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Effect of Grains of Paradise (GP) Extract Intake on Obesity and Sympathetic Nerve Activity


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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 tissues in breeding mice, with a greater effect on mice fed a high-fat diet (HFD) than on those fed a normal diet (ND). Other significant effects of GP intake included increased serum triglyceride (TG) concentration and reduced hepatic total cholesterol (TC) and TG concentrations. 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, activated BAT SNA. This suggested that GP exerts a potential anti-obesity effect by a different mechanism from that of capsaicin.
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American Journal of Plant Sciences, 2017, 8, 85-95
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
The methanol extract of grains of paradise (GP), the seed of
, 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
er significant effects of GP intake included increased serum triglyceride (TG)
concentration and reduced hepatic total cholesterol (TC) and TG concentr
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
tivated BAT SNA. This suggested that GP exerts a potential anti-
obesity effect
by a different mechanism from that of capsaicin.
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-
T. (2017) Effect of Grains of Para-
dise (GP) Extract Intake on Obesity and
Sympathetic Nerve Activity
American Jou
nal o
f Plant Sciences
, 85-95.
December 7, 2016
January 16, 2017
January 19, 2017
Copyright © 201
7 by authors and
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
Open Access
H. Hattori et al.
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
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,
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.
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,
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)
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.
ences was evaluated using the Student’s t-test. The difference was considered to
be significant if
< 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 (
< 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
Body weight
Liver weight
fat (g)
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-
dents t-test. n = 9. a,c:
< 0.05, 0.01 compared with ND values respectively. d,f:
< 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:
< 0.01 compared with
HFD values.
-10 -5 0 5 10 15 20 25 30 35 40
Body we ight (g)
Time (day)
HFD +2% GP seed
HFD +1% GP e xt.
HFD +0.3% GP ext.
H. Hattori et al.
(0.3% GP extract group:
< 0.001, 1% GP extract group:
< 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
< 0.001 and < 0.01, respectively; 1% GP extract group:
< 0.001 and <
0.01, respectively; 2% GP group:
< 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:
< 0.05; 1% GP extract group:
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.
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-
dents t-test. n = 9. e:
< 0.001 compared with ND values. b,d,f:
< 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):
< 0.01,
0.001 compared with ND values respectively. (b, f):
< 0.05, 0.001 compared with HFD values, respectively.
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
Liver TG
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
TC concentration (mg/dl)
TG concentration (mg/dl)
Liver TC
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
Liver weig ht (g)
Liver weight
H. Hattori et al.
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):
< 0.001 compared with ND values. (b, d):
< 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
-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.
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
TC concentration (mg/dl)
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
TG concentration (mg/dl)
ND HFD HFD + 0.3%
GP extract
HFD + 1%
GP extract
HFD + 2%
GP seed
HDL-C concentration (mg/dl)
Serum TC Serum TG Serum HDL-C
H. Hattori et al.
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-
Time (min)
Oral administration
H. Hattori et al.
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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... 25 It has been reported that the GP extracts exert thermogenic effects in rodent models. Hattori et al 26 previously studied the antiobesity effects of GP seed extract in a high-fat diet (HFD)-induced mice model. In another study, 6-gingerol, one of the active constituents in GP seeds, has been shown to have profound antiobesity activity in HFD mice. ...
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Thermogenesis-mediated energy expenditure is a promising strategy to combat obesity. Aframomum melegueta commonly known as grains of paradise (GP) is a popular spice with medicinal attributes in promoting health. We have demonstrated the thermogenic effects of a standardized A melegueta seed extract (AMSE) containing not <10% 6-paradol in high fat diet-fed (HFD) mice. The 6-week oral ingestion of 20 and 40 mg/kg AMSE significantly limited the weight gain, improved the brown adipose tissue (BAT) activity in HFD mice. Interestingly, AMSE markedly induced the beige adipocytes in epididymal white adipose tissue (eWAT). AMSE treatment led to the upregulation of marker proteins i.e., uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma-coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor gamma (PPARγ) in eWAT and BAT. Our findings add to the current understanding of the thermogenic potentials of GP seed extract and report that the extract can stimulate the browning of WATs in addition to enhanced BAT activity. AMSE requires clinical validation to be explored as a dietary supplement/functional ingredient with thermogenic effect in food and beverages.
