Hidden Potential of Tropical Fruit Waste Components as a Useful

Review pubs.acs.org/JAFC

Hidden Potential of Tropical Fruit Waste Components as a Useful Source of Remedy for Obesity Mohamed Rashid Asyifah,† Kaihui Lu,†,∥ Hui Lin Ting,‡,∥ and Dawei Zhang*,† †

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore ‡ School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore ABSTRACT: The array of comorbidities that comes with obesity and the propelling surge of this disease globally today make the urgent need for treatment vital. Although promoting a healthy physical regimen and controlled diet to affected patients are the main bulk of present treatment, prescriptions of weight-loss medications have also been introduced to complement this treatment. However, the use of synthetic medications may produce adverse side effects and consequently affect the patient’s quality of life. In view of these problems, the use of natural sources as alternative remedies has recently become very popular. Tropical fruit “waste components”, namely, the seed, flower, leaf, peel, and part of the fruit, which are often discarded after consumption, have recently been studied and showed evidence suggesting their potential as promising future alternative sources of remedy. The high amounts of phytochemicals present in these components were believed to be responsible for the antiobesity effect observed experimentally. This review aims to introduce some of the recently discussed tropical fruit waste components that have been discovered to possess antiobesity effects. The major bioactive compounds of the respective fruit components identified and deduced to be responsible for the overall bioactivity will be evaluated. Following this, the subsequent need for the development of an effective processing or recycling technique required to effectively tap the maximum potential of these fruit parts will also be addressed. KEYWORDS: tropical fruits, fruit waste, obesity, phytochemicals, antiobesity

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INTRODUCTION Obesity, defined as an abnormal or excessive fat accumulation in adipose tissues, has become a prominent health problem in both developed and developing countries.1 Triggered by multiple environmental and genetic factors, obesity is also strongly associated with psychological and medical morbidities, metabolic abnormalities, and cardiovascular diseases as well as several types of cancers.2 The prevalence of obesity as well as its associated diseases has been reported to be rapidly increasing globally, and its growth has become a major challenge for health care professionals to combat.3,4 In the most recent report by the World Health Organization (WHO), more than 1.4 billion adults worldwide were reported overweight, and over 500 million of them are obese. In addition, at least 40 million children were also reported overweight or obese, globally (WHO 2011 Report). Because of the array of comorbidities that comes with obesity and the propelling surge in popularity of this disease globally, an urgent treatment is vital. Whereas promoting a healthy physical regimen and controlled diet to affected patients constitutes the bulk of present treatment, the prescription of weight-loss medications such as Lorcaserin (Belviq) and Phentermine-topiramate (Qsymia) has also been introduced to complement this treatment.5 In severe cases, bariatric surgery has been used for treatment.6 However, some of these treatments do have risks. The use of synthetic medications may produce adverse effects and affect therapy compliance and patient life quality.7,8 Therefore, a host of complementary and alternative supplementary treatments, such as the use of natural herbs and dietary supplements, is required.9 © 2014 American Chemical Society

Adipocyte dysfunction is a major cause of obesity. When in vivo homeostasis that controls lipid and glucose dynamics cannot be maintained under conditions of excess energy, adipose tissue differentiates preadipocytes into adipocytes, and excessive accumulation of lipid and triglycerides in adipose tissue then causes an obese condition.10,11 This suggests that with tight regulation of adipogenesis, the energy homeostasis can therefore be maintained and this phenomenon could be used to treat obesity. Multiple adipogenic transcription factors such as peroxisome proliferator activated receptors (PPARs), the sterol regulatory element binding protein (SREBP) family, and the CCAAT-enhancer binding protein (C/EBP) family are involved in the regulation of adipogenesis.10,12,13 Of these factors, PPARs play essential roles in fatty acid metabolism and, thus, serve as the major drug targets in treating obesity.14 In recent years, a collection of studies as highlighted by Yadav et al. have looked into the roles of bioactive nutraceuticals in fruit flesh to beneficially alter diabetes and obesity pathophysiology. This can be done via the upregulation of the PPARα as well as the down-regulation of the expression of PPARγ and C/EBPα, which consequently attenuates fat cell differentiation.15 However, whereas that review focuses on the phytochemicals present in fruit flesh, the other components of the fruit, often regarded as “waste” components, were not discussed. In a cross study with a series of recent research papers, it has been found that phytochemReceived: October 23, 2013 Accepted: March 26, 2014 Published: March 26, 2014 3505

dx.doi.org/10.1021/jf5007352 | J. Agric. Food Chem. 2014, 62, 3505−3516

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Figure 1. Chemical structures of polyphenols that have been extracted and isolated and found to effectively inhibit adipogenesis via in vitro test on 3T3-L1 preadipocyte cells.

