Medicinal plants and phytochemicals with anti-obesogenic potentials: A review

Volume 89, May 2017, Pages 1442-1452 Biomedicine & Pharmacotherapy Review Author links open overlay panelRamgopalMopuriMd. ShahidulIslam Biomedical Research Lab, Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa Received 20 December 2016, Revised 27 February 2017, Accepted 28 February 2017, Available online 29 March 2017. crossmark-logo https://doi.org/10.1016/j.biopha.2017.02.108 Get rights and content Abstract Human mortality has been significantly increased in last few decades due to the increased prevalence of obesity and associated chronic disorders such as type 2 diabetes, non-alcoholic fatty liver disease, coronary heart disease and atherosclerosis. Apart from genetic and medicine or drug related side effects, nearly 90–95% people became obese due to the imbalanced calorie intake and lack of nutritional knowledge. The anti-obesogenic drugs, Orlistat and Sibutramine, which have been duly approved by Food and Drug Administration (FDA), USA, work very well on diet-induced obesity however they are not getting popular to the people with overweight/obesity due to the higher cost and severe side effects. In contrast, plant based drugs have been considered as a better alternative due to their lower cost and negligible side effects. A number of medicinal plants and their bioactive constituents have received attention from scientists not only for their anti-obesity activity in vitro and in vivo but also in clinical trials. However, there is no systematic review of data available in the scientific domain in order to guide researchers to conduct further in depth research. In our present review, we differentiated the anti-obesogenic effects of various medicinal plant extracts, fractions and their bioactive compounds at in vitro, in vivo and clinical conditions. During our review, we could also identify the most effective plants with strong anti-obesogenic effects at in vitro or in vivo studies with lack of clinical trials when no one tried to isolate pure bioactive compounds from these plants. Hence, scientific community, government agencies/pharmaceutical industries should work together not only to isolate pure bioactive compounds but also to conduct clinical trials including toxicity to develop better alternative anti-obesity drugs. Graphical abstract Download high-res image (328KB)Download full-size image Previous article in issue Next article in issue Abbreviations Aqp7aquaporin 7 aP2apo protein 2 Apo-Aapolipoprotein A ATGLadipose triglyceride lipase Aebp1adipocyte enhancer binding protein 1 ALTalanine transaminase ASTaspartate transaminase AMPKAMP-activated protein kinase CATcatalase ACCacetyl-CoA carboxylase AUCarea under the curve C5L2C5a like receptor 2 CPT-ILcarnitine palmitoyl transferase CYP7A1cholesterol 7α-hydroxylase C/EBPaCCAAT/enhancer-binding protein a CPT-1carnitine palmitoyl transferase-1 DGATdiacylglycerol acyltransferase FASfatty acid synthase FABP2fatty acid binding protein2 FGF-2fibroblast growth factor2 GDPHglyceraldehyde 3-phosphate dehydrogenase GLUT4glucose transporter type 4 GPxglutathione peroxidase HDLhigh density lipoproteins HSLhormone sensitive lipase HMG-Co AR3-OH-3-methylylutaryl coenzyme A reductase Lepleptin LDLlow density lipoproteins LPLlipoprotein lipase IL6interleukin 6 MCP-1monocyte chemoattractant protein-1 MDAmalonaldehyde MMP-2matrix metalloproteinase-2 NF-kβnuclear factor-kappa-β OGTToral glucose tolerance test PDEphosphodiesterase PGC-1αperoxisome proliferator-activated receptor-gamma coactivator-1 α TGHtriglyceride hydroplase PPAR γperoxisome proliferators activated receptor γ PPARcperoxisome proliferator-activated receptor c ROSreactive oxygen species SREBP 1csterol regulatory element-binding protein-1c SODsuperoxide dismutase TSPthrombospondin TIMPtissue inhibitors of metalloproteinases TNFαtumor necrosis factor α UCP3uncoupling protein 3 VLDLvery low density lipoproteins VEGF-Avascular endothelial growth factor A Keywords Obesity Medicinal plants Bioactive compounds In vitro In vivo Clinical 1. Introduction Obesity is a severe metabolic disorder and well known risk factor for a number of life style related chronic diseases. Usually it develops due to the imbalance of energy consumption versus energy expenditure, lack of nutritional knowledge and characterised by the accumulation of excess fat in adipose tissue, which is associated with a number of chronic diseases such as type 2 diabetes, hypertension, coronary heart disease, hyperlipidemia, cancer and so on [1,2]. On a global scale, obesity is an epidemiological problem and a major contributor to the global burden of non-communicable chronic diseases and disability. According to the recent data from World Health Organization (WHO), more than 1.9 billion adults worldwide are overweight and at least 600 million of them are clinically obese [3]. Obesity will be a cause of major global medical expenditures over the next 25–50 years since the numbers of global overweight people have been tripled in last 30 years [4]. The prevalence of obesity and overweight individuals is highest in the USA (26% obese and 62% overweight in both sexes) when lowest rate of obesity (3%) and overweight (14%) has