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American Journal of Plant Sciences, 2017, 8, 85-95
http://www.scirp.org/journal/ajps
ISSN Online: 2158-2750
ISSN Print: 2158-2742
DOI: 10.4236/ajps.2017.82007 January 19, 2017
Effect of Grains of Paradise (GP) Extract Intake
on Obesity and Sympathetic Nerve Activity
Hiroyuki Hattori1, Kosei Yamauchi2, Siaw Onwona-Agyeman3, Tohru Mitsunaga1*
1Faculty of Applied Biological Science, Gifu University, Gifu, Japan
2Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, Temple, TX, USA
3Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
Abstract
The methanol extract of grains of paradise (GP), the seed of
Aframomum
melegueta
, which is distributed throughout West Africa, was administered
during an animal breeding test. The extract suppressed body weight gain and
decreased the weight of adipose tiss
ues in breeding mice, with a greater effect
on mice fed a high-fat diet (HFD) than on those fed a normal diet (ND). Ot
h-
er significant effects of GP intake included increased serum triglyceride (TG)
concentration and reduced hepatic total cholesterol (TC) and TG concentr
a-
tions. GP intake markedly prevented fat accumulation and improved hepatic
lipid metabolism in HFD-
fed mice. In addition, GP extract at a dosage of 5
mg/kg body weight decreased sympathetic nerve activity (SNA) in brown
adipose tissue (BAT), while capsaicin, a major component of chili pepper, a
c-
tivated BAT SNA. This suggested that GP exerts a potential anti-
obesity effect
by a different mechanism from that of capsaicin.
Keywords
Anti-Obesity Effect, Grains of Paradise,
Aframomum melegueta
,
Vanilloid, BAT SNA
1. Introduction
Obesity is defined as an abnormal or excessive fat accumulation and is recog-
nized as a major risk factor for diabetes, cardiovascular disease, and cancer by
the World Health Organization (WHO). The number of obese people increased
more than two times between 1980 and 2014. Reducing lipid accumulation
causing body weight loss is crucial to management of obesity. The development
of effective treatments for overweight and obese patients has become very desir-
able in recent years.
How to cite this paper:
Hattori, H., Ya-
mauchi, K., Onwona
-Agyeman, S. and Mit-
sunaga,
T. (2017) Effect of Grains of Para-
dise (GP) Extract Intake on Obesity and
Sympathetic Nerve Activity
.
American Jou
r-
nal o
f Plant Sciences
,
8
, 85-95.
http://dx.doi.org/10.4236/ajps.2017.82007
Received:
December 7, 2016
Accepted:
January 16, 2017
Published:
January 19, 2017
Copyright © 201
7 by authors and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
H. Hattori et al.
86
Adipose tissue is a major metabolic organ, and roughly divided into two types:
one is white adipose tissue (WAT) that stores energy in the form of triglyceride;
the other is brown adipose tissue (BAT). BAT is involved in the dissipation and
expenditure of energy as heat. This process of thermogenesis is induced by high-
fat diets and cold exposure [1] [2]. Therefore, adipocytes play a key role in ener-
gy homeostasis. Activating BAT by stimulating sympathetic nerve activity (SNA)
is one of the principal strategies to enhance energy expenditure and lipolysis [3]
[4] [5]. This is an effective and practical approach to treating obesity-related
diseases.
Aframomum melegueta
is an herbaceous plant, widely distributed throughout
Nigeria, Ghana, Guinea, and other countries in West Africa [6]. Its seeds are
called grains of paradise (GP), Guinea pepper, alligator pepper, or melegueta
pepper. It has been traditionally used as a spice for flavouring food and as a re-
medy for digestive and intestinal health, dysentery, migraine, and fever [7]. Re-
cently, a number of studies have reported that GP extract has a range of activities
such as antibacterial, repellent [8] [9], antioxidant, anti-inflammatory [10] [11],
and hypoglycemic [12] effects. Moreover, GP contains many non-volatile pun-
gent compounds such as 6-paradol, 6-gingerol, and 6-shogaol [13]. These com-
pounds possess a vanillyl moiety, and are structurally similar to capsaicin and
capsiate, which are found in chili pepper [14]. It is well known that capsinoids,
including capsaicin and capsiate, exert an anti-obesity effect by stimulating SNA
and hence BAT thermogenesis [15]. Similarly, it might be expected that GP ex-
tract containing vanilloids would activate BAT SNA and BAT thermogenesis. In
the present study, GP extract was administered during an animal breeding test to
investigate its efficacy in obesity prevention. Furthermore, electrical activity in
BAT interscapular nerves was recorded using an electrophysiological method to
investigate the anti-obesity mechanism of GP.
