
1Department of Medical Education, 2Department of Medicine and Bioregulatroy Sciences,
4Department of Cardiovascular Medicine, 6Department of Natural Medicines, 7Department of
Medical Pharmacology, 8Department of Pharmacology, The University of Tokushima
Graduate School of Medical Sciences, 3Clinical Trial Center for Developmental Therapeutics,
Tokushima University Hospital, 5Support Center for Medical Education, School of Medicine,
The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
Correspondence author: Masashi Akaike, MD, PhD. Department of Medical Education,
University of Tokushima Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho,
Tokushima 770-8503, Japan
Submission date: May 9, 2014; Acceptance date: June 27, 2014; Publication date: July 1,
2014
ABSTRACT
Objective: This study was undertaken to explore the efficacy and safety of Citrus sudachi
peel for metabolic risk factors in obese male and female adults.
Background: Citrus sudachi Hort. ex Shirai (Rutaceae), called “sudachi”, is a small, round,
green citrus fruit that is mainly cultivated in Tokushima Prefecture in Japan. Our group
reported that Citrus sudachi peel powder improved glucose tolerance and dyslipidemia in
Zucher-fatty rats and reduced hyperglycemia and hypertriglyceridemia in GK diabetic rats.
Materials and Methods: We conducted a randomized, double-blind, placebo-controlled trial
in 40 participants with abdominal obesity and metabolic risk factors including hypertension,
impaired glucose tolerance and elevated triglyceride levels. Participants were randomized to
receive either tablets that contained 1.3 g dried Citrus sudachi peel powder or placebo tablets
for 12 weeks. The sudachi peel group included 14 males and 5 females with a mean age of
54.5 years, and the placebo group included 18 males and 2 females with a mean age of 51.9
years.
Results: Physical status including body weight, waist circumference and blood pressure and
laboratory markers including metabolic parameters were not different at any observation point
between the two groups. However, among participants with serum triglyceride levels of more
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 277 of 284
than 120 mg/dl, body weight, waist circumference and serum triglyceride levels were
significantly decreased at several observation points after the start of treatment in the sudachi
peel group but not in the placebo group. No serious adverse events were observed in the
sudachi peel group.
Conclusions: Citrus sudachi peel has the potential effect to safely improve abdominal obesity
and lower serum levels of TG in obese individuals with hypertriglyceridemia. A large-scale
randomized, double-blind clinical study targeting subjects with both abdominal obesity and
high TG levels is needed to confirm the metabolic effects of Citrus sudachi peel.
Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002682.
Accession number of the Ethics Committee for Clinical Trials of Food in Tokushima
University Hospital is F5.
Key words: health functional food, anti-obesity, triglyceride
BACKGROUND:
Citrus sudachi Hort. ex Shirai (Rutaceae), called “sudachi”, is a small, round, green citrus
fruit that is mainly cultivated in Tokushima Prefecture in Japan [1]. Slices of this fruit are
often used for Japanese dishes as food flavoring in place of vinegar and the peel is also edible.
Our group reported that Citrus sudachi peel powder improved glucose tolerance and
dyslipidemia in Zucher-fatty rats and reduced hyperglycemia and hypertriglyceridemia in GK
diabetic rats [2]. However, the effects of Citrus sudachi peel on lifestyle-related risk factors in
humans have not been clarified. Metabolic syndrome is a combination of lifestyle-related risk
factors that increase the risk of developing cardiovascular disease and diabetes [3]. The aim of
this study was to explore the efficacy and safety of Citrus sudachi peel for improving
lifestyle-related risk factors including obesity, hypertension, impaired glucose tolerance and
dyslipidemia in humans.