been observed in south-East Asia [4]. Over 50% people are either overweight or obese in India, Indonesia, Pakistan, Russia, Mexico, Brazil, Egypt, South Africa, Europe, the Eastern Mediterranean, and Americas [5]. Nearly half to quarter of the women are obese in South Africa, Europe, the Eastern Mediterranean and USA (42%, 23%, 24% and 29% respectively) [4,5]. According to recently and previously published epidemiological studies [6,7], genetic, metabolic, social, behavioural and cultural factors are involved in the rapidly increasing prevalence of obesity [8,9]. Although medical community is aware of the various health risks concerning obesity [10], every year, the number of people with obesity is increasing around the world for past few decades. The obesity has been observed in the people those who consume more daily calories compared to their requirement [11]. Over consumption of calories causes the rapid growth of adipocytes in humans and animal systems by impairing the function of neural palpation (brain) and causing leptin resistance [12]. It is very well known that the number and size of adipose tissue can be regulated by the inhibition of adipocyte generation from precursor cells and inhibition of adipocyte development to control the adipocyte size. Obesity is usually induced by the increased size of adipocytes and by recruiting new adipocytes from precursor cells. These two processes are fully dependent on the regulation of the adipocytes differentiation [13] and most of the anti-obesogenic drugs are developed based on these mechanisms. Mainly two different types of anti-obesogenic drugs are currently available in the market [14]. One of these is orlistat, which reduces intestinal fat absorption through inhibition of pancreatic lipase activity [15–18] (Table 1) and the other one is sibutramine, which is an anorectic or appetite suppressing drug [19–21]. Both drugs have been reported to have side-effects including blood pressure induction, dry mouth, constipation, headache, and insomnia [22–24,18] and these drugs are not affordable for the people particularly in the developing countries. Although a number of new anti-obesity drugs are currently under clinical trial, including centrally-acting drugs (e.g. radafaxine and oleoylestrone), drugs targeting peripheral episodic satiety signals (e.g. rimonabant and APD356) and drugs blocking fat absorption (e.g. cetilistat and AOD9604) [25] (Table 1), they still need to be approved by FDA based on the results of clinical trials. Hence, the demand of natural anti-obesity drugs has been increased in the recent years not only due to their lower side effects but also for their lower cost. A huge number medicinal plant parts and their extracts, fractions and isolated pure compounds have been investigated to examine their anti-obesity activity and possible mode of actions (Figs. 1 and 2). However, there is no intensive review is written in order to further evaluate and summarise their anti-obesity efficacy. Table 1. Pharmaceutical drugs and their effects on obesity. Drug class Mechanism of action Example Side effects Reference HMG-Co A Reductase enzyme inhibitor Lowering total LDL by inhibiting cholesterol biosynthesis Atorvastatins, fluvastatin, lovastatin, Simvastatin Congestive cardiac failure. Halford [25] Fibrates Enhancing activity of enzyme lipoprotein lipase Gemfibrozil, Fenofibrate Upper gastrointestinal disturbance, headache, myalgia. Halford [25] Nicotinic acid Derivative Inhibit lipolysis within adipocytes Niacin Hyperglycemia, increase uric acid. Halford [25] Bile acid Sequestrants (Resin) Bind with bile acid and promote bile acid excreation Cholestipole, Cholestyramine Abdominal fullness, constipation Halford [25] Lipase Reduces intestinal fat absorption through inhibition of pancreatic lipase Orlistat GI symptoms (oily spotting, flatus with discharge, fecal urgency, oily stools incontinence) Thurairajah et al. [18], Karamadoukis et al. [23] HMG-Co A Reductase enzyme inhibitor Central: Inhibits synaptic reuptake of nor epinephrine and serotonin Sibutramine Dry mouth, constipation, headache,insomnia, increased blood pressure De et al. [22] Slovacek et al. [24] Fig. 1 Download high-res image (458KB)Download full-size image Fig. 1. Phytochemical compounds and their mode of actions. Fig. 2 Download high-res image (2MB)Download full-size image Fig. 2. Structural futures of plants and their bioactive anti obesogenic compounds. Hence, the principle aim of the present review was to evaluate the anti-obesity efficacy of various medicinal plant parts and their extracts, fractions and isolated pure compounds which have been published in last decay or during January 2006–May 2016. 