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REVIEW ARTICLE H.D.Ramachandran et.al / IJIPSR / 2 (7), 2014, 1606-1624

Department of Biochemistry ISSN (online) 2347-2154

Available online: www.ijipsr.com July Issue 1606

ROLE OF PHYTOCHEMICALS IN COMBATING OBESITY

1Ramachandran. H. D*

Department of Biochemistry, Bangalore University, Bangalore-560 001, INDIA

Corresponding Author:

Dr. H. D. Ramachandran

Department of Biochemistry

Central College Campus,

Bangalore University,

Bangalore -560 001, INDIA

Email: [email protected]

Phone: +91-9448422287 / 080-22961248

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

Phytochemicals are plant chemicals possesing potential for inducing apoptosis, inhibiting

adipogenesis and are anti-obetic. Anti-obesity mechanisms of phytochemicals appear to involve

mediation of complex and interconnected cell signaling pathways. Phytochemicals like polyphenols,

carotenoids and organosulphurs have anti-obesity, anti-inflammatory and apoptotic effects

respectively. Obese individuals generally have high leptin levels. The regulation of adipocyte

lifecycle by regulating both size and number of adipocytes may provide a better approach for

treating obesity. Two different obesity treatment drugs currently in the market are Orlistat, which

reduces intestinal fat absorption via inhibition of pancreatic lipase and Sibutramine, which is an

anorectic or appetite suppressant. Both drugs have hazardous side-effects including increased blood

pressure, dry mouth, constipation, head ache and insomnia. The objective of this review is to

determine the dosages of phytochemicals in leptin regulation and its efficacy in reducing obesity.

Key words: Phytochemicals, leptin, adiposity, obesity, polyphenols, carotenoids, organosulphurs.

mailto:[email protected]




INTRODUCTION

The World Health Organization (WHO) defines obesity as an abnormal or excessive fat

accumulation detrimental to human health. WHO defines overweight as a BMI (Body Mass

Index) greater than or equal to 25 and BMI greater than or equal to 30 as obese. Obesity and

obesity-related complications are rapidly increasing both in developed and developing countries,

presenting an increase in the risk of morbidity and mortality. Around 3.4 million adults die each

year as a result of being overweight or obese. (WHO, 2014) [1]. The United States is the most

obese country in the World with 34% of the adult population classified as obese, according to the

latest OECD (Organization for Economic Cooperation and Development) survey. In India the

prevalence of overweight rose from 2 to 17.1% from 1989 till 2012. In a total of 6940

subjects(3433 women and 3507 men) selected from various cities in India, the overall

prevalence of obesity was 6.8% (7.8 vs 6.2% P< 0.05) and of overweight was 33.5% ( 35vs 32%

P< 0.05) (Ambika et al., 2012) [2]. Obesity is a multifactorial complex disease influenced by life

style, behavioural, environmental as well as genetic factors. The development and continuation of

obesity is closely associated with a state of chronic, low grade inflammation characterized by

abnormal cytokine production and activation of inflammatory signaling pathways (Tsukomo et

al., 2007) [3]. Obese individuals generally have high leptin levels and a highly significant

correlation between body fat content and plasma leptin concentration has been observed. The

protein leptin regulates appetite and energy balance of the body. Adipose tissue growth involves

formation of new adipocytes from precursor cells, further leading to an increase in adipocyte size.

Preadipocytes can proliferate throughout life to increase fat mass. A number of natural products

were shown to inhibit preadipocyte proliferation and induce apoptosis. (Rayalam et al., 2008) [4].

Leptin is an adipocyte derived 167 amino acid protein hormone which is produced in proportion

to fat stores. The production of leptin by adipose tissue is regulated by energy balance. Regulation

of leptin secretion depends on the activation of mTOR, increase in ATP, adenosine, malonyl CoA

and the increase in cAMP and fatty acids decrease the secretion of leptin. Mutations in the leptin

gene (ob-gene) can result in low levels of functional leptin leading to obesity in individuals. So

the only way to increase leptin is to increase its expression on the genomic level. Phytochemicals

are natural chemical compounds formed during normal metabolic processes in plants (Okigbo et

al., 2009) [5]. These chemicals are often referred to as secondary metabolites of which there are

several classes including alkaloids, flavanoids, coumarins, glycosides, gums, polysaccharides,




phenols, tannins, terpenes and terpenoids (Okwu, 2004) [6]. Phytochemicals were studied for

their weight loss, efficacy based on five broad mechanisms of actions, namely (1) decreased lipid

absorption (2) decreased energy intake (3) increased energy expenditure (4) decreased pre-

adipocyte differentiation and proliferation, or (5) decreased lipogenesis and increased lipolysis