2. Materials and Methods
2.1. General Experimental Procedures
Tween 80 was purchased from MP Biomedicals, LLC (Santa Ana, CA, USA). Sa-
line was purchased from Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). A
Bioelectric Amplifier ER-1 (Bio Research Center Co., Ltd., Nag) was used for
amplifying and filtering sympathetic efferent nerve impulses. A PowerLab (AD
Instruments Japan Inc., Nagoya, Japan) was used for converting the amplified
signals, which were then recorded on a computer using Chart 5 software (AD
Instruments Japan Inc.). Other commercially available products, including ure-
thane for anesthesia, were purchased from Wako Chemicals (Richmond, VA,
USA).
2.2. Sample Preparation
GP was provided by Share Trade Inc (Tokyo, Japan). Dried GP seed powder
(about 5 kg) underwent methanol extraction all night at room temperature
(20˚C ± 2˚C) and the extract was obtained in 5.6% yield based on the powder.
H. Hattori et al.
87
The extract was dissolved in 10% Tween 80 saline solution containing 10%
ethanol, and was used for oral administration during neural recording [16] [17].
2.3. Animal Breeding
Five-week-old male mice (24.8 ± 0.9 g) were purchased from Japan SLC Inc.
(Hamamatsu, Japan) and placed in a breeding environment (25˚C ± 1˚C, 12 h
light-dark cycle). The mice were fed a normal diet (ND) for a period of one
week. Both feed and water were available ad libitum. After preliminary breeding,
they were divided into five groups. Three of the groups were fed a high-fat diet
(HFD),composed of ND, 20% lard, 1% cholesterol powder, and 0.25% sodium
cholate, containing either 2% GP seed powder, 0.3% GP extract, or 1% GP ex-
tract [18]. Two control groups were fed either an ND or HFD only. At 11 weeks
of age, the mice were dissected to obtain samples of serum, the liver, and fat.
All experimental procedures were approved by the Gifu University Animal
Care and Use Committee.
2.4. Determination of Total Cholesterol (TC), Triglyceride (TG),
and High-Density Lipoprotein-Cholesterol (HDL-C)
Accumulation in Serum and the Liver
Blood samples were stored at room temperature (20˚C ± 2˚C) for 1 h, and then
centrifuged at 3500 rpm for 15 min at room temperature (20˚C ± 2˚C). Liver
tissue (40 mg) was homogenized with 0.1 M ethyl acetate, methanol, and chlo-
roform (4:10:5) at 4000 rpm for 1 min, and the homogenates were centrifuged at
5800 rpm for 10 min. The TC, TG, and HDL-C analyses were performed using
TC, TG, and HDL-C E-test kits, respectively (Wako Pure Chemical Industries,
Ltd.).
2.5. Neural Activity Measurement
The electrical activity of interscapular nerves innervating BAT was recorded as
previously described [19]. In brief, a rat was anesthetized using urethane solu-
tion (1 g urethane/1kg body weight), and a small incision was made above the
scapula to find sympathetic nerves entering BAT. Four sympathetic nerves were
isolated and separated from the connective tissues. The isolated nerves were each
placed on a pair of silver electrodes (0.3 mm, AG 401325, Nilaco Corp., Tokyo,
Japan) to detect SNA, and the electrodes were immersed in mineral oil to pre-
vent drying and for electrical insulation. Sympathetic efferent discharges were
amplified and filtered, with the amplified impulses being converted to digital
signals using PowerLab, and recorded using a computer software. Spikes above a
threshold voltage, set just above background levels, were counted by spike histo-
gram. Baseline BAT SNA was recorded for at least 30 min. Following oral ad-
ministration of GP extract (5 mg/kg body weight)
via
a gastric tube, BAT SNA
was recorded for every five minutes.
2.6. Statistical Analysis
All data were expressed as means ± SD values. Statistical significance of differ-
H. Hattori et al.
88
ences was evaluated using the Student’s t-test. The difference was considered to
be significant if
p
< 0.05.
