Effects of Saponins on Lipid Metabolism: A Review of Potential Health Benefits in the Treatment of Obesity

Abstract

Obesity is one of the greatest public health problems. This complex condition has reached epidemic proportions in many parts of the world, and it constitutes a risk factor for several chronic disorders, such as hypertension, cardiovascular diseases and type 2 diabetes. In the last few decades, several studies dealt with the potential effects of natural products as new safe and effective tools for body weight control. Saponins are naturally-occurring surface-Active glycosides, mainly produced by plants, whose structure consists of a sugar moiety linked to a hydrophobic aglycone (a steroid or a triterpene). Many pharmacological properties have been reported for these compounds, such as anti-inflammatory, immunostimulant, hypocholesterolemic, hypoglycemic, antifungal and cytotoxic activities. The aim of this review is to provide an overview of recent studies about the anti-obesity therapeutic potential of saponins isolated from medicinal plants. Results on the in vitro and in vivo activity of this class of phytochemicals are here presented and discussed. The most interesting findings about their possible mechanism of action and their potential health benefits in the treatment of obesity are reported, as well.

Full text

molecules
Review
Effects of Saponins on Lipid Metabolism: A Review
of Potential Health Benefits in the Treatment
of Obesity
Mariangela Marrelli 1, *, Filomena Conforti 1, Fabrizio Araniti 2and Giancarlo A. Statti 1
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria,
Rende (CS) I-87036, Italy; filomena.conforti@unical.it (F.C.); g.statti@unical.it (G.A.S.)
2Department of AGRARIA, University “Mediterranea” of Reggio Calabria,
Reggio Calabria (RC) I-89124, Italy; fabrizio.araniti@unirc.it
*Correspondence: mariangela.marrelli@unical.it; Tel.: +39-0984-493-168; Fax: +39-0984-493-107
Academic Editors: Min-Hsiung Pan and Filomena Conforti
Received: 3 August 2016; Accepted: 12 October 2016; Published: 20 October 2016
Abstract:
Obesity is one of the greatest public health problems. This complex condition has reached
epidemic proportions in many parts of the world, and it constitutes a risk factor for several chronic
disorders, such as hypertension, cardiovascular diseases and type 2 diabetes. In the last few decades,
several studies dealt with the potential effects of natural products as new safe and effective tools for
body weight control. Saponins are naturally-occurring surface-active glycosides, mainly produced
by plants, whose structure consists of a sugar moiety linked to a hydrophobic aglycone (a steroid or
a triterpene). Many pharmacological properties have been reported for these compounds, such as
anti-inflammatory, immunostimulant, hypocholesterolemic, hypoglycemic, antifungal and cytotoxic
activities. The aim of this review is to provide an overview of recent studies about the anti-obesity
therapeutic potential of saponins isolated from medicinal plants. Results on the
in vitro
and
in vivo
activity of this class of phytochemicals are here presented and discussed. The most interesting
findings about their possible mechanism of action and their potential health benefits in the treatment
of obesity are reported, as well.
Keywords: lipid metabolism; medicinal plant; obesity; phytochemicals; saponins
1. Introduction
Obesity is a serious and increasing health problem consisting of an excessive growth of adipose
tissue. Introduced in the International Classification of Diseases (ICD) only in the 1950s, it is now
reaching epidemic proportions worldwide, tripling its prevalence since the 1980s in many European
countries and affecting a large percentage of the population [
1
]. The prevalence of overweight and
obese people is extremely high in parts of Europe, the U.S. and Mexico. However, a rising obesity
incidence was observed also in regions such as South America and Asia, where the incidence is still
low [2]. Referring to this global phenomenon, a new word, “globesity”, has been coined [3].
The rise of obesity has been attributed to different potential factors, genetic background, diet and
physical activity being the major ones. A genetic predisposition to obesity has been recognized to
affect the energy balance equation resulting from energy input and output. However, metabolic factors,
high-fat diets and sedentary lifestyle are considered important causes in obesity etiology [4,5].
This severe health problem is associated with an increased risk of several diseases, including type
II diabetes, cardiovascular diseases, cancer and osteoarthritis, as well as asthma and chronic back pain.
Therefore, the prevention and the treatment of obesity is extremely important [6].
Nowadays, the treatment of obesity consists of a reduction of caloric dietary intake combined with
an increase in physical activity. A pharmacologic treatment is preferred when the behavioral approach
Molecules 2016,21, 1404; doi:10.3390/molecules21101404 www.mdpi.com/journal/molecules

Molecules 2016,21, 1404 2 of 20
is not enough to obtain weight control. Different drugs have been marketed in the last few years,
which have been successively withdrawn because of their serious adverse effects. Dinitrophenol was
the first drug used for weight loss. It was introduced in the 1930s for the treatment of obesity, but rapidly
substituted by amphetamines, chosen for their ability to suppress appetite. Furthermore, these last
molecules were banned by the Food and Drug Administration (FDA) because of their severe side
effects. Among other kinds of drugs whose use was attempted (e.g., phentermine and fenfluramine),
sibutramine was one of the most important. This norepinephrine and serotonin reuptake inhibitor was
approved for the treatment of obesity in 1997 by the FDA and in 1999 in the European Union. This drug
is able to affect both food intake and energy expenditure. However, also sibutramine was withdrawn
from European, U.S. and Canadian markets, because of cardiovascular concerns. The cannabinoid
receptor antagonist rimonabant, which acts in the nervous system by blocking cannabinoid type 1 (CB1)
receptors involved in the control of food intake, followed a similar trend of its predecessors. In fact,
its sale was approved in Europe in 2006 and suspended due to the risk of psychiatric disorders [
7
].
Actually, orlistat, a semisynthetic hydrogenated derivative of the natural lipase inhibitor produced by
Streptomyces toxytricini [
8
], is the only commonly-used anti-obesity drug. This compound is the only
anti-obesity medication currently approved by the European Agency for the Evaluation of Medicinal
Products (EMEA) in Europe for long-term use, while in the USA, besides orlistat, phentermine is also
available, even if only for short-term use [7].
Approved in 1998, orlistat is a potent gastrointestinal lipase inhibitor able to prevent dietary fat
absorption by 30%, inhibiting both pancreatic and gastric lipase. However, orlistat might not be well
tolerated since side effects, such as diarrhea, fecal incontinence, flatulence, bloating and dyspepsia,
are commonly developed [9].
Because of the adverse effects associated with this available lipid-lowering agent, there is
a growing interest in herbal remedies, aiming to find well-tolerated naturally-effective drugs [10].
Different natural compounds are able to modulate obesity through various mechanisms of
action. In the last decade, a high number of reviews has been focused on the potential use of natural
products in the treatment of obesity, and different classes of phytochemicals have been explored and
reviewed [11–23].
For instance, the potential role of polyphenols has been largely investigated and recently reviewed.
Commonly-consumed phenols, such as green tea catechins, curcumin and resveratrol, are able to
reduce adipocytes viability, suppress adipocyte differentiation and triglyceride accumulation and
stimulate lipolysis [24–27].
Among the biologically-active classes of phytochemicals, several saponins have been
demonstrated to lower body weight and serum lipid levels. In the present manuscript, the most
interesting findings about the
in vitro
and
in vivo
anti-obesity activity of this class of phytochemicals
and saponins containing plant extracts, their mechanisms of action and their potential health benefits
in the treatment of obesity are reviewed. The literature search was conducted using various electronic
databases, mainly PubMed and Google Scholar. More than forty interesting manuscripts dealing with
the anti-obesity activity of saponins or saponin-containing extracts were found, together with various
publications about the anti-obesity potential of plant extracts.
2. Obesity and Plant Secondary Metabolites
Plant natural products are a priceless source of medicinal compounds [
28
,
29
], fibers [
30
],
flavorings [31], fragrances [32,33], natural herbicides [34–37] and pesticides [38,39].
According to the WHO, medicinal plants are important tools for healthcare in developing
countries. Nowadays, since synthetic anti-obesity drugs are characterized by important side effects,
we are currently assisting to increase the scientific interest towards natural products. Moreover,
the “omics” technologies (genomics, proteomics, transcriptomics and metabolomics) allow one to
validate the use of traditional medicines easily and to identify new natural compounds and their
mechanism of action [13].