... It has been used as a spice and a folk remedy, and its extract shows antiobesity effect in mice. (Hattori et al. 2017(Hattori et al. , 2018 (Huang et al. 2011;Huang et al. 2013) Furthermore, 6-shogaol inhibits melanogenesis through the stimulation of extracellular responsive kinase (ERK) and phosphatidylinositol-3-kinase (PI3K/Akt) that degrade MITF. (Yao et al. 2013;Huang et al. 2014b) However, the structure-activity relationship for the vanilloid Fig. 3 Cell viability, intracellular melanogenesis activity, and extracellular melanogenesis activity of 1, 2, and 5. IC 50 : The concentration of the compounds that shows 50% extracellular melanognesis inhibition. ...
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The components in the methanol extract of Zingiber officinale var rubrum (red ginger) were isolated by a series of column chromatography and identified by Nuclear Magnetic Resonance (NMR) and Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOFMS). Thirteen components, including eleven vanilloid compounds, were isolated from the extract. All the isolated components reduced extracellular melanin contents. Structure-activity relationship studies suggested that elongation of the carbon chain of shogaol and gingerol increased the extracellular melanogenesis inhibitory activity, and that the carbonyl and hydroxyl groups on the carbon chain in gingerol played an important role in this effect. In order to reveal the importance of the vanillyl group for the melanogenesis inhibitory activity, 6-gingerol (1) and 6-shogaol (5), which were the main compounds in the extract, were glucosylated and their effects were evaluated. The glucosylated 6-shogaol resulted in improved melanogenesis inhibitory activity, while the glucosylated 6-gingerol had no such effect. These results indicated different mechanisms for the melanogenesis inhibitory activity of the two vanilloid compounds.
... The seeds have long been used in folkloric herbal remedies [2] and are known to have, among other properties, antioxidant [3], antibacterial [4] and antinociceptive [1] activity. In preliminary studies [5] it was found that intake of a methanol extract of Grains of Paradise has an anti-obesity effect in mice and lowers hepatic and serum fats. A reduction in visceral fat has also been observed in humans, using an ethanol extract [6]. ...
Two vanilloids, (5E)-8-(4-hydroxy-3-methoxyphenyl)oct-5-en-4-one (1) and 4-[3-hydroxydecyl]-2-methoxyphenol (2), isolated from the dried seeds of Grains of Paradise (Aframomum melegueta), were synthesized; the latter compound was made as the S-enantiomer and the material derived from the seeds was found to be a 1:1.7 mixture of the R and S isomers. The synthetic route used should allow the preparation of analogs having extended alkyl chains and consequently different lipophilicity, and 3, a homolog of 2, was also prepared.
Pre-diabetes is a stage that usually precedes the onset of type 2 diabetes with a slight increase in fasting glucose, between 5.6 and 6.9 mmol/L; decreased glucose tolerance, between 7.8 and 11 mmol/L; and glycated hemoglobin, between 5.5 and 6.4% (ADA 2020). These biochemical abnormalities are usually caused by defects in insulin secretion from pancreatic cells, low insulin activity, or both (Unwin et al. 2002). Pre-diabetes can eventually lead to type 2 diabetes, which is characterized by hyperglycemia due to the inability of cells to respond fully to insulin, or to be resistant to insulin. Insulin resistance is characterized by insulin inefficiency in promoting glucose uptake by tissues and low intracellular glucose concentration signals for increased insulin production by the pancreas. Over time, depleted pancreatic beta cells reduce or stop insulin production, further elevating blood glucose levels (>6.9 mmol/L), characteristic of the diabetes condition. According to epidemiological data, type 2 diabetes is common in the elderly, but its frequency has increased in children and young adults due to high rates of obesity, sedentary lifestyle, and unbalanced diet, with excess fat and sugar. All of these factors indicate that both type 1 and type 2 diabetes result from a combination of genetic predisposition and environmental triggers (IDF 2020). Type 2 diabetes symptoms are similar to those of type 1 diabetes, but they are difficult to be identified in the early stages due to the long pre-diagnosis process, and, therefore, up to one third of the population may not be diagnosed early (Bansal 2015; Kaur 2014; Buchanan et al. 2002). This can be detrimental for a favorable prognosis after a long period of latent disease, and complications such as retinopathy or ulcers in the lower limbs that do not heal may occur (Chiasson et al. 