flesh, thereby making them a potentially more prospective therapeutic source for further studies.19,25,26 Ideally, with enough studies to support their antiobesity capabilities, the idea of utilizing these waste components as potential therapeutics will not only help to supplement more alternatives for antiobesity treatment but also potentially reduce environmental concern as this simultaneously offers a solution to reduce landfill waste problems as well.

icals that exhibit antioxidant and anti-inflammatory capabilities are also present in the less studied components of the fruits, which includes the rinds, seeds, peels, flowers, and leaves of the fruit. In this paper, the role of these aforementioned components in altering the obesity pathophysiology will be reviewed. Following this, the need for the development of effective fruit waste processing/recycling techniques to effectively tap the maximum potential of tropical fruit waste components as future potential therapeutics will be addressed.

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TROPICAL FRUIT WASTE COMPONENTS AND THEIR BIODEFENSIVE POTENTIAL AS ANTIOBESITY THERAPEUTICS Different components of tropical fruit wastes, mainly the seeds, flowers, and leaves as well as rinds, have been found to successfully regulate lipid accumulation. This section introduces these previous discoveries brought by the scientific community in the pursuit of novel phytochemical-based antiobesity therapeutics. Various methods have been developed to identify and analyze the qualitative and quantitative occurrence of bioactive compounds in the fruit waste extracts (Table 1) such as normal phase silica gel column chromatography, reversed phase high-performance liquid chromatography (HPLC), liquid chromatography−mass spectrometry (LC-MS), HPLC-linked with photodiode array detector (HPLC-PDA), and the sophisticated methods involving electrospray ionization tandem mass spectrometry (ESI-MS). Seeds. Although some seeds may be edible such as those of corn and nuts, the majority of the tropical fruit seeds are inedible and are often discarded after consumption of the fruit. Phytochemicals present within these seeds have been found to exhibit properties that are capable of preventing oxidative stress, a process linked to being overweight and to the onset of diseases including diabetes.17

POTENTIAL OF TROPICAL FRUIT WASTE COMPONENTS AS ANTIOBESITY SUPPLEMENTARY TREATMENT Multiple studies have shown that phytochemical compounds present in tropical fruits possess the ability to inhibit adipogenesis and essentially may offer a suitable therapy against obesity.7,16,17 These phytochemicals could work as fatty acid synthase (FAS) inhibitors, preventing the formation of fatty acids and their accumulation in the body.18 Alternatively, they may inhibit the differentiation of preadipocytes to adipocytes (adipogenesis).10,19,20 Tropical fruits are rich in a diverse array of bioactive phytochemicals that can do so.21,22 Among the bioactive phytochemical compounds in tropical fruits, quercetin20 and hydroxytyrosol and oleuropein16 (Figure 1) are some of the well-known polyphenols that have been identified and found to effectively inhibit adipogenesis in vitro, via the different mechanistic pathways mentioned. Interestingly, these bioactive phytochemicals have recently been discovered to be present in the inedible or waste components of the tropical fruit parts.17,23,24 In addition, a series of comparative studies have found that the extracts of these “fruit waste components” have higher polyphenol content than the main 3506


3507

rind/peel

leaves

flowers

seed

fruit component

not applicable

column chromatography column chromatography

oleuropein, hydroxytyrosol

oleuropein, hydroxytyrosol, luteolin, luteolin-4-O-β-D-glucopyranoside, luteolin-7-O-β-Dglucopyranoside quercetin-3-O-(6-feruloyl)-β-D-galactopyranoside (QFG), quercetin

ellagic acid, gallic acid, ascorbic acid, tannins emblicannin A and B, kaemferol, rutin, kaempferol-3-O-glucoside no isolation/identification of bioactive compounds