Molecules 2016,21, 1404 3 of 20
Different classes of phytochemicals have been shown to modulate body weight. It has been
demonstrated that polyphenols, such as catechins and anthocyanins, modulate molecular pathways
involved in energy metabolism [25].
The anti-obesity properties of polyphenols may be due to their ability to interact with
preadipocytes, adipose stem cells and immune cells of the adipose tissues [24].
Some clinical and epidemiological studies have suggested the beneficial effects of the
consumption of green tea, rich in catechins, for its anti-obesity properties. Green tea catechins,
above all epigallocatechin gallate (EGCG), are able to inhibit fat absorption and suppress adipocyte
differentiation and proliferation [25].
Resveratrol (3,4
0
,5-trihydroxystilbene), contained in grapes and red wine, is another example of
a phenolic compound with anti-obesity potential. This naturally-occurring polyphenolic compound
is able to inhibit preadipocyte differentiation, decrease adipocyte proliferation and lipogenesis and
promote lipolysis [24].
Furthermore, some terpenes have been pointed out for potential effects in body weight
control [11,40]
. The diterpene carnosic acid, isolated from the leaves of Salvia officinalis L., is a pancreatic
lipase (PL) inhibitor and has been demonstrated to suppress fat weight increase in high-fat diet-fed
mice [
41
]. Phytosterols [
42
] and some alkaloids [
23
,
40
] are other plant secondary metabolites that
appear to be important in body weight control. Interestingly, also soy proteins’ consumption has been
suggested to have efficacy against obesity [43].
According to these findings, a minimum daily intake of 400 g of fruits and vegetables is
recommended for the prevention of obesity and other diseases, such as cancer and heart problems [
18
].
Some natural anti-obesity agents from medicinal plants have reached clinical trials. However,
thousands of plants, some of which are traditionally used against obesity, have not been investigated
yet. Thus, potentially, new effective molecules could be discovered, and further research in this field is
needed to deeply investigate herbal anti-obesity products, their mechanisms of action and, above all,
to verify the lack of toxicity and side effects [13].
The potential anti-obesity activity of different saponins has been also highlighted in the last few
decades, and the activity of some of these secondary metabolites has been reported in previous reviews
about the therapeutic anti-obesity potential of natural compounds [11,23,40].
The purpose of the present review is to specifically focus attention on this class of compounds,
summarizing all obtained results and actual knowledge. Different saponins and active plant extracts
are here grouped based on different mechanisms of action, such as lipase inhibition, suppression of
appetite signals or adipogenesis regulation.
3. Saponins: Structure and Medicinal Properties
Saponins are naturally-occurring surface-active glycosides mainly produced by plants,
besides some bacteria and lower marine animals. Their structure consists of a sugar moiety linked
to a hydrophobic aglycone called sapogenin. The sugar moiety may contain glucose, galactose,
rhamnose, methylpentose, glucuronic acid or xylose, while the aglycone portion may be a steroid
or a triterpene [
44
]. Steroidal saponins are mainly abundant in monocotyledons, while dicotyledons
predominantly contain triterpenoid saponins [
45
]. These phytochemicals are so called because of their
ability to form stable soap-like foams in aqueous solutions [
44
]. Thanks to this property, saponins are
used as natural surfactants in cleansing products for personal care, such as foam baths, shower gels,
liquid soaps, shampoos and toothpastes [45].
Saponins can be toxic if given intravenously [
46
]. These compounds are known for their hemolytic
activity on human erythrocytes, which depends on the type of aglycone and sugar chains. This property
is due to the interaction with sterols present in the erythrocyte membrane, which lead to an increase of
membrane permeability and the consequent loss of hemoglobin [
47
]. These molecules can also act as
fish poison [
48
], and some saponin-containing plants are toxic for ruminants, leading to gastroenteritis,
diarrhea and even liver and kidney degeneration [49].