2002). Furthermore,visceral obesity common in overweight and obese patients is related to the local and systemic inflammatory process, closely linked to the development of these comorbidities (ADA 2020). Regarding the healthy population, individuals with pre-diabetes and diabetes have a higher risk over the time of developing cardiovascular disease, metabolic syndrome, and polycystic ovaries, in addition to higher morbidity and mortality rates (Bansal 2015; Kaur 2014). Considering the close relationship between pre-diabetes, obesity, and diet, it is important to examine the influence of intestinal microbiota in this context. Intestinal microbiota is characterized by a diverse community of bacteria responsible for influencing nutrient metabolism, immune responses, and resistance to infectious pathogens (Nicholson et al. 2012; Belkaid and Hand 2014; van Nood et al. 2013). In the diabetic population, the intestinal microbiota presents a pattern of dysbiosis, which can be the starting point for the evolution of pre-diabetes to type 2 diabetes and other chronic diseases (Pratley 2013; Ziemer et al. 2008; Tsui et al. 2008; Stefanakia et al. 2018). Current scientific evidence has shown that probiotics or prebiotics, including phenolic compounds, can play a widely recognized role in the regulation of the intestinal microbiota, altering microbial composition and the metabolism of the bacteria and host (Tsai et al. 2019; Wang et al. 2020). Based on these fundamentals, this chapter will address the intrinsic relationships between the consumption of probiotics and prebiotics in individuals with pre-diabetes and type 2 diabetes.
Since the prehistoric times, at least 60,000 years back as per fossil records, humans have been using natural products, such as plants, animals, microorganisms, and marine organisms, in medicines to alleviate and treat diseases. The use of natural products as medicines must have a great challenge to early humans because when seeking food in forests and hills, early humans often consumed poisonous plants, which led them to vomiting, diarrhea, coma, or other toxic reaction-even death. Subsequently, they were able to develop knowledge about edible plant materials and to use many plants as natural medicines for treatment of diseases and ailments, which are the basis of traditional medicine. Such forms of traditional medicines, namely, traditional Chinese medicine (TCM), Indian Ayurveda, Greek-Arabic Unani, Japanese Kampo, and traditional Korean medicine, known as Sasang constitutional medicine (SCM) have been practiced worldwide for more than thousands of years and have blossomed into the present systems of modern medicines. The advancement of modern technology helped us to evaluate the pharmacology and mechanism of action of many medicinal herbs in treatment of diseases and to use them as cornerstones of modern medicine. In the historic year 1805, German pharmacist Friedrich Serturner isolated morphine from the opium plant, Papaver somniferum L., and laid the foundation of modern medicine. Subsequently, countless active natural molecules, known as phytochemicals have been separated from natural plant and microbial extracts, and many of them have potential anticancer, antihypertensive, hypolipidemic, antiobese, antidiabetic, antiviral, antileishmanial, and antimigraine medicative properties. These phytochemicals, which have evolved over millions of years, have a unique chemical structural diversity, which results in the diversity of their biological actions to alleviate and treat critical human diseases. A group of evidence advocates that a “multidrugs” and “multi-targets” approach would be more effective compared to a “single-drug” and “single-target” approach in the treatment of complex diseases like obesity, diabetes, cardiovascular disease, and cancer. Phytochemicals present in a single herb or in a herbal formulation can function alone or synergistically with other phytochemicals in a “multi-targets” approach to produce desired pharmacological effect in prevention and cure of complex diseases. The optimal efficacy of the herbal/polyherbal extract depends on its correct dosage containing the optimal concentration of bioactive phytochemical (s) and the method of preparing and processing of the herbal/polyherbal composition and the appropriate time of collection of plant parts. Therefore, the research on natural products is a thrust area for future research in drug discovery (Yuan et al. 2016). This chapter summarizes the current progress in the study of the antiobesity and antidiabetic potentials of natural products and their main bioactive phytochemicals, major molecular mechanisms in preventing and treating obesity and diabetes, and their associated complications.