2. Literature review method PubMed, Science direct, Medline, Scopus, Google scholar, Iran Medex, Web of Science databases were searched from January 2006 to May 2016 to collect relevant data for this review study. The search terms or keywords obesity; high fat diet; medicinal plants; anti-obesity; bioactive compounds; folk medicines for obesity; traditional medicines; anti hyperlipidemic; and hypolipidemic were used either alone or in combination to search the articles. The publications with available abstract and/or full text were reviewed for this study along with few existing reviews. The anti-obesity effects of the different plant parts and their extracts; fractions or isolated pure compounds were characterised by evaluating various parameters including body weight; lipid profile; oxidative stress related factors; liver metabolism and expression of obesity related genes. Medicinal plants are defined in this review as crude extracts; bio active compounds isolated from various parts of plants along with bio assay guided fractions of respective medicinal plants and their activity on in vitro; in vivo and clinical studies. Although this study is not limited to a specific geographical area; most of the plants included in the study are native to Asian and African countries. 3. Results and discussion A number of studies showed that natural food ingredients such as spices, pulse or green legumes, cereals and various parts of medicinal plants were used as remedies for obesity in most of the studies. The botanical medicines are a heterogeneous collection of wide variety of non-volatile and volatile phytochemicals obtained from dried parts of plants such as leaves, stem bark, roots, fruits and seeds. Many scientific reports proved that crude extracts, fractions and bioactive compounds from the plants are able to suppress appetite, body weight, regulate fatty acid and carbohydrate metabolism, and ameliorate fatty liver problems and adipogenesis [26]. As per our search, most of the studies were conducted either in vitro or in animal-based in vivo studies when very few of them were conducted at clinical level. In this review, we tried to discuss the anti-obesity effects of various medicinal plants individually at in vitro and in vivo studies when a very few medicinal plants were studied up to clinical level. 3.1. In vitro studies Most of the in vitro studies were conducted via enzyme inhibition assay and using cell culture techniques which poses more advantage not only due to less chemical usage but also due to the early determination of the efficacy of drugs or plant compounds. Many medicinal plants were exposed to scientific world via identifying their anti-obesogenic activity only by in vitro methods (Table 1). Nelumbo nucifera belongs to the family of nymphaeaceae shown to decrease the activity of pancreatic lipase and amylase in vitro at a dose of 0.46 mg/ml or 0.82 mg/ml [27]. N. Nucifera exposed to 3T3-L1 adipocytes cell lines at a concentration of 500 μg/ml shown to increase glycerol levels and up regulated the UCP-3 gene expression in 3T3-L1adipocytes cell lines [27]. The alkaloids rich fraction (2 μg/ml) isolated from N. Nucifera was also reported to increase glucose consumption in 3T3-L1 adipocytes cell lines [28]. Water extract of Wasabia japonica 333–1333 μg/ml [29] shown to decrease triglycerides accumulation, glycerol 3-phosphate dehydrogenase (GPDH) activity and down regulated the PPARγ, C/EBPα and aP2 in 3T3-L1 cell lines. Boussingaulti gracilis Miers var. pseudobaselloides Bailey ethanolic extract at a concentration of 10, 50 and 100 μg/ml was shown to decreases lipid accumulation in adipocytes and down regulated the PPARγ, C/EBP-α expression, up regulated the AMPK-1α and Acetyl CoA-corboxylase at in vitro [30]. Crude Saponins (Ginsenosides) isolated from the fractions of Panax quinque folius[31], Protopanaxdiol Ginsenosides of P. quinque folius L [32] showed the inhibition of in vitro pancreatic lipase activity at a concentration of 0.25-1.00 mg/ml. The water extract of Sida rhombodea (10–200 μg/ml) was reported to inhibit lipogenesis, decreases leptin and triglyceride accumulation and down regulated the Glyceraldehyde 3-phosphate dehydrogenase (GPDH) activity in adipocyte cell lines [33]. Desacylescins, deacetylescins and escins saponins isolated from the seeds of Aesculus terbinata Blume showed a strong inhibitory action toward the activity of pancreatic lipase at a concentration of 400 μM/ml or 1 mg/ml in vitro [34,35]. Saponins rich extracts of Cassia tora seeds at a concentration of 1 μg/ml was also shown to decrease triglycerides uptake in 3T3-L1 cell lines [36]. Ursolic acid (51.21 μM) isolated from the roots of Actinidia arguta[37,38], Panax ginseng Saponins (500 μg/ml) isolated from Panax japonicus[39] have shown pancreatic lipase and phosphodiesterase inhibitory action in addition to increasing lipolysis activity in vitro (Table 2). Atractylodes macrocephala[40] at a concentration of 1–25 μg/ml resulted in inhibition of adipocytes differentiation, decreased triglyceride accumulation and down regulated the expression of adipogenic genes. Based on the results of the above-mentioned studies, most of the studies were conducted to examine the effects of plant extracts or fractions on adipocyte differentiation, pancreatic lipase activity, triglycerides uptake and accumulation, GPDH activity, lipolysis and lipid metabolism related gene expression. Although, potential activities were confirmed from the in vitro experimental results, they are not fully acceptable to prepare drugs. However, anti-obesity activities of some plants were continued up to in vivo level, which is discussed below. Table 2. In vitro activities of potential medicinal plants against obesity. Plant Family Part