METHODS:
Subjects: Inclusion criteria were males and females aged 20 - 74 years who had abdominal
obesity defined as waist circumference >85cm for males or >90cm for females or body mass
index (BMI) >25 and any one of the following: 1) fasting plasma glucose (FPG) >100 mg/dL
(5.6 mmol/L) or specific treatment for type 2 diabetes, 2) serum triglycerides (TG)
>150 mg/dL (1.7 mmol/L) or high-density lipoprotein cholesterol (HDL-C) <40 mg/dL
(1.03 mmol/L) or specific treatment for its abnormality, and 3) systolic blood pressure (BP)
>130 or diastolic BP >85mmHg or treatment of hypertension. The following subjects were
excluded: 1) subjects with complications in the brain, heart, kidney, lungs or liver
(cerebrovascular accident, myocardial infraction, angina pectoris, history of cardiovascular
intervention, heart failure, arteriosclerosis obliterans, nephropathy, bronchial asthma,
pulmonary emphysema, pneumonitis, pulmonary fibrosis, viral hepatitis, cirrhosis, diabetic
complications, and diabetes treated with insulin), 2) subjects in whom additional
pharmaceutical agents should be considered for hypertension, lipid disorder, diabetes mellitus
and/or other diseases, 3) subjects with overt systemic diseases, 4) subjects with a history of
malignant diseases, 5) subjects who participated in another clinical trial, and 6) subjects who
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 278 of 284
were not appropriate in the attending physicians' opinion.
Experimental design: This study was designed as a randomized, double-blind,
placebo-controlled trial. Participants were randomized to receive either 5 tablets that in total
contained 1.3 g dried Citrus sud achi peel powder (sudachi peel group) or 5 placebo tablets
(placebo group) every day for 12 weeks. Daily intake in the sudachi peel group was
equivalent to 1/3 of a whole Citrus sudachi. Since analysis carried out by the Japan Food
Research Laboratories showed that the content of synephrine in Citrus sudachi peel is 2.5
mg/g, estimated intake of synephrine, which is contained in abundance in citrus peel and has
pharmacological effects similar to those of ephedrine, was only 3.25 mg/day in the sudachi
peel group. Analysis carried out by the Japan Food Research Laboratories also showed that
the content of hesperidin, a flavonoid found abundantly in citrus fruits, was 7.4 mg/g in Citrus
sudachi peel, indicating that the estimated intake of hesperidin was only 9.62 mg/day in the
sudachi peel group. The study period was 17 weeks including a 1-week observation period
before treatment, 12-week treatment period with Citrus sudachi peel powder or placebo
tablets and 4-week observation period after treatment. The subjects made visits to the hospital
1 week before the treatment, 4, 8 and 12 weeks after the start of treatment, and 4 weeks after
the treatment period. A life diary including physical activity and exercise was recorded every
day during the study period and a diet diary including content of meals was recorded for three
days before each visit. The number of remaining tablets was checked at each point of visit to
assess the compliance of subjects. Physical examination including measurements of height,
body weight, BMI, waist circumference, BP and pulse was performed at each visit. Urine and
blood samples were drawn from the antecubital vein after an overnight fast at each visit.
Biochemical analysis: General laboratory tests were also carried out at each visit. The tests
included urinalysis to assess urinary protein, occult blood, urobilinogen, sugar and ketone
bodies, measurements of peripheral blood including white blood cells, red blood cells,
hemoglobin, hematocrit and platelets, assessment of liver function including measurements of
GOT, GPT, LDH, total bilirubin, alkaline phosphatase, γGTP, total protein and albumin,
assessment of renal function including measurements of BUN and creatinine, measurements
of electrolytes including sodium, potassium, chloride, and calcium concentrations, and
assessment of metabolic function including measurements of low-density lipoprotein
(LDL)-C, HDL-C, TG, FPG, HbA1c (National Glycohemoglobin Standardization Program),
immunoreactive insulin (IRI), and uric acid (UA). In addition, blood levels of remnant-like
particles (RLP)-C, free fatty acid (FFA), high-sensitivity C-reactive protein (hs-CRP), tumor
necrosis factor (TNF)- and adiponectin and urinary excretion of
8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of oxidative stress were examined 1
week before treatment, 12 weeks after the start of treatment and 4 weeks after the treatment
period. Hs-CRP levels were measured at Bio Medical Laboratories (Tokyo, Japan) by
nephelometry, a latex particle-enhanced immunoassay (N Latex CRP II). TNF- was
measured by ELISA (Human TNF- TNFSF1A, R&D Systems, Inc., Minneapolis, USA).
Adiponectin was measured by ELISA (Human adiponection ELISA Kit, Otsuka
Pharmaceutical Co., Ltd, Tokyo, Japan). Urinary excretion of 8-hydroxydeoxyguanosine
(OHdG) was determined by ELISA (new 8-OHdG Check ELISA Kit, Japan Institute for the
Control of Aging, Nikken SEIL Corporation, Shizuoka, Japan) and expressed in g/g
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 279 of 284
creatinine after correction by urinary creatinine concentration.