(Yun, 2010) [7]. Phytochemicals have gained increased interest due to their anti-oxidant activity,

apoptotic, anti-adipogenic, cholesterol lowering properties, and other potential health benefits

(Awaika and Rooney, 2004) [8]. Furthermore, latest studies on phytochemicals suggest that they

are potential agents in the treatment of obesity. Various studies suggest that anti-obesity effects

could be achieved by consuming lower levels of phytochemicals but in specific combinations.

(Baile et al., 2011; Dooley et al., 2005) [9,10]. Phytochemical combinations that included

polyphenols such as stilbene, resveratrol, genistein and naringenin have proven the most effective.

1. Polyphenols are a class of phytochemicals that are likely anti-obesity agents, as several

studies have suggested they can modulate the adipocyte lifecycle. (Rayalam et al., 2008; Yun,

2010).4, 7

Polyphenols possessing at least two phenol subunits include the flavonoids and those

compounds possessing three or more phenol subunits are referred to as the tannins

(hydrolysable and non- hydrolysable). Polyphenols including their functional derivatives,

esters and glycosides have one or more phenol groups with one hydroxyl substituted aromatic

ring. (Dey and Harborne, 1989) [11]. The three main types of polyphenols are phenolic acids,

flavonoids and stilbenoids.

A. The flavonoid subclasses, flavonols eg. Quercetin, kaempferol, myricetin, and rhamnetin,

the flavones eg.luteolin and apigenin. (Williams et al., 2013) [12] Flavanols, flavanones,

proanthocyanidins and anthocyanins, isoflavones, chalcones and dihydrochalcones. (FGE.

3.2) [13].

B. Stilbenoids comprises the polyhydroxylated stilbenes, the main representative being

resveratrol.

C. The simple phenolic acids such as chlorogenic, coumaric, ferulic, gallic , gentisic and

caffeic acids.

Laboratory studies indicate that the anti-obesity effects of polyphenol rich diet may be

attributed to the ability of polyphenols to interact, directly or indirectly, with adipose tissues

(preadipocytes, adipose tissues and immune cells) (Wang et al., 2014) [14]. Many lines of




research indicate that dietary polyphenols prevent obesity development through the following

possible mechanisms: a) Lowered food intake b) Decreased lipogenesis c) Increased lipolysis

d) Stimulated fatty acid β-oxidation e) Inhibition of adipocyte differentiation and growth, and

f) Attenuation of inflammatory responses and suppress oxidative stress.

Most dietary polyphenols have relatively short half lives once ingested due to rapid metabolism,

so it is important that their consumption is maintained throughout the life span. After eating

polyphenol-rich foods or taking dietary supplement, humans achieve peak plasma polyphenol

concentration at less than 10µM. (Lee et al., 2002; Anand et al., 2007; Baur et al., 2006; Conquer

et al., 1998) [15,16,17,18].

A. Flavonoids comprises of flavonols, flavones, flavanols, flavanones, isoflavones,

anthocyanins, chalcones. Both flavonols and flavones usually occur in plant as glycosides.

a) Flavonols: quercetin, isorhamnetin, kaempferol, myricetin:

(i) Quercetin (3, 3’, 4’, 5, 7-Pentahydroxyflavone): This compound has been shown to inhibit

adipogenesis (Strobel et al., 2005) [19] and induce apoptosis in mouse pre-adipocytes. (Fang et

al., 2008; Kuppusamy and Das, 1992) [20,21] It also provides some protective effects against

obesity-related inflammation. (Al Fayez et al., 2006; Chuang et al., 2010) [22,23]. A recent study

(Ahn et al., 2008) [24] provided useful insights into the molecular mechanisms by which

quercetin influences the regulation of fat cell differentiation and apoptosis. Combination of

quercetin and isoflavone, genistein and the stilbene, resveratrol to human adipocytes enhanced

inhibition of lipid accumulation in maturing human adipocytes than the individual compounds.