used Extract/fraction Dose In vitro (Enzyme inhibition/cell line) Activity Reference Nelumbo nucifera Nymphaeaceae Leaves Ethanol 0.46 mg/ml Enzyme inhibition Inhibition of Lipase and α-amylase Ono et al. [27] 500 μg/ml 3T3-L1 adipocytes ↑Release of glycerol levels ↑UCP3 Ono et al. [27] Leaves Alkaloids 2 μg/ml 3T3-L1 adipocytes ↑Glucose consumption Ma et al. [28] Seeds Ethanol 100 μg/ml Human adipocytes – Inhibition of lipid accumulation Jeong et al. [41] Terminalia sericea Combretaceae Root Sericoside 0.001–0.003% 3T3-L1 cells – Stimulated glycerol into the cytosol from deposited TG Muchizuki et al. [42] Afromomum meleguetta Zingiberaceae Seeds 70% ethanol 0.75–2 mg/ml Enzyme inhibition – Inhibit pancreatic lipase Ekanem et al. [43] Spilanthes acmella Compositae Flower buds 70% ethanol 0.75–2 mg/ml Enzyme inhibition – Inhibit pancreatic lipase Ekanem et al. [43] Panax japonicus Araliaceae Rhizome Saponins 500 μg/ml Enzyme inhibition – Inhibited pancreatic lipase activity Karu et al. [39] Platycodon grandiflorum A. Campanulacae Herb Water Dose dependent Enzyme inhibition 3T3-L1 pre adipocytes – Inhibited pancreatic lipase activity, ↓pre adipocyte differentiation Park et al. [44] Garcinia cambogia Clusiaceae Fruit rind Hydroxycitric acid – Pre adipocytes – Lipase inhibition, ↑leptin and ↓adipogenic genes Roy et al. [45] Aesculis turbinata Blume Sapindaceae Seed Saponins (desacylescins, deacetylescins, escins) 400 μM/ml Enzyme inhibition – Inhibited pancreatic lipase activity Kimura et al. [34] Seeds Escins 1 mg/ml Enzyme inhibition – Inhibited lipase activity Hu et al. [35] Actinidia argute Actinidiaceae Root Ethyl acetate (Triterpenes) – Enzyme inhibition – Inhibition of pancreatic lipase Jang et al. [37] Ursolic acid 51.21 μM Rat fat cells ↓Phosphodiesterase, ↑Lipolysis Kim et al. [38] Penax quinquefolius Araliaaceae Leaves Crude saponins (Ginsenosides) 0.5 mg/ml Enzyme inhibition – Inhibition of pancreatic lipase Liu et al. [31] Protopanaxdiol Ginsenosides 0.25–1 mg/ml Enzyme inhibition – Inhibition of pancreatic lipase Liu et al. [32] Rhizoma Alismatis Alismataceae Herb Crude extract 0.1 mg/ml 3T3-L1 cells ↓Triglycerides, ↑Apo-A Guo et al. [46] Morus bombycis Moraceae Root Ethyl acetate 2.07 μg/ml 3T3-L1 cells ↓Lipase activity, intracellular TG, PDE Kim et al. [47] Grape Vitaceae Seeds Polyphenol rich – Human adipocytes – LPL inhibition, ↓adipocyte differentiation, TNFα, MAPK, IL-6 Overman et al. [48] Wasabia japonica Matsum Brassicaceae Leaves Water extract 333,667,1333 μg/ml 3T3-L1 cells ↓TG accumulation, GPDH, ↓PPARγ, C/EBPα, aP2 Ogawa et al. [29] Atractylodes macrocephala koidzumi Compositae Rhizome Aqueous 1–25 μg/ml 3T3-L1 adipocytes cells ↓Adipocytes differentiation, Phospho-Akt Kim et al. [40] Hippophae rhamnoides Elaeagnaceae Leaves Pentamethylquercetin 10 μM 3T3-Li adipocytes ↑Adiponectin, ↓PPARγ, TNFα, IL-6 Chen et al. [49] Sida rhomboidea Malvaceae Leaves Water 10–200 μg/ml 3T3-L1 cells – Inhibited adipogenesis ↓Leptin, Triglyceride accumulation, GDPH Thounaojam et al. [33] Boussingaulti gracilis Miers var. Basellaceae Leaves Ethanol 10,50, 100 μg/ml 3T3-Preadipocytes ↓Lipid accumulation, ↓PPARγ, C/EBP-α, SREBP-1c, ↑AMPK, Acetyl Co-A carboxylase Kim and Choung [30] Curcuma longa L. Zingiberaceae Rhizome Ethyl acetate fraction 20 μg/ml 3T3-L1 adipocytes Cellular glucose, GLUT4, TG, HSL Lee et al. 2010 Curcumin 10–20 μM 3T3-L1 adipocytes ↓TNFα, Periling protein Xie et al. [50] Ethanol IC50 5.2 μg Enzyme inhibition −Lipase inhibition. Sun et al. [51] Boesenbergia pandurate Gingiberaceae Rhizome 90% Ethanol 25 μg/ml 3T3-L1, HePG2 cells ↓TG accumulation, ACC, FAS, SREBP-1c, PPARγ, ↑PPARα, UCP, PGC-1α, CPT-1L Kim et al. [52] Rhizoma polygonati falcatum Asparagaceae Rhizome Kaempferol 200–600 μg/ml 3T3-L1 cells ↓Adipocytes differentiation, ↓PPARγ, SREBP-1c, Rxrβ, Lxrβ, Rorβ, Gpd1, Agpat2, Dgat2, ↑TNFα, Lsr, Cel Park et al. [53] Sasa quelpaertensis Graminceae Leaves P-coumaric acid 1000 μg/ml 3T3-L1 cells ↓C/EBP α, PPARγ, SREBP-1c, aP2, FAS, ↑AMPK, ACC, CPT-1 Kang et al. [54] Terminalia bellirica Combretaceae Fruit Aqueous 65.7 μg/ml Enzyme inhibition – Pancreatic lipase inhibition Makihara et al. [55] Allium sativum L. Amaryllyda-acae Garlic Thiacremonone – 3T3-L1 cells ↓Adipogenesis, ↑AMPK Kim et al. [56] Crude extract – Enzyme inhibition – Lipase inhibition Ado et al. [57] Cassia tora Caesulipinceae Seed Ethanol 1 μg/ml 3T3-L1 cells ↓Triglycerides Tzeng el al. [36] Tecomella undulata Bignoniaceae Bark Ethyl acetate (Ferulic acid and rutin) 10, 25, 50 μg/ml 3T3-L1 fibroblast cells ↓Adipogenesis, lipogenesis, ↑SIRT1, adiponectin, ↓LPL PPARγ, C/EBP α, leptin Alvala et al. [58] Hippophae rhamnoides L. Elaeagnaceae Seeds Flavonoglycosides hippophaeosides – 3T3-L1 cells ↓Triglyceride, Adipocyte differentiation Yang et al. [59] Taraxacum officinale Asteraceae Leaves 90% Ethanol 250 μg/ml Enzyme inhibition – Lipase inhibition Zhang et al. [60] 60% ethanol (chlorogenic acid, caffeic) 300, 450, 600 μg/ml 3T3-L1 cells ↓Triglyceride, lipids accumulation, – regulate gene expressions Marta et al. [61] Ficus deltoidea (var. deltoidea var. deltoidea) Moraceae Leaves Methanol and water 150–400 μg/ml 3T3-L1 adipocytes – Inhibit adipogenesis Woon et al. [62] Centella