3. Results
3.1. GP Intake Suppresses Body Weight Gain and
Lipid Accumulation
To investigate the anti-obesity effect of GP and GP extract, the mice were di-
vided into five groups after preliminary breeding. Mice willingly ate the feed
provided in five meals, including those in the group receiving 2% GP. Despite
this, the 2% GP group exhibited significantly lower body weight gain over the
five weeks of feeding compared with the HFD group (
p
< 0.01) (Table 1 and
Figure 1). The body weight gain of the groups fed GP extract with the HFD
notably decreased, to a similar level as those of the mice in the ND control group
Table 1. Food intake, body weight gain, and liver, epididymal fat, and mesenteric fat
weight of mice (n = 9) fed a normal diet (ND), high-fat diet (HFD), HFD including 0.3%
GP extract, HFD including 1% GP extract, and HFD including 2% GP.
Group Food intake
(g)
Body weight
(g)
Liver weight
(g)
Epididymal
fat (g)
Mesenteric
fat (g)
ND (Normal Diet) 198.3 ± 21.0 44.0 ± 4.7 1.89 ± 0.23 1.13 ± 0.47 0.82 ± 0.19
HFD (High Fat Diet) 195.3 ± 22.2 52.3 ± 5.8c 2.59 ± 0.48c 2.16 ± 0.75c 1.36 ± 0.51c
HFD + 0.3% GP ext. 200.2 ± 26.5 42.1 ± 3.2f 2.63 ± 0.29 0.80 ± 0.15f 0.68 ± 0.10d
HFD + 1% GP ext. 220.6 ± 27.3 40.6 ± 3.1f 2.69 ± 0.32 0.90 ± 0.29f 0.69 ± 0.20d
HFD + 2% GP seed 245.8 ± 15.6a 42.5 ± 4.6d 2.63 ± 0.53 0.90 ± 0.28f 0.53 ± 0.24f
All data were expressed as the mean ± S.D. Differences were examined for statistical significance using Stu-
dent’s t-test. n = 9. a,c:
p
< 0.05, 0.01 compared with ND values respectively. d,f:
p
< 0.01, 0.001 compared
with HFD values respectively.
(a) (b)
Figure 1. Body weight over time in mice (n = 9) fed a normal diet (ND), high-fat diet (HFD), HFD including 0.3% GP extract,
HFD including 1% GP extract, and HFD including 2% GP (a) and the total food intake per mouse (b). d:
p
< 0.01 compared with
HFD values.
20
25
30
35
40
45
50
55
60
-10 -5 0 5 10 15 20 25 30 35 40
Body we ight (g)
Time (day)
d
ND
HFD
HFD +2% GP seed
HFD +1% GP e xt.
HFD +0.3% GP ext.
AB
H. Hattori et al.
89
(0.3% GP extract group:
p
< 0.001, 1% GP extract group:
p
< 0.001). Epididymal
fat and mesenteric fat weights significantly decreased in the groups receiving GP
in HFD when compared with those in the ND control group (0.3% GP extract
group:
p
< 0.001 and < 0.01, respectively; 1% GP extract group:
p
< 0.001 and <
0.01, respectively; 2% GP group:
p
< 0.01 and < 0.001, respectively).
Lipid accumulation was further investigated to explore the anti-obesity effect
of GP on mice. HFD intake significantly increased the total cholesterol (TC) and
triglyceride (TG) concentration in the liver. GP intake had no significant impact
on liver weight (Table 2 and Figure 2). However, the GP and GP extract groups
had significantly decreased levels of hepatic TC and TG. This effect was most
marked in the 1% GP extract group, whose TC and TG levels (190 and 260
mg/dL, respectively) were far lower than those of the HFD group (257 and 388
mg/dL, respectively). In contrast, there was no significant difference in serum
levels of either TC or high-density lipoprotein-cholesterol (HDL-C) among any
of the groups on the HFD. Serum TG concentrations significantly increased in
the GP intake group (0.3% GP extract group:
p
< 0.05; 1% GP extract group:
p
<
0.01) (Table 2 and Figure 3).
Table 2. Total cholesterol (TC), triglyceride (TG), and high-density lipoprotein- choles-
terol (HDL-C) concentrations in serum and the livers of mice (n = 9) fed a normal diet
(ND), high-fat diet (HFD), HFD including 0.3% GP extract, HFD including 1% GP ex-
tract, and HFD including 2% GP.