Molecules 2016,21, 1404 4 of 20
Besides these effects, many pharmacological properties, such as antifungal, insecticidal,
anthelmintic, cytotoxic, anti-inflammatory, immunostimulant, hypocholesterolemic and hypoglycemic,
have been ascribed to these compounds [44,45,50].
The cytotoxic activity of saponins, especially those of ginseng and soy, was deeply investigated
and reviewed [
50
–
52
]. These molecules are effective against different cancer cell lines, such as
Hep-G2 (hepatocellular carcinoma cell line), HT1080 (fibrosarcoma cell line), HeLa (cervical cancer),
HL-60 (promyelocytic leukemia cells) and MDA-MB-453 (breast cancer) [
45
]. A cytotoxic activity was
demonstrated for different compounds, such as saxifragifolin B, saxifragifolin D [
53
],
α
-hederin [
54
],
glochierioside A [55] and filiasparoside C [56].
Interestingly, this class of phytochemicals has been also investigated for its potential antidiabetic
properties, with the aim to find new effective drugs in the treatment of diabetes mellitus.
The hypoglycemic action of saponins seems to be due to different mechanisms of action, such as
the restoration of the insulin response, the increase of plasma insulin levels and the induction of the
release of insulin from the pancreas. For example, the saponin platyconic acid, isolated from Platycodi
radix, was demonstrated to increase insulin-stimulated glucose uptake in 3T3-L1 adipocytes, whereas
arjunolic acid, present in Terminalia arjuna Wight & Am. and other species, showed
α
-amylase and
α-glucosidase inhibitory activity [57].
The aim of the present review is to summarize the studies concerning the potential therapeutic
efficacy of saponins against obesity. The obtained results about the various metabolites and active
plant extracts are here grouped based on the different mechanisms of action observed (Figure 1).
Molecules2016, 21, 1404 4 of 19
Besides these effects, many pharmacological properties, such as antifungal, insecticidal,
anthelmintic, cytotoxic, anti-inflammatory, immunostimulant, hypocholesterolemic and hypoglycemic,
have been ascribed to these compounds [44,45,50].
The cytotoxic activity of saponins, especially those of ginseng and soy, was deeply investigated
and reviewed [50–52]. These molecules are effective against different cancer cell lines, such as
Hep-G2 (hepatocellular carcinoma cell line), HT1080 (fibrosarcoma cell line), HeLa (cervical cancer),
HL-60 (promyelocytic leukemia cells) and MDA-MB-453 (breast cancer) [45]. A cytotoxic activity
was demonstrated for different compounds, such as saxifragifolin B, saxifragifolin D [53], α-hederin
[54], glochierioside A [55] and filiasparoside C [56].
Interestingly, this class of phytochemicals has been also investigated for its potential antidiabetic
properties, with the aim to find new effective drugs in the treatment of diabetes mellitus. The
hypoglycemic action of saponins seems to be due to different mechanisms of action, such as the
restoration of the insulin response, the increase of plasma insulin levels and the induction of the
release of insulin from the pancreas. For example, the saponin platyconic acid, isolated from Platycodi
radix, was demonstrated to increase insulin-stimulated glucose uptake in 3T3-L1 adipocytes, whereas
arjunolic acid, present in Terminalia arjuna Wight & Am. and other species, showed α-amylase and
α-glucosidase inhibitory activity [57].
The aim of the present review is to summarize the studies concerning the potential therapeutic
efficacy of saponins against obesity. The obtained results about the various metabolites and active
plant extracts are here grouped based on the different mechanisms of action observed (Figure 1).
Figure 1. Schematic representation of the modes of action of saponins on lipid metabolism. Numbers
between the brackets represent the molecules reported in Figures 2–5 and 7.
4. Saponins and Pancreatic Lipase Inhibition
4.1. Lipase Inhibition
Lipases are enzymes responsible for fat digestion able to cleave long-chain dietary triglycerides
into polar lipids. Lingual and gastric lipases are the first enzymes involved in fat digestion. They
cleave short and medium chain triglycerides more efficiently than longer chain ones and cannot
process sterols or phospholipids. Pancreatic lipase (PL) and other two lipolytic enzymes, carboxyl
ester hydrolase and phospholipase A2, are secreted by the pancreas [58].
Pancreatic lipase is the most important human lipase and is associated with the hydrolysis of
50%–70% of total dietary fats. Lipase inhibition is one of the most important strategies advanced by
pharmaceutical industries to decrease fat absorption after its ingestion. Orlistat (tetrahydrolipstatin,
Figure 1.
Schematic representation of the modes of action of saponins on lipid metabolism.
Numbers between the brackets represent the molecules reported in Figures 2–5and 7.
4. Saponins and Pancreatic Lipase Inhibition
4.1. Lipase Inhibition
Lipases are enzymes responsible for fat digestion able to cleave long-chain dietary triglycerides
into polar lipids. Lingual and gastric lipases are the first enzymes involved in fat digestion. They cleave
short and medium chain triglycerides more efficiently than longer chain ones and cannot process
sterols or phospholipids. Pancreatic lipase (PL) and other two lipolytic enzymes, carboxyl ester
hydrolase and phospholipase A2, are secreted by the pancreas [58].
Pancreatic lipase is the most important human lipase and is associated with the hydrolysis
of 50%–70% of total dietary fats. Lipase inhibition is one of the most important strategies advanced by
pharmaceutical industries to decrease fat absorption after its ingestion. Orlistat (tetrahydrolipstatin,
Xenical
®
) is a potent PL inhibitor and has been demonstrated to be effective in the treatment of
obesity [8].

Molecules 2016,21, 1404 5 of 20
4.2. Lipase inhibition by Saponin-Containing Plant Extracts
Han and coworkers demonstrated the anti-obesity activity of the aqueous extract of
Platycodon grandiflorum (Jacq.) A.DC. radix (Table 1). This extract was able to inhibit dietary fat
absorption by inhibiting pancreatic lipase activity, and its ability to prevent obesity was also tested
in vivo
. Mice fed with a high-fat diet enriched with a 5% aqueous extract of Platycodi radix showed
parametrial adipose tissue weights significantly lower than control-fed mice. Moreover, they were
also characterized by a significantly lower plasmatic triacylglycerol concentration. It was supposed
that the observed activity could be due to the total saponin fraction isolated from the aqueous extract.
Interestingly, it was found that this fraction effectively inhibited pancreatic lipase activity
in vitro
[
59
].
Table 1. Saponin-containing plant extracts with anti-obesity activity.
Plant Species Plant Part Study Action Reference
Platycodon grandiflorum
(Jacq.) A.DC. Roots In vitro
In vivo Lipase inhibition [10,59]
Momordica charantia L. _ In vitro
In vivo Lipase inhibition [60]
Aesculus turbinata Blume Seeds In vitro
In vivo
Lipase inhibition, suppression of body weight
increase, hepatic triacylglycerol content and total
cholesterol content
[61]
Gypsophila oldhamiana (Miq.) Root In vitro Lipase inhibition [62]
Chenopodium quinoa Willd. Seeds In vitro Downregulation of adipogenic transcription factors [63]
Panax ginseng C.A. Meyer Roots In vitro
In vivo
Lipase inhibition, downregulation of hypothalamic
NPY and serum leptin [64,65]
Camellia sinensis L Flower buds In vivo Suppression of mRNA levels of neuropeptide Y [66]
Solanum anguivi Lam. Fruits In vivo Antihyperlipidemic activity [67]
Achyranthes aspera L. Seeds In vivo Antihyperlipidemic activity [68]
Panax quinquefolium L. Leaves In vitro
In vivo Lipase inhibition, decrease of adipose tissue weight [69]
Gymnema sylvestre R. Br. Leaves In vivo Decrease of food consumption and body weight [70]
Oishi and colleagues evaluated the anti-obesity potential of a saponin fraction from
Momordica charantia L., discovering that it was able to inhibit the pancreatic lipase activity, as well as
the elevation of the serum neutral fat level after corn oil loading in mice [60].
A pancreatic lipase inhibitory activity was also demonstrated by Hu and his colleagues for the
hydroalcoholic extract of Aesculus turbinata Blume and its saponin fraction. The seeds of this plant
contain a mixture of triterpenoidal saponins named escins. The anti-obesity potential of total escins was
also evaluated
in vivo
, pointing out, in mice liver, a strong suppression of the increase in body weight,
parametrial adipose tissue weight, hepatic triacylglycerol content and total cholesterol content [61].
Zheng and colleagues tested the activity of Gypsophila oldhamiana (Miq.). Interestingly, the water-
soluble fraction obtained from the 95% EtOH extract of the plant roots, containing triterpenoid saponins,
showed a strong inhibitory activity against pancreatic lipase (IC50 value of 0.54 mg/mL) [62].
4.3. Saponins Inducing Lipase Inhibition
An interesting pancreatic lipase inhibitory activity was demonstrated for some triterpenoidal
saponins isolated from the roots of Platycodon grandiflorum (Jacq.) A.DC. [
71
], whose anti-obesity
potential had been previously demonstrated by Han and coworkers [
59
]. Different known saponins
were isolated and tested by Xu and coworkers. Among these molecules, a significant inhibitory
effect on PL was demonstrated for platycodins A (
1
) and C (
2
; Table 2, Figure 2), with 3.3% and 5.2%
pancreatic lipase activity vs. control, respectively, at a concentration of 500
µ
g/mL. A good activity
was also observed for deapioplatycodin D (
3
) and platycodin D (
4
) (11.67% and 34.8% pancreatic lipase
activity vs. control) [71].