α-mangostin

α-mangostin, β-mangostin, γ-mangostin, 9-hydroxycalabaxanthone, garcinone E, 1,5dihydroxy-3-methoxy-2-(3-methylbuten-1-yl)-9H-xanthen-9-one, 1,3/7-trihydroxyxanthone, 2,4,6,7-tetrahydroxyxanthone, 3,4,5,30-tetrahydroxybenzophenone, 2,4,6,30,50-pentahydroxybenzophenone, neosmitilbin, epicatechin, egonol

guava (Psidium guajva)

amla (Emblica of f icinalis) papaya (Carica papaya)

mangosteen (Garcina mangostana)

LC/DAD/ESI-MS

foliamangiferosides A, iriflophenone-3-C-β-glucoside, maclurin-3-C-β-D-glucoside, mangiferin

mango (Mangifera indica L.) olive (Olea europaea)

column chromatography, octadecylsilyl silica gel (0DS) HPLC HPLC

column chromatography, HPLC (isolated) HPLC

gentisic acid, epicatechin, ferulic acid

longan (Dimocarpus longons L.)

HPLC-PDA

HPLC

HPLC-PDA

4-hydroxybenzoic acid, chlorogenic acid, protocatechuic acid

oleanolic, gallic, ursolic

HPLC-PDA

quercetin, rutin, catechin

pomegranate (Punica granatum L.)

HPLC

furocoumarins: xanthotoxin, isopimpinellin, (+)-oxypeucedanin

bishop’s weed (Ammi majus) prickly pear (Opuntia joconostle)

Waters Acquity UPLC

catechin, hydroxycinnamic acids, procyanidin coloration tests

HPLC-ESI-MS

procyanidin

alkaloids, flavonoids, saponins identification

HPLC-PDA

method used for identification

protocatechuic acid

major compounds identified

Hunteria umbellata

avocado (Persea americana Mill)

name of fruit

FAS inhibitor (antiobesity treatment)

antiobesity

antioxidant and antidiabetic capacities hypoglycemic effect

AGE end-products (diabetes treatment) antiobesity, antioxidant

antiobesity

antiobesity

hypolipidemic effect (antiobesity)

hypolipidemic (antiobesity), anti-hyperglycaemic, anti-inflammation

antioxidants

antihyperlipidemic, antiinflammatory, analgesic hypolipidemic effect (antiobesity)

antiobesity and antihyperlipidemic effects

antioxidant

antioxidant capacities

hypolipidemic effect (antiobesity)

biological activity

in vitro 3T3-L1 preadipocyte cells FAS inhibitory activity (assay, spectrophtometer absorbance at 340 nm)

in vivo streptozotocin-induced diabetic rats in vivo streptozotocin induced diabetic rats

in vitro 3T3-L1 preadipocyte cells in vitro 3T3-L1 preadipocyte cells in vitro experimental model in vitro 3T3-L1 preadipocyte cells

in vivo high fat dietinduced hyperlipidemia (HDF) mice and Zucker diabetic fatty in vivo Sprague−Dawley (SD) rats, 9 weeks old

in vivo model, 8-week-old CD-1 mice mean weight 28 ± 2 g

in vivo model, 8−10-weekold adult male CD-1 mice with an average weight of 28 ± 2 g in vitro oxygen radical absorbance capacity (ORAC) assay, DPPH assay in vitro ABTS assay, DPPH assay in vivo olive oil-induced and Triton-induced hyperlipidemic rats in vivo albino rats

study design

ref

63

18

68

69−71

20

55

16

54

23

41

7

39

36

29, 31, 32

28

27

17

Table 1. Major Phenolic Compounds Identified in the Respective Fruit Waste Extracts That May Be Responsible for the Overall Biological Activity Observed in the Respective Experimental Model

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19

82

antiobesity no isolation/identification of bioactive compounds mango (Mangifera indica L.) Irwin & Nam Doc

not applicable

antiobesity, prevent metabolic disorders coloration of flavanoids presence of flavanoids detected pomelo (Citrus grandis)

study design biological activity

antiobesity HPLC polymethoxyflavonones (PMFs), namely, tangeretin and nobiletin small oranges (Citrus sunki)

method used for identification major compounds identified name of fruit fruit component

Table 1. continued

in vivo high-fat diet-induced obese mice and in vitro 3T3-L1 adipocyte cells in vivo high-fat diet-induced metabolic disorders in C57BL/6 mice test three different cultivars on in vitro 3T3-L1 preadipocyte cells

