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Review of Medicinal Plants for Anti-Obesity Activity

Obesity is a complex health issue to address, it is a serious and chronic disease that can have a negative effect on many systems in your body. Overweight and obesity may increase the risk of many health problems, including diabetes, heart disease, osteoarthritis and certain cancers. Obesity is increasing at an alarming rate throughout the world. Today it is estimated that there are more than 300 million obese people world-wide. Obesity is regarded as a disorder of lipid metabolism and the enzymes involved in this process could be targeted selectively for the development of antiobesity drugs. However, most of the anti-obesity drugs that were approved and marketed have now been withdrawn due to serious adverse effects. The naturopathic treatment for obesity has been explored extensively since ancient times and gaining momentum in the present scenario. Traditional medicinal plants and their active phytoconstituents have been used for the treatment of obesity and their associated secondary complications. Some active medicinal plants and their respective bioactive compounds were also tested by clinical trials and are effective in traemnet of obesity. This review focus on natural phytoextracts with their mechanism of action and their preclinical experimental model for further scientific research.


Introduction
In the present scenario, obesity is the major public health problem with about 1.9 billion adults (18 years and older) worldwide are overweight and about 600 million of them are clinically obese [1]. Obesity is characterized by increase in adipose cell size which is determined by amount of fat accumulated in the cytoplasm of adipocytes [2]. This change in the metabolism in the adipocytes is regulated by various enzymes such as fatty acid synthase, lipoprotein lipase and adipocyte fatty acid-binding protein [3].
Obesity results from an imbalance between energy intake and expenditure. It is caused by altered lipid metabolic processes including lipogenesis and lipolysis [4]. Lipogenesis is the process that stores free fatty acids in the form of triglyceride (TG) [5]; similarly, lipolysis is the process whereby the TG stored is metabolized to free fatty acids and glycerol [6]. Obesity accompanied by hyperlipidemia which is indicated by abnormally high concentration of lipids in blood [7]. The adipose tissue, an endocrine organ, has a major role in the regulation of metabolism and homeostasis, through the secretion of several biologically active adipokines [8]. During adipose tissue development, three major transcription factors, peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (C/EBP) α, and sterol regulatory element-binding protein (SREBP) 1c, regulate the expression of these lipid-metabolizing enzymes [9]. 5' AMPactivated protein kinase (AMPK) plays a major role in glucose and lipid metabolism by inactivating acetyl-CoA carboxylase (ACC) and stimulates fatty acid oxidation by up-regulating the expression of carnitine palmitoyltransferase-1 (CPT-1), PPARα, and uncoupling protein [10].
Nowadays, changes in human lifestyle and high energy diet have increased the incidence of obesity and even have become a risk factor to the population of children [11,12]. There are several pharmacologic substances available as antiobesity drugs, however they have hazardous side effects and hence natural products have been used for treating obesity in many Asian countries [13]. The potential of natural products for the treatment of obesity is still largely unexplored and can be an excellent alternative for the safe and effective development of antiobesity drugs [14].
Currently drugs available in the market for treatment of obesity can be divided into two major classes one being orlistat, which At present, because of high cost and potentially hazardous side effects, the need for natural products against obesity is under exploration which may be an alternative strategy for developing effective, safe antiobesity drugs [22]. In 2000, Moro and Basile reported the use of certain well known medicinal plants that had claimed to be useful in treating obesity. The antiobesity effects of natural products from more diverse sources [23]. The aim of the present review was to update data on potential antiobesity herbal plants.

Methods
Databases used for this study to search include PubMed, Scopus, Google Scholar, Web of Science, and IranMedex with information reported between September 2, 2006 to September 22, 2014. Search of literatures was focused on human or animals investigating the benefits and harms of herbal medicines to treat obesity. The search terms were "obesity" and ("herbal medicine" or "plant", "plant medicinal" or "medicine traditional") without narrowing or limiting search items. Publications with abstract from the mentioned databases were used to prepare this review. The main outcome measures were defined as body weight, body fat, including fat mass/fat weight or fat percentage/visceral adipose tissue weight, waist or hip circumference, triceps thickness and appetite, and the amount of food/energy intake. Abstracts of publications on plants used to evaluate the activity on human, animals, cell lines studies with the main outcome as mentioned above were included. In vitro studies, review articles and letters to the editor were excluded. Two reviewers reviewed the articles for abstracts and title. Due to our inclusion and exclusion criteria, the duplicate articles were eliminated. The review includes active components and mechanism of action against obesity in animals and presented in Table 1. Some of the plants are tested for their activity against obesity in cell lines listed in Table 2 and plants that were tested on human volunteers or clinical trails are listed in Table 3. In some instances scientist have evaluated the anti-obesity activity in isolated cell organelles, isolated cellular enzymes specifically pancreatic lipase are listed in Tables 3 and 4 respectively. Table 4 present the plant which was studied for its activity against obesity in an in silico model.