Group
Serum Liver
TC (mg/dl) TG (mg/dl) HDL-C
(mg/dl) TC (mg/dl) TG (mg/dl)
ND (Normal Diet) 127.9 ± 23.2 126.4 ± 51.7 88.7 ± 27.8 91.4 ± 34.1 96.5 ± 28.8
HFD (High Fat Diet) 199.9 ± 37.9e 66.6 ± 11.0e 88.1 ± 16.1 256.5 ± 47.4e 388.4 ± 92.2e
HFD + 0.3% GP ext. 207.1 ± 29.9 82.8 ± 23.6d 88.0 ± 23.6 204.5 ± 39.7f 251.9 ± 106.0f
HFD + 1% GP ext. 230.4 ± 33.5 107.3 ± 83.8b 87.5 ± 19.7 189.5 ± 58.7f 258.8 ± 80.2f
HFD + 2% GP seed 224.7 ± 39.5 75.3 ± 15.6 84.6 ± 7.9 198.0 ± 85.6b 236.9 ± 51.8f
All data were expressed as the mean ± S.D. Differences were examined for statistical significance using Stu-
dent’s t-test. n = 9. e:
p
< 0.001 compared with ND values. b,d,f:
p
< 0.05, 0.01, 0.001 compared with HFD
values, respectively.
Figure 2. Liver weight, total cholesterol (TC), and triglyceride (TG) concentrations in mice (n = 9) fed a normal diet (ND),
high-fat diet (HFD), HFD including 0.3% GP extract, HFD including 1% GP extract, and HFD including 2% GP. (c, e):
p
< 0.01,
0.001 compared with ND values respectively. (b, f):
p
< 0.05, 0.001 compared with HFD values, respectively.
0
50
100
150
200
250
300
350
400
450
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
Liver TG
0
50
100
150
200
250
300
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
TC concentration (mg/dl)
TG concentration (mg/dl)
ff
e
b
e
fff
Liver TC
0
0.5
1
1.5
2
2.5
3
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
Liver weig ht (g)
c
Liver weight
H. Hattori et al.
90
Figure 3. Total cholesterol (TC), triglyceride (TG), and high density lipoprotein-cholesterol (HDL-C) concentrations in serum of
mice (n = 9) fed a normal diet (ND), high-fat diet (HFD), HFD including 0.3% GP extract, HFD including 1% GP extract, and
HFD including 2% GP. (e):
p
< 0.001 compared with ND values. (b, d):
p
< 0.05, 0.01 compared with HFD values, respectively.
3.2. GP Extract Decreases Brown Adipose Tissue
Sympathetic Nerve Activity (BAT SNA)
To clarify the anti-obesity effect of GP extract in mice, BAT SNA was deter-
mined using an electrophysiological method. An initial intragastric infusion of
GP extract (5 mg/kg body weight) immediately decreased BAT SNA by around
10%, and this decrease lasted for at least 1 h. After BAT SNA recovery, a second
intragastric infusion of GP extract at same concentration produced the same ef-
fect on BAT SNA (Figure 4). This procedure was performed on three rats, and
produced similar results for each mouse.
4. Discussion
The animal breeding experiment in this study was performed to investigate the
anti-obesity effects of GP and GP extract. The results are shown in Figures 1-3
and Table 1 & Table 2. The feeding of HFD containing 1% GP extract for five
weeks greatly suppressed body weight gain and fat accumulation in mice. This
suggested that GP has the potential to inhibit lipid accumulation. GP intake sig-
nificantly decreased TC and TG concentrations in liver tissue, and prevented the
pale discoloration of the liver, which was observed in the HFD group; however,
it had no significant impact on liver weight. The serum TC and HDL-C concen-
trations in the GP intake groups were unchanged compared with those in the
HFD group mice. Serum TG concentrations in the GP intake groups significant-
ly increased. These results suggested that hepatic lipid metabolism was improved
by GP intake. Consequently, GP intake potently decreases fat accumulation in
HFD mice. De Creamer
et al
. (1994) reported that hepatomegaly was observed in
mice fed a diet rich in fish oil, with no significant changes in body, heart, or
kidney weights. They concluded that this could be caused by induction of a liver
peroxisome, which regulates
β
-oxidation and biosynthesis of bile acid. This me-
tabolic change occurs via peroxisome proliferator-activated receptors (PPAR),
which are involved in adipocyte differentiation [20] [21] [22] [23]. One of the
components of GP, 6-shogaol, has been proven to activate PPAR [24]. Hence,
the unchanged liver weight of mice in the GP groups compared with those of
mice in the HFD group observed in this present study might be due to increased
PPAR-stimulated hepatic peroxisome induction.