The increased worldwide prevalence of pre-diabetes and diabetes, especially type 2 diabetes, requiring different strategies for their prevention and management. A new focus is the reversal of diabetes dysbiosis, a disruption of gut microbiota homeostasis, which is closely related to elevated blood glucose levels and altered metabolic parameters. In this sense, a balanced diet plays a key role, and, particularly, probiotic and prebiotic have shown a promising role. This chapter explored current knowledge on the potential of probiotic and prebiotic to modulate glucose homeostasis. We showed that the consumption of probiotics and prebiotics is a promising strategy with a beneficial impact on gut microbiota and glycemic control. Furthermore, specific probiotic strains, such as L. acidophilus, L. casei strain Shirota, and B. lactis Bb12, have demonstrated the ability to improve parameters related to pre-diabetes and type 2 diabetes. In addition, polyphenols are emerging as a new alternative in glycemic control through the production of short chain fat acids (SCFA) and decreased lipopolysaccharides (LPS) translocation that leads to metabolic endotoxemia. Finally, the ingestion of beneficial bacteria, and foods rich in fiber and polyphenols, or a combination of them, is a good strategy for the control of pre-diabetes and type 2 diabetes, but more studies are still needed, mainly clinical trials, for these strategies are improved and widely used.
Scope Grains of Paradise (GOP), the seeds of Aframomum melegueta, has anti‐obesity effects. However, the mechanisms underlying the effects remain unclear. Methods and Results We set up to study the anti‐obesity impact and homeostatic effects of 6‐paradol, a major vanilloid found in GOP, and investigated the physiological outputs and the lipometabolism‐related gene in fat and liver in high‐fat‐induced obese mice with a comparison with structurally similar vanilloids (6‐gingerol and 6‐shogaol). The vanilloids were synthesized in adequate quantities for performing animal experiments and orally administered to six‐week‐old male mice over two weeks. We found that 6‐paradol decreased body weight gain and visceral and subcutaneous fats in two weeks, whereas 6‐gingerol and 6‐shogaol had no effect. Additionally, 6‐paradol suppressed the hepatic cholesterol and triglyceride and significantly decreased the gene expression related to fatty acid synthesis, lipid transportation, and adipocyte differentiation in both liver and adipose tissue. Moreover, phosphorylation of AMP‐activated protein kinase (AMPK) that greatly contributes to lipometabolism was promoted by 6‐gingerol but not 6‐paradol. Conclusion These results suggest that 6‐paradol regulates several obesity‐related genes in an AMPK‐independent manner. Therefore, it could be the principal active vanilloid in GOP giving it anti‐obesity properties with a different mechanism. This article is protected by copyright. All rights reserved
Background: Grains of Paradise (GP) is the seed of Aframomum melegueta, which is widely distributed throughout West Africa and has been used as a spice and a folk remedy for a long time. The anti-obesity effect by GP intake was demonstrated in our previous report. In this present study, we tried to isolate some compounds in GP and clarify the anti-obesity mechanism. Results: Ten vanilloid compounds were determined. Among ten vanilloids, 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol and 1-(4'-hydroxy-3'-methoxyphenyl)-3-octen-5-one were determined as novel compounds and 6-gingerol, 6-paradol, and 6-shogaol were identified as the major constituents in GP extract. Moreover, the extract and 6-gingerol, which is one of the principal components of GP extract, were orally administered to rats to investigate the effect on sympathetic nerve activity (SNA) in brown adipose tissue (BAT). The injection of GP extract and 6-gingerol decreased BAT-SNA, whereas capsaicin, which is a major component of chili pepper, activates the sympathetic nervous system. Conclusion: This study suggested that GP extract and 6-gingerol were largely unrelated to the anti-obesity effect by the activation of interscapular BAT-SNA and had a different anti-obesity mechanism to capsaicin.
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Adipose tissue is a complex, multicellular organ that profoundly influences the function of nearly all other organ systems through its diverse metabolite and adipokine secretome. Adipocytes are the primary cell type of adipose tissue and play a key role in maintaining energy homeostasis. The efficiency with which adipose tissue responds to whole-body energetic demands reflects the ability of adipocytes to adapt to an altered nutrient environment, and has profound systemic implications. Deciphering adipocyte cell biology is an important component of understanding how the aberrant physiology of expanding adipose tissue contributes to the metabolic dysregulation associated with obesity. © 2015 Rutkowski et al.