Ethics: The present clinical study is in compliance with the Helsinki Declaration. Prior
written informed consent was obtained from all subjects before enrollment in this study in
accordance with protocols approved by the Ethics Committee for Clinical Trials of Food in
Tokushima University Hospital (accession number F5). This study was registered in the
UMIN Clinical Trials Registry (UMIN-CTR) with the trial number of UMIN000002682.
Statistical Analysis: All parameters before and after treatment were compared between the
sudachi peel group and the placebo group using generalized linear mixed model analysis.
Differences in baseline patient characteristics between the two groups were analyzed by the
unpaired t-test. The Wilcoxon signed rank test was used to assess significant changes in
parameters after the start of treatment in each group. All data are expressed as means ± S.D.
The analyses were performed on a Microsoft Windows computer running SPSS software.
Differences were considered statistically significant at p < 0.05.
RESULTS:
Basal characteristics: Forty subjects were enrolled in this study, but one subject could not
visit our hospital due to personal reasons. Finally, the sudachi peel group included 14 males
and 5 females with a mean age of 54.5 years (one patient having dropped out), and the
placebo group included 18 males and 2 females with a mean age of 51.9 years. The patients’
characteristics are summarized in Table 1. The first, second and third quartile of TNFα levels
is 1.3, 3.4 and 4.7 pg/mL in the placebo group, respectively, and 2.1, 2.3 and 3.2 pg/mL in the
Sudachi peel group, respectively. There were no differences in basal parameters including age,
sex, BMI, waist circumference, pulse, BP, TG, HDL-C, HbA1c and FPG between the sudachi
peel group and the placebo group.
Intake rate of tablets: There was no difference between the intake rates of tablets in the two
groups (95.36.7 % in the sudachi peel group and 96.16.0 % in the placebo group).
Live and diet diary: Physical activity and dietary intake of total calories and nutrients
including carbohydrates, proteins and lipids were not different before, during and after
treatment in either the sudachi peel group or placebo group. There were also no differences in
these parameters at every observation point between the two groups.
Changes in parameters before, during and after treatment: Physical status including body
weight, BMI, waist circumference, pulse and BP and laboratory markers including urinalysis,
peripheral blood, liver function, renal function, electrolytes, LDL-C, TG, HDL-C, RLP-C,
FFA, HbA1c, FPG, IRI, UA, hs-CRP, urinary 8-OHdG, TNF- and adiponectin were not
different at any observation point between the two groups. There were also no differences in
theses parameter before and 4, 8 and 12 weeks after the start of treatment and at 4 weeks after
the treatment period in either the sudachi peel group or placebo group.
Adverse effects: One patient in the placebo group developed dizziness and palpitation due to
paroxysmal atrial fibrillation. None of the patients in the sudachi peel group showed
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 280 of 284
expression or worsening of symptoms.
Table 1. Baseline parameters in all subjects
Variables
Placebo group
n=20
Sudachi peel group
n=19
P-value
Age
51.911.0
54.5 8.9
ns
Male : Female
18:2
14:5
ns
Body weight (kg)
76.2 10.8
75.610.9
ns
BMI
26.2 3.4
26.8 3.0
ns
Waist circumference(cm)
93.7 6.1
97.3 6.3
Ns
Pulse (bpm)
73.5 5.8
71.9 8.2
ns
Systolic BP (mmHg)
128.9 13.0
134.6 10.5
ns
Diastolic BP (mmHg)
82.3 6.2
87.9 8.3
ns
LDL-C (mg/dL)
134.7 25.2
140.8 20.4
ns
TG (mg/dL)
143.8 67.0
146.6 60.3
ns
HDL-C (mg/dL)
62.9 15.1
67.7 15.8
ns
RLP-C (mg/dL)
9.6 5.8
9.8 5.4
ns
FFA (Eq/L)
538.5 133.1
548.6 197.2
ns
HbA1c (%)
6.0 0.3
5.9 0.4
ns
FPG (mg/dL)
112.2 13.3
108.7 14.1
ns
IRI (g/dL)
8.0 3.1
7.7 3.6
ns
UA (mg/dL)
6.2 1.4
5.8 1.0
ns
hsCRP (g/dL)
100 116
93 98
ns
U-8OHdG(g/gCr)
9.9 4.6
11.9 7.5
ns
TNFα (pg/mL)
4.0 4.1
6.2 15.4
ns
Adiponectin(g/mL)
6.1 2.3
6.5 2.4
ns
Analysis in a subgroup with serum TG levels of more than 120 mg/dL: Since none of the
parameters were changed by treatment with Citrus sudachi peel, we next analyzed the data in
subjects with serum TG levels of more than 120 mg/dl. Although age and blood pressure of
the sudachi peel subgroup with serum TG levels of more than 120 mg/dl were slightly higher
than those of the placebo subgroup with serum TG levels of more than 120 mg/dl, there were
no significant differences in other baseline parameters between the two subgroups (Table 2).