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ref

Avocado Seeds (Persea americana Mill). Avocado seeds (P. americana Mill) have been found to contain elevated levels of phenolic compounds and exhibit antioxidant properties.17,27 The seed, which is inedible, represents the majority bulk of the fruit that is often discarded. In an experimental study conducted by Gu et al. on a variety of avocado cultivars, it was found that seeds contained the highest antioxidant capacities, phenolic content, and procyanidins, whereas the pulp had the lowest. A series of compounds were identified in peels and seeds using a normal-phase HPLC-ESI-MS analytical technique including catechin, epicatechin, A- and B-type dimers, trimers, tetramers, pentamers, and hexamers. On the basis of the close correlations and further in vitro analysis between the total phenolic content in the avocado and the antioxidant capacities, the study concluded that procyanidins were the major phenolic compounds that contributed to this effect.27 In a separate in vivo experimental model reported by PahuaRamos et al. using a hypercholesterolemia mouse, treatment with avocado seed flour (ASF) was reported to drastically reduce the levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and atherogenic index. This effect could be attributed to the phenolic content, antioxidant activity, and/ or dietary and crude fiber content of the seed. Further analysis of the chemical composition of the ASF using HPLC-PDA found that protocatechuic acid was the major phenolic compound identified in ASF to contribute to the overall hypolipidemic effect on the in vivo model.17 Such differences in the major phenolic compounds contributing to the different bioactive effects on experimental models as reported by the above studies highlight the wide array of potential therapeutic capabilities that avocado seeds may possess. The various chemical compositions of phytochemical compounds identified in avocado seeds as reported by Rodriguez-Carpena et al. that include catechins (sum of catechin and epicatechin), hydroxycinnamic acids (p-hydroxybenzoic, protocatechuic, vanillic, syringic, and gallic), and procyanidins28 implied that therapeutic effects exhibited by avocado seed extracts in both in vivo and in vitro experimental model could be due to a collective effect of several phenolic compounds acting together. This further suggests that a study involving the isolation of such compounds from these seed extracts, and testing its individual effects on various biological activities would therefore be useful to understand this phenomenon. The overall in vitro and in vivo experimental models have indicated how avocado seeds, typically regarded as industrial wastes during avocado processing, do have therapeutic properties that can potentially be exploited as a future source of alternative remedy. Phenolic compounds present within the seed have been hypothesized to be responsible for the antioxidant capacities and hypolipidemic effect observed. However, studies involving the isolation of the individual bioactive compounds on the overall lipid regulation effect are still understudied. Hunteria umbellata (HU) Seeds. Traditionally, HU seeds have been widely used for the local management of obesity, diabetes, and hyperlipidemia among the Nigerian folk medicine community.29,30 Understanding the dearth of scientific reports on the therapeutic potential of this plant, particularly in the management of obesity and hyperlipidemia, Adeneye et al. investigated its respective effects via in vivo experimental models (i.e., rats). These rats included normal, olive-induced hyperlipidemic, and Triton-induced hyperlipidemic rats. In their study, they found that with dose-dependent dosage of 3508



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Figure 2. Summary of some examples of tropical fruit waste components that have been experimentally found to possess special properties in their extract that may potentially be used to treat obesity and its associated diseases through its ability to regulate lipid accumulation in living cells.

aqueous seed extract HU, reductions of weight gain pattern and levels of serum lipids, adiposity (measured using Lee’s index), and coronary artery risk index (represents the ratio of LDL-c to HDL-c and antherogenic indices (AI), ratio of total cholesterol to HDL-c) were observed. Their assessment of the histopathological effect of hepatic fatty degeneration on the test rat’s liver further revealed the biochemical evidence of the antihypertriglyceridemic and hypocholesterolemic activities of HU.31 With prior identification of primary phytochemical compounds present in the extract that mainly consist of alkaloids, flavonoids, and saponins,29,32 the author concluded that the antiobesity and antihyperlipidemic effects observed were likely mediated via inhibition of intestinal lipid absorption and de novo triglyceride and cholesterol biosynthesis. This conclusion was collectively made in close reference to several other studies done by Schoenfelder et al. as well as Han et al. that highlight phytocomponents’, such as saponins’, capacity to increase intestinal absorption of dietary lipid bioactivity, respectively.33,34 The isolation of bioactive compounds from this crude seed extract, however, has yet to be done. Bishop’s Weed (Ammi majus) Seeds. Among some of the lesser known species would be A. majus that is typically grown in Egypt. The initial study of this species of seed was inspired from its common use in folk medicine to treat various ailments such as vitiligo.35 Koriem et al. used an in vivo experimental