(Park et al., 2008) [25].

(ii)Isorhamnetin (3-Methylquercetin; 3’-Methoxy 3,4’,5,7tetrahydroxyflavone): Antiviral

agent, antioxidant. (Yokozawa et al., 2002), [26] antitumor compound (Ito et al., 1999) [27] and

apoptosis inducer (Ma et al., 2007) [28].

(iii) Kaempferol (3, 4’, 5, 7-Tetrahydroxyflavone): Antioxidant flavonoid (Evans et al., 1996)

[29] apoptosis inducer, reversible inhibitor of fatty acid synthase (FAS) (Li et al., 2003, Lupu et

al., 2006) [30, 31]

(iv)Myricetin (3, 3’, 4’, 5, 5’, 7- Hexahydroxyflavone): Antioxidant flavonoid, posseses

antitumor and chemopreventive properties (Lee et al., 2007) [32] anti-inflammatory, inhibits NF-

κB activation (Ong and Khoo, 1997) [33].




b) Flavones : luteolin, apigenin, baicalein.

(i) Luteolin: Anti-adipogenic effect of luteolin on murine 3T3-L1 pre-adipocytes is mediated

through decreased lipid accumulation and inhibition of differentiation (Park et al., 2009) [34].

(ii) Apigenin (4’, 5, 7-Trihydroxyflavone): Apigenin induces apoptosis (Shukla and Gupta,

2007) [35].

(iii) Baicalein (5, 6, 7- Trihydroxyflavone): Induces cell cycle arrest and apoptosis (Lee et al.,

2005) [36].

c) Flavanols: Catechins [(±)-Catechin, (-)- Epigallocatechin gallate]

(i) (±)-Catechin ((±)-3, 3’, 4’, 5, 7-Flavanpentol): Antioxidant flavonoid, Free radical scavenger

(Williamson, et al., 2005) [37] and has chemopreventive and antitumor properties. (Lazaro, 2002)

[38].

(ii) (-)-Epigallocatechin gallate: Antitumor reagent, antioxidant, protects cells from lipid

peroxidation and DNA damage, inhibits inducible nitric oxide synthase (iNOS; NOS II),

chemopreventive anticancer agent (Chen and Zhang, 2007) [39], inhibits - MAP kinase signaling,

angiogenesis, inhibits telomerase and DNA methyltransferase and is also anti-inflammatory

(Khan et al., 2006) [40].

d) Flavanones: Bavachin and related compounds

(i) Bavachin: Weak antioxidant, antimutagenic, stimulates bone formation and has potential

activity against osteoporosis. Also exhibits inhibitory activity against the antigen-induced

degranulation and weak estrogen-like activity. (Wang et al., 2001) [41].

e) Isoflavones: Genistein and related compounds

(i) Genistein (Genistein-7-O-glucoside):

Selective inhibitor of terminal deoxyribonucleotidyltransferase (TdT). (Uchiyama et al., 2005)

[42] and displays antioxidant and anticarcinogenic properties (Choi et al., 2007) [43].

f) Anthocyanins:

Anthocyanins have potential for anti-obesity related effects which is responsible for the red, blue

and purple colours in vegetables (Clifford, 2000) [44]. Cyanidin, the most common anthocyanin

foods, reduced blood glucose level as well as downregulating inflammatory protein cytokines




such as monocyte chemoattractant protein-1(MCP-1) in the adipose tissue of mice. (Sasaki et al.,

2007) [45].

g) Chalcones:

(i)Curcumin(1,7-bis(4-Hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione;

Diferuloylmethane: Plays an important role in inflammation, apoptosis, angiogenesis,

autoimmune diseases and cancer. (Rayalam et al., 2008) [6]

B: Stilbenoids are polyhydroxy stilbenes.

(i) Resveratrol (trans-3,4´,5- Trihydroxy stilbene): It is a polyphenol from red wine possessing

anti-oxidant, anti-inflammatory, anti-thrombogenic, cardioprotective, neuroprotective, cancer

preventive and therapeutic activities.(Rayalam et al., 2008) [6].

C. Phenolic acids are substances containing a phenolic ring and an organic carboxylic acid

function (C6-C1 skeleton). Hydroxycinnamates and hydroxybenzoic acids are the naturally

occurring phenolic acids, in which hydroxybenzoic acid derivatives are mainly present as

glycosides (Williams et al., 2013) [46]. Common hydroxycinnamic acids, comprising nine carbon

atoms, derivatives are coumaric, caffeic and ferulic acids. Hydroxybenzoic acids contain seven

carbon atoms. Gentisic acid and gallic acids are hydroxybenzoic acids. Administration of

phenolic acids at a dose of 10 mg/kg p.o (per os) daily for 4 weeks to ovariectomized or non-

ovariectomized rats slowed their body mass gain. (Zych et al., 2009) [47].

(I) Caffeic acid (3- (3, 4- dihydroxyphenyl) – 2 - propenoic acid): It exhibits anti tumor,

antiviral, antioxidant and anti-inflammatory effects. Also inhibits 5- and 12- lipoxygenase.

(Oztruk et al., 2012) [48].

(ii) Chlorogenic acid (3-O-caffeoylquinic acid): This is an analog of caffeic acid, which exhibits

antioxidant, analgesic, antipyretic and chemopreventive activity. (Rayalam et al., 2008) [6]

(iii)Ferulic acid ((E)-3-(4-hydroxy-3-methoxy-phenyl) prop-2-enoic acid): Recent studies

evaluated that the dietary phenolic acid, ferulic acid, suppressed the weight gain due to the high

fat diet and inhibited fatty acid biosynthesis. (Son et al., 2010) [49].

(iv)p-coumaric acid ((E)-3-(4-hydroxyphenyl)-2-propenoic acid): is a hydroxycinnamic acid

with antioxidant properties. p-coumaric acid protects the myocardial infarcted rat's heart against

apoptosis by inhibiting oxidative stress. (Prince et al., 2013) [50].

http://en.wikipedia.org/wiki/Phenol

http://en.wikipedia.org/wiki/Carboxylic_acid




(v)Gallic acid (3, 4, 5- trihydroxybenzoic acid): This is an organic acid which exists in two

forms as free molecule and as part of tannins (gallotanins). (Nasr et al., 2012) [51]. It exhibits

cytotoxicity against cancer cells, without harming healthy cells (Elvira et al., 2006) [52] and also

has antifungal and antiviral properties (Kinjo et al., 2002) [53] which is used as an antioxidant

and helps to protect human cells against oxidative damage (Jittawan, 2008) [54], it can be used as

a remote astringent in cases of internal hemorrhage (Hurrell et al., 1999) [55] and can also used

to treat psoriasis (Cook et al., 1995) [56].

(vi) Gentisic acid (2, 5 - dihydroxybenzoic acid): Possesses greater anti-radical activities

(Williams et al., 1995) [12].

2. Carotenoids:

Carotenoids are a subclass of terpenoids possessing anti-obesity and anti-inflammatory abilities.

(Castejon et al., 2011) [57]. Carotenoids are classified into hydrocarbons (carotenes) and their

oxygenated derivatives (xanthophylls).

α-carotenes and β- carotenes possess the anti-obesity effects. Carotenoids containing an allene

bond, such as fucoxanthin and fucoxanthinol, showed anti-obesity effects. Carotenoids with an

allene bond and an additional hydroxyl substituent on the side group show suppressive effects on

adipocyte differentiation in 3T3-L1 cells. These findings show a great potential for application in

the field of therapeutics for the development of novel anti-obesity compounds. (Miyashita et al.,

2007) [58].

3. Organosulphurs:

Glucosinolate hydrolysis products found in Brassica vegetables are anti-obesity organosulphurs

(Castejon et al., 2011) [57]. Organosulphur compounds isolated from Allium vegetables (Ajoene)

have induced apoptosis of human tumour cells. (Nishikawa et al., 2002, Siegers et al., 1999) [59,

60]. Several garlic derived organosulphur compounds have shown inhibitory effect on

adipogenesis. (Ambati et al., 2009) [61]. Ajoene is more potent on adipocytes when compared to

several other garlic organosulphur compounds, in addition ajoene significantly suppresses cell

viability, adipogenesis and increases apoptosis in different stages of 3T3- L1 adipocytes. Zinc

complexes with garlic components serve as insulin mimetic (Banos et al., 2008) [62], a new

therapeutic approach to treat diabetes, leptin resistance and to suppress progression of obesity in

rodent models.(Adachi et al., 2004) [63].

http://www.sciencedirect.com/science/article/pii/S0023643895800085




Fig. 1: Adipocyte life cycle [64].

Fig. 2: Flow diagram of biological response to differing leptin levels [65].

NPY: Neuropeptide Y; ART: Agouti- related transcript;

MSH: Melanocyte Stimulating Hormone; CRH:Corticotropin Releasing Hormone; GnRH:

Gonadotropin Releasing Hormone; PNS: Parasympathetic Nervous System.

Fig. 3: Leptin is secreted by adipocytes as a signal of fat storage [66].

LRb: Leptin Receptor B.




Fig. 4: Effect of natural products and their combinations on different stages of Adipocyte

life cycle [4].

GSPE: Grape Seed Proanthocyanidin Extract; DHA: Docosahexaenoic Acid

CLA: Conjugated Linoleic Acid; EGCG: Epigallocatechin gallate

1, 25(OH) 2D3: 1,25 dihydroxy Vitamin D3 (Calcitriol)

Quercetin Isorhamnetin Kaempferol

Myricetin Luteolin Apigenin




Baicalein Catechin Epigallocatechin gallate

Anthocyanins Curcumin Bavachin

Genistein Resveratrol Caffeic acid

Chlorogenic acid Ferulic acid p-coumaric acid




Gallic acid Gentisic acid Carotene

Table 1: Effect of reviewed phytochemicals on adipogenesis in vivo and in vitro. 67

Phytochem

ical

Proliferatio

n

of

Adipocytes

Apoptosis

of

pre-

adipocytes

Lipid

accumu-

lation

Adipogeni

c

gene

expression

Apoptosi

s

of

adipocyte

s

Lipolysis

of

adipocyte

s

BW

of

rodents

Adipose

tissue

mass

in

rodents

Effect

In

Clinical

studies

EGCG M NE ↓ ↓ ↑ NE ↓ ↓ M

Genistein ↓ NE ↓ ↓ ↑ ↑ HD HD NE

Resveratrol ↓ ↓ ↓ ↑ ↑ HD HD

Xanthohum

ol NE ↓ ↓ ↑ ↑ NE ↓

Quercetin ↓ ↓ M ↑ ↑

Rutin ↓ ↓ ↓ ↓

Curcumin ↓ NE ↑ ↓ ↓

Capsaicin ↓ ↓ ↑ M M Small

o- coumaric

acid ↓ ↓ ↓ ↓

Berberine NE ↓ ↓ ↓ ↓

Evodiamine ↓ ↓ M ↓ ↓

Retinol ↓ ↓ ↑ M ↓

Negative

correlatio

n with

BMI

1.25(OH)2D

3 ↓ ↓ ↓ ↑ ↑

Associatio

n with

adiposity

Guggulstero

ne NE NE ↓ ↓ ↑ ↑

Ajoene ↓ ↓ ↓ ↑

Esculetin ↓ NE ↓ ↑

Withaferin

A ↓ ↓ ↓ ↓ ↑

NE- No Effect, HD- High Dose, M- Mixed Effects, BW- Body Weight




OVERVIEW

Table 2: Modified from “Quercetin: A Versatile Flavonoid” [68]

Groups Compounds Rich sources

Flavonols

Quercetin

Isorhamnetin

Kaempferol

Myricetin

Yellow onion, leek, cherry tomato, broccoli, apple,

green and black tea, black grapes, blueberry.

Flavones

Luteolin

Apigenin

Baicalein

Parsley, celery, capsicum, pepper.

Flavanols

(±)- Catechin

(-)- epigallo

catechin gallate

Chocolate, beans, apricot, cherry, grapes, peach, red

wine, cider, green tea, black tea, black berry.

Flavanones Bavachin Psoralea corylifolia (Babchi plant)

Isoflavones Genistein Soy cheese, soy flour, soy bean

Anthocyanins Cyanidin Black berry, black grapes, cherry, plum, strawberry,

red wine, red cabbage.

Chalcones Curcumin Turmeric

Stilbenoids Resveratrol Red grapes, blue berries.

Hydroxycinnamic

acids

Caffeic acid

Chlorogenic acid,

ferulic acid,

p-coumaric acid

Blue berries, kiwis, plums, cherries, apples.

Hydroxybenzoic acids Gallic acid, gentisic acid. Black radish, onion, tea

Carotenoids Carotene

Xanthophyll

Carrot.

Green plants.

Organosulphurs Ajoene Garlic

Table 3: Mechanism of action of some phytochemicals [69,70,71]

Name of phytochemical Mechanism of action

Quercetin Inhibiting NO production and iNOS protein expression.

Inhibits both cyclooxygenase and lipoxygenase activities.

Isorhamnetin Anti oxidant activity, shows anti adipogenic activity mediated by the

stabilization of β- catenin.

Kaempferol Induces apoptosis, induced apoptosis in glioma cells by elevating

intracellular oxidative stress.

Myricetin Inhibits NO production.

Luteolin

Inhibiting the upregulation of THP-1 adhesion and VCAM-1

expression.

Inhibiting the activity of NF-κB.

Apigenin

Blocking the expression of intercellular adhesion molecule-1(ICAM

1), VCAM 1and E- selectin.

Inhibiting prostaglandin synthesis and IL- 6,8 production.

Baicalein Modulation of angiogenic processes.

(±)-Catechin Shows anti oxidative, anti mutagenic, anti carcinogenic and free radical

scavenging effects

(-)-Epigallo

catechin gallate

Inhibits the expression of iNOS

Reducing the activity of NF-κB and AP -1

Bavachin Induction of NO production which stimulates angiogenesis.




Genistein

Inhibits the activity of ATP utilizing enzymes. Induces apoptosis,

exerts antioxidant effects, inhibits angiogenesis, suppress osteoclast

and lymphocyte functions.

Anthocyanins &

Hydroxycinnamic acids

Localizes into endothelial cells.

Reduces upregulation of IL-8, MCP -1 and ICAM-1.

Curcumin

Decreasing MPO activity and TNF-α on chronic colitis.

Reducing nitrites levels and the activation of p38 MAPK.

Downregulating COX-2 and iNOS expression.

Resveratrol

Inhibiting stimulation of caspase-3 and cleavage of PARP induced IL-

1β.

Suppressing the expression of iNOS mRNA and protein by inhibiting

the activation of NF-κB inhibiting NO generation.

Upregulating MAP kinase phosphatase -5.

Carotenoids Act as anti oxidants by reducing the toxic effects of reactive oxygen

species.

Organosulfurs

Modulates the activity of several metabolizing enzymes that activate

(cytochrome P450s) or detoxify (glutathione S-transferases)

carcinogens and inhibit the formation of DNA adducts in several target

tissues.

CONCLUSION AND FUTURE PROSPECTS

Obesity, a global health problem, is associated with increase in the size and mass of the adipose

tissue. Adipose tissue growth involves formation of new adipocytes from precursor cells, further

leading to an increase in adipocyte size. Thus, adipose mass can be decreased by removing

adipocytes, inturn aiding the reduction and control of obesity. Inhibiting adipogenesis at various

stages of adipocyte life cycle, inducing apoptosis and lipolysis are the processes that can be

employed to decrease the adipose mass. Although two main drugs - orlistat and sibutramine are

being currently used for the treatment, both have shown deleterious side effects. Hence, the

spotlight shifts to natural products or phytochemicals. Therefore, screening of indigenous plants

for the various phytochemicals found in them, which specifically target adipogenesis and

adipocyte apoptosis pathways possess better potential for treatment and prevention of obesity.

These phytochemicals can be explored for safer and more effective pharmacological treatment of

obesity, either individually or in combination. Thus, identification, isolation and characterization

of the effective phytochemical components, the target site of these phytochemicals in adipocyte

life cycle individually and in combination and dosage determination in regulating leptin levels

promise great scope in this direction and have to be undertaken.




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