A review on possible therapeutic targets to contain obesity: The role of phytochemicals

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Obesity Research & Clinical Practice (2015) xxx, xxx—xxx

REVIEW

A review on possible therapeutic targets to contain obesity: The role of phytochemicals Meriga Balaji a,∗, Muni Swamy Ganjayi a, Gali E.N. Hanuma Kumar a, Brahma Naidu Parim a, Ramgopal Mopuri b, Sreenivasulu Dasari a a

Animal Physiology & Biochemistry Laboratory, Department of Biochemistry, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India b Department of Biochemistry, School of Life Science, University of KwaZulu Natal, Durban 4000, South Africa Received 25 September 2015 ; received in revised form 26 November 2015; accepted 8 December 2015

KEYWORDS Anti-obesity; Lipid lowering; Multiple targets; Natural products

∗

Summary The prevalence and severity of obesity has increased markedly in recent decades making it a global public health concern. Since obesity is a potential risk factor in the development of hypertension, type-2 diabetes, cardiovascular diseases, infertility, etc., it is no more viewed as a cosmetic issue. Currently, only a few FDAapproved anti-obesity drugs like Orlistat, Lorcaserin and Phentermine-topiramate are available in the market, but they have considerable side effects. On the other hand, bariatric surgery as an alternative is associated with high risk and expensive. In view of these there is a growing trend towards natural product-based drug intervention as one of the crucial strategies for management of obesity and related ailments. In Asian traditional medicine and Ayurvedic literature a good number of plant species have been used and quoted for possible lipid-lowering and anti-obesity effects; however, many of them have not been evaluated rigorously for a definite recommendation and also lack adequate scientific validation. This review explores and updates on various plant species, their used parts, bioactive components and focuses multiple targets/pathways to contain obesity which may pave the way to develop novel and effective drugs. We also summarised different drugs in use to treat obesity and their current status. Nature is future promise of our wellbeing. © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +91 9849086856. E-mail address: [email protected] (M. Balaji).

http://dx.doi.org/10.1016/j.orcp.2015.12.004 1871-403X/© 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

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M. Balaji et al.

Contents Introduction .................................................................................................... 00 The potential of phytochemicals ............................................................................... 00 Phytocompounds: possible mode of action......................................................................00 Phytochemicals as pancreatic lipase inhibitors ............................................................. 00 Phytochemicals as appetite suppressants .................................................................. 00 Phytochemicals as energy expenditure regulators .......................................................... 00 Phytochemicals as lipid metabolism regulators.............................................................00 Phytochemicals as adipocyte differentiation regulators .................................................... 00 Role of phytochemicals in other mechanisms...............................................................00 In hormone sensitive lipase (HSL) (mobilisation of stored fats).......................................00 In gut microbes ...................................................................................... 00 Conclusion ..................................................................................................... 00 Conflict of interest ............................................................................................. 00 Acknowledgements ............................................................................................. 00 References ..................................................................................................... 00

Introduction Obesity is a persistent chronic metabolic disorder that results from an imbalance between energy intake and expenditure. In recent times lifestyle changes, reduced physical activity and wide access to high calorie foods have led to a considerably positive energy balance among the people of this generation. The excess and unutilised food taken in is converted into lipid components, primarily triglycerides, and is stored in liver, adipose and other tissues; if the positive energy balance extends a longer period it leads to overweight and obesity (Fig. 1). Obesity occurrence and its comorbidities are on the rise in developed and developing countries cutting across age and sex [1]. Obese individuals are more likely to develop diabetes, cardiovascular diseases, hypertension, metabolic syndrome, osteoarthritis, infertility, urinary incontinence, pulmonary disease, and certain types of cancer, psychological issues, prejudice and discrimination, negative self image and are more likely to suffer an early death [2—6]. Overweight—obesity and its severity are traditionally defined by BMI, waist circumference, and waist—hip ratio. BMI is defined by WHO as the weight in kilograms divided by the square of the height in metres (kg/m2 ). However, it should be a rough measure as it may not correspond to the same body fat percentage in different individuals like muscular athletes. The other way to measure obesity is by waist circumference (WC). Men with a waist measurement of 102 cm (40 Inc) or more and women with 88 cm (35 Inc) or more are at increased risk of developing lifestyle diseases. The risk worsens with increasing waist circumference. Overweight—obesity has been a commonly neglected public health problem, which adversely

Figure 1 Obesity and its associated morbidities.

affects health, wellbeing, work output and life expectation. Currently, about more than two billion adults worldwide are overweight and at least 600 million of them are clinically obese [7]. Obesity is set to become the major investment theme over the next 25—50 years as the number of overweight people has tripled globally over the last three decades [8]. It is estimated that presently more than £4 billion are incurred per year on obesity treatment and are likely to double by 2040 [9]. The prevalence of obesity and overweight has been the highest in the US (26% obesity and 62% overweight in both sexes) and less in south East Asia. In Europe, the Eastern Mediterranean and Americas, over 50% of women are overweight [10,11]. In developing countries like India and China, although the percent of obese people look minimal, considering their vast population, it is