asiatica Apiaceae Leaves Aqueous – Enzyme inhibition ↓Pancreatic lipase, ↓α-amylase Supkamonseni et al. [63] Coccinia grandis L. Voigt Cucurbitaceae Root Ethanol 500, 1000 μg/ml 3T3-L1 cells ↓Intracellular fat accumulation, ↓PPARγ, C/EBP α, FAS, LPL, GLUT4 Bunkrongcheap et al. [64] Hyrpagophytum procumbens Pedaliaceae Root Aqueous 1 mg/ml HeK cell ↑Cellular calcium influx Cristina et al. [65] Punica granatum Lythraceae Peel extract Essential oil 30 μg/ml Enzyme inhibition – Antioxidant and inhibition of lipase Hadrich et al. [66] Coccinia grandis Cucrbitaceae Root Hexane fraction 500–1000 μg/ml 3T3-L1 adipocytes – ↓PPARγ, inhibition of adipocyte differentiation Ruthaiwan et al. [67] Terminalia paniculata Combretaceae Bark Ethanol 200 μg/ml Enzyme inhibition – Lipase inhibition Mopuri [68] Alismatis rhizoma Alismataceae Rizhome Ethanol 20–40 μg/ml OP9 cells ↓PPARγ, C/EBPβ, FAS aP2, Atg7 and Atg12 Park et al. [69] Ligustrum robustum Oleaceae Leaves Crude extract 37.18 μg/ml Enzyme inhibition – α glucosidase inhibition Yu et al. [70] Vitis thunbergii Vitaceae Root Ethyal acetate fraction (vitisin B, vitisin A) IC50 1.02, 1.22 μM Enzyme inhibition – Glucosidase and lipase inhibition Lin et al. [71] Doratoxylon apetalum Sapindaceae Leaves Polyphenol rich 25 μM 3T3-Preadipocytes ↓ROS production, IL6, MCP-1, TNF-α, LPL, ↑SOD expression and ↓NF-kB expression Marimoutou et al. [72] Gouania mauritiana Rhamnaceae Leaves Polyphenol rich 25 μM 3T3-Preadipocytes Antirhea borbonica Rubiaceae Leaves Polyphenol rich 25 μM 3T3-Preadipocytes Tecoma stans Bignoniaceae Leaves Chrysoeriol and other polyphenols 158 μM Enzyme inhibition – Lipase inhibition Ramirez et al. [73] Melissa officinalis Lamiaceae Leaves Ethyl acetate fraction 10 μg/ml 3T3-L1 cells ↓Lipid accumulation, VEGF-A, FGF-2, MMP-2, MMP-9, ↑TSP-1, TIMP-1, TIMP-2 Woo et al. [74] 3.2. In vivo studies Based on the results of in vitro studies some most potent anti-obesogenic plants were continued to study at in vivo levels by using various animal models (Table 3). The flavonoid rich fraction of N. nucifera[75] and hot water extract of N. nucifera in combination with taurine [76] at oral dosages of 400 mg or 1.2 g/kg bw or 0.5-1.5% in diet resulted in lower adipose tissue weight, hepatic TG and up regulation of UCP3 gene in ICR mice. Ethanolic extract and flavonoid rich fraction of Perilla frutescens at 1–3% dietary dose or 50–200 mg/kg bw have been shown to decrease body weight, food efficiency, body fat mass, lipid profiles, in addition to the down regulation of PPARγ, ACC, GPDH activity in C57BL/J mice [77]. Boussingaulti gracilis Miers var. pseudobaselloides Bailey ethanolic extract at a dose of 300–900 mg/kg bw shown to decrease bw, levels of serum and hepatic lipids and down regulated the PPARγ and C/EBP-α gene expression and up regulated the expression of AMPK-1α, UCP-2, PPARα in SD rats [30]. Protopanaxdiol Ginsenosides of P. quinque folius L [32] at a composition of 0.05% (w/w) in diet shown to decrease body weight, plasma lipid profiles in Kunming mice. Oral administration of the water extract of Sida rhombodea (10–200 μg/ml) was reported to inhibit lipogenesis, decreases leptin and triglyceride accumulation and down regulated the GPDH activity in mice [33]. Table 3. In vivo studies of potential medicinal plants against obesity. Plant Family Part used Extract/fraction Dose In Vivo Activity Reference Nelumbo nucifera Nymphaeaceae Leaves Leaves 1.2 g/kg bw ICR mice ↓Adipose tissue weight, ↓liver triacylglycerol levels, ↑UCP3 expression Ono et al. [27] Flavonoid rich extract 0.5–1.5%/kg bw C57BL/6Mice ↓Body weight, ↓TG, TC, ↓FAS Acetyl-CoA carboxylase, HMG-CoA, ↑AMPK kinase Wu et al. [75] Hot water extract and taurine 400 mg/kg bw SD Rats ↓Body weights, ↓adipose tissue, ↓Total cholesterol, TG, LDL and ↑HDL Du et al. [76] Seeds 400 mg/kg bw SD Rats ↓body weights, leptin, PPARγ, GLUT4 Jeong et al. [41] Salacia oblonga Celastraceae Root Aqueous 100 mg/kg bw Zucker rats ↓Plasma and cardiac TG, FA, ↓FA transport protein-1, Heart PPARα, CPT-1, Acyl-Co-A oxidase, ↑ACC Huang et al. [82] Aqueous 50 mg/kg bw Wistar rats ↓blood glucose, serum TG, TC, ↑insulin, HDL Bhat et al. [83] Coccinia grandis Cucrbitaceae Leaves Polyphenol 10, 25, 50 mg/kg bw Golden Syrian hamster ↓Serum TG, TC, glycerol Singh et al. [84] Punica granatum Lythraceae Leaves Leaf extract 400, 800 mg/kg bw ICR mice ↓Body weight, energy intake, fat pad weight, ↓Serum TG, TC, glucose Lei et al. [85] Panax japonicus Araliaceae Rhizome Saponins 3%/kg bw Balb/c mice ↓Body weight, adipose tissue weight, ↑Fecal TG, ↓Plasma TG, lipase activity Karu et al. [39] Garcinia cambobia Clusiaceae Seeds Ethanol 200, 400 mg/kg bw Wistar rats ↓Enterobacter in caecal. ↑RBC count, ↓Body weights, ↓TG, VLDL, LDL, ↑HDL Oluyemi et al. [86] Fruit Water extract 400 mg/kg bw Wistar rats ↓Body weights, Glucose intolerance, Plasma leptin, TNF α Sripradha et al. [87] Lagerstroemia speciosa Lythraceae Leaves Corosolic acid 0.023% KK-Ay mice ↓Body weight, total fat%, ↓Plasma TG, TC, ↑Insulin sensitivity, adiponectin, AdipoR1, PPAR α and γ Yamada et al. [88] Platycodon grandiflorum A. Campanulaceae Herb Water 150 mg/kg bw SD Rats ↓Body weight, TC, TG, adipose tissue, ↓FABP↑ LPL, Leptin Park et