model, particularly on albino rats, to evaluate the antihyperlipidemic, anti-inflammatory, and analgesic as well as antipyretic activities of the extract. In their study, they discovered that the administration of alcoholic A. majus seed extract resulted in a significant decrease in concentrations of cholesterol, triglycerides, and LDL as well as an increase in HDL in a dosedependent manner. The aforementioned results therefore suggested positive antihyperlipidemic, anti-inflammatory, analgesic, and antipyretic effects of the seed extract.36 Although the study did not isolate the chemical compounds responsible for the respective effects mentioned, 12 furocoumarins that may be responsible for the aforementioned effects were identified. The identification of these 12 furocoumarins (Figure 2) was in line with several other studies previously done on the same species.37,38 Further studies involving the isolation of the furocoumarins along with other compounds is required to further investigate the mechanistic angle of the respective effects addressed. Prickly Pear Seeds (Opuntia joconostle). The prickly pear (O. joconostle) is a species in the cactus family, Cactaceae, that grows widely in North American deserts, mainly in the southwestern part of the United States, Mexico, and Canada. High antioxidant activities of different parts of prickly pear have been reported (62.96% in pericarp, 42.27% in mesocarp, and 51.70% in endocarp) and are related to phenolic and flavonoid 3509



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composition.7 This content was found to be especially higher in seeds than in peel (23-fold), mesocarp (34-fold), and endocarp (47-fold).39 Clinical studies have reported that consumption of the O. joconostle pericarp may reduce glucose and cholesterol levels and modify LDL-C levels in patients with both type 1 and 2 diabetes.7 In addition to these papers, a study reporting the influence of the O. jocostle seed methanolic extract on the plasma lipid profile in mouse models showed that the seed extract was also able to prevent an increase in total cholesterol, LDL-C, triglyceride level, and atherogenic index. Of the seven polyphenol compounds identified in the fruit component via the HPLC-PDA analytical system (Figure 2), the study concluded that the observable effects were believed to be caused by the flavonoids present in the seed, specifically quercetin, rutin, and catechin. It possibly occurs through the up-regulation of LDL receptor expression and inhibition of hepatic lipid synthesis and lipoprotein secretion, thereby enhancing cholesterol elimination through bile acids.40 Overall, the ability of the methanolic extract of prickly pear seeds to exhibit hypolipidemic activity with no apparent toxic manifestations suggests that this could be an ideal supplement to short-term hypercholesterolemia treatment. Such seed extracts from P. americana, H. umbellata, A. majus, and O. joconostle could potentially be used as future antiobesity therapeutics in the long run with the development of a proper processing and extraction technique for these seed components. Flowers. The flower is a structure specialized for sexual reproduction. Many flowers have evolved traits such as brightly colored petals and attractive chemical scents to attract pollinators. In addition to facilitating the reproduction of flowering plants, the polyphenols, flavonoids, and anthocyanin present in flowers have recently been discovered to potentially exhibit medicinal properties.41,42 We could gain much from exploring and tapping the antiobesity potential of the phytochemicals that flowers contain as some studies have shown. Pomegranate Flower (Punica granatum L.). The pomegranate (P. granatum L.) is considered to be one of the oldest known edible fruits and is the symbol of abundance and prosperity in some cultures. The pomegranate has been known to be a fruit of multiple health purposes for many centuries. Recently, there has been scientific evidence suggesting the therapeutic activity observed in pomegranate such as antiatherogenic, antioxidant, anticarcinogenic, and anti-inflammatory effects.41,43,44 These beneficial effects were attributed to the antioxidative properties of pomegranate phenolic compounds, such as tannins and anthocyanin, present in its fruit components.44 A series of in vivo and in vitro experimental models using pomegranate flower (PGF) extract have been found to result in hypoglycemic, hypolipidemic, and anti-inflammatory effects in type 2 diabetes, obesity, and related cardiovascular diseases based on its modulation of PPARα- and/or PPARγ-mediated gene transcription. It is hypothesized in a review by Li et al. that the components present in PGF extract were able to promote a dual function activating both PPARα and PPARγ that accounts for the desired bioactivity required for treatment of diseases such as type 2 diabetes and obesity.45 The biologically active components that have been identified in PGF extract via HPLC methods46 include gallic, ursolic, and oleanolic acids. In a study done by Jang et al., commercially obtained gallic acid was seen to effectively an exhibit hypolipidemic effect on high fat dietinduced hyperlipidemia mice.47 Ursolic and oleanolic acids are