Molecules 2016,21, 1404 6 of 20
Table 2. Saponins with anti-obesity activity.
Saponin Plant Species Study Action Reference
Platycodin A (1)Platycodon grandiflorum (Jacq.) A.DC. In vitro Lipase inhibition [71]
Platycodin C (2)Platycodon grandiflorum (Jacq.) A.DC. In vitro Lipase inhibition [71]
Deapioplatycodin D (3)Platycodon grandiflorum (Jacq.) A.DC. In vitro Lipase inhibition [71]
Platycodin D (4)Platycodon grandiflorum (Jacq.) A.DC. In vitro
In vivo
Lipase inhibition, AMPK activation,
prevention of abdominal fat accumulation [71,72]
Momordin Ic (5)Kochia scoparia (L.) Schard In vitro Lipase inhibition [73]
Escin Ia (6)Aesculus turbinata Blume In vitro Lipase inhibition [74]
Escin IIa (7)Aesculus turbinata Blume In vitro Lipase inhibition [74]
Escin Ib (8)Aesculus turbinata Blume In vitro Lipase inhibition [74]
Escin IIb (9)Aesculus turbinata Blume In vitro Lipase inhibition [74]
Mogroside IV(10)Siraitia grosvenorii C. Jeffrey In vitro Lipase inhibition [75]
Mogroside V (11)Siraitia grosvenorii C. Jeffrey In vitro Lipase inhibition [75]
Silphioside F (12)Acanthopanax senticosus (Rupr. et Maxim.) Harms In vitro Lipase inhibition [76]
Copteroside B (13)Acanthopanax senticosus (Rupr. et Maxim.) Harms In vitro Lipase inhibition [76]
Gypsogenin 3-O-β-D-glucuronide (14)Acanthopanax senticosus (Rupr. et Maxim.) Harms In vitro Lipase inhibition [76]
Sessiloside (15)Acanthopanax sessiliflorus (Rupr. et Maxim.) Seem In vitro Lipase inhibition [77]
Chiisanoside (16)Acanthopanax sessiliflorus (Rupr. et Maxim.) Seem In vitro Lipase inhibition [77]
Damulin A (17)Gynostemma pentaphyllum Makino In vitro AMPK activation [78]
Damulin (18)Gynostemma pentaphyllum Makino In vitro AMPK activation [78]
Foenumoside B (19)Lysimachia foenum-graecum Hance In vitro
In vivo
AMPK activation, reduction of body weight gain
[79]
Soyasapogenol B (20) Korean fermented soy food named cheonggukjang In vitro AMPK activation [80]
Dioscin (21) Several species In vitro Influence on AMPK/MAPK [81]
Trillin (22)Dioscorea nipponica Makino In vivo Antihyperlipidemic activity [82]
Ginsenoside Rb1 (23) Ginseng In vivo Modulation of serum levels of PYY and NPY [67]

Molecules 2016,21, 1404 7 of 20
Molecules2016, 21, 1404 7 of 19
Figure 2. Structure of some saponins with inhibitory effects on pancreatic lipase [71,73].
The anti-obesity effect of platycodin saponins from Platycodi radix was also confirmed in vivo
by Zhao and coworkers, which demonstrated their ability to induce body weight reduction in
diet-induced obese rats [83].
Han and coworkers found that the ethanol extract of Kochia scoparia (L.) Schard. fruits was able
to prevent the increases in body weight induced by the high-fat diet in mice. Moreover, they
demonstrated that both raw extract and its saponin fraction were able to inhibit the elevation of the
plasma triacylglycerol level after the oral administration of a lipid emulsion. The authors isolated
and tested seven saponins from K. scoparia fruit. Some of these compounds, such as momordin Ic (5;
Figure 1), were effective in inhibiting pancreatic lipase activity. According to these findings, the
anti-obesity potential observed for K. scoparia was supposed to be linked to the effectiveness of isolated
compounds on pancreatic lipase activity [73].
A very interesting lipase inhibitory activity was observed for escins extracted from horse
chestnut (Aesculus turbinata Blume). Kimura and coworkers examined the inhibitory effect of these
triterpenoidal saponins. Escins Ia (6), IIa (7), Ib (8) and IIb (9) strongly inhibited pancreatic lipase activity,
with IC50 values of 48, 61, 24 and 14 µg/mL, respectively (Figure 3). The derivatives deacetylescins and
desacylescins were less active than escins [74].
Figure 2. Structure of some saponins with inhibitory effects on pancreatic lipase [71,73].
The anti-obesity effect of platycodin saponins from Platycodi radix was also confirmed
in vivo
by
Zhao and coworkers, which demonstrated their ability to induce body weight reduction in diet-induced
obese rats [83].
Han and coworkers found that the ethanol extract of Kochia scoparia (L.) Schard. fruits was able to
prevent the increases in body weight induced by the high-fat diet in mice. Moreover, they demonstrated
that both raw extract and its saponin fraction were able to inhibit the elevation of the plasma
triacylglycerol level after the oral administration of a lipid emulsion. The authors isolated and tested
seven saponins from K. scoparia fruit. Some of these compounds, such as momordin Ic (
5
; Figure 1),
were effective in inhibiting pancreatic lipase activity. According to these findings, the anti-obesity
potential observed for K. scoparia was supposed to be linked to the effectiveness of isolated compounds
on pancreatic lipase activity [73].
A very interesting lipase inhibitory activity was observed for escins extracted from horse chestnut
(Aesculus turbinata Blume). Kimura and coworkers examined the inhibitory effect of these triterpenoidal
saponins. Escins Ia (6), IIa (7), Ib (8) and IIb (9) strongly inhibited pancreatic lipase activity, with IC50
values of 48, 61, 24 and 14
µ
g/mL, respectively (Figure 3). The derivatives deacetylescins and
desacylescins were less active than escins [74].

Molecules 2016,21, 1404 8 of 20
A strong
in vitro
and
in vivo
anti-obesity activity was also observed for saponins extracted from
Siraitia grosvenorii C. Jeffrey (Cucurbitaceae). The fruits of this plant contain a mixture of cucurbitane
triterpene glycosides, named mogrosides, which were frequently used as an alternative to sugar for
diabetic and obese patients due to their high sweetness. Sun and coworkers recently demonstrated the
inhibitory effects of total mogrosides and mogrosides IV (
10
) and V (
11
; Figure 3) on pancreatic lipase
in vitro (IC50 values of 517.73, 289.09 and 256.00 µg/mL, respectively). The in vivo effects of samples
were also evaluated on male C57BL/6 mice fed a high-fat diet. Total mogrosides were able to suppress
body weight increase, as well as abdominal and epididymal fats weight. Hepatic triacylglycerol and
total cholesterol content in mice liver were also significantly affected [75].
Molecules2016, 21, 1404 8 of 19
A strong in vitro and in vivo anti-obesity activity was also observed for saponins extracted from
Siraitia grosvenorii C. Jeffrey (Cucurbitaceae). The fruits of this plant contain a mixture of cucurbitane
triterpene glycosides, named mogrosides, which were frequently used as an alternative to sugar for
diabetic and obese patients due to their high sweetness. Sun and coworkers recently demonstrated
the inhibitory effects of total mogrosides and mogrosides IV (10) and V (11; Figure 3) on pancreatic
lipase in vitro (IC50 values of 517.73, 289.09 and 256.00 µg/mL, respectively). The in vivo effects of
samples were also evaluated on male C57BL/6 mice fed a high-fat diet. Total mogrosides were able
to suppress body weight increase, as well as abdominal and epididymal fats weight. Hepatic
triacylglycerol and total cholesterol content in mice liver were also significantly affected [75].
Figure 3. Other saponins able to inhibit pancreatic lipase [74,75].
Some triterpenoid saponins inhibiting pancreatic lipase were also isolated from the fruits of
Acanthopanax senticosus (Rupr. et Maxim.) Harms. Some of these molecules, such as silphioside F
(12), copteroside B (13) and gypsogenin 3-O-β-D-glucuronide (14; Figure 4), showed a good
inhibitory activity (IC50 values ranging from of 0.22–0.29 mM) [76].
Figure 3. Other saponins able to inhibit pancreatic lipase [74,75].
Some triterpenoid saponins inhibiting pancreatic lipase were also isolated from the fruits of
Acanthopanax senticosus (Rupr. et Maxim.) Harms. Some of these molecules, such as
silphioside F (12)
,
copteroside B (
13
) and gypsogenin 3-O-
β
-D-glucuronide (
14
; Figure 4), showed a good inhibitory
activity (IC50 values ranging from of 0.22–0.29 mM) [76].