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Aframomum melegueta is a commonly used African spice. Through a hepatoprotective bioassay-guided isolation, the chloroform fraction of A.melegueta seeds yielded one new diarylheptanoid named 3-(S)-acetyl-1-(4'-hydroxy-3', 5'-di methoxyphenyl)-7-(3″,4″, 5″-trihydroxyphenyl)heptane (1), and two new hydroxyphenylalkanones, [8]-dehydrogingerdione (2) and [6]-dehydroparadol (3), in addition to six known compounds (4-9). The hepatoprotective effect of A. melegueta methanol extract, sub-fractions and isolated compounds was investigated using carbon tetrachloride (CCl4)-induced liver injury in a rat hepatocytes model. The methanol, chloroform extracts and compounds 1, 5, 8 and 9 of A. melegueta significantly inhibited the elevated serum alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), tumor necrosis factor (TNFα), interleukin-1beta (Il-1β), caspase3 and 9 and enhanced the reduced liver glutathione (GSH) level caused by CCl4 intoxication. These results indicate that A.melegueta extracts, and isolated compounds play a protective role in CCl4 induced acute liver injury which might be due to elevated antioxidative defense potentials, suppressed inflammatory responses and apoptosis of liver tissue.
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Aframomum melegueta Schum (Zingiberaceae) is a perennial herb widely cultivated for its valuable seeds in the tropical region of Africa. The present study evaluated the antioxidant effects of methanolic seed extract of A. melegueta. The antioxidant effects were evaluated using in vitro, 2, 2-diphenylpicrylhydrazine photometric assay and in vivo serum catalase, superoxide dismutase and thiobarbituric acid reactive substance assay method. The extract (25–400 μg/mL concentration) produced concentration dependent increase in antioxidant activity in 2, 2-diphenylpicrylhydrazine photometric assay. The extract (400 mg/kg) showed a significant ( P < 0.05 ) increase in serum catalase and superoxide dismutase activity when compared with the control group. The extract (400 mg/kg) showed a significant ( P < 0.05 ) decrease in the serum level of thiobarbituric acid reactive substance when compared with the control group. These findings suggest that the seed of A. melegueta has potent antioxidant activity which may be responsible for some of its reported pharmacological activities and can be used as antioxidant supplement.
Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% [76/1013]) than in men (3.1% [30/959]); the female:male ratio was 2.4:1.0 (P 64) (P 64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.
Brown adipose tissue (BAT) is a site of sympathetically activated adaptive nonshivering thermogenesis, thereby being involved in the regulation of energy balance and body fatness. Recent radionuclide imaging studies have revealed the existence of metabolically active BAT in adult humans. Human BAT is activated by acute cold exposure and contributes to cold-induced increase in whole-body energy expenditure. The metabolic activity of BAT is lower in older and obese individuals. The inverse relationship between the BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. In fact, repeated cold exposure recruits BAT in association with increased energy expenditure and decreased body fatness. The stimulatory effects of cold are mediated through the activation of transient receptor potential (TRP) channels, most of which are also chemesthetic receptors for various naturally occurring substances including herbal plants and food ingredients. Capsaicin and its analog capsinoids, representative agonists of TRPV1, mimic the effects of cold to decrease body fatness through the activation and recruitment of BAT. The well-known antiobesity effect of green tea catechins is also attributable to the activation of the sympathetic nerve and BAT system. Thus, BAT is a promising target for combating obesity and related metabolic disorders in humans.
Aframomum melegueta is a spice widely used in African folk medicine. The chloroform soluble fraction of A. melegueta seeds yielded four new diarylheptanoids named gingerenone D (1), dihydrogingerenone A (2), dihydrogingerenone B (3), and dihydrogingerenone C (4), in addition to six known diarylheptanoids and hydroxyphenylalkanones. The most potent oestrogen receptor binding ability in an oestrogen receptor alpha (ERα) competitive-binding assay was for compounds 1, 2 and 5 with IC 50 values of 50, 79 and 39 μM, respectively, compared with 18 nM for the natural steroid 17β-oestradiol (E2). In addition, the diarylheptanoids 1, 2 and 5 showed anti-oestrogenic activity in a receptor cofactor assay system for ERα, while the hydroxyphenylalkanone, [6]dehydrogingerdione, (7) exhibited an agonistic action. Results were interpreted via virtual docking of the active compounds to an ERα crystal structure, in comparison with the known oestrogenic compounds: enterodiol (END), enterolactone (ENL), genistein and E2. The anti-oestrogenic compounds 1, 2 and 5 showed a binding similarity to that of END and ENL while compound 7 was similar in binding to genistein and E2 interpreting its agonistic effect.