two triterpenoids that have long been recognized to have significant medicinal properties to the extent that these compounds have been isolated, treated, and marketed in countries such as China as an oral drug for human liver disorders as early as the 1980s.48 The possible mechanisms for the pharmacological effects and the prospects for these two compounds exhibiting antihyperlipidemia, antitumor activity, and anti-inflammation have also been discussed by Liu et al., suggesting that the presence of these two compounds identified in PGF makes it a potentially useful source not just for antiobesity but other associated diseases as well.49 In close relation to this, an in vivo experimental model study of Zucker diabetic fatty (ZDF) rats conducted by Li et al. showed that the administration of PGF extracts was able to exert a protective effect, preventing the increase in blood glucose level, total cholesterol, triglycerides, LDL-C, and lipid peroxidation levels of infected mice.41,42 This phenomenon could be explained by the ability of the bioactive components present within PFG extract to enhance the expression of PPARα and acyl-CoA oxidase (ACO) mRNAs as observed in the liver-derived HepG2 cell line.41 These series of studies thereby highlighted the ability of PGF to ameliorate obesity via a varied series of mechanistic pathways that essentially leads to the decrease of lipid accumulation in liver. Longan Flower (Dimocarpus longans Lour.). Longan (D. longans Lour.) is a tropical tree that produces edible fruit which is widely grown in Myanmar through southern China and Southeast Asia. Unpollinated longan flowers are generally regarded as disposable byproducts. Yang et al. have identified several phenolic acids and flavonoids present in longan flower water extract (LFWE) via HPLC methods running against several commercially available phenolic acid and flavonoid standards, of which gentisic acid, epicatechin, and ferulic acid were among the major compounds identified. The study went on to investigate the effects of administration of LFWE on 9week-old Sprague−Dawley hypercaloric rats. It was found that LFWE was able to lower the liver cholesterol and triglyceride levels as well as inhibit pancreatic lipase activities by upregulation of LDL-receptor and PPARα mRNA expression. It was also found to have lowered the rate of lipid biosynthesis via the down-regulation of sterol regulatory element binding protein-1c (SREBP-1c), a critical transcription factor that stimulates several lipogenic enzymes involved in fatty acid biosynthesis, as well as fatty acid synthase (FAS) gene expression.23 This observation is further supported by a series of other studies highlighting the similar ability of naturally occurring polyphenols contributing to similar effects.50,51 Overall, Yang et al. have shown the ability of LFWE to result in antiobesity and hypolipidemic effects via a combined effect of decreased exogenous lipid absorption, normalization of hepatic PPARα gene expression, suppression of pancreatic activity and SREBP1c and FAS gene expression, and higher fecal triglyceride. Hsieh and colleagues have also demonstrated the role of epicatechin as the major component in longan flowers that promotes antioxidant effects on cells.52 These series of studies have shown a collectible amount of findings, which significantly indicated the ability of longan flowers to be used as future therapeutics against not just obesity but also a series of other associated diseases. Leaves. Leaves are organs of the plants where photosynthesis takes place by which captured solar energy is converted into useful chemical energy, which liberates oxygen required for 3510