The first, second and third quartile of TNFα levels is 3.5, 4.1 and 5.9 pg/mL in the placebo
group, respectively, and 2.2, 2.7 and 3.2 pg/mL in the Sudachi peel group, respectively.
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 281 of 284
Table 2. Baseline parameters in subjects with serum TG levels of more than 120 mg/dl
Variables
Placebo group
n=11
Sudachi peel group
n=11
P-value
Age
47.311.0
56.3 8.2
0.046
Male : Female
9:2
8:3
ns
Body weight (kg)
79.1 12.9
76.911.9
ns
BMI
26.8 4.0
27.5 3.4
ns
Waist circumference (cm)
95.4 6.8
99.1 6.3
ns
Pulse (bpm)
74.5 6.6
73.8 9.7
ns
Systolic BP (mmHg)
126.7 9.7
135.5 8.1
0.049
Diastolic BP (mmHg)
82.0 6.1
89.5 9.6
0.042
LDL-C (mg/dL)
138.6 27.8
143.4 21.5
ns
TG (mg/dL)
189.4 56.3
184.7 49.4
ns
HDL-C (mg/dL)
58.4 14.5
64.7 11.8
ns
RLP-C (mg/dL)
13.1 5.7
13.0 5.0
ns
FFA (Eq/L)
524.0 141.3
609.5 233.1
ns
HbA1c (%)
6.0 0.4
5.8 0.4
ns
FPG (mg/dL)
110.4 13.0
104.6 4.4
ns
IRI (g/dL)
8.7 1.8
8.6 4.4
ns
UA (mg/dL)
6.0 1.6
5.8 1.2
ns
hsCRP (g/dL)
100 89
125 119
ns
U-8OHdG(g/gCr)
13.6 8.5
10.5 5.7
ns
TNFα (pg/mL)
5.4 3.7
8.8 19.8
ns
Adiponectin(g/mL)
5.8 2.1
6.7 2.3
ns
In subjects with serum TG levels of more than 120 mg/dl, body weight significantly
decreased from 76.9±11.9 kg before treatment to 76.1±11.1 kg (p<0.05) and 76.0±11.1 kg
(p<0.05) at 8 and 12 weeks after the start of treatment, respectively, and the decrease in body
weight was maintained 4 weeks after the treatment period (75.6±11.4 kg, p<0.01 vs before the
treatment) in the sudachi peel subgroup, but no significant changes in body weight were
observed in the placebo subgroup (Figure 1A).
Waist circumference also significantly decreased from 99.1±6.3 cm before treatment to
97.5±6.8 cm (p<0.01) and 97.3±7.3 cm (p<0.05) at 8 and 12 weeks after the start of treatment,
respectively, in the sudachi peel subgroup with serum TG levels of more than 120 mg/dL but
not in the placebo subgroup (Figure 1B). Serum TG level also significantly decreased from
184.7±49.4 mg/dL before treatment to 158.1±40.7 mg/dL (p<0.05) at 8 weeks after the start
of treatment and to 141.2±37.1 mg/dL (p<0.01) at 4 weeks after the treatment period in the
sudachi peel subgroup (Figure 1C). However, no significant changes in serum TG levels were
observed in the placebo subgroup with serum TG levels of more than 120 mg/dL (Figure 1C).
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 282 of 284
However, there was no difference in these parameters at any observation point between the
two groups.