al. [44] Root Saponins (Platycodins) 10.9–1% Golden hamsters ↓TC in plasma and liver, ↑Feces TC Zhao et al. [89] Taraxacum officinale Asteraceae Leaves 90% ethanol 250 μg/ml ICR mice ↓Plasma triglycerides, AUC of plasma Zhang et al. [60] Aesculus turbinata Blume Sapindaceae Seeds Saponins (desacylescins, deacetylescins, escins) 0.5%/kg bw ICR mice ↓Body weight, adipose tissue, ↓plasma TG Kimura et al. [34] Seeds Escins 2%/kg bw ICR female mice ↓Body weight, Adipose weights, ↓plasma TG, liver TG, TC Hu et al. [35] Seed shells Polymeric proanth-ocyanidins 0.26, 052% kg bw ICR mice ↓Body weights, adipose tissue, ↓plasma TC, leptin ↓OGTT. Kimura et al. [78] Actinidia arguta Actinidiaceae Root Ursolic acid 100 mg/kg bw Wistar rats ↓Plasma TG, FFA Kim et al. [38] Grape (Vitis vinifera) Vitaceae Seeds Procyanidins 345 mg/kg bw Male Zucker fa/fa rats ↓Plasma CRP, TNF α, IL6, ↑Adiponectin, GSH Terra et al. [90] Seeds Crude extract 500 mg/kg bw Wistar rats ↓Body weights, adipose tissue, relative heart weight, plasma CRP, ↑plasma free ions – regulate heart rate, ↓TG, TC, phospholipids, apo B, Myocardial ↓MDA, ↑GPx SOD, CAT Charradi et al. [91] Seeds and skin Phenolic compounds 500 mg/kg bw Wistar rats ↓Brain phospholipids, cholesterol, ↓MDA, carbonyl protein, ↑Reducing powder, GPx, SOD, ↓Brain NO, and calcium Charradi et al. [92] Perilla frutescens Labiatae Leaves 70% ethanol 11–3%/kg bw C57BL/6J mice ↓Body weight, food efficiency ratio, fat mass, ↓Plasma TG, TC, LDL, ↓PPARγ, ACC, GPDH Kim et al. [93] Leaves Alkaloids Flavonoids 50–200 mg/kg bw SD rats ↓Serum cholesterol, TG, LDL, adipose tissue lipid, ApoB, accumulation, ↑HDL, ApoA, ↑SOD, CAT and ↓MDA levels Feng et al. [77] Seeds Apigenin 10 mg/kg bw C57BL/6J ↑POMC, CART, ↓Food intake Myoung [96] Panax quinquefolius L Araliaaceae Leaves Crude saponins (Ginsenosides) 1 g/kg bw Female ICR mice ↓Body weights, ↓Plasma TG, adipose tissue weights Liu et al. [31] Protopanaxdiol Ginsenosides 0.05%/kg bw Kunming mice ↓Body weights, adipose weight, ↓Plasma TG Liu et al. [32] Glycyrrhiza glabra Fabaceae Root Glycyrrhizic acid 50 mg/kg bw SD rats ↑Lipoprotein lipase, HDL, ↓adipocyte size, FFA, TC, TG, LDL Lim et al. [94] ” 100 mg/kg bw SD rats ↓Blood glucose, Serum FFA, TC, LDL, ↑HDL insulin sensitivity, lipoprotein lipase Eu et al. [95] Peucedanum Japonicum Umbelliferae Leaves Crude powder 0–20%/kg bw C57BL/6J mice ↓Body weight, ↓Serum TG, leptin ↓hepatic TG, saturated fatty acids, ↑unsaturated fatty acid, n-3 fatty acids, ↓FAS, ↑Carnitine palmitoyl transferase Okabe et al. [97] Houttuynia cordata Saururaceae Leaves Water extract 1000 mg/kg ddY mice ↓Plasma TG, TC, hepatic TG, TC, glycerol, NEFA Miyata et al. [98] Murraya koenigii Rutaceae Leaves Ethyl acetate 300 mg/kg bw SD rats ↓Body weight, plasma TC, plasma TG, blood glucose Birari et al. [99] Mehanimbine 30 mg/kg bw Corchorus olitorius L. Tiliaceae Leaves Group of polyphenols 1–3%/kg bw LDLR-/-mice ↓Body weight, liver TG, liver weights, ↓NOX2, ↑PPAR α, CPT1A Wang et al. [100] Hippophaerhamnoides Elaeagnaceae Seeds Total flavonoids 50, 100, 150 mg/kg bw ICR mice ↓Body, liver, fat pad weights, ↓Serum TC, LDL, liver TG, TC, serum glucose Wang et al. [101] Sida rhomboidea. Malvaceae Leaves Water 1%/kg bw C57BL/6J ↓Body weight, food intake, ↓plasma lipids, leptin, ↓PPARγ2, FAS, SREBP1c, LEP, ↑CPT-1 Thounaojam et al. [33] Terminalia arjuna Combretaceae Bark Ethanol 200 mg/kg bw Rabbits ↓Serum TC, TG, LDL, AI, ↑HDL Subramaniam et al. [102] Atractylodes macrocephala koidzumi Compositae Rhizome Aqueous 0.5 g/kg bw SD rats ↓Body weight, plasma TG Kim et al., [40] Boesenbergia pandurata Gingiberaceae Rhizome 90% Ethanol 200 mg/kg bw C57BL/J6 ↓Body, fat pad weight, ↓serum TC, LDL, TG, hepatic TG, ↑AMPK Kim et al. [52] Aloe vera Xanthorhceae Leaves Water 200 mg/kg bw SD rats ↓Body weight, fat%, visceral fat weight, ↓Serum lipid levels, ↑energy expenditure Misawa et al. [103] Boussingaulti gracilis Miers var. pseudobaselloides Bailey Basellaceae Leaves Ethanol 300, 600, 900 mg/kg bw SD rats ↓Body weights, fat pad weights, ↓serum and hepatic lipids, ↑PPARα, Acyl-CoA, UCP-2, ↓SREBP-1c, PPARγ Kim and Choung [30] Chinchona bark Rubiaceae Bark Chinchonine 0.05%/kg bw C57BL/6N ↓Body weight gain, visceral fat, plasma TG, FFA, TC, glucose, ↓WNT10b, galanin mediated signalling molecules and key adipogenesis genes, ↓TLR2, TLR4 mediated signalling cascades Jung et al. (2012) Hippophae rhamnoides Elaeagnaceae Leaves Ethanol 500,1000 mg/kg bw C57BL/J6 ↓Body weights, energy intake, fat pad weights, ↓Serum TC, leptin, ↓Hepatic TC, ↑ PPAR α, PPARγ, CPT-1 ↓ACC Pichiah et al. [104] Jaboticaba (Myrciaria spp) Myrtaceae Peel Freeze dried (anthocyanins) 1, 2, 4%/kg bw SD rats ↓Serum glucose, serum insulin, HOMA-IR, ↑HDL Lenquiste et al. [105] Terminalia bellirica Combretaceae Fruit Aqueous 1–3%/kg bw ddY mice ↓Body weight, ↓HOMA-IR, plasma TG, TC, liver TG, TC Makihara et al. [55] Cinnamomum verum Lauraceae Dried Cinnamaldehyde 0.1–1%/kg bw C57BL/6J ↓Body weight, mesenteric adipose tissue, ↑UCP1 Tamura et al. [106] Portulaca oleracea L Portulacaceae Herb Ethanol 200, 400, 800 mg/kg bw Rats ↓Serum TC, TG, LDL, ↑HDL Saeed et al. [107] Cinnamomum cassia Lauraceae Bark Water extract 5%/kg bw C57BL/J6 ↓Body