Molecules 2016,21, 1404 9 of 20
Molecules2016, 21, 1404 9 of 19
Figure 4. Further saponins inhibiting pancreatic lipase [76,77].
An interesting activity on pancreatic lipase was also observed for the novel saponin sessiloside
(15) and the known saponin chiisanoside (16) isolated from the leaves of Acanthopanax sessiliflorus
(Rupr. et Maxim.) Seem. These two compounds inhibited lipase activity in a dose-dependent manner,
with IC50 values equal to 0.36 and 0.75 mg/mL, respectively. Moreover, the administration of the
saponin-rich fraction isolated from the extract of the plant was able to suppress body weight gain of
mice fed a high-fat diet [77].
Gypenosides are other saponins that were found to inhibit porcine pancreatic lipase (PL)
activity in a dose-dependent manner [84].
5. Saponins and Adipogenesis Inhibition
5.1. Adipogenesis
Excess energy is normally stored, through lipogenesis, in adipocyte cytoplasm in the form of
triglycerides. However, severe obesity is characterized by an increased number of adipocytes through
preadipocyte differentiation. The process by which undifferentiated preadipocytes are converted into
fully-differentiated adipocytes is called adipogenesis, and it is a finely-regulated process involving
concerted transcriptional and cellular events [79,81].
The control of adipogenesis through its many potential regulators could be a useful tool against
obesity. For example, according to recent studies, the activation of AMP-activated protein kinase
Figure 4. Further saponins inhibiting pancreatic lipase [76,77].
An interesting activity on pancreatic lipase was also observed for the novel saponin sessiloside (
15
)
and the known saponin chiisanoside (
16
) isolated from the leaves of Acanthopanax sessiliflorus
(
Rupr. et Maxim.
) Seem. These two compounds inhibited lipase activity in a dose-dependent manner,
with IC
50
values equal to 0.36 and 0.75 mg/mL, respectively. Moreover, the administration of the
saponin-rich fraction isolated from the extract of the plant was able to suppress body weight gain of
mice fed a high-fat diet [77].
Gypenosides are other saponins that were found to inhibit porcine pancreatic lipase (PL) activity
in a dose-dependent manner [84].
5. Saponins and Adipogenesis Inhibition
5.1. Adipogenesis
Excess energy is normally stored, through lipogenesis, in adipocyte cytoplasm in the form of
triglycerides. However, severe obesity is characterized by an increased number of adipocytes through
preadipocyte differentiation. The process by which undifferentiated preadipocytes are converted into
fully-differentiated adipocytes is called adipogenesis, and it is a finely-regulated process involving
concerted transcriptional and cellular events [79,81].
The control of adipogenesis through its many potential regulators could be a useful tool against
obesity. For example, according to recent studies, the activation of AMP-activated protein kinase
(AMPK) represents a potential strategy against obesity. AMPK is an important regulator of fat
metabolism, which is able to control fatty acid synthesis and uptake, insulin secretion and glucose
uptake in many tissues [
80
]. In particular, its activation stimulates
β
-oxidation and glucose uptake

Molecules 2016,21, 1404 10 of 20
in skeletal muscle and inhibits hepatic fat and cholesterol synthesis. Because of these effects, this
protein kinase appears to be an important emerging target for the treatment of metabolic syndrome,
including not only obesity, but also type 2 diabetes [85].
Besides the role of AMPK, different adipogenic transcription factors, such as peroxisome
proliferator-activated receptor
γ
(PPAR
γ
), CCAAT/enhancer-binding protein alpha (C/EBP
α
) and
sterol regulatory element-binding protein-1c (SREBP-1c), are key regulators of adipogenesis, as their
suppression can inhibit preadipocyte differentiation [63].
5.2. Saponin Fraction and Pure Compounds Inhibiting Adipogenesis
Two dammarane-type saponins with anti-obesity potential linked to AMPK regulation, damulin A
(
17
; Figure 5) and damulin B (
18
), were isolated from Gynostemma pentaphyllum Makino (Cucurbitaceae).
These two compounds were able to activate AMPK in cultured L6 myotubes [78].
Molecules2016, 21, 1404 10 of 19
(AMPK) represents a potential strategy against obesity. AMPK is an important regulator of fat
metabolism, which is able to control fatty acid synthesis and uptake, insulin secretion and glucose
uptake in many tissues [80]. In particular, its activation stimulates β-oxidation and glucose uptake in
skeletal muscle and inhibits hepatic fat and cholesterol synthesis. Because of these effects, this
protein kinase appears to be an important emerging target for the treatment of metabolic syndrome,
including not only obesity, but also type 2 diabetes [85].
Besides the role of AMPK, different adipogenic transcription factors, such as peroxisome
proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα) and
sterol regulatory element-binding protein-1c (SREBP-1c), are key regulators of adipogenesis, as their
suppression can inhibit preadipocyte differentiation [63].
5.2. Saponin Fraction and Pure Compounds Inhibiting Adipogenesis
Two dammarane-type saponins with anti-obesity potential linked to AMPK regulation,
damulin A (17; Figure 5) and damulin B (18), were isolated from Gynostemma pentaphyllum Makino
(Cucurbitaceae). These two compounds were able to activate AMPK in cultured L6 myotubes [78].
Figure 5. Saponins activating AMPK [78–81].
The anti-obesity potential of this plant extract has been previously successfully evaluated by
Megalli and coworkers. They demonstrated its ability to reduce triglyceride, total cholesterol and
low density lipoprotein cholesterol levels in the obese Zucker fatty diabetic rat model [86]. Gauhar
and coworkers evaluated the ability of the ethanol extract of G. pentaphyllum to activate AMPK. This
extract was then subjected to physical modification by autoclaving at 121 °C for four hours. This
Figure 5. Saponins activating AMPK [78–81].
The anti-obesity potential of this plant extract has been previously successfully evaluated by
Megalli and coworkers. They demonstrated its ability to reduce triglyceride, total cholesterol and low
density lipoprotein cholesterol levels in the obese Zucker fatty diabetic rat model [
86
]. Gauhar and
coworkers evaluated the ability of the ethanol extract of G. pentaphyllum to activate AMPK. This extract
was then subjected to physical modification by autoclaving at 121
◦
C for four hours. This process
increased AMPK phosphorylation in L6 cells, and this result was correlated with elevated levels of
AMPK activators, damulins A and B [85].