Figure 1. Changes of parameters in the placebo subgroup (□) and the sudachi peel subgroup
(■) with serum triglyceride levels of more than 120 mg/dL. Body weight was significantly
decreased at 8 and 12 weeks after the start of treatment and the decrease in body weight was
maintained 4 weeks after the treatment period in the sudachi peel subgroup (A). Waist circumference
was also significantly decreased at 8 and 12 weeks after the start of treatment in the sudachi peel
subgroup (B). Serum triglyceride (TG) levels were significantly decreased at 8 weeks after the start of
treatment and at 4 weeks after the treatment period in the sudachi peel subgroup (C). Serum TG levels
after the start of treatment significantly decreased compared with the baseline level in the sudachi peel
group (p<0.05) (C). All data are expressed as ratios to baseline level before the start of treatment and
means ± SEM. * p<0.05 and ** p<0.01 vs before treatment.
DISCUSSION:
This study is the first randomized, double-blind, placebo-controlled trial to clarify the effects
and safety of Citrus sudachi peel in humans. We did not find any significant differences in
clinical parameters between the placebo group and sudachi peel group in the present study.
However, subgroup analysis using serum TG levels showed that intake of Citrus sudachi peel
significantly decreased body weight, waist circumference and serum TG level in subjects with
serum TG levels of more than 120 mg/dL, but such decreases were not observed in the
placebo subgroup. On the other hand, the subgroup analysis did not show significant
differences in parameters at any observation point after the start of treatment between the
placebo group and the sudachi peel group. These findings suggested that number of enrolled
subjects in this study is too small to show a significant difference between the two groups.
In addition, Taskinen et al. reported that serum TG level in obese subjects is increased by the
combination of increased secretion and severely impaired clearance of TG-rich VLDL1
particles and that increased secretion of TG-rich VLDL1 particles is linked to increased liver
and subcutaneous abdominal fat [4], indicating that obesity with high TG levels has a
metabolic pathology different from that in other types of obese patients with normal TG
levels. Taken together, a large-scale clinical study enrolling obese subjects with high TG
levels should be designed to clarify the clinical effects of sudachi peel.
There are several reports about the effects of components in citrus peel on metabolic
syndrome. Hesperidin, a flavanone glycoside found abundantly in the peel of citrus fruits,
was reported to improve hypercholesterolemia, hypertriglyceridemia or fatty liver in rat
models [5,6]. Morand et al. reported that in healthy, middle-aged, moderately overweight men,
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 283 of 284
orange juice decreases diastolic blood pressure and postprandially increases
endothelium-dependent microvascular reactivity [7]. In Morand’s study, daily intake of
hesperidin was 292 mg. However, in our study, estimated intake of hesperidin was quite
low (only 9.62 mg/day) in the sudachi peel group. Synephrine contained in the peel of
bitter orange citrus also has beneficial effect on obesity as a thermogenic agent like the
action of ephedrine. In our study, estimated intake of synephrine was only 3.25 mg/day.
Colker et al. conducted the first study on the effects of a bitter orange extract containing
58.5 mg p-synephrine and 528 mg caffeine daily on body fat loss and lipid levels in 20
overweight adult subjects [8]. A review of human studies on Citrus aurantium (bitter
orange) extract and its primary protoalkaloid p-synephrine showed that products
containing a low dose of synephrine, such as in our study, have no anti-obesity effect [9].
Taken together, we speculate that the effect of Citrus sudachi peel on obesity and TG
levels may not be due to synephrine.
Nakagawa et al. identified sudachitin (4',5,7-trihydroxy-3',6,8- trimethoxyflavone)
and 3¢-demethoxysudachitin from Citrus sudachi peel as the most active compounds
with antimicrobial activity against methicillin-resistant Staphylococcus aureus and
Helicobacter pylori [10]. Yuasa et al. also reported that sudachitin inhibited nitric oxide
production by suppressing the expression of inducible nitric oxide synthase in
lipopolysaccharide-stimulated macrophages, indicating that sudachitin has an
anti-inflammatory effect [11]. However, no components having an anti-obesity effect or
TG-lowering effect have so far been identified from the peel of Citrus sudachi. Further
studies are needed to clarify the mechanisms by which the peel of Citrus sudachi
improves obesity and lowers serum TG levels.
In our study, there were no adverse effects of the intake of 1.3 g dried Citrus sudachi
peel every day for 12 weeks. There are concerns about side effects of citrus peel on the
cardiovascular system since it contains a large amount of synephrine with ephedrine-like
action. In Guidelines for the Use of Synephrine in Natural Health Products revised by
Health Canada in 2010, 30 mg/day is the maximum allowable dose for total synephrine.