0
50
100
150
200
250
300
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
TC concentration (mg/dl)
0
20
40
60
80
100
120
140
160
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
TG concentration (mg/dl)
0
10
20
30
40
50
60
70
80
90
100
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
HDL-C concentration (mg/dl)
e
d
b
e
Serum TC Serum TG Serum HDL-C
H. Hattori et al.
91
Figure 4. Effect of GP extract on sympathetic nerve activity in the brown adipose tissue.
After recording stable sympathetic nerve activity for 30 min, the GP extract of 5 mg/kg
body weight was administered using gastric tube. Similar results were observed from
three individuals of rat.
Adipose tissues are classified as either WAT or BAT, which have different
functions and morphology [25]. BAT is found in infants, young children, and
rodents. Recently, BAT has been observed around the scapula, axilla, and verte-
bral column of adult humans using 18F-fluorodeoxyglucose (18F-FDG) and posi-
tron-emission tomography (PET) [3] [26] [27]. Thermogenesis in BAT is me-
diated by sympathetic stimulation of BAT mitochondrial uncoupling protein 1
(UCP1). We hypothesized that the anti-obesity activity of GP intake in this
mouse breeding test was due to this mechanism, and BAT SNA was involved in
the effect of GP extract.
Capsaicin, which is the major ingredient in chili pepper, has the potential to
increase energy expenditure and decrease body fat by activating BAT in humans
and rodents [28] [29] [30]. This results in stimulation of SNA by transient re-
ceptor potential vanilloid 1 (TRPV1), which is expressed in the gastrointestinal
tract and sensory nervous system and specifically combines with capsaicin at the
vanillyl moiety [15] [31]. The results of the present study were consistent with
data obtained from experiments with capsaicin and capsiate, which is also found
in chili peppers. Surprisingly however, GP extract exhibits a different mode of
action from that of capsaicin and capsiate; GP extract decreases SNA, rather
than increasing it as seen with capsaicin and capsiate.
Capsaicin and capsiate bear structural similarities to the non-volatile vanillo-
ids found in GP [32] [33] [34]. It has also been reported that 6-paradol and
6-shogaol in GP extract were found to activate TRPV1 through non-covalent
bonding [35]. The HPLC analysis showed that GP extract contains many vanil-
loid compounds possessing hydrocarbon side chains with a double bond and/or
carbonyl group (data not shown). These substructures of vanilloids may be re-
0
50
100
150
200
250
300
5
15
25
35
45
55
65
75
85
95
105
115
125
135
145
155
165
175
185
195
205
215
225
235
245
255
265
275
285
295
305
315
BAT-SNA (%)
Time (min)
Oral administration
H. Hattori et al.
92
sponsible for activating BAT SNA. This might suggest that the vanilloids in GP
contribute to the anti-obesity effect by stimulating BAT SNA. However, contrary
to expectations, BAT SNA was decreased by oral administration of GP extract.
Crocin, ezetimibe, catechins, and caffeine inhibit intestinal absorption of cho-
lesterol and fat by inactivating pancreatic lipase [36] [37] [38]. The aqueous ex-
tract of
Zingiber officinale
Roscoe also prevents intestinal lipid absorption [39]
through the actions of vanilloid compounds such as 6-gingerol and 6-shogaol
[40]. These reports suggest that GP may inhibit body weight gain in mice by
suppressing lipid absorption rather than by activating BAT SNA.
5. Conclusion
In summary, the present study demonstrated that GP and its extract exert an an-
ti-obesity effect in HFD-fed mice. Prevention of body weight gain and fat accu-
mulation occurs through improved hepatic lipid metabolism. In addition, BAT
SNA decreased with intragastric infusion of GP extract. In general, decreasing
BAT SNA would increase parasympathetic nerve activity, thus having a relaxa-
tion effect in humans. Therefore, GP or GP extract may have the additional ben-
efit of promoting relaxation while controlling obesity in both humans and ani-
mals. Further research is required to clarify the mechanisms of the anti-obesity
properties of GP extract; this may require investigation of lipid absorption in the
small intestine.
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