A Review on Obesity Management through Natural Compounds and a Green Nanomedicine-Based Approach

Obesity is a serious health complication in almost every corner of the world. Excessive weight gain results in the onset of several other health issues such as type II diabetes, cancer, respiratory diseases, musculoskeletal disorders (especially osteoarthritis), and cardiovascular diseases. As allopathic medications and derived pharmaceuticals are partially successful in overcoming this health complication, there is an incessant need to develop new alternative anti-obesity strategies with long term efficacy and less side effects. Plants harbor secondary metabolites such as phenolics, flavonoids, terpenoids and other specific compounds that have been shown to have effective anti-obesity properties. Nanoencapsulation of these secondary metabolites enhances the anti-obesity efficacy of these natural compounds due to their speculated property of target specificity and enhanced efficiency. These nanoencapsulated and naive secondary metabolites show anti-obesity properties mainly by inhibiting the lipid and carbohydrate metabolizing enzymes, suppression of adipogenesis and appetite, and enhancing energy metabolism. This review focuses on the plants and their secondary metabolites, along with their nanoencapsulation, that have anti-obesity effects, with their possible acting mechanisms, for better human health.


Introduction
In past few decades, overweight and obese cases among people of all age groups have become a serious health issue. According to the WHO, obesity is mainly considered as excessive and abnormal fat accumulation that can lead to improper health functioning. Approximately 1.9 billion adults were overweight with a basal metabolic index (BMI ≥ 25) and among these, 650 million adults were obese (BMI ≥ 30), in 2016. The frequency of obesity almost tripled from 1975 to 2016. In 2019, an estimated 38.2 million children under 5 years old were obese all over the world and almost 50% of total children in Asia were obese or overweight [1]. Obesity is mainly due to genetic, environment and behavioral factors [2]. It mainly occurs due to an increase in the ratio of calories or energy intake to the calories or energy expenditure, which results from genetic susceptibility and lethargic lifestyle modifications [3]. Obesity and excessive weight gain can be controlled by modifications in diet and increased physical exercise, but these approaches are not rapid, so many people prefer chemical medications over these approaches for effective results [4]. Various chemical medications are available in the market that have anti-obesity property, such as orlistat, fenfluramine, coreaserin, rimonabant, cetlistat, sibutramine, and phentermine with ti-obesity property, such as orlistat, fenfluramine, coreaserin, rimonabant, cetlistat, sibutramine, and phentermine with topiramate, with different efficacy to control obesity [5,6]. These medications have several adverse effects on health like cardiometabolic abnormalities, anxiety, high blood pressure and pulse rate, and depressive disorders [7]. Therefore, more sophisticated efforts should be done to discover natural anti-obesity agents with less side effects and more efficiency. Accordingly, several natural secondary metabolites present in different plants like polyphenols, flavonoids, terpenoids, alkaloids, saponins, carboxylic acids, glycosides and tannins are reported to have anti-obesity efficacy through different mechanisms of action. Several bioactive compounds in edible plants, such as green tea with epigallocatechins, nobiletin in citrus peel, resveratrol, pterostilbene in berries, curcumin in turmeric, and anthocyanins in Hibiscus sabdariffa, are reported to suppress the obesity-causing factors [8,9]. Nanotechnology and nanoencapsulation of these secondary metabolites opens up a new horizon for overcoming this aforementioned health issue. These biochemicals can be encapsulated with biocompatible nanoparticles, which enhances their target specificity, bioavailability, stability and aqueous solubility [10]. The basic pathogenesis of obesity mainly includes an increase in appetite and a decrease in calorie expenditure by modulating physical activity and cellular functioning. These abnormalities increase the process of adipogenesis, which in turn increases the release of cytokines and vascular complications leading to cardiovascular system disorders like atherosclerosis and hyperlipidemia. The various factors responsible for the induction of obesity and other related health disorders are shown in Figure 1.