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Phytochemicals as therapeutic targets of obesity obviously alarming. In India, states like Punjab, Kerala, Goa and Tamil Nadu occupy the first four positions in obesity (35%, 30%, 25% and 20%) with more obese females than males [6]. One may wonder that in spite of alarming figures on obesity, hardly there exist effective treatments for it. Currently, a few FDA-approved anti-obesity drugs like Orlistat, Lorcaserin, and Phenterminetopiramate are available in the market, but they have side effects (gastroesophageal reflux disease, increased blood pressure, constipation, headache, dry mouth, heart disease, depression, nausea, liver failure, insomnia, psychiatric and cognitive effects, and even lethal effects) [2—4,12]. Due to side effects, some drugs have been even withdrawn, for instance, in 2010, the FDA has directed the withdrawal of Sibutramine/Meridia forcing its manufacturers, Abbott Laboratories to withdraw it from the US and Canadian markets. Rimonabant, another drug, often referred to as ‘‘the munchies’’, had been approved by the European authorities, but FDA has not approved it for sale so far in Canada and US on safety considerations. In 2012, the US Food and Drug Administration approved Phentermine/Topiramate (ER) (Qsymia) for weight loss, but due to side effects like hypertension, heart-related diseases, psychiatric and cognitive side effects, the European regulatory authorities have disallowed its sale. On the other hand, most folk medicines available in the market lack proper clinical investigation, scientific validation and authentication. The option of bariatric surgery to get rid of obesity is fraught with risks and high cost. In view of these drawbacks and dissatisfaction with synthetic medications, there is a growing shift towards natural product-based drugs/formulations [13,14]. Therefore, research efforts have been intensified to explore the potential of natural product-based drugs to combat obesity and associated co-morbidities. There is also a kind of faith among most people that natural sources are reliable, safer, and also cheaper than current therapies based on synthetic chemicals and surgeries with attendant adverse effects. Fig. 2 shows that, ‘‘Poor Nutrition’’ is the major contributing factor (41.4%) for obesity . Other reasons cited are ‘‘Not Enough Exercise’’ (20.7%) and ‘‘Over-eating’’ (26.7%) and a few (11.2%) believe in genetics or stress.

The potential of phytochemicals Nature represents an enormous reservoir of biologically active compounds to treat various ailments from times immemorial [15]. In view of the

3

Figure 2 Percentage of different sources for obesity.

side effects encountered with long time usage of synthetic drugs and due to stringent guidelines to be fulfilled during drug approvals, plant—herbal drugs have gained much attention as a reliable option to clinical remedy and the claim for these herbal remedies has greatly increased recently. A variety of phytochemicals such as polyphenols, alkaloids, terpenoids, flavonoids, tannins, saponins, glycosides, steroids and proteins present in plants and their products are key factors in the treatment of several disorders [16]. A good number of phytoconstituents such as guggulsterone, hydroxycitric acid, apigenin, genistein, gymnemic acid, caffeine, theophylline, ephedrine, capsaicin, piperine, ellagic acid and catechins have been reported to possess anti-lipidaemic and pro health properties [13,17—22]. Although some of these compounds are used in preparing antiobesity drugs/formulations, they lack adequate clinical investigations and scientific validation to be authentic and recommended for obesity therapy. In other words, the potential of plants, herbs and their derivatives for the treatment of obesity is still largely unexplored and can be an excellent alternative to develop safe and effective natural product-based anti-obesity drugs [23]. The potential of phytochemicals as a source of new drugs opens a wide field for scientific investigation owing to the abundant availability of (2,50,000—5,00,000) known species, of which only a small percentage has been phytochemically investigated and evaluated for pharmacological potential [24]. Even from the plants known for traditional medicinal use, many still have not been studied for their effectiveness and safety. Therefore, a necessity has arisen for alternative therapies, especially based on natural products with minimal or no side effects in place of the present therapeutics. In this review, we discussed different possible targets that can be focused to develop drugs to

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M. Balaji et al. Table 1

The available anti-obesity drugs in the market and their current status [25,26].

Drug

Mechanism of action

Adverse effects

Current status

Dinitrophenol

Diethylpropion

Sympathomimetic amine

Aminoxaphen (Aminores) Phenylpropanol amine Fenfluramine

Rimonabant

Indirect sympathomimetic action, pulmonary Central ␣1adrenergic receptor agonist Dexfenfluramine selective serotonin reuptake inhibitor Norepinephrine and serotonin reuptake inhibitor Cannabinoid receptor antagonist

Cataracts, neuropathy, sensation of warmth, sweating Addiction, headache, nausea, dry mouth, nervousness, anxiety, hypertension, tachycardia Headache, insomnia, irritability, palpitations, nervousness and increased blood pressure Dry mouth, insomnia, palpitation and headache Hypertension

Withdrawn

Phentermine

Uncouples oxidative phosphorylation in mitochondria Increases the neurotransmitters dopamine, noradrenaline and serotonin in brain Sympathomimetic amine

Orlistat

Lipase inhibitor

Lorcaserin

Selective 5HT2C receptor agonist

Qnexa (Topiramate and Phentermine)