We have previously reported the effects of Kaempferia parviflora (KP), including anti-obesity, preventing various metabolic diseases, and regulating differentiation of white adipose cells. In this study we used Tsumura, Suzuki, Obese Diabetes (TSOD) mice-an animal model of spontaneous obese type II diabetes-and primary brown preadipocytes to examine the effects of the ethyl acetate extract of KP (KPE) on brown adipose tissue, which is one of the energy expenditure organs. TSOD mice were fed with MF mixed with either KPE 0.3 or 1 % for 8 weeks. Computed tomography images showed that whitening of brown adipocytes was suppressed in the interscapular tissue of the KPE group. We also examined mRNA expression of uncoupling protein 1 (UCP-1) and β3-adrenalin receptor (β3AR) in brown adipose tissue. As a result, mRNA expression of UCP-1 significantly increased in the KPE 1 % treatment group, indicating that KPE activated brown adipose tissue. We then evaluated the direct effects of KPE on brown adipocytes using primary brown preadipocytes isolated from interscapular brown adipocytes in ICR mice. Triacylglycerol (TG) accumulation in primary brown preadipocytes was increased by KPE in a dose-dependent manner. Each mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ), UCP-1, and β3AR exhibited an upward trend compared with the control group. Moreover, some polymethoxyflavonoids (PMFs), the main compound in KP, also increased TG accumulation. This study therefore showed that KPE enhanced the thermogenesis effect of brown adipocytes as well as promoted the differentiation of brown adipocyte cells.
The ethanolic extract of grains of paradise (Aframomum melegueta Schum, Zingiberaceae) has been evaluated for inhibitory activity on cyclooxygenase-2 (COX-2) enzyme, in vivo for the anti-inflammatory activity and expression of several pro-inflammatory genes. Bioactivity guided fractionation showed that the most active COX-2 inhibitory compound in the extract was [6]-paradol. [6]-Shogaol, another compound from the extract, was the most active inhibitory compound in pro-inflammatory genes expression assays. In a rat paw edema model, the whole extract reduced inflammation by 49% at 1000 mg/kg. Major gingerols from the extract [6]-paradol, [6]-gingerol, and [6]-shogaol reduced inflammation by 20%, 25% and 38% respectively when administered individually at a dose of 150 mg/kg. [6]-shogaol efficacy was at the level of aspirin, used as a positive control. Grains of paradise extract has demonstrated an anti-inflammatory activity, which is in part due to the inhibition of COX-2 enzyme activity and expression of pro-inflammatory genes.
Background Obesity represents a rapidly growing threat to the health of populations and diet intervention has been proposed as one of the strategies for weight loss. Ginger and its constituents have been used for their anti-flatulent, expectorant and appetizing properties and they are reported to possess gastro protective and cholesterol-lowering properties. The present study investigated the effects of gingerol on the changes in body weight, serum glucose, insulin, insulin resistance and lipid profile in plasma and liver as well as on the activity of amylase, lipase and leptin in high fat diet (HFD) - induced obese rats. ResultsHigh-fat diet (HFD)-induced obese rats were treated orally with gingerol (25, 50 and 75 mg kg−1) once daily for 30 days. Lorcaserin treated group (10 mg kg−1) was included for comparison. The levels of body weight, glucose, lipid profile and insulin, insulin resistance, leptin, amylase and lipase were increased significantly (P < 0.05) in HFD rats. Rats treated with gingerol and fed a HFD showed significantly (p < 0.05) decreased glucose level, body weight, leptin, insulin, amylase, lipase plasma and tissue lipids when compared to normal control. The effect at a dose of 75 mg kg−1 of gingerol was more pronounced than that of the dose 25 mg kg−1 and 50 mg kg−1. Lorcaserin-treated group also manifested similar effects like gingerol. Conclusion These findings suggested that ginger supplementation suppresses obesity induced by a high fat diet and it might be a promising adjuvant therapy for the treatment of obesity and its complications.