Molecules 2016,21, 1404 11 of 20
The triterpene saponin foenumoside B (
19
; Figure 5), isolated as an active component of
Lysimachia foenum-graecum Hance, is another compound that inhibits adipocyte differentiation.
The anti-adipogenic effect of foenumoside B was evaluated using preadipocyte 3T3-L1 cells that were
differentiated into mature adipocytes in the presence of various concentrations of tested compound.
Foenumoside B suppressed lipid accumulation with an IC
50
value equal to 0.2
µ
g/mL. It was found
that this molecule increased the phosphorylation of AMPK in a dose-dependent manner, suggesting
a direct regulatory role on AMPK activation in adipocytes. Foenumoside B was also tested
in vivo
in
a mouse model, and the oral administration was found to significantly reduce high-fat diet-induced
body weight gain [79].
Hwang and coworkers verified the effects of the saponin fraction obtained from the aqueous
extract of the roots of Platycodon grandiflorum (Changkil saponins) on AMP-activated protein kinase
(AMPK) and hepatic lipogenesis in HepG2 cells. The obtained results indicated that saponins effectively
stimulated AMPKαactivation in HepG2 cells and inhibited lipid accumulation in HepG2 cells [10].
Furthermore, platycodin D (
4
; Figure 2) isolated from the root of Platycodon grandiflorum (Jacq.)
A.DC., whose capability to inhibit pancreatic lipase has been already discussed [
71
], was tested
for its capacity to inhibit adipogenesis. Lee and coworkers investigated its ability to decrease the
expression of adipogenic factors through AMP-activated protein kinase
α
(AMPK
α
) in adipocytes.
The ability to prevent abdominal fat accumulation in high-fat diet-induced obese C57BL/6 mice was
also verified.
In vitro
results confirmed that platycodin D was able to reduce fat accumulation through
the inhibition of adipogenic signal transcriptional factors, which function via AMPK signaling, such as
CCAAT/enhancer binding protein
α
(C/EBP
α
) and peroxisome proliferator-activated receptor
γ
2
(PPARγ2) [72].
Kim and coworkers, interestingly, evaluated the anti-obesity effect of saponin compounds
present in a traditional Korean fermented soy food named cheonggukjang, testing the capacity to
affect triglycerides’ accumulation and AMPK activity in 3T3-L1 preadipocyte cells. Two groups of
saponins were identified in cheonggukjang: soyasapogenols A and B. Triglycerides’ content in 3T3-L1
cells treated with the saponin extracts was significantly lower (17%–28%) than that in the control.
Moreover, the saponins’ extract was able to increase AMPK activation. In particular, the saponin
compound soyasapogenol B (
20
; Figure 5) effectively induced AMPK activation at the concentration
of 2.5 µg/mL [80].
The steroidal saponins dioscin (
21
), which is present in several medicinal plants, was also
demonstrated to be an effective inhibitor of adipogenesis. This molecule was able to suppress lipid
accumulation
in vitro
in 3T3-L1 cells and its anti-adipogenic effect was linked to an influence on
AMPK/MAPK during adipogenesis [81].
Yao and coworkers evaluated the influence of quinoa (Chenopodium quinoa Willd.) saponins on
the differentiation of 3T3-L1 preadipocytes. The fraction isolated from this plant was able to inhibit
triglyceride accumulation in the mature adipocytes. The authors demonstrated that quinoa saponins
significantly down-regulated the mRNA and protein expression of key adipogenic transcription factors
PPARγand C/EBPαand also reduced mRNA and protein expression of sterol SREBP-1c [63].
6. Saponins and Appetite Regulation
6.1. Control of Food Intake and Energy Homeostasis
An important role in the regulation of body weight is played by the central nervous system (CNS),
which receives numerous neural impulses from the gastrointestinal mucosa and fat tissue and controls
food intake and energy expenditure (thermogenesis) [87,88].
The involved neurons modulate the hypothalamic–pituitary–adrenal axis. The gut peptides
signaling to the hypothalamus mediate the appetite-stimulating effect through the activation of
neurons containing neuropeptide Y (NPY) and agouti-related peptide (AgRP) or, on the contrary,
an appetite-inhibitory effect via other neurons. NPY constitutes an important regulator: it increases

Molecules 2016,21, 1404 12 of 20
food intake and reduces dietary fat oxidation [
89
,
90
]. The role of many peptides, such as NPY, AgRP,
cholecystokinin (CCK), ghrelin and glucagon-like peptide 1 (GLP-1), has been taken into account.
Leptin and insulin are also involved in hypothalamic appetite regulation, and they constitute potential
therapeutic targets to treat obesity [89].
Leptin is an adipocyte-derived protein that acts as a regulator of energy homeostasis.
This regulator acts centrally, inhibiting the synthesis of NPY [91].
6.2. Saponins Affecting the Expression of Appetite Peptides
Kim and coworkers investigated the
in vivo
anti-obesity effects of the crude saponin fraction
of Korean red ginseng (Panax ginseng C.A. Meyer). Both rats fed a high-fat diet and control rats fed
a normal diet were treated with this fraction, and body weight and food consumption were monitored.
The authors also investigated the expression of appetite peptides, such as leptin and NPY. The saponin
fraction was demonstrated to reduce body weight by 20%–30% and food intake in both normal and
high-fat diet rats. Moreover, the treatment reduced the expression of hypothalamic NPY and serum
leptin in high-fat diet rats [64].
A further study dealt with the evaluation of the
in vivo
anti-obesity activity of the two major active
compounds isolated from crude saponins of red ginseng: protopanaxadiol and protopanaxatriol type
(Figure 6) [
89
,
92
]. The first group was more active, suggesting that protopanaxadiol type saponins are
the principal phytochemicals responsible for the anti-obesity activity of ginseng saponins. However,
both saponin types were able to reduce body weight, food intake and leptin in the high-fat diet
group rats. It was observed that, after both treatments, the hypothalamic expression of orexigenic
neuropeptide Y was significantly decreased, whereas the anorexigenic cholecystokinin was increased
compared with the control high-fat diet group [89].
Molecules2016, 21, 1404 12 of 19
cholecystokinin (CCK), ghrelin and glucagon-like peptide 1 (GLP-1), has been taken into account.
Leptin and insulin are also involved in hypothalamic appetite regulation, and they constitute
potential therapeutic targets to treat obesity [89].
Leptin is an adipocyte-derived protein that acts as a regulator of energy homeostasis. This
regulator acts centrally, inhibiting the synthesis of NPY [91].
6.2. Saponins Affecting the Expression of Appetite Peptides
Kim and coworkers investigated the in vivo anti-obesity effects of the crude saponin fraction of
Korean red ginseng (Panax ginseng C.A. Meyer). Both rats fed a high-fat diet and control rats fed a
normal diet were treated with this fraction, and body weight and food consumption were monitored.
The authors also investigated the expression of appetite peptides, such as leptin and NPY. The
saponin fraction was demonstrated to reduce body weight by 20%–30% and food intake in both
normal and high-fat diet rats. Moreover, the treatment reduced the expression of hypothalamic NPY
and serum leptin in high-fat diet rats [64].
A further study dealt with the evaluation of the in vivo anti-obesity activity of the two major active
compounds isolated from crude saponins of red ginseng: protopanaxadiol and protopanaxatriol type
(Figure 6) [89,92]. The first group was more active, suggesting that protopanaxadiol type saponins are
the principal phytochemicals responsible for the anti-obesity activity of ginseng saponins. However,
both saponin types were able to reduce body weight, food intake and leptin in the high-fat diet group
rats. It was observed that, after both treatments, the hypothalamic expression of orexigenic neuropeptide
Y was significantly decreased, whereas the anorexigenic cholecystokinin was increased compared with
the control high-fat diet group [89].
Figure 6. Protopanaxadiol and protopanaxatriol type saponins [89,92].
The flower buds of Camellia sinensis L. were also demonstrated to have anti-obesity effects
through the suppression of the appetite signals in the hypothalamus. Hamao and coworkers observed
that the methanolic extract of this plant was able to inhibit body weight gain in high-fat diet-fed mice
and to suppress liver weight, liver triglyceride and the weight of visceral fat. Food intake was also
inhibited in a dose-dependent manner. In particular, the n-butanol soluble fraction of C. sinensis was
able to inhibit food intake at a dose of 250 mg/kg. It was demonstrated that this fraction significantly
suppressed mRNA levels of neuropeptide Y [66].
7. Further Effect of Saponins on Lipid Metabolism: Anti-Hyperlipidemic Activity
7.1. Hyperlipidemia
Hyperlipidemia has been defined as elevated cholesterol and triglycerides levels in plasma, and
it represents one of the major risk factors associated with coronary heart disease [93]. The incidence of
hyperlipidemia has increased worldwide because of an augmented fat consumption [84]. Statins and
fibrates are some effective available hypolipidemic drugs. However, the use of synthetic drugs may
cause some adverse effects, such as nausea, diarrhea, myositis, gastric irritation and hyperuricemia.
Therefore, as previously observed for obesity, the interest of the researchers is towards new natural
products with hypolipidemic properties and with minimal or no side effects [82,94].
Figure 6. Protopanaxadiol and protopanaxatriol type saponins [89,92].
The flower buds of Camellia sinensis L. were also demonstrated to have anti-obesity effects through
the suppression of the appetite signals in the hypothalamus. Hamao and coworkers observed that
the methanolic extract of this plant was able to inhibit body weight gain in high-fat diet-fed mice
and to suppress liver weight, liver triglyceride and the weight of visceral fat. Food intake was also
inhibited in a dose-dependent manner. In particular, the n-butanol soluble fraction of C. sinensis was
able to inhibit food intake at a dose of 250 mg/kg. It was demonstrated that this fraction significantly
suppressed mRNA levels of neuropeptide Y [66].
7. Further Effect of Saponins on Lipid Metabolism: Anti-Hyperlipidemic Activity
7.1. Hyperlipidemia
Hyperlipidemia has been defined as elevated cholesterol and triglycerides levels in plasma, and it
represents one of the major risk factors associated with coronary heart disease [
93
]. The incidence of
hyperlipidemia has increased worldwide because of an augmented fat consumption [
84
]. Statins and
fibrates are some effective available hypolipidemic drugs. However, the use of synthetic drugs may
cause some adverse effects, such as nausea, diarrhea, myositis, gastric irritation and hyperuricemia.