Topiramate blocks voltage-dependent sodium channels, glutamate receptors and carbonic anhydrase, and augments GABA activity; phentermine is sympathomimetic Norepinephrine, dopamine and serotonin reuptake inhibition Lipases inhibitor

Amphetamine

Sibutramine

Tensofesine Cetilistat Contrave

Metformin

Bupropion increases activity of proopiomelanocortin (POMC) neurons. Naltrexone blocks opioid receptors on the POMC neurons preventing feedback inhibition and increasing POMC activity Works by suppressing glucose production in the liver, thereby decreasing blood glucose levels. It is thought to work in weight loss because of its appetite-suppressing properties

contain obesity. A list of plants and herbs, their used parts, extracts/bioactive components and their mode of action is described. We also mentioned the drugs that have been used for obesity treatment, their side effects, mode of action and their current status (Table 1).

Banned as an anti-obesity drug Short-term use (<1 week) Short-term use (<12 weeks) Withdrawn

Haemorrhagic stroke, psycosis

Banned in USA

Pulmonary hypertension valvulopathy Headache, insomnia, dry mouth and constipation Depression, nausea, dizziness, arthralgia and diarrhoea Diarrhoea, flatulence, bloating, abdominal pain and dyspepsia Headache, dizziness and nausea, difficult breathing; swelling of face, lips, tongue, or throat

Withdrawn

Diarrhoea, possible harm to foetus, increased heart rate

Dry mouth, nausea, increased anger and hostility Diarrhoea, flatulence, bloating, abdominal pain, fatty stool Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhoea

Abdominal or stomach discomfort, cough or hoarseness, diarrhoea

Withdrawn Withdrawn from Europe Marketed Initially approved, awaiting final approval Marketed

Not approved Not approved Still under investigation

Still under investigation

Phytocompounds: possible mode of action Broadly, the potential sites that can be targeted to contain obesity include the brain to alter neural signals related to hunger, the gastro intestinal tract

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Phytochemicals as therapeutic targets of obesity

Figure 3 Phytochemicals and their major possible targets to contain obesity.

involved in nutrient absorption and adipose tissue that plays vital role in fat storage/degradation. Based on the possible mode of action to combat obesity, phytoconstituents are classified into six major types: (1) lipase inhibitors, (2) appetite suppressants, (3) energy expenditure regulators (thermogenesis), (4) lipid metabolism regulators, (5) adipocyte differentiation regulators and (6) others (Fig. 3).

Phytochemicals as pancreatic lipase inhibitors One of the prominent strategies to combat obesity is through interfering at gastrointestinal level through inhibition of specific enzymes like lipase and amylase. Lipase is a digestive subclass of the esterases (triacylglycerol hydrolase E.C. 3.1.1.3) that catalyses the hydrolysis of ester bonds in water-insoluble lipid substrates. Lipase performs essential roles in digestion, and processing of dietary lipids (e.g. triacylglycerols, fats and oils) to monoglycerides and free fatty acids in humans. The decreased digestion and absorption of ingested fats lead to overall decreased caloric absorption ultimately leading to decreased obesity [27—29]. Presently, there are very few drugs which can interact with lipases and inhibit their action; Orlistat is one among them [2]. Orlistat’s lipase inhibitory activity occurs through a covalent bond at the

5 lipase’s active site (serine). Although the pancreatic lipase inhibitor is clinically approved for obesity treatment, Orlistat has some unpleasant gastrointestinal side effects [4,30] like oily spotting, faecal urgency or incontinence, flatulence, liquid stools and abdominal cramping [31]. Therefore, researchers continue to focus for screening novel side effects-free lipase inhibitors derived from plants and other natural sources [23]. Plant based products provide a good number of pancreatic lipase inhibitors with potential for development into clinical products [32], for instance phytochemicals of Panax japonicas [33], Platycodi radix [34], Salacia reticulate [35] and Nelumbo nucifera [36]. The phytochemicals under this group include mainly saponins, polyphenols, tannins, flavonoids and caffeine [37—39]. The most studied natural sources of lipase inhibitors are derived from different teas (e.g., green, oolong and black tea). Green tea leaves possess significantly different types of polyphenols, which have strong pancreatic lipase inhibitory activity, with EGCG being its most active component [40]. These compounds require galloyl moieties within their chemical structure and/or polymerisation of their flavon-3-ols, 2-O-digalloyl-1,3,4,6-tetraO-galloyl-D-glucose [41] for enhanced pancreatic lipase inhibition [42]. Besides, bioactive compounds isolated from marine and microbial sources such as esterastin, lipstatin, caulerpenyne and vibralactone [43—46] provide a good pool of pancreatic lipase inhibitors with potential clinical product development. Therefore, the scientific community can target the kinetics, thermodynamics and interaction with PL to develop promising drugs (Table 2).

Phytochemicals as appetite suppressants Body weight regulation through satiety control is a multifunctional event from neurological and hormonal interrelationship. Studies reveal that neurotransmitters such as serotonin, histamine and dopamine and some phytoconstituents like caffeine, ephedra, foods containing lipotropic nutrients or oat meal play key role in appetite and satiety regulation [64,65]. In general, the expression of fullness or being hungry may result in no consumption of food. There are two ways by which they suppress appetite: • Reduce appetite (make you not feel hungry) • Increase satiety (make you feel full) These effects are achieved by action on various brain neurotransmitter pathways like psychological and behavioural expression of appetite, metabolism and peripheral physiology and CNS

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M. Balaji et al. Table 2

Medicinal plants and their active components with lipase inhibitory activity.

Plant

Used parts

Active component

References

Salix masudama Aesculus turbinate Coffea canephora

Leaf Seed

[47] [48] [38]

Xylopia aethiopica Scorodophloeus zenkeri Baccharis trimera Murrayakoenigii (L.) Aronia melanocarpa (L.) Black berry Pomegranate leaf Platicodi radix Juniperus communis Illicium religiosum Panax japonicas Vitis vinifera Cudrania tricuspidata Setaria italic Eisenia bicyclis Opuntia ficus-indica N. nucifera petal Afromomum meleguetta, Spilanthes acmella Camellia sinensis, Theaceae Salacia reticulate

Fruit Husk, seed Stem Spreng leaves Water exract

Polyphenol fraction Aescin/escin Caffeine, chlorogenic acid, neochlorogenic acid, feruloylquinic acid Aqueous extract Aqueous extract Methanolic extract Mahanimbine Anthocyanidin Ellagic acid Platicodin saponins Ethanolic extract Water extract Chikusetsu saponins Ethanolic extract Ethanolic extract Methanolic extract Phloroglucinol derivatives Aqueous extract Methanol extraction Crude ethanolic extract

[53] [54] [55] [37] [33] [56] [39] [56] [56] [57] [58] [36] [59] [60] [35]

Milletia pinnata Terminalia paniculata Oolong tea

Bark Bark Leaves

EGCG (−)-4-Omethylepigallocatechin Aqueous extract job Ethanolic extract

Stem bark Bark Wood Rhizomes Bark, seed Leaves Seeds Brown algae Fructus Petals — Tea Nut

neural pathway functioning [66]. Usually, the appetite suppressants are dietary constituents that aid in appetite control. The mechanism of action of appetite suppressants characteristically affects hunger control centre in the brain resulting in a sense of fullness or satiety. Leptin and ghrelin are peripheral signals with central effects. In other words, they are secreted in other parts of the body (peripheral) but affect brain (central). They are key players in appetite regulation, which consequently influences body weight/fat. In animals and humans when less food is taken in, secretions of ghrelin may increase in the gastrointestinal tract and stomach, thus stimulating increased food intake. Hence, ghrelin antagonism may decrease appetite leading to decreased food intake and thus, may be a potential means for obesity treatment [67]. Leptin is majorly secreted by adipose tissue and in small amounts by stomach, heart, placenta and skeletal muscle into circulatory system [68]. Leptin reduces a person’s appetite by acting on specific centres of the brain to reduce urge to eat. It also

[49] [49] [50] [51] [52]

[61] [62] [63]

seems to control how the body manages its storage of body fats, whose levels tend to be higher in obese people than individuals. However, despite having higher levels of this appetite-reducing hormone, obese people are not leptin-sensitive as a result tends not to feel full during and after a meal. Current research is directed to find why leptin messages are not getting through to the brain in obese subjects [69]. Melanocortin receptor 4 (MC4R) is a protein that in humans is encoded by MC4R gene. It is a Gprotein coupled receptor that binds ␣-melanocyte stimulating hormone (␣-MSA). In murinae models MC4 receptors have been reported for their role in feeding behaviour, in regulation of metabolism, sexual behaviour and male erectile function. Antagonism of melanin concentration hormone (MCH) receptors (MCH-R1, MCH-R2) is a novel approach in the treatment of obesity through appetite regulation [70]. Recently, one of the two popular FDA-approved drugs for treating obesity, Sibutramine, which suppresses appetite or increases

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Phytochemicals as therapeutic targets of obesity the feeling of satiety by controlling noradrenaline, serotonin and dopamine, has been withdrawn [71], but Lorcaserin and Phentermine are presently available drugs [25,72]. Some studies show that inhibition of fatty acid synthase (FAS) can reduce food intake and body weight. In mice treated with FAS inhibitors, suppression of appetite and decrease in body weight occurred [73]. A few plants and their products have been shown to inhibit FAS and hence impact appetite and lipid storage negatively. Epigallocatechin gallate from green tea was found to be a strong inhibitor of FAS in chicken liver both by reversible fast binding and irreversible slow binding. It has been cited that hypothalamic neuropeptide Y (NPY) or serum leptin expression levels are mediated by some natural appetite suppressants [74]. Although some of the plants and their products and herbal supplements, including Robinia pseudoaccacia [75], Phaseolus vulgaris [76], Citrus aurantium [77], sunflower oil and ependra [78] have been used in traditional medicine as appetite-suppressants, they lack either systematic investigation or adequate clinical studies or both. Moreover, their mechanism of action is still unclear. Hence, researchers may target such neurotransmitters or/and their receptors, to develop effective drugs/formulations to treat obesity through energy intake reduction (Table 3).

Phytochemicals as energy expenditure regulators The precise function of beige/brown adipose tissue is thermogenesis in many species. Daily energy expenditure consists of three aspects: (i) basal metabolic rate, (ii) diet-induced thermogenesis, and (iii) energy cost of physical activity [88,89]. Activity thermogenesis is an important mode of energy expenditure. It can be divided into exercise activity thermogenesis (EAT) and non-exercise activity thermogenesis (NEAT). NEAT clearly explains why an active person can expend about 2000 more calories per day than an inactive person of the same size. NEAT indicates the energy expenditure towards all activities other than volitional sporting like exercise. Recent studies identify three types of fat cells: white adipose tissue, brown adipose and beige cells [90]. BAT plays an important role in obesity control by controlling energy balance. The body weight and energy expenditure are regulated in mammalian BAT tissue through non-shivering thermogenesis by dissipation of excess energy as heat instead of ATP in response to cold/␤ adrenogen-1 [91]. Uncoupling

7 proteins play key role in this process. For instance, UCP1 discharges the proton gradient generated in oxidative phosphorylation dissipating energy as heat [92]. Therefore, researching for substances that can upregulate UCPs gene expression may be an effective strategy to combat obesity through increased energy expenditure [93]. Likewise, UCP3, an analogue of UCP1, is also a potential antiobesity agent because it mediates thermogenesis through thyroid hormone [94]. In another study, ethanolic extract of Solanum tuberosum, which activates the expression UCP3 in BAT and liver, had reduced fat weight in HFD-fed rats significantly [95]. Many naturally occurring compounds including capsaicin [13] and caffeine [96] have been proposed as factors for weight loss via enhanced energy expenditure. We have reported from our lab that piperine reduces body weight through upregulation of UCP1 [22]. Intake of resveratrol increases mitochondrial genes like mitochondrialprotein-cytochrome-C-oxidase subunit-2 (COX2), mitochondrial-transcription-factor-A (TFAM), peroxisome-proliferator-activated-receptor-␤/␦ (PPAR␤/␦), sirtuin-1 (SIRT1) and proliferatoractivated-receptor-gamma-coactivator1-␣ (PGC-1␣) in BAT and increased UCP1 protein expression. Resveratrol also increases the UCP expression in thermogenic tissues which may contribute energy dissipation [97]. Previous reports suggest that EGCG (epigallocatechin-3-gallate) also stimulates thermogenesis through inhibition of the catecholO-methyltransferase involved in the degradation of norepinephrine [13,98]. Likewise, fucoxanthine (marine source) and n-3-polyunsaturated fatty acids stimulate the process of thermogenesis in BAT and promote WAT deposition in in vivo acquisition of BAT features in rodents [99,100]. More recently, additional secreted factors important to thermogenic fat biology have been reported [101—104]. Table 4 lists plant-based compounds and their thermogenic activity. Recent studies show that combining capsaicin from chilli with medium-chain triglycerides enhances diet-induced thermogenesis and satiety [105]. Other studies demonstrate that MCFAs and MCTs suppress the fat deposition through thermogenesis and oxidation of fat. Activated macrophages (by cytokines) have been reported to cause and sustain thermogenesis in both WAT and BAT [106]. When the ambient temperature falls, the brain sends chemical signals (catecholamines) to white and brown fat tissues activating the latter to generate heat. The major source of energy for heat production is lipids stored in white fat which are activated in response to catecholamines and reach brown fat through the bloodstream [107].

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M. Balaji et al. Table 3

Medicinal plants and their active components that decrease hunger and food intake.

Name of the plant

Used parts

Active component

References

Panax ginseng Gracina combogia Camellia sinensis Caralluma fimbriata H. gordonii Hoodia gordonii and H. pilifera Pinus karaiensis Cynanchum auriculatum Coleus forskohlii Morus australis Poir

Root — Leaf Cactus Plant — Pine nut Root Leaf Mulberry

Saponin Hydroxycitric acid Epigallocathechin gallate Ethanolic extract Dichloromethane—methanol Steroidal glycoside Pine nut fatty acid Pregnane glycosides, Extract Anthocyanins

[74] [79] [80] [81] [82] [83] [84] [85] [86] [87]

Table 4

Medicinal plants and their active components with thermogenic activity.

Name of the plant

Used parts

Active component

References

Nelumbo nucifera Pinellia ternate Panax ginseng Glycine max Undaria pinnatifida Camellia sinensis Dietary products (Camellia sinensis, Theaceae) Garcinia cambogia Chilli Grains of paradise Green tea

Leaf — Berry Soybean Sea weed

Ethanolic extract Aqueous extract Ethanolic extract B-conglycinin, glycinin EPA and DHA Fucoxanthin EGCG Medium-chain triglycerides (MCT) EGCG Garcinic acid Capsaicin Alcohols Extract

[108] [109] [110,111] [112,113] [114,115] [98] [116] [60] [117] [104] [118] [119]

Tea

Seeds Leaves

Phytochemicals as lipid metabolism regulators In general enhanced lipolysis or reduced lipogenesis is vital in the regulation of fat deposits. The pharmacological approach revolves around targeting key enzymes like acetyl CoA carboxylase, carboxylesterase (CE), fatty acid synthase, HMG-CoA reductase, melanyl CoA, etc. Targeting of lipolysis can be envisaged in two different ways. The first one is through stimulation of triglyceride hydrolysis that leads to reduced fat stores and ultimately to reduced adipose tissue growth. Conversely, considering the fact that excessive lipolysis results in high levels of circulating fatty acids and development of dyslipidaemia, prevention of such a fatty acid release may be of therapeutic interest [120]. Earlier studies led to the discovery of novel microbial metabolites with inhibitory activity against lipid metabolism in general, fatty acid and cholesterol metabolic pathways in particular. Some of the compounds they discovered include cerulenin, beauverolides and ferroverdins, chlorogentisylquinone, thiotetromycin and pyripyropenes

[120]. Cerulenin is a potential fatty acid synthase inhibitor, triacsin C is a good inhibitor of acyl-CoA synthetase and hymeglusin effectively inhibits HMG-CoA synthase [45]. Caffeine, one of the major components of Oolong tea, and other compounds bring about lipolysis by binding to phospholipid phosphate groups through interactions between the lipase and triglyceride portions of lipid droplets [121,122]. Flavonoids from N. nucifera (Nn) are involved in ␤-adrenergic receptor activation. Through this pathway, Nn extract containing dietary supplementation resulted in significant suppression of body weight gain in A/J mice fed on HFD [108]. Previous studies in our laboratory showed that the extracts of Bauhinea pupuria, Terminalia panniculata, piperine and piperonal present in Piper nigrum reduced the body weights of HFD-fed obese rats by downregulation of FAS and SREBPS [123—125]. AMPK signalling plays a key role in regulating lipid metabolism. It is expressed in many tissues, like the skeletal muscle, liver, heart and brain, etc. AMPKs regulate lipogenesis genes including, sterol regulatory element-binding protein-1 (SREBP1). Inactivation of AMPK decreases

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Phytochemicals as therapeutic targets of obesity

Figure 4 Lipid metabolism through AMPK regulation.

expression of ACC, FAS, and HMG-CoA reductase which are important enzymes in fatty acid synthesis and cholesterol synthesis [126]. AMPK may also regulate capacity for fatty acid oxidation by phosphorylation of transcription factors such as CREB or co-activators such as PGC-1␣. AMPK is now recognised as a potential target to develop drugs/formulations for effective treatment of obesity and associate ailments (Fig. 4 and Table 5).

Phytochemicals as adipocyte differentiation regulators Adipocytes are the fat cells and lipolytes which play vital role in energy balance and lipid homeostasis in human body. Adipocytes primarily store triglycerides and release them in the form of monoglycerides and free fatty acids based on the energy demand of the body [89]. Adipogenesis is a complex process that includes cell proliferation, cell contact inhibition/growth arrest, clonal expansion, permanent growth arrest and lipid accumulation which are regulated by a cascade of transcription factors. Imperative adipogenic transcription factors responsible for adipocyte differentiation belong to peroxisome proliferator activator receptor family (PPARs) and CCAAT/enhancer-binding proteins (C/EBPs). They are considered to be key regulators of adipogenesis, inducing downstream adipocyte specific gene activation and maintaining the phenotype of adipocytes [148]. Furthermore, the expression of the transcription factor sterol

9 regulatory element binding protein (SREBP-1) also increases PPAR-␥ activity during adipocyte differentiation. AMP activated protein kinase (AMPK) is a key factor that controls cellular energy balance and metabolism. Ca2+ /calmodulin dependent protein kinase kinase 2 (CaMKK2) has been identified to act as an upstream kinases of AMPK and regulates AMPK activity in mammalian cells including adipocytes. Recently, one study reported activation of the CaMKK2—AMPK signalling regulates the early phase of adipogenesis. In addition, AMPK also attenuates SREBP-1, PPAR-␥, and C/EBP-␣ expression to inhibit fat accumulation during adipogenesis. The family of C2H2 zinc-finger proteins includes Kruppel-like factors (KLFs) and KLF15 that regulate apoptosis, proliferation and differentiation. Polyunsaturated fatty acids (PUFAs), vital components of the phospholipids of cell membranes, act as signal transducers regulating adipocyte-specific gene expression involved in lipid metabolism and adipogenesis [149,150]. Currently, 3T3-L1 pre-adipocytes are used as excellent in vitro model to carry out studies on anti-obesity activity of different molecules [151]. Current studies on 3T3-L1 cells reported that cyclic AMP responsive element binding protein (CREB) is necessary and sufficient to induce adipogenesis, whereas silencing of CREB expression blocks adipogenesis. Several transcription factors contain adipogenesis, which include members of the GATA-binding and Forkhead Box families FOXA2 and FOXO1 [152]. In addition there are some cotranscriptional factors playing regulatory roles in adipogenesis. For instance, TRAP220 is a PPAR-␥ binding partner, and the depletion of this protein inhibits the process of adipogenesis. Moreover, some cell cycle regulatory proteins like cyclins and cyclin dependent kinases have also been reported to work as cofactors in adipogenesis [153]. The cyclin dependent kinase-6 (CDK6) complex binds to and phosphorylates PPAR-␥ leading to enhanced expression of PPAR-␥, the master regulator of adipogenesis. In contrast, cyclin D1 represses PPAR-␥ activity and inhibits adipocyte differentiation [152]. Phytochemicals can be researched to target the above said transcriptional and co-transcriptional factors so as to contain obesity. In literature, various phytoconstituents like polyphenols (quercetin, catechin), phytosterols, guggulsterone, tannins (shikimic acid, ellagic acid) and dietary flavonoids (gallic acid) found in green tea, vegetables, fruits, and herbs are reported to downregulate the adipogenesis through transcriptional regulation of PPAR-␥, C/EBP-␣ SREBP-1, coactivator-associated arginine methyltransferase 1 (CARM) leading to inhibition of adipocyte

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10 Table 5

M. Balaji et al. Medicinal plants and their active components that regulate lipid metabolism.

Name of the plant

Used parts

Active component

References

Nelumbo nucifera Curcuma longa L. Commiphora mukul Momordica charantia Cinnamoni cassiae Salacia oblonga C. aronia L. (Rosaceae) Arachis hypogaea Sechium edule Glycyrrhiza Garlic Coffea canephora Cortidis rihzoma L. Sechium edule Morus alba L. C. ceramicus Soybean Phytochemicals Codonopsis lanceolata Phytochemicals

Leaf — Gum

Flavonoids Curcumin Guggulsterones Ethanolic extract Cinnamon Aqueous extract Aqueous extract Arachis hypogaea Aqueous extract polyphenols Licochalcone A S-allyl cysteine Chlorogenic acid Berberine Polyphenols Crude aqueous extract Ceramicines L-Cartine (soy isoflavone) Resveratrol (R), quercetin (Q) Aqueous extract Caffein + arginine + soy isoflavones + L-carnitine CASL Crude ethanolic extract Ethanolic extract/Rutin Crude ethanolic extract Peparine Seed

[108] [127] [128] [129] [130] [131] [132] [39] [133] [134] [135] [38] [136] [137] [138] [139] [140] [141] [142] [143]

Extract

[147]

Solanum tuberosum Centella asiatica (L.) Terminalia panniculata Piper nigrum Black bean (Phaseolus vulgaris L.) B. pandurata

— Root Fruits/leaves Shell Shoots Root Bean Shoots Leaf Seed

Bark Seed

Rhizome parts

differentiation during the early stage [154,155]. Interestingly, tea epigallocatechin gallate (EGCG) and catechins decreased the weight of subjects’ adipose tissue. Moreover, several naturally occurring phytochemicals have displayed apoptotic effects on maturing adipocytes, e.g., capsaicin, resveratrol, piperine, mahanimbidine, esculetin, quercetin, genistein, catechin, epicatechin, ajoene and conjugated linoleic acid-induced apoptosis of maturing 3T3-L1 pre-adipocytes through suppression of Notch pathway, ERK1/2 phosphorylation, activation of the mitochondrial pathway and AMPK activation/antioxidant activity (Table 6) [156—159].

Role of phytochemicals in other mechanisms In hormone sensitive lipase (HSL) (mobilisation of stored fats) Obesity treatment includes dietary restriction of carbohydrates and lipids, and reducing the accumulation of fat in adipocytes. In mammalian tissues free fatty acids are a major source of energy and these are derived from adipose tissue, which is

[144] [145] [62] [125] [146]

the main storage source of triacylglycerols. HSL is responsible for the liberation of free fatty acids from adipose tissue through lipolysis. During late stage of adipogenesis, cAMP-dependent protein kinase activates the HSL, which is also called as LIPE, is an 84-kDa phosphoprotein, a rate limiting enzyme in the catalytic breakdown of triglycerides. The human 775 amino acid form is active in adipose tissue and skeletal muscle. HSL translocates the triglyceride-metabolising lipid droplets in response to epinephrine or contraction in skeletal muscle. HSL functions to hydrolyse the first fatty acid from a triacylglycerol molecule, liberating a fatty acid and diglyceride [194]. It is also known as triglyceride lipase, while the enzyme that cleaves the second fatty acid in the triglyceride is known as diglyceride lipase, the third one that cleaves the final fatty acid is called monoglyceride lipase. Only the initial enzyme is affected by hormones, hence it got hormone-sensitive lipase name. The diand monoglyceride enzymes are tens to hundreds of times faster, hence HSL is the rate-limiting step in cleaving fatty acids from the triglyceride molecule [195,196].

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Phytochemicals as therapeutic targets of obesity Table 6

11

Medicinal plants and their active components that regulate adipocyte differentiation.

Name of the plant

Used parts

Active component

References

Garcina cambogia Chili pepper (Capsicum) Commiphora mukul Cortidis rhizome Glycine max Camellia sinensis Zizyphus jujube Garlic Lagerstroemia speciosa Wasabia japonica Coriolus versicolor Cordyceps militaris Ipomoea batatas Rosmarinus officinalis Curcuma longa Linum usitatissimum Taraxacum officinale

Rind Capsicum Gum

Hydroxycitric acid Capsaicin Cis-guggulsterone Berberine Genistein Epigallocatechin gallate Chloroform fraction Ajoene Ellagitannins Hot water extract Ternatin Mycelia extract Sporamin Carnosic acid Curcumin Secoisolariciresinol Flavonoid-rich Dandelion extracts Anthocyanin Extract n-Hexane, CHCl3 Hot water Dichloromethane Fractionated extract Methanolic extract Methanol Lyophilised juice (LJ) Extract Methanol Ethyl acetate extract Ethanol extract Ethyl acetate extract Methanol extract

[160] [161] [162] [138] [163] [164] [165,166] [167] [168] [169] [170] [171] [172] [173] [174] [175,176] [177] [178]

Glycine max Lindera obtusiloba Morinda officinalis Carthamus tinctorius L. Magnolia officinalis Toddalia asiatica (L.) Cheilanthes albomarginata Clarke Ficus deltoidea var Stellaria media (Linn.) Vill Soy Idesia polycarpa Zingiber officinale Roscoe Olea europaea (L) S. pseudo-lasiogyne Alnus hirsuta f. sibirica

Soybean Green tea Fruit Leaf Leaf Mushroom Root

Flax seed Leaves and roots Black soybeans Root Seeds Bark Stem Leaves Leaves Fruits Rhizomes Leaves Twigs Leaves

HSL is activated when the body requires mobilising energy stores, and so responds positively to ACTH, catecholamines, is inhibited by insulin. Earlier, glucagon was thought to activate HSL; however the removal of insulin inhibitory effects causes its activation. Phytochemicals like Grape seed extracts, Rosemerynus [197,198] extracts and some other plant extracts can be investigated for their possible inhibitory effects on lipases like pancreatic lipase, HSL, lipoprotein lipase and as a means to treat obesity. With more research, combinations of gut hormone analogues possibly found that imitate the effects of bariatric surgery. In gut microbes In recent years, researchers have become more convinced that important hidden players literally lurk in human bowels: millions and millions of gut microbes. The bacterial metabolism of nutrients

[179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193]

in the gut is able to drive the release of bioactive compounds like short-chain fatty acids or lipid metabolites, which interact with host cellular targets to control energy metabolism and immunity. Bacteroidetes and Firmicutes are two main gut microbial communities which play important roles in regulating fat storage and obesity [199]. Phytochemicals like Rhizoma coptidis and berberine have shown gut antimicrobial and anti-obesity activity through decreased polysaccharide degradation, increasing fasting induced adipose factor (Fiaf) and associated gene expressions [200]. Although gut microbes are potential targets, no appropriate drugs that target them have been developed thus far. It is hypothesised that, changes in the microbiome profile ushers an increase in bacterial strains that are more efficient at generating energy, leading to augmented obesity or vice versa. New evidence indicates that gut bacteria alter the way we store fat, how we balance

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12 the levels of glucose in the blood stream and response to hormones that make us feel hungry or full [201]. The wrong mix of microbes, it seems, can assist set the stage for metabolic defects from the moment of birth. Although researchers have known well that the human body is an abode to all kinds of microorganisms, but they come to realise that these microbes greatly outnumber our own cells in 10:1. Advanced gene-sequencing techniques have revealed that a larger and most diverse metropolis of ‘‘microbiota’’ inhabit in gastrointestinal tract (GIT) [202]. This extends the scope for manipulating the gut microbiome that could facilitate weight loss or prevent obesity in humans. The prebiotic and probiotic approaches are presented as fascinating research tools to alter gut microbial profile thereby to study their relevance in the improvement of host metabolism towards containing metabolic disorders [203,204].

Conclusion Although obesity is a complex disorder, it has not received the needed research attention and might be considered a cosmetic issue. But, it cannot be neglected anymore as it predisposes to diabetes, hypertension, CVDs, etc. Over the past three decades, a few drugs have been developed and in use for obesity treatment, but some of them have been withdrawn and at present, even the existing FDA-approved drugs have considerable side effects. This scenario has necessitated researchers to intensify efforts to explore novel and potential therapeutic molecules from natural sources like phytochemicals to contain obesity. In this review a wide variety of plant species, their bioactive compounds and different possible targets to treat obesity have been discussed with latest updates. Our study provides basis to develop novel drugs/formulations that can work on multiple targets with no/minimum side effects to effectively treat or prevent obesity and associated co-morbidities. A better understanding of the basic mechanisms and aetiologies of obesity will lead to better treatment.

Conflict of interest The authors do not have any potential conflict of interest.

M. Balaji et al.

Acknowledgements The authors are acknowledging UGC-42666/2013(SR) Dated 22-03-2013, DBT: BT/PR7799/PBD/17/849/2013 Dated 17/09/2013, and DST: SB/EMEQ/-012/2013 Dated: 29/10/2013, New Delhi, for the financial support.

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Please cite this article in press as: Balaji M, et al. A review on possible therapeutic targets to contain obesity: The role of phytochemicals. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.12.004