Peel of Citrus sudachi may be safe for consumption because it contains less synephrine
than that in other citrus peels. However, since the subjects of our study had no
cardiovascular complications, the safety for patients with cardiovascular diseases was not
confirmed. In addition, since the period of Citrus sudachi peel intake was only 12
weeks in our study, further study is needed to show the safety of long-term Citrus
sudachi peel intake.
CONCLUSIONS:
Citrus sudachi peel has the potential effect to safely improve abdominal obesity and lower
serum levels of TG in obese individuals with hypertriglyceridemia. A large-scale randomized,
double-blind clinical study targeting subjects with both abdominal obesity and high TG levels
is needed to confirm the metabolic effects of Citrus sudachi peel.
Competing interests: The authors have no financial interests or conflicts of interest.
Author’s contributions: All authors contributed to this study.
Abbreviations: BMI, body mass index; BP, blood pressure; C, cholesterol; FFA, free fatty
acid; FPG , fasting plasma glucose; HDL, high-density lipoprotein; hs-CRP, high-sensitivity
Functional Foods in Health and Disease 2014; 4(6):276-284 Page 284 of 284
C-reactive protein; IRI, immunoreactive insulin; LDL, low-density lipoprotein; OHdG,
hydroxydeoxyguanosine; RLP, remnant-like particles; TG, triglycerides; TNF, tumor necrosis
factor; UA, uric acid
Acknowledgments and Funding: We thank Kazue Ishikawa for her technical assistance in
measurements of TNF-, adiponectin and 8-OHdG. This study was funded by KTT
Corporation (Osaka, Japan). Tablets of Citrus Sudachi peel or placebo were synthesized and
provided by KTT Corporation.
REFERENCES:
1. Iuchi A, Hayashi K, Tamura K, Kono T, Miyashita M, Chakraborty SK: Technique of
quality control for Sudachi (Citrus sudachi Hort. Ex Shirai) juice by high pressure
treatment. In: High Pressure Bioscience and Biotechnology (Hayashi R and Balny C,
ed.) Elsevier B.V., Amsterdam, 1996, pp. 387-390.
2. Ikeda Y, Tsuchiya K, Tajima S, et al. The effect of SUDACHI peel, a specialty of
Tokushima, as anti-metabolic syndrome. J Pharmacol Sci 2010;112(Suppl 1):21.
3. Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J. The metabolic syndrome: a
global public health problem and a new definition. J Atheroscler Thromb
2005;12:295-300.
4. Taskinen MR, Adiels M, Westerbacka J, et al. Dual metabolic defects are required
to produce hypertriglyceridemia in obese subjects. Arterioscler Thromb Vasc Biol
2011;31:2144-2150.
5. Wang X, Hasegawa J, Kitamura Y, et al. Effects of hesperidin on the progression of
hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats. J
Pharmacol Sci 2011;117:129-138.
6. Akiyama S, Katsumata S, Suzuki K, Nakaya Y, Ishimi Y, Uehara M. Hypoglycemic
and hypolipidemic effects of hesperidin and cyclodextrin-clathrated hesperetin in
Goto-Kakizaki rats with type 2 diabetes. Biosci Biotechnol Biochem
2009;73:2779-2782.
7. Morand C, Dubray C, Milenkovic D, et al. Hesperidin contributes to the vascular
protective effects of orange juice: a randomized crossover study in healthy volunteers.
Am J Clin Nutr 2011;93:73–80.
8. Colker CM, Kalman DS, Torina GC, Perlis T, Street C. Effects of Citrus aurantium
extract, caffeine, and St. John’s wort on body fat loss, lipid levels, and mood states in
overweight healthy adults. Curr Therap Res 1999;60:145-153.
9. Stohs SJ, Preuss HG, Shara M. A review of the human clinical studies involving
Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine.
Int J Med Sci 2012;9:527-538.
10. Nakagawa H, Takaishi Y, Tanaka N, Tsuchiya K, Shibata H, Higuti T. Chemical
constituents from the peels of Citrus sudachi. J Nat Prod 2006;69:1177-1179.
11. Yuasa K, Tada K, Harita G, Fujimoto T, Tsukayama M, Tsuji A. Sudachitin, a
polymethoxyflavone from Citrus sudachi, suppresses lipopolysaccharide-induced
inflammatory responses in mouse macrophage-like RAW264 cells. Biosci Biotechnol
Biochem 2012;76:598-600.