Molecules 2016,21, 1404 13 of 20
Therefore, as previously observed for obesity, the interest of the researchers is towards new natural
products with hypolipidemic properties and with minimal or no side effects [82,94].
7.2. Saponin-Rich Extracts and Pure Compounds with Antihyperlipidemic Activity
Trillin (
22
; Figure 7), a steroidal saponin isolated from Dioscorea nipponica Makino rhizome,
showed a strong anti-hyperlipidemic activity. The n-butanol fraction obtained from the ethanol
extract of the plant was able to reduce the high-fat diet-induced upregulation of cholesterol and
triglyceride in rats and to restore HDL and LDL to the normal status. Different beneficial effects
were exerted by the intra-peritoneal administration of trillin: bleeding and blood coagulation time
were significantly improved, and the levels of cholesterol, LDL and HDL were restored back to the
normal conditions. Moreover, this saponin improved the levels of lipid peroxidation and superoxide
dismutase activity [82].
Molecules2016, 21, 1404 13 of 19
7.2. Saponin-Rich Extracts and Pure Compounds with Antihyperlipidemic Activity
Trillin (22; Figure 7), a steroidal saponin isolated from Dioscorea nipponica Makino rhizome,
showed a strong anti-hyperlipidemic activity. The n-butanol fraction obtained from the ethanol extract
of the plant was able to reduce the high-fat diet-induced upregulation of cholesterol and triglyceride in
rats and to restore HDL and LDL to the normal status. Different beneficial effects were exerted by
the intra-peritoneal administration of trillin: bleeding and blood coagulation time were significantly
improved, and the levels of cholesterol, LDL and HDL were restored back to the normal conditions.
Moreover, this saponin improved the levels of lipid peroxidation and superoxide dismutase activity [82].
Figure 7. Further saponins with anti-obesity properties [65,95].
Elekofehinti and coworkers evaluated the antihyperlipidemic activity of the saponin fraction
from Solanum anguivi Lam. fruits. The effects were evaluated in alloxan-induced diabetes rats. The
administration of saponins (20–100 mg/kg for 21 days) significantly reduced the elevated glucose
levels, total cholesterol, total triglycerides and LDL compared to the diabetic control, while HDL
levels were increased [67].
A significant hypolipidemic effect was also observed for Achyranthes aspera L. seeds. The
saponin fraction isolated from this plant was tested on the serum lipid profile of albino rats fed a
high cholesterol diet. The sample was administered for four weeks inducing a significant decrease of
total cholesterol, total triglycerides and LDL and a significant increase of HDL level [68].
8. Other Saponin Containing-Fractions Affecting Weight Reduction
Panax ginseng CA Meyer, a species already discussed, is known for the elevated content of
bioactive saponins. Karu and coworkers assayed the effects of the saponin fraction extracted from
the roots of the plant on male Balb/c mice. Ginseng saponins were able to inhibit the increase in body
weight and decrease the hypertriacylglycerolemia induced by a high-fat diet. The same authors also
tested the ability to inhibit pancreatic lipase in vitro, demonstrating a dose-dependent inhibition [65].
Crude saponins from stems and leaves of Panax quinquefolium L. showed in vivo anti-obesity
activity, as well [69]. The ginsenoside fraction was administered (1 g/kg body weight) to female ICR
mice fed a high-fat diet for eight weeks. The treatment decreased parametrial adipose tissue weight
and inhibited the elevations of plasma triacylglycerol. Furthermore, crude saponins were also
demonstrated to inhibit pancreatic lipase in vitro. In a further study, Liu and coworkers tested the
effects of the two types of ginsenosides isolated from the leaves of P. quinquefolius L.: protopanaxadiol
and protopanaxatriol types [96]. The first group was effective, inhibiting pancreatic lipase activity in
a dose-dependent manner, while protopanaxatriol saponins showed no activity. The anti-obesity
effect of the active saponin fraction was then tested in vivo in mice fed a high-fat diet, and the
obtained results demonstrated that it was able to reduce the adipose tissue weights and serum and
liver triglycerides level compared to the control high-fat diet group.
An interesting anti-obesity potential was demonstrated for Ilex paraguariensis A. St. Hilaire (mate)
[97]. Mate preparations were traditionally considered to be appetite stimulators [95], but more recent
studies have instead demonstrated the effectiveness in weight management [97–101]. More recently,
de Resende and colleagues evaluated the effectiveness of a purified saponin fraction extracted from
I. paraguariensis [95]. This fraction was significantly more effective in reducing fat weight and glucose
oxidation of hepatic and adipose tissue in healthy rats fed a standard diet than the whole extracts
Figure 7. Further saponins with anti-obesity properties [65,95].
Elekofehinti and coworkers evaluated the antihyperlipidemic activity of the saponin fraction
from Solanum anguivi Lam. fruits. The effects were evaluated in alloxan-induced diabetes rats.
The administration of saponins (20–100 mg/kg for 21 days) significantly reduced the elevated glucose
levels, total cholesterol, total triglycerides and LDL compared to the diabetic control, while HDL levels
were increased [67].
A significant hypolipidemic effect was also observed for Achyranthes aspera L. seeds. The saponin
fraction isolated from this plant was tested on the serum lipid profile of albino rats fed a high cholesterol
diet. The sample was administered for four weeks inducing a significant decrease of total cholesterol,
total triglycerides and LDL and a significant increase of HDL level [68].
8. Other Saponin Containing-Fractions Affecting Weight Reduction
Panax ginseng CA Meyer, a species already discussed, is known for the elevated content of
bioactive saponins. Karu and coworkers assayed the effects of the saponin fraction extracted from the
roots of the plant on male Balb/c mice. Ginseng saponins were able to inhibit the increase in body
weight and decrease the hypertriacylglycerolemia induced by a high-fat diet. The same authors also
tested the ability to inhibit pancreatic lipase
in vitro
, demonstrating a dose-dependent inhibition [
65
].
Crude saponins from stems and leaves of Panax quinquefolium L. showed
in vivo
anti-obesity
activity, as well [
69
]. The ginsenoside fraction was administered (1 g/kg body weight) to female
ICR mice fed a high-fat diet for eight weeks. The treatment decreased parametrial adipose tissue
weight and inhibited the elevations of plasma triacylglycerol. Furthermore, crude saponins were also
demonstrated to inhibit pancreatic lipase
in vitro
. In a further study, Liu and coworkers tested the
effects of the two types of ginsenosides isolated from the leaves of P. quinquefolius L.: protopanaxadiol
and protopanaxatriol types [
96
]. The first group was effective, inhibiting pancreatic lipase activity in
a dose-dependent manner, while protopanaxatriol saponins showed no activity. The anti-obesity effect
of the active saponin fraction was then tested
in vivo
in mice fed a high-fat diet, and the obtained results
demonstrated that it was able to reduce the adipose tissue weights and serum and liver triglycerides
level compared to the control high-fat diet group.
An interesting anti-obesity potential was demonstrated for Ilex paraguariensis A. St. Hilaire
(mate) [
97
]. Mate preparations were traditionally considered to be appetite stimulators [
95
],