weight, liver and adipose tissue weights, ↓Leptin, PPARγ, C/EBPα, SREBP-1c, ↑PPAR α, Adiponectin Yamasaki et al. [108] Wasabia japonica Matsum Brassicaceae Leaves Adenophora triphylla Campanulacae Root Ethanol 0.1–0.5%/kg bw C57BL/6J mice ↓Body weight, adipose tissue, ↓AST, ALP, ALT, TG, TC, LDL, glucose, ↑HDL, AMPK adiponectin, PPAR α, ↓GPDH, PPARγ, TNF α Lee et al. [109] Bombax ceiba Bombacaceae Bark Methanol 200, 400 mg/kg bw Wistar rats ↓Body weight, LEE indices, serum glucose, TG, LDL, VLDL, FFA, ALT, AST, TBARS Gupta et al. [110] Cassia tora Caesulipinceae Seed Ethanol 100, 200, 300 mg/kg bw Wistar rats ↓Body weights, adipose tissue, plasma TG, TC, LDL, FFA, ↑HDL, ↑AMPK, CPT-1, ↓ACC SREBP-1c, FAS Tzeng et al. [36] Tecomella undulata Bignoniaceae Bark Ferulic acid and rutin 100, 200 mg/kg bw Mice ↓Lipid profiles, glucose levels Alvala et al. [58] Holoptelea integrifolia (Roxb) Ulmaceae Bark Methanol 200, 400 mg/kg bw SD rats ↓Body weight, serum lipid profiles, apo B, ↑HDL, apo A1, LCAT, fecal lipids Subash et al. [111] Dysoxylum binectariferum Meliaceae Bark Rohitukine 50 mg/kg bw Charles foster strain ↓Plasma lipid profiles, ↑HDL Mishra [112] Magnolia grandiflora Magnoliaceae Bark Ethanol 2.5–10 mg/kg bw C57BL/6J mice ↓TNF α, plasminogen activator inhibitor 1,3-nitrotyrosine,4-hydroxy-2-nonenal, ↑PGC-1α, hexokinase II Cui et al. [113] Ethanol 5–10 mg/kg bw C57BL/J mice ↓Insulin resistance, cardiac lipids accumulation, cardiac inflammation, oxidative stress down regulating ICAM1, TNF α, PAI-1, 3-NT, 4-HNE Sun et al. [114] 4-O-Methylhonokiol 0.5–1 mg/kg bw C57BL/J mice ↓Body weight, plasma and hepatic lipid profiles, ALT, insulin resistance Zhang et al. [115] Ficus carica Moraceae Leaves – 100 mg/kg bw SD rats ↓Lipid profiles, ↓Adhirognic risk factors, ↓IL-6, ↑HDL Joerin et al. [116] Allium sativum L. Amaryllydacae Stem Ethanol 100, 250, 500 mg/kg bw C57BL/J6 mice ↓Body weight, adipose cell size, leptin, ↑Adiponectin, ↓Serum TC, HOMA-IR, insulin, liver TG, TC, FAS, HMG-Co-A, G6PDH, ↑Feces TG, SOD, GST, GPx, GSH, ↓MDA Kim et al. [117] Garlic Garlic oil 25,50,100 mg/kg bw C57Bl/6J ↓Release of pro-inflammatory cytokines in liver, ↑antioxidant capacity, ↓ACC, FAS SREBP-1c, HMG-CoA, ↑PPAR α, CPT-1 Lai et al. [118] Centella asiatica Apiaceae Leaves Aqueous 2 g/kg bw SD rats ↓Plasma glucose, ↓total cholesterol, TG levels Supkamonseni et al. [63] Ligustrumn lucidum Oleaceae Fruit Secoiridoid (8-E)-nuzhenide 30 mg/kg bw C58BL/J6 ↓Body weights, ↓food efficiency ratio, ↓Serum TG levels Liu et al. [119] Vitis thunbergii Vitaceae Root 70% aqueous ethanol 0.375% C57BL/6J ↓Blood glucose, Insulin, HOMA-IR, serum TC, LDL, GOT, GPT, ↑CPT-1, AMPK, ↓SREBP-1c Hsu et al. [120] (+)-vitisin A 25 mg/kg bw C57BL/6J ↓Body weights, plasma TG, TC, LDL, FFA Lin et al. [121,122] Terminalia paniculata Combretaceae Bark Ethanol 200 mg/kg bw SD rats ↓Body weights, ↓total fat, ↓fat%, ↓blood glucose, ↓liver markers, ↓liver TG levels, ↑SOD, CAT, ↓leptin, PPARγ, FAS, SREBP-1c, ↑AMPK-1α, Adiponectin Mopuri et al. [80] Glycine max. L. Merr (Soybean) Fabaceae Leaves Kaempferol glycosides 0.15%/kg bw C57BL/6J ↓Body weight, adipose tissue, ↓Serum TG, HbA1c, blood glucose, ↓PPARγ, SREBP-1c Zang et al. [123] Ligustrum robustum Blume Oleaceae Leaves Phenyl propanoid glycosides 0.3,0.6,1.2 g/kg C57BL/J6 ↓Body weight, fat mass, Lee’s index, ↓TC, hepatic TG, Acyl Co A. ↓HSL, ATGL, TGH, DGAT, ↑Serum leptin, Lep mRNA, CYP7A1 Yang et al. [124] Curcuma longa L Zingiberaceae Raw 50% ethanol extract from fermented C. longa L. 500 mg/kg bw Obese rats ↓Adipose tissue, TG, TC, FAS, Act-CoA, Adipocyte protein 2, lipoprotein lipase Kim et al. [125] Alismatis rhizome Alismataceae Dried rhizome Triterpene fraction 180–720 mg/kg bw Mice ↓Body weight, serum TC, LDL-, AI, Lyso PCs ↑HDL Li et al. [126] Melissa officinalis Lamiaceae Leaves Ethyl acetate fraction 0.8% kg/bw C57BL/6J ↓Body weight, adipose tissue mass and size, VEGF-A and FGF-2, MMP-2 and MMP-9, ↑TSP-1, TIMP-1, and TIMP-2 Woo et al. [74] Oral administration of the aqueous extract of Sida rhombodea at a composition of 1% (w/w) in diet was reported to reduce bw, plasma lipids, leptin levels and down regulated the expression of PPARγ, FAS, SREBP-1c in high-fat diet (HFD) fed-mice [33]. Escins and polymeric proanthocyanidins of Aesculus terbinata Blume mixed with diet (2% w/w) and oral dose 1-1.5 g/kg bw reduced bw, plasma and liver triglyceride levels in female ICR mice [35,78]. Crude extract of Cassia tora at a dose of 100–300 mg/kg bw reduced bw, plasma lipid profiles, increased AMPK, CPT-1 and decreased AMPK, SREBP-1c, FAS gene expressions in Wistar rats [36]. Seed ethanolic extract of N. nucifera at a dose of 400 mg/kg bw reduced leptin, PPARγ, GLUT4 expression in HFD fed obese rats [41]. Acacia polyphenols such as robinetinidol, fisetinidol isolated from stembark of Acacia meansii decreased bw, plasma glucose, insulin, up regulated the energy expenditure related genes and down regulated the fatty acid synthesis related genes at a concentration of 2.5-5% (w/w) in diet composition [79]. Rutin and ferulic acid isolated from ethyl acetate extract of Tecomella undulata at a concentration of 100–200 mg/kg bw decreased serum lipid profile and blood glucose in HFD fed mice models [58]. Mopuri et al. [80,81] reported that the ethanolic extract of T. paniculata at a dose of 200 mg/kg bw reduced the levels of serum ALT, AST, ALP, lipid profiles, and down regulated the expression of PPARγ, SREBP-1c, FAS, leptin and up regulated the AMPK-1α and adiponectin genes in rats [81]. At in vivo studies, effects of most of the plants were reported on bw, food intake, serum and liver lipid profiles, antioxidants, when very few plants were extensively studied for their potential activities in metabolic as well as molecular studies. Hence, still more research needs to be done not only to isolate the pure compounds from each bioactive fraction but also to confirm their anti-obesity activities to suggest the plants or their phytochemical compounds for further clinical studies. 3.3. Clinical studies There are very few clinical studies were conducted on the anti-obesogenic effects of various extracts (Table 4). Hydroxyl citric acid isolated from Garcinia cambogia reported to have potent lipogenesis and ATP-citratelyase inhibitory activity, and decreased serum triglyceride in obese women [127]. Curcumin from Curcuma longa, Terpenoids from Emblica officinalis, Polyphenols from Salacia oblonga composition (500 mg/capsule) shown to have hypolipidemic, blood glucose lowering and antioxidant activity in diabetic and obese patients [128]. Tea extract of Salacia oblonga shown to improve lipid profile and decrease fasting blood glucose and HbA1c levels in diabetic and obese patients [129]. Consumption of two capsules (500 mg each/day) of Portulaca oleracea L seeds extract shown to ameliorate lipid profiles in obese adolescents [130]. Due to negligible side effects people showing more interest towards plant based compositions or drugs. So, studies must not be limiting to in vitro or in vivo levels. Table 4. Clinical trial experiments of potential medicinal plants against obesity. Plant Family Part used Extract/fraction Dose In vivo Activity Reference Garcinia cambogia Clusiaceae Fruit rind Hydroxycitric acid 2.4 g/day Obese women ↓potentially inhibiting lipogenesis ATP-citratelyase, TG Vaasques et al. [127] Curcuma longa Zingiberaceae Rizhome Curcumin Tablet (500 mg) Diabetic and obese patients Antidiabetic, hypolipidemic and antioxidant effect, ↓serum AST and ALT Faizal et al. [128] Emblica officinalis Phyllanthaceae Bark Terpenoids Salacia oblonga Celastraceae Stem bark Polyphenols Salacia oblonga Celastraceae Flowers Tea extract Capsule Diabetic and obese patients ↓FPG, HbA1c, TG, LDL, ↑HDL Nakata et al. [129] Portulaca oleracea L Portulacaceae Seeds Crude 1 g/day Obese adolescents ↓TC, TG, LDL, ↑HDL Ali et al. [130] 4. Conclusion Although different therapeutic approaches reported with pharmacological drugs to reduce obesity, the higher cost and severe side effects such as increasing blood pressure, dry mouth, constipation, headache, oily stools and insomnia made them less popular to the people for long-term use. In order to develop safer alternative medicines for reducing obesity a number of natural products have been evaluated from various medicinal plants. Although a wide range of studies were conducted on in vitro and in vivo models targeting different cell signalling pathways, none of these studies were either isolated or examined the anti-obesity effects of pure bioactive compounds from anyone of these plants. However, our close analysis of the reports and potential activity of extracts and fractions from Garcinia cambogia, Nelumbo nucifera, Grape seeds, Curcuma longa, Emblica officinalis, Salacia oblonga shown excellent anti-obesity effects, particularly in terms of in vitro lipase inhibition, appetite suppression, inhibition of adipocytes differentiation and adipogenesis, regulation of lipid metabolism and thermogenic activation and so on. Hence, further study can be conducted to isolate, purify and examine the anti-obesity effects of above-mentioned plants in various experimental levels e.g. from in vitro to clinical studies including their toxicological effects. Although, the anti-obesity effects of the extracts and fractions from many plants were investigated at in vitro and in vivo studies, the number of clinical trials are lacking to evaluate their efficacy in humans. In this concern, the co-involvement of researchers, government bodies and pharmaceutical industries is essential not only to isolate pure compounds but also to examine their anti-obesity effects in clinical trials to overcome the obesity epidemic with safer alternative natural medicines. Conflict of interest Authors declare that there is no conflict of interest. Acknowledgments The study was supported by a competitive research grant from the University of KwaZulu-Natal, Durban; and a grant support for Women and Young researchers from National Research Foundation (NRF), Pretoria, South Africa. First author received a Postdoctoral Fellowship from the College of Agriculture, Engineering and Science of the University of KwaZulu-Natal, Durban, South Africa. References [1] P.G. Kopelman Obesity as a medical problem Nature, 404 (2000), pp. 635-643 CrossRefView Record in Scopus [2] K. Lois, S. Kumar Obesity and diabetes Endocrinol. 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