Discussion
In this review, we have report the antiobesity effects of different herbal plants or compounds containing minerals or chemical extracts of plants. Plants having reported antiobesity effects are listed in Table 1 with information about their active components and their effects. From the review it was suggested that, plant showing anti-obesity potential mainly belongs to the family Leguminoseae, Lamiaceae, Liliaceae, Cucurbitaceae, Asteraceae, Moraceae, Rosaceae and Araliaceae. Majority of the studies indicates decrease in body weight or body weight gain in animals and humans with or without changes in body fat indicating antiobesity effects. The antiobesity effects such as body weight reduction, decrease in the levels of triglycerides, total cholesterol, and low density lipoprotein cholesterol with simultaneous increase in high density lipoprotein cholesterol was observed in the animals treated with the plants [1,15,29,31,39,54,60,78,79,83 ,85,98,100,101,133,145,152,165,190,196,201]. In one study [41], it has been reported that a compound chakasaponin II, suppressed mRNA levels of neuropeptide Y (NPY) and enhanced the release of serotonin (5-HT) that suppressed the appetite signals in the hypothalamus of the mice. Clinical trials were conducted on humans for various plant extracts [45,49,135] which showed a significant decrease in body weight and body fat reduction. There

Roots
Reduces high-fat diet-induced increases in body weight, white adipose tissue mass, serum triglyceride and total cholesterol levels, and hepatic lipid levels and decreases lipogenic and adipogenic gene expression. Acetylshikonin, active constituent of L. erythrorhizon suppresses adipocyte differentiation and attenuates adipogenic transcription factor expression.
C57BL/6J mice were fed a normal or high-fat diet [113,114] 69 Reduces body weight and fat mass. It increases glucose tolerance and reduced plasma triglycerides level.
Leaves Reduces body weight gain, plasma total cholesterol and triglyceride levels in mice.

Fruit
Reduces animal body weights of the fat in white adipose tissues, glucose, total cholesterol, triglycerides, and LDL-c and insulin blood levels. An increase in HDL-c levels also seen.
Wistar rats with obesity induced by subcutaneous injection of monosodium glutamate [122] 75 Myrtus communis L.

Shoot
The extract supresses increase in body and fat mass weight, and decreases triglycerides and LDL-cholesterol levels and enhances gene expression related to lipid homeostasis in liver showing anti-obesity actions.
Leaf Up-regulation of PPARγ 2 and SREBP-1c expression in the epididymal adipose tissue, leading to attenuation of adipogenesis.
Fruit AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation in liver is elevated, and HMG-CoA reductase expression is decreased. It strongly decreases expression of peroxisome PPAR-γ, CCAAT/enhancerbinding protein alpha and perilipin in the adipose tissue.
Fruit pulp, pulp, seed coat Levels of plasma total cholesterol, lowdensity lipoprotein, and triglyceride is decreased and it increases high-density lipoprotein, with the concomitant reduction of body weight.

Bark
The extract shows a significant increase in SIRT1 and adiponectin levels and decrease in PPAR, C/EBP, E2F1, leptin and LPL levels in preadipocytes and adipocytes and shows improvement in lipid profile and glucose levels.
Peel It inhibits lipid accumulation and decreases expression of C/EBPβ, as well as the C/EBPα and PPARγ genes during the differentiation of preadipocytes into adipocytes. It downregulates adipocyte-specific genes such as aP2 and FAS.
Whole plant It reduces weight gain and the fat pad weight in high fat diet-induced obese mice.
High-fat diet-induced obese mice [134] 111 High fat diet-induced obesity in rats [168] 112 Vigna nakashimae Seeds It decreases expression of peroxisome proliferator activated receptorγ and its target genes. It enhances the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC), and increases the expression of fatty acid oxidation genes.

Leaves
Active compounds umbelliferone and esculetin depletes lipid content in the adipocytes and by decreasing the hyperlipidemia in obese rats fed with high-fat diet.

Seeds
By regulating the C/EBPα, C/EBPβ and PPARγ gene and protein expressions.
Flowers, flower buds, stem, roots, stem bark, seeds, leaves it reduces increased level of total cholesterol, triglycerides, LDLP and increases the level of HDLP, brain serotonin level. β -sitosterol in the stem induces secretion of serotonin in brain and in turn exhibits anti-obesity activity.
Fruits, leaves It inhibits Akt activation and GSK3β phosphorylation, which induces the down-regulation of lipid accumulation and lipid metabolizing genes, ultimately inhibiting adipocyte differentiation.

Rhizome
It inhibits lipid accumulation in 3T3-L1 cells. The five alkaloids present in this plant significantly reduces expression levels of several adipocyte marker genes including proliferator activated receptor and CCAAT/ enhancer-binding protein. Isolated alkaloids found to inhibit adipogenesis.
Rhizomes Increase hormone-sensitive lipase and adipose triglyceride lipase mRNA levels and decreases perilipin mRNA level via AMPK, resulting in lipolysis.
In adipose tissue, curcumin inhibits macrophage infiltration and nuclear factor κB activation induced by inflammatory agents.

Stems
Mangiferin, hesperidin inhibits intracellular triglyceride and fat accumulation, and decreases PPAR2 expression and in in vitro it can inhibit adipogenesis.

Leaves
Inhibits pancreatic lipase and can be used as an antiobesity agent in suitable form.
Rhizome Decreases expression of PPAR-γ. Batatasin I compound from the extract was found to increase p-AMPK and CPT-1 in 3T3-L1 adipocytes, resulting in inhibiting adipogenesis.

Bean
It inhibits adipocyte differentiation in 3T3-L1 preadipocyte cells. Accumulation of triglycerides is inhibited and activation of AMPK.

Leaf
Attenuates expression of fatty acid synthase, sterol regulatory element-binding protein-1 and glycerol 3-phosphate acyltransferases. The extract inhibits the elevation of plasma TG levels in mice. The extracts possibly suppress the uptake of NEFA and glycerol by blocking FAT/CD 36 and also suppress aquaproin-7.

Seed
Inhibits adipogenesis in adipocytes. The effect appears to be mediated through the down regulated expression of adipogenic transcription factors (PPAR-γ) and adipocyte-specific proteins (leptin), and by upregulated expression of adiponectin.

Root
Increases lipolytic effects such as decreased intracellular triglyceride and the release of glycerol.
Seed epicarp, leaves, seed, petals The extracts effective in inhibiting preadipocyte differentiation. The flavonoids inhibits effect on both adipocyte differentiation and pancreatic lipase activity, accumulation and decreases expression PPARγ, GLUT4, and leptin in cultured human adipocytes, indicating that it inhibits the differentiation of pre-adipocytes into adipocytes.

Seed
Decreases expression of the adipogenesis-related transcription factor, PPAR-γ and PPAR-γ-target genes, such as adipocyte protein 2 (aP2), fatty acid synthase (FAS) and other adipocyte markers and also decreases levels of CCAAT/enhancer-binding protein β (C/EBPβ) in a dose-dependent manner.

Leaves
Pteryxin down regulates genes SREBP-1c, fatty acid synthase, and acetyl-coenzyme A carboxylase-1 in treated 3T3-L1 adipocytes and HepG2 hepatocytes and up-regulates lipid catabolizing genes. In aother study it was proved that the extract downregulates a key lipogenic activator, SREBP1 c and adipocyte size marker gene, paternally expressed gene 1/mesoderm-specific transcript (PEG1/MEST) in adipose tissue in vivo.

Leaves
The extract increases adipogenesis and increases expression of adiponectin and leptin. In the early phase of adipogenesis, extract increases the mRNA expression of adipogenic transcription factors CCAAT/ enhancer binding protein α and PPAR-γ.
Whole plant The anti-obesity effect is modulated by cytidinecytidine-adenosine-adenosine-thymidine/enhancer binding proteins, and peroxisome proliferatoractivated receptor, gene and protein expressions.
Leaves Polyphenol and flavonoid, exhibits α-glucosidase and lipid accumulation inhibition properties.

Whole plant
The anti-obesity effect is modulated by cytidinecytidine-adenosine-adenosine-thymidine/enhancer binding proteins, and peroxisome proliferatoractivated receptor, gene and protein expressions.
Whole plant It decreases lipid accumulation and the expressions of two major adipogenesis factors, PPAR and C/EBP, in 3T3-L1 cells.
Fruits, leaves The active constituent p-synephrine increases metabolic rate, energy expenditure and increase in weight loss. The leaf extract down-regulates the expression of C/EBPβ and subsequently inhibits the activation of PPARγ and C/EBPα. The anti-adipogenic activity of is mediated by the inhibition of Akt activation and GSK3β phosphorylation, which induces the down-regulation of lipid accumulation and lipid metabolizing genes, ultimately inhibiting adipocyte differentiation.
Commercial Nigella sativa oil prepared by steam distillation.
N. sativa reduces total cholesterol, low density lipoprotein (LDL) and fasting blood glucose. The oil is effective as an add-on therapy in patients with metabolic syndrome.

Root
Significant weight and body-fat reduction was observed in S. reticulata treated animals and also BMI reduction is seen.

Seed
Daily fat consumption, expressed as the ratio fat reported energy intake/total energy expenditure (fat-REI/ TEE), is decreased in overweight subjects administered the fenugreek seed extract. Significant decrease in the insulin/glucose ratio in subjects treated with fenugreek seed extract.

Leaves
The herbal preparation capsules delays gastric emptying, reducing the time to perceived gastric fullness and induces weight loss.

Leaf
Fat elimination usually occurred within 2 sec, 2 min of extract intake. The blood glucose lowers effects of V. amygdalina leaf extract were usually exerted in 2 sec, 2 min of extract intake by the patient.

Fruit
The extract suppresses lipid accumulation and glycerol-3-phosphate dehydrogenase. Z. jujuba extract elicits the most inhibitory effect with attenuation of the expression of key adipogenic transcription factors, including PPAR-γ and CCAAT enhancer binding proteins (C/EBPs) at the protein level.
Human clinical trials [209][210][211]  Aerial parts 4β-cinnamoyloxy,1β,3α-dihydroxyeudesm-7,8-ene is the active constituent present in V. persicifolia induces bioenergetic collapse in rat liver mitochondria, demonstrating typical uncoupling agent. It acts as a mild uncoupler droping Δψ and increases respiratory state 4. The energy collapse, mild uncoupling, and the fact that V. persicifolia is largely used in folk medicines, this plant may be viewed as a potentially effective anti-obesity drug.

Stems and barks
Major active components are secoiridoids ligstroside, oleuropein, 2"-hydroxyoleuropein and hydroxyframoside B. These compounds significantly inhibit pancreatic lipase and hydroxyframoside B being the most active inhibitor in a mixed mechanism of competitive and noncompetitive manner.
Seed flours, peel, roots, fruit By up-regulating hepatic genes related to cholesterol (CYP51) and bile acid (CYP7A1) synthesis as well as LDL-cholesterol uptake. Lipid metabolismassociated genes Mlxp1, Stat5a, Hsl, Plin1, and Vdr were down-regulated. The extract treatment decreases expression of aP2, Fas, and Tnfa, known markers of adipogenesis, as measured by real-time polymerase reaction. Expression of PPAR-γ in liver and adipose tissue is lowered by regulating the lipid metabolism and suppressed obesity.  [115,120]. P. granatum exhibits potential antiobesity mechanism including inhibition of pancreatic lipase activity and suppression of energy intake. Its effect on energy intake was similar to subutramine but with a different mechanism.
A study reported that Green tea possessed higher antioxidant activity than antiobesity activity due to its high concentration of catechins, including epicatechins, ECG and EGCG. It was proved that antiobesity activity of catechins resulted from the combined actions of appetite reduction, greater lipolytic activity, energy expenditure and adipocyte differentiation.
The active compounds umbelliferone and esculetin from the plant Aegle marmelos have shown marked effect by depleting the lipid content in the adipocytes and by decreasing the hyperlipidemia. Similarly, galangin a compound from Alpinia galangal showed a significant decrease in serum lipids, liver weight, lipid peroxidation and accumulation of hepatic Triglycerides. Decursin a compound from Angelica gigas significantly improved glucose tolerance and reduced the secretion of HFD-induced adipocytokines. The phytoconstituent compound sitosterol found in Boerhaavia diffusa is structurally similar to cholesterol has been suggested to reduce cholesterol by lowering the level of LDL-cholesterol. p-synephrine compound from the plant Citrus aurantium showed increased metabolic rate, energy expenditure and increase in weight loss. In Nelumbo nucifera flavonoids showed mild inhibitory effect on both adipocyte differentiation and pancreatic lipase activity. Among the flavonoids, flavones without glucose inhibited pancreatic lipase activity, whereas flavone glycosides did not show inhibition. The presence of ephedrine and pseudoephedrine in the plant Sida rhomboidea induced appetite suppression that inhibits body weight gain.

Conclusion
Natural products identified from traditional medicinal plants have always paved the way for development of new types of therapeutics. Generally most of the compounds were isolated from natural sources despite which orlistat a semi-synthetic derivative of lipstatin have been approved by the US food and drug administration for the treatment of obesity. Orlistat is a potent inhibitor of pancreatic lipase (PL) which is a lipolytic enzyme which hydrolyses dietary fats in the initial step of lipid metabolism. There have been many reports on other effects such as anti-oxidative stress effects which may be important in the management of other diseases like cardiovascular diseases and diabetes. The antiobesity drugs are generally preferred based on high efficacy and effectiveness. The active exploration of natural sources has provided new developments based on the understanding of complex and redundant physiological mechanisms. Such exploration will lead to a safe and effective pharmacological treatment.