Molecules 2016,21, 1404 14 of 20
but more recent studies have instead demonstrated the effectiveness in weight management [
97
–
101
].
More recently, de Resende and colleagues evaluated the effectiveness of a purified saponin fraction
extracted from I. paraguariensis [
95
]. This fraction was significantly more effective in reducing fat
weight and glucose oxidation of hepatic and adipose tissue in healthy rats fed a standard diet than the
whole extracts obtained from mate leaves and unripe fruits and induced also a significant lowering of
the blood triglycerides level in rats. Thus, the observed
in vivo
activities could be ascribed to the mate
saponin fraction.
Latha and coworkers assessed the anti-obesity potential of Achyranthes aspera L. saponin-rich
extract on male Wistar rats fed a high-fat diet [
102
]. A dose of 120 mg/kg induced a significant
reduction of food intake, body weight and visceral organ weights. Moreover, serum levels of total
cholesterol, triglycerides, very low density lipoproteins (VLDL) and low density lipoproteins (LDL)
were reduced, while the levels of high density lipoproteins (HDL) were increased compared to the
high-fat diet control group.
As already observed for flower buds of Camellia sinensis L. [
66
], an anti-obesity activity was
also demonstrated for the fruit peel extract of this plant. Chaudhary and coworkers observed that
the administration of this extract (100 mg/kg/day) significantly decreased body weight in rats fed
high-fat diet [103].
An
in vivo
anti-obesity activity was also observed for the saponin fraction isolated from
Gymnema sylvestre
R. Br. aqueous leaf extract [
70
]. The sample was administered to high-fat
diet-induced obese rats at a dose of 100 mg/kg body weight for eight weeks. Food consumption
and body weight were significantly decreased, as well as visceral organs’ weight and triglycerides,
total cholesterol, low-density lipoproteins and very low-density lipoproteins.
Lin and colleagues tested the
in vivo
anti-obesity potential of ginsenoside Rb1 (
23
, Figure 7),
the major component of ginseng [
104
]. The sample was injected intraperitoneally in mice at the
dose
of 20 mg/kg
for three weeks, and both decreased weight gain and food intake were observed
compared to the control high-fat group. Moreover, Rb1 caused the reduction of blood glucose and
some lipids, and it was demonstrated to modulate serum levels of peptide YY (PYY) and NPY.
A significant
in vivo
anti-obesity potential was also observed for Chikusetsu saponins isolated
from rhizomes of Panax japonicus C.A. Meyer [
105
]. This saponin fraction was able to prevent the
increases in body weight and parametrial adipose tissue weight induced by a high-fat diet and
inhibited the elevation of the plasma triacylglycerol level in female ICR mice. Moreover, the inhibition
of pancreatic lipase activity was also demonstrated in vitro.
9. Conclusions
Obesity is a chronic disease of increasing prevalence worldwide closely associated with
hyperlipidemia, diabetes, hypertension and cardiovascular diseases. The pathogenesis of obesity
is very complex, and it involves different factors, such as dietary habits, genetic predisposition
and metabolism.
Weight control programs often include diet control, physical activity and drugs. The effectiveness
of medicinal plants as natural supplements to reduce body weight has been taken into account with the
aim to find new remedies with better efficacy and lower adverse effects compared to drugs used until
now. Different secondary metabolites from plants have been demonstrated to modulate body weight.
Besides their known biological activities, saponins have been recently investigated for their anti-obesity
potential. Emerging evidence suggests that these compounds can have beneficial effects against obesity
through different mechanisms of action. Both saponin-rich extracts and pure compounds have been
demonstrated, for instance, to inhibit pancreatic lipase or to modulate adipogenesis and appetite.
However, at present, there is not sufficient evidence able to support the clinical application of
saponins in the treatment of obesity. Future clinical trials on the safety and effectiveness of these
compounds are needed to validate the effects of saponins observed in vitro and in animal models.

Molecules 2016,21, 1404 15 of 20
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
AgRP agouti-related peptide
AMPK AMP-activated protein kinase
C/EBPαCCAAT/enhancer-binding protein alpha
CB1 cannabinoid type 1 receptors
CCK cholecystokinin
CNS central nervous system
EGCG epigallocatechin gallate
EMEA
European Agency for the Evaluation of Medicinal Products
FDA Food and Drug Administration
GLP-1 glucagon-like peptide 1
HDL high density lipoproteins
HeLa human cervical cancer cells
Hep-G2 hepatocellular carcinoma cell line
HL-60 promyelocytic leukemia cells
HT1080 fibrosarcoma cell line
ICD International Classification of Diseases
LDL low density lipoproteins
MAPK mitogen-activated protein kinase
MDA-MB-453 breast cancer cell line
NPY neuropeptide Y
PL pancreatic lipase
PPARγperoxisome proliferator-activated receptor γ
PYY peptide YY
SREBP-1c sterol regulatory element-binding protein-1c
VLDL very low density lipoproteins
WHO World Health Organization
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