Role of Natural Products in Obesity: Regulation of Metabolism
The natural products present in different plant resources alter the regulation of various enzymes and genetic factors through different acting mechanisms ( Figure 2). These secondary metabolites inhibit carbohydrate and lipid metabolizing enzymes like α-amylase, α-glucosidases and different lipases present in the gastrointestinal tract. Amylases and glucosidases are the main key enzymes responsible for digesting the carbohydrates and result in release of glucose via glucose transporters [11]. An increase in the level of glucose above normal ultimately results in the release of insulin from pancreatic cells and initiation of three pathways (glycogenesis, glycolysis and de novo lipogenesis) to decrease glucose in the blood [12]. The synthesis of lipids and fatty acids from glucose and esterification of these lipids into triglycerides for storage in adipose tissue

Role of Natural Products in Obesity: Regulation of Metabolism
The natural products present in different plant resources alter the regulation of various enzymes and genetic factors through different acting mechanisms ( Figure 2). These secondary metabolites inhibit carbohydrate and lipid metabolizing enzymes like α-amylase, α-glucosidases and different lipases present in the gastrointestinal tract. Amylases and glucosidases are the main key enzymes responsible for digesting the carbohydrates and result in release of glucose via glucose transporters [11]. An increase in the level of glucose above normal ultimately results in the release of insulin from pancreatic cells and initiation of three pathways (glycogenesis, glycolysis and de novo lipogenesis) to decrease glucose in the blood [12]. The synthesis of lipids and fatty acids from glucose and esterification of these lipids into triglycerides for storage in adipose tissue causes obesity [13]. On the other hand, lipases, mainly secreted from the different regions of the gastrointestinal tract, are mainly involved in the digestion of fatty acids, phospholipids and triglycerides and hydrolyze Molecules 2021, 26, 3278 3 of 28 them into monoglycerides. These monoglycerides form chylomicrons and the micellar structure with sugars, lysophosphatidic acid and bile salts. This structure then passes into the enterocytes and subsequently results in the synthesis and storage of triglycerides in adipose tissue [14]. The inhibition of these enzymes, after treatment with plant products, ultimately results in the reduction of obesity. These secondary metabolites reduce obesity through modulation of different hormones such as leptin, ghrelin and insulin. Leptin is primarily secreted by white adipose tissue (WAT) [15] and regulates the "brain-gut axis" by activating its receptors in the central nervous system (CNS), subsequently reducing food intake and enhancing the calorie expenditure pathways [16]. Insulin is secreted from the pancreatic beta cells and transforms signals to the brain that result in a reduction in food intake over the long term and more rapid energy expenditure. Signals from both leptin and insulin communicate in a way to reduce the food and energy intake [17]. Plants with antiobesity properties increase the level of both hormones. Adiponectin (an adipokine secreted from adipose tissue) increases hepatic insulin activity, increases fatty acid oxidation, and enhances glucose uptake in both skeletal muscle and the liver [16]. It mainly acts through the activation of adenosine monophosphate-activated protein kinase (AMPK) activity and AMPK impedes acetyl Co~A carboxylase activity and decreases the content of malonyl Co~A [18]. causes obesity [13]. On the other hand, lipases, mainly secreted from the different regions of the gastrointestinal tract, are mainly involved in the digestion of fatty acids, phospholipids and triglycerides and hydrolyze them into monoglycerides. These monoglycerides form chylomicrons and the micellar structure with sugars, lysophosphatidic acid and bile salts. This structure then passes into the enterocytes and subsequently results in the synthesis and storage of triglycerides in adipose tissue [14]. The inhibition of these enzymes, after treatment with plant products, ultimately results in the reduction of obesity. These secondary metabolites reduce obesity through modulation of different hormones such as leptin, ghrelin and insulin. Leptin is primarily secreted by white adipose tissue (WAT) [15] and regulates the "brain-gut axis" by activating its receptors in the central nervous system (CNS), subsequently reducing food intake and enhancing the calorie expenditure pathways [16]. Insulin is secreted from the pancreatic beta cells and transforms signals to the brain that result in a reduction in food intake over the long term and more rapid energy expenditure. Signals from both leptin and insulin communicate in a way to reduce the food and energy intake [17]. Plants with anti-obesity properties increase the level of both hormones. Adiponectin (an adipokine secreted from adipose tissue) increases hepatic insulin activity, increases fatty acid oxidation, and enhances glucose uptake in both skeletal muscle and the liver [16]. It mainly acts through the activation of adenosine monophosphate-activated protein kinase (AMPK) activity and AMPK impedes acetyl Co~A carboxylase activity and decreases the content of malonyl Co~A [18]. Ghrelin is also called the hunger hormone and inhibition of the secretion of ghrelin has an anti-obesity effect [19]. The process of adipogenesis and adipocyte differentiation can be interfered by regulating various transcriptional factors involved in different steps of these processes to manage obesity [20]. These transcriptional factors are proliferator-activated receptors (PPAR), sterol regulatory elementary binding proteins (SREBP) and CCAAT/enhancer binding proteins (C/EBP) [21]. Repression at the level of SREBP [22,23] and C/EBP [24] and enhancement of the PPAR level [25] are also strategies to manage obesity by different plant metabolites. Regulation of lipid metabolism at the level of synthesis and lipid degradation by different enzymes and hormones can reduce the Ghrelin is also called the hunger hormone and inhibition of the secretion of ghrelin has an anti-obesity effect [19]. The process of adipogenesis and adipocyte differentiation can be interfered by regulating various transcriptional factors involved in different steps of these processes to manage obesity [20]. These transcriptional factors are proliferatoractivated receptors (PPAR), sterol regulatory elementary binding proteins (SREBP) and CCAAT/enhancer binding proteins (C/EBP) [21]. Repression at the level of SREBP [22,23] and C/EBP [24] and enhancement of the PPAR level [25] are also strategies to manage obesity by different plant metabolites. Regulation of lipid metabolism at the level of synthesis and lipid degradation by different enzymes and hormones can reduce the obesity effect [26]. SREBP1a (sterol regulatory element binding protein 1a), SREBP2, low density lipoproteins (LDL), and receptors-3-hydroxy-3-methylglutaryl Co~A reductase mainly regulate the process of synthesis of cholesterol from acetyl Co~A [27]. SREBP-1c upregulates the transcription of the lipogenic enzymes stearoyl Co~A desaturase and fatty acid synthase (FAS) [28]. Activation of AMPK interferes with SREBP-1c and FAS and reduces the synthesis of cholesterol and fatty acids [29]. In a similar way, carnitine palmitoyl transferase 1A (CPT1A) decreases the concentration of hepatic triglycerides and increases the process of fatty acid oxidation [30]. Therefore, regulation of all of these factors imparts a beneficial effect in preventing obesity with the help of natural products that are secondary metabolites obtained from plants. Their role in treating obesity is described below.

Polyphenols
Polyphenols are phenolic compounds with at least one or more aromatic ring/s with a hydroxyl group and other functional groups like glycosides, methyl ethers and esters associated with its chemical structure [31]. On the basis of the number of aromatic rings, polyphenols can be categorized into, among others, tannins, stilbenes, phenolic acid, flavonoids, lignans, lignins and coumarins [32,33]. Among all the categories of phenolic compounds, flavonoids can be distinguished by the presence of two aromatic rings, connected by a 3-C bridge. Resveratrol, catechins, quercetin, procyanidins, epigallocatechins gallate, anthocyanins and procyanidins are gaining much interest due to their significant anti-obesity properties. Several studies have reported anti-obesity efficacy of different phenolic compounds in both animals and cell models. The polyphenols (extracted from Vitis rotundifloia) [34], ellagitannins, and proanthocyanidins extracted from raspberries and strawberries [35] are reported to inhibit pancreatic lipase with an IC 50 value of 16.90 and 5 µg/mL, respectively. Gallic acid, epigallocatechin's gallate (EGCG) and epigallocatechin are reported to inhibit the lipase activity with an IC 50 value of 387.2, 273.3 and 39.2 µM, respectively [36]. Liu et al. [37] reported the inhibition of pancreatic lipase, α-amylase and α-glucosidases with an IC 50 value of 1.86, 0.38 and 2.20 mg/mL, respectively, by phenolic compounds extracted from Nelumbo nucifera. Polyphenols extracted from Citrus aurantium [38] and Coralluma fimbriate [39] are reported to show appetite suppressive effects. MacLean and Luo [40] reported that Bushman's Hat (Hoodia Gordoni) extracts increased ATP (adenosine triphosphate) in hypothalamic neurons and positively regulated hunger and food intake in rats. Epigallocatechins-3-gallate (EGCG) extracted from green tea reduced food intake by inhibition of ghrelin hormone and stimulation of adiponectin [41]. Stimulation of thermogenesis and energy consumption is also a significant way to decrease obesity. BAT is unique as it involves release of excess energy by the process of thermogenesis. An uncoupling protein (UCP1) regulates the process of thermogenesis in BAT by reducing the proton gradient and uncoupling ATP synthesis from oxidation [42]. UCP3 is another homologous protein to UCP1 and exerts its anti-obesity action by regulating the level of leptin, thyroid hormones and β-adrenergic agonists [43]. EGCG extracted from green tea is reported to induce thermogenesis and energy consumption [44]. Other compounds like quercetin, isoflavones, gallic acid, resveratrol, and curcumin induce thermogenic activity by modulating the signaling pathway of adenosine monophosphate protein kinase (AMPK), SIRT1 (sirtuin 1), proliferator activated receptor gamma coactivator 1-α (PGC-1α), and catechol O-methyl transferase, which are mainly involved in the regulation of transcription and physiology of adipose tissue ( Figure 3). Curcumin, resveratrol, epigallocatechin-3-gallat, and genisten are able to inhibit the process of differentiation of adipocytes [45]. Carvacrol [46] and phenolic compounds from chokeberries [47] inhibited the process of adipocyte differentiation by modulating the level of PPAR-γ, C/EBP-α and SREBP-1c. Lipid and triglyceride accumulation is mainly responsible for excessive weight gain and obesity. The process of synthesis of cholesterol from acetyl Co~A is mainly regulated by SREBP1α, SREBP2, LDL receptors and 3-hydroxy methylglutaryl Co~A reductase [27]. AMPK stimulates fatty acid oxidation and reduces the synthesis of cholesterol by interfering with fatty acid synthase and SREBP-1c [29]. Polyphenols extracted from Hibiscus sabdariffa [48] and combined with the extract of Lippia citridora [49] exhibited anti-obesity efficacy.

Flavonoids
Flavonoids, commonly present in a variety of plants, are mainly responsible for the flavor and colour of the vegetables and fruits [50]. The chemical structure of flavonoids mainly consists of a heterocyclic pyran ring and two aromatic rings associated with it, which forms a 15-C phenylpropanoid core. Flavonoids are grouped into six categories on the basis of the double bond present in the heterocyclic ring and its oxidation status. These groups are anthoxanthins (flavonols or catechins), anthocyanins (cyanin pigment), flavonones (narigenin and herpertin), flavones (luteolin, apigenin), isoflavones (genistein, flavin) and chalcones (butein, xanthoangelol) [51]. These different groups of flavonoids show demarcated anti-obesity properties with different modes of action. Flavonoids inhibit weight gain by reducing food intake and increasing the feeling of satiety. Flavonoids extracted from the spinach leaf and the combination of flavonoids and procyanidin [52] had a significant effect in treating overweight by reducing the cravings for food and increasing satiety. WAT is specialized in storage of excess energy in the form of triglycerides [53] and BAT is mostly specialized for high metabolism and energy expenditure. It is predominantly present in the suprarenal, spinal and supraclavicular regions [54]. Both adipocytes express UCP-1 protein, which is mainly responsible for thermogenesis and energy consumption. Thermogenesis is mainly regulated by various mechanisms and improves the activity of the sympathetic nervous system, which results in the secretion of norepinephrine, which ultimately results in energy consumption and reduction of fat accumulation [55]. PGC1-α is the main transcription factor that regulates the process of thermogenesis [56]. AMPK and SIRT1 are mainly increased by flavonoids and are the factors mainly responsible for the expression of PGC1α. AMPK/PGC1α signaling is primarily responsible for browning of adipose tissue and thermogenesis [57]. The gastrointestinal tract comprises a diverse bacterial population, including Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes [58], and out of which 1.9% of total flora are heritable and more than 20% of the diversity mainly depends on environmental factors such as dietary habits [59]. Imbalance in the diversity of the gut microflora may cause endotoxic accumulation in the circulatory system, which in turn may induce chronic inflammation and obesity [60]. Short chain fatty acids (SCFAs) are produced after bacterial fermentation of some indigestible biochemicals such as polyphenols, polysaccharides and protein, which are mainly involved in energy expenditure, oxidation of fatty acids, regulation of sympathetic activity and intestinal gluconeogenesis [61]. Bile acid produced from cholesterol in the liver can be metabolized by intestinal bacteria and bile acid also regulates the composition of microbes and facilitates their growth [62]. The aforementioned factors reveal the role of flavonoids in obesity regulation ( Figure 4).

Diterpenoids
Diterpenoids are chemical compounds that contain two terpene units, with each having four isoprene units with the molecular formula C 20 H 32 [63]. The anti-obesity mechanism of diterpenoids is depicted in Figure 5. Diterpenoids have several therapeutic effects, such as anti-obesity effects from taxanes from Taxus [64] carnosic acid, and steviol and its derivatives [65]. Diterpenoids and their derivatives showed anti-obesity properties through different strategies. Teucrin A isolated from Teucrin chaemodrys and Carnosic acid isolated from Rosmarinus officinalis are reported to reduce body weight in obese Sprague Dawley rats [66] and mice [67], respectively. Secondly, PTP-1B (protein tyrosine phosphatase 1B) was shown to mainly have adverse effects on leptin transduction and insulin signaling, and the inhibition of this enzyme is reported to speed up the insulin signaling pathways and in turn have positive effects in treating obesity [68]. Acanthoic acid, isolated from Acanthopanax koreanum [69] and Ent-16βH, 17-isobutryloxy-kauran-19-oic acid and Ent-16βH, 18-isobutryloxy-kauran-19-oic acid isolated from Siegesbeckia glabrescens [70], and Hueafuranoid A isolated from Huea sp. are reported to inhibit PTP-1B activity in a dose dependent manner (IC 50 = 30 µg/mL and 13.9 µM, respectively). Diterpenoids also showed lipase inhibitory effects as they inhibited the activity of pancreatic lipase and triglyceride accumulation. Carnosic acid (CA) (isolated from R. officinalis) and carnasol (isolated from Salvia officinalis [71] showed lipase inhibitory activity and modulated body weight gain [3] and lipoprotein-lipase mRNA expression in mouse adipose tissue [72]. Diterpenoids showed anti-obesity effects by inhibiting adipocyte differentiation. Carnosic acid [72,73] and 14-deoxy-11,12-didehydroandrographolide isolated from Andrographis paniculata [74] are reported to interfere with mitotic clonal expansion, block the expression C/EBPα and PPAR-α, reduce lipoprotein mRNA expression via tumor necrosis factor (TNF-α) and interleukin-6, alter the ratio of different C/EBP-β proteins, and activate the mTOR pathways. In a study on the geranylgeraniol (alcoholic derivatives of diterpenoids), which are mostly found in some herbs and fruits, it was reported that they activate human PPARα and PPARγ in CV1 cells and regulate the expression of target genes mainly responsible for lipid metabolism in 3T3-L1 cells and Hep G2 [75].

Diterpenoids
Diterpenoids are chemical compounds that contain two terpene units, with each having four isoprene units with the molecular formula C20H32 [63]. The anti-obesity mechanism of diterpenoids is depicted in Figure 5. Diterpenoids have several therapeutic effects, such as anti-obesity effects from taxanes from Taxus [64] carnosic acid, and steviol and its derivatives [65]. Diterpenoids and their derivatives showed anti-obesity properties through different strategies. Teucrin A isolated from Teucrin chaemodrys and Carnosic acid isolated from Rosmarinus officinalis are reported to reduce body weight in obese Sprague Dawley rats [66] and mice [67], respectively. Secondly, PTP-1B (protein tyrosine phosphatase 1B) was shown to mainly have adverse effects on leptin transduction and insulin signaling, and the inhibition of this enzyme is reported to speed up the insulin signaling pathways and in turn have positive effects in treating obesity [68]. Acanthoic acid, isolated from Acanthopanax koreanum [69] and Ent-16βH, 17-isobutryloxy-kauran-19-oic acid and Ent-16βH, 18-isobutryloxy-kauran-19-oic acid isolated from Siegesbeckia glabrescens [70], and Hueafuranoid A isolated from Huea sp. are reported to inhibit PTP-1B activity in a dose dependent manner (IC50 = 30µg/mL and 13.9µM, respectively). Diterpenoids also showed lipase inhibitory effects as they inhibited the activity of pancreatic lipase and triglyceride accumulation. Carnosic acid (CA) (isolated from R. officinalis) and carnasol (isolated from Salvia officinalis [71] showed lipase inhibitory activity and modulated body weight gain [3] and lipoprotein-lipase mRNA expression in mouse adipose tissue [72]. Diterpenoids showed anti-obesity effects by inhibiting adipocyte differentiation. Carnosic acid [72,73] and 14-deoxy-11,12-didehydroandrographolide isolated from Andrographis paniculata [74] are reported to interfere with mitotic clonal expansion, block the expression C/EBPα and PPAR-α, reduce lipo-

Nanotechnology Associated with Anti-Obesity Effects
Nanotechnology and nanoencapsulation of secondary metabolites is an emerging and more beneficial strategy for the treatment of obesity with amplified efficiency and minimized side effects [117]. Various types of phytochemicals such as flavonoids, terpenoids, polyphenols, glycosides and tannins have been reported as promising agents in treating obesity but their low target specificity, low aqueous solubility, stability and toxicity at high dose put some restrictions on their clinical use. These biomolecules are mainly responsible for the reduction of metal ions from their metallic precursor and green synthesis of metallic nanoparticles. These limitations can be overcome by using metallic nanoparticles and nanoencapsulated phytochemicals, as they increase their target specificity, bioavailability, and solubility, and more importantly, prevent them from pre-term degradation [10]. They also have a high surface to volume ratio and tunable surface chemistry. Table 2 shows the list of some nanoparticles synthesized from the biological material and some nanoencapsulated biological molecules with their anti-obesity effects on obese animal models and/or cell lines.   The anti-obesity effect of the nanocellulose compound isolated from Vitis vinifera was reported by Abdelbaky et al. [118] on a rat model. They reported the regulation of body weight, organ weight, blood serum lipid profile and food intake after induction of cellulose NPs in their diet. The nanoparticles isolated from red grape seed, especially cellulose nanocrystals (CNC), had a significant positive effect on obesity and hyperlipidemia compared to grape seeds powder, while the chemical constituents of the crude leaf extract of Vitis vinifera [100] inhibited pancreatic lipase, affecting lipid metabolism and consequently obesity. In a similar way, the gold nanoparticles from Salacia chinensis [119], Smilax glabra [120], Poria cocos [122], Dendropanax morbifera [130] and chitosan NPs [121] were reported to show anti-obesity efficacy by regulating the serum lipid profile and the level of hormones related to lipid metabolism and regulation of the transcriptional factors mainly responsible for the metabolism of lipid digestion and lipid accumulation. Nanoencapsulation increased the delivery of the specific molecule/secondary metabolite to the specific target with much greater efficacy and stability. Nanoencapsulation of quercetin with a succinyl chitosan alginate shell [124] and PLGA [128] in rat models revealed that the serum lipid profile and glucose level were regulated after the induction of these nanoencapsulated structures. On the other hand, quercetin, being one of the chemical constituents in extracts of different plant parts-flowers of Capsicum annuum [94], plums of Prunus salicina [98], leaves of Vitis vinifera [100], fruits of Rhus coriaria [100], leaves of Cosmos cadatus Kunth [78], fruits of Malus prunifolia [102], fruits of Malus huphenesis [102], Hibiscus sabdariffa [103], Solenostemma argel [103], and Vibrunum opulus [105], twigs of Ranulus mori [111], leaves of Nelumbo nucifera [81], soybean embryo and enzymatically modified Isoquercetin [115]-has contributed to obesity management as mentioned above.
EGCG is a secondary metabolite mainly present in green tea and many other plant products and its encapsulation with Soy PC, α-tocopherol and Kolliphor HS15 [126] and Kodia-PC and α-tocopherol [125] was reported in C57BL/6J mice and Human THP1 cells, respectively. In mice, it regulated the serum lipid profile and decreased the surface lesion of aortic arches and inflammatory factors, and in monocytes, it mainly decreased the expression of the transcription factors responsible for lipid accumulation and in turn decreased the cholesterol level in these monocytes.
Similarly, the anti-obesity studies on Curcuma longa [76] and the nanoencapsulated curcumin [72,127] molecule showed that the curcumin molecule capsulated with a PLA-PEG molecule enhanced the anti-obesity effect in terms of modification of the serum lipid profile (p ≤ 0.01) and modulation of transcription factors (p ≤ 0.01) compared to native curcumin molecules [76].
Resveratrol and oxy resveratrol are chemical ingredients of twigs of Ranulus mori [111], root extract of Polygonum cuspidatum [92], and a nanocellulose compound isolated from Vitis vinifera [118]. Trans resveratrol-encapsulated NPs [131] regulated the expression of signal pathways, lipid parameters and conversion of WAT to BAT related to obesity management. These chemicals acted individually (NPs) and/or in combination (crude/extract) in obesity management. Resveratrol was encapsulated with PLGA by Wan et al. [129], who used HepG2 cells to evaluate the anti-obesity efficacy of these nanoencapsulated structures. They found a significant decrease in the lipid accumulation, hepatocellular differentiation and triglyceride accumulation in these hepatocytes.
More studies are required, which will certainly open new avenues and add further to existing knowledge to establish the contribution of the constituent chemical/s (nanoencap-sulated or constitutent of extract), individually or synergistically, that may act as efficacious nanomedicines assisting in obesity management, specifically acting through its regulatory parameter/s.

Conclusions
The human population has witnessed the health benefits of natural compounds due to the presence of secondary metabolites in medicinal plants. The secondary metabolites have modulating effects in various disorders. The natural compounds have less side effects. Obesity is an ordinary underrated health disorder but is now considered a serious public health issue globally, which leads to the emergence of other chronic health disorders. This review summarizes the natural products in plant extract(s)/isolated or purified compound(s) and the nanomedicine-enhanced effect of these natural compounds to reduce the comorbidities related to obesity. The nanomedicine-based approach showed curative effects for obesity management by their gene target specific activity and this drug delivery system opens up a new horizon to improve the ameliorative efficiency of these natural compounds. To cite an example, the nanoencapsulated curcumin (PLA-PEG) molecule showed significantly enhanced anti-obesity effects compared to the native curcumin molecule. The nanoparticles and nanoencapsulation treatment enhanced the anti-obesity efficacy. This article also aimed to explain the mechanism of these secondary metabolites in regulating the obesity parameters by modulating the gene/transcriptional factors amenable for adipogenesis, adipocyte differentiation, energy and lipid metabolism, and gut microbiota. Future perspective studies of such natural molecules in terms of drug specificity, efficacy and ethical issues/trials need to be conducted for their specific validation in the interest of better human health.