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product (AGE) inhibitors, which may potentially be useful for treatments for associated diseases that include diabetes.58,59 Guava Leaves (Psidium guajava). Guava (P. guajava) leaves have been used as traditional medicine for various kinds of diseases over centuries.60 The rich content of antioxidants, antibacterial agents, anti-inflammatory agents, and tannins present in P. guajava leaves makes it a medicinally useful tool for traditional remedy. In a recent study, Yang et al. reported that quercetin-3-O-(6″-feruloyl)-β-D-galactopyranoside (QFG), an active compound isolated and extracted from P. guajava via octadecylsilyl silica gel (ODS) HPLC, has suppressive effects on adipogenesis in 3T3-L1 preadipocytes through downregulation of PPARγ and C/EBPα expression.20 Quercetin is a typical flavonoid proven to play a pivotal role in the prevention of obesity61,62 and is abundant in guava leaves. It was extracted and its suppressive effects on adipogenesis were compared with QFG. The efficacy of the two respective compounds was analyzed via Oil Red O staining63 and triglyceride assay. It was found that QFG inhibited adipogenesis in a dose- and time-dependent manner and exerted a stronger suppressive effect than quercetin in all setups. Both mRNA and protein expressions of the key adipogenic transcriptional factors, PPARγ and C/EBPα, were inhibited by QFG. These series of results suggest that both QFG and quercetin present in P. guajava leaves were able to effectively suppress adipogenesis.20 In a separate study, it was also found that quercetin was able to inhibit adipogenesis in 3T3-L1 preadipocytes by adenosine monophosphate kinase (AMPK) and mitogen-activated protein kinase (MAPK) pathways and that the combination of quercetin and resveratrol enhanced the inhibition.62,64 Essentially, these series of studies showing the therapeutic capabilities of the major bioactive components identified in guava leaves have certainly shown the potential of such fruit waste components to be used as alternative sources of remedy. Potential Antidiabetic Properties of Tropical Fruit Leaves. Although this review mainly highlights the key tropical fruits that have been discovered to exhibit antiobesity potential, a series of related diseases that often can be associated with obesity cannot be neglected. A commonly related disease that can be linked with obesity is type 2 diabetes. A review by Kahn et al. discussed how obesity subsequently leads to an increased risk of developing insulin resistance and, consequently, type 2 diabetes. As mentioned, “in obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet β-cells, failure to control blood glucose levels results. Abnormalities in β-cell function are therefore critical in defining the risk and development of type 2 diabetes.”65 Understanding how obesity can lead to diabetes via several underlying mechanisms, we will then discuss some examples of tropical fruit leaf components that have been found to exhibit antidiabetic activity. To name some examples, the amla and papaya leaves will be discussed in the following section. There have yet to be studies done on the same component exhibiting antiobesity effects. Papaya Leaves (Carica papaya). Traditionally, papaya leaves have been widely used in Mexican folk medicine to treat diabetes and inflammation as well as diarrhea.66,67 In a study done by Juárez-Rojop et al. the hypoglycemic effect of the

respiration by living organisms. Besides the photosynthetic roles, leaves also serve as a chemical energy storage point for plants. Tapping this knowledge, several studies have been done to investigate the efficacy of phytochemical compounds present in leaves as potential therapeutics for obesity. Mango Leaves (Mangifera indica L.). Mango leaves (M. indica L.) have proven to be beneficial in alleviating diabetes and inhibiting triglyceride accumulation in 3T3-L1 cells. It is thus a prospective candidate for such tropical fruit waste component to be recycled and used as potential therapeutics for related diseases, namely, diabetes and obesity. In a study conducted by Kumar et al., mangiferin, a bioactive phytochemical component, was extracted and isolated from stem bark of M. indica and subjected to a glucose utilization test with 3T3-L1 cells. The results showed that treatment of the 3T3-L1 cells with mangiferin increased the glucose utilization in a dose-dependent manner.53 Zhang et al. isolated 12 active fractions, as highlighted in Figure 2, via ordinary and reversed phase silica gel column chromatography as well as HPLC from M. indica L. leaf extracts and tested each compound against 3T3-L1 cells to monitor their respective effects on gene expression. The study indicated that of the 12 compounds (summarized in Figure 2), foliamangiferoside A, iriflophenone3-C-β-glucoside, iriflophenone-3-C-(2-O-p-hydroxybenzoyl)-βD-glucopyranoside, maclurin-3-C-β-D-glucoside, and mangiferin were able to significantly suppress the accumulation of triglyceride in mature 3T3-L1 cells and inhibit the expression of genes including SREBP1c, FAS, and hormone-sensitive lipase (HSL), all associated with triglyceride biosynthesis.54 Olive Leaves (Olea europaea). Several studies have suggested that oleuropein and hydroxytyrosol present in O. europaea leaves are the key antioxidants responsible for preventing LDL oxidation and protecting cells against numerous diseases.55−57 Oleuropein is a principal phenolic compound in olive leaves, which can produce other bioactive substances such as hydroxytyrosol upon hydrolysis. Drira et al. obtained these bioactive compounds commercially to study their respective in vitro inhibition activity on adipocyte differentiation using 3T3-L1 preadipocyte cells. The results showed that oleuropein and hydroxytyrosol dose-dependently suppressed intracellular triglyceride accumulation during adipocyte differentiation without effect on cell viability. PPARγ, C/EBPα, and SREBP-1c transcription factors and their downstream targets (GLUT4, CD36, and FASN), all of which are adipogenesis-related genes, were down-regulated after treatment by oleuropein and hydroxytyrosol. In addition, a flow cytometry study also revealed that both polyphenols were able to inhibit the division of 3T3-L1 preadipocytes during mitotic clonal expansion and cause cell cycle delay. This combinative effect of the bioactive compounds extracted and isolated from olive leaves was observed to collectively result in an overall reduction of lipid accumulation in 3T3-L1 cells and thus regulate the size of fat cells, giving them potential as useful obesity-preventive additives to foods and drinks.16 In addition, besides oleuropein and hydroxytyrosol, among other phenolic compounds that were identified in the most recent study conducted by Kontogianni et al. via liquid chromatography−ultraviolet−visible (UV−vis) diode array coupled to electrospray ionization multistage mass spectrometry (LC/DAD/ESI-MS) were luteolin, luteolin-4′-O-β-Dglucopyranoside, and luteolin-7-O-β-D-glucopyranoside. These compounds were assigned as potent advanced glycation end 3511



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aqueous extract of C. papaya leaves in streptozotocin-induced diabetic rats was evaluated. It was found that the administration of this extract was able to significantly reduce the blood glucose level in diabetic rats and decrease cholesterol and triacylglycerol as well as amino-transferase blood levels. Additionally, the cell size preservation observed under histological reference of the diabetic rat’s pancreas further suggested the ability of C. papaya aqueous extract to help in islet regeneration. In the liver histopathological examination, it was further revealed that the aqueous extract was able to prevent hepatocyte disruption, as well as accumulation of glycogen and lipids. On the basis of the collective data gathered from their study, the author confirmed the hypoglycemic effect of C. papaya leaves and their ability to prevent further disruption produced by diabetes.68 However, admittedly, the lack of studies investigating the implicated phytochemical constituents and the exact mechanism of action responsible for the overall positive activity mentioned has yet to be addressed. Amla Leaves (Emblica of ficinalis). In traditional Indian medicine, all parts of E. of f icinalis Gaertn. plant including the fruit, seed, leaves, root, bark. and flowers are used in various herbal preparations for the treatment of diabetes mellitus and chronic diarrhea and as an anti-inflammatory and antipyretic. In a study conducted by Nain et al. using in vivo streptozotocininduced diabetic rats as an experimental model, they discovered that the extract of leaves of E. off icinalis Gaertn. (HMELEO) was able to effectively normalize the impaired antioxidant status in streptozotocin-induced diabetic rats in a dose-dependent manner. In addition to this, its ability to exert rapid protective effects against lipid peroxidation by scavenging free radicals thereby contributes to the overall reduction in the risk of diabetic complications.69 Although the study did not isolate or identify the phytochemicals that were responsible for the observed bioactivity, the author cross-linked with a series of previous studies of the same species suggesting that ellagic acid, gallic acid, ascorbic acid, tannins emblicannin A and B, and tannoids kaempferol, kaempferol-3-O-glucoside, and rutin may be the bioactive compounds.70,71 Rind/Peel. The outer covering of a fruit is known as the peel or rind. However, there is a subtle difference between the rind and the peel. The rind generally is harder and thicker, whereas the peel/skin is generally thin and soft. Rinds, peels, and skins of fruits contain several phytochemicals that can help maintain good health, which is evident in several studies.18,19,24,72 Mangosteen Rind (Garcina mangostana). A potentially useful tropical fruit rind that has shown to exhibit antiobesity potentials would be that of the G. mangostana fruit. The fruit hulls of G. mangostana, just like P. guajava leaves, have long been used throughout Southeast Asia as a medical plant for a wide variety of treatments.73 Modern research has identified and isolated 13 phenolic compounds from the hulls of G. mangostana by column chromatography, which are αmangostin, β-mangostin, γ-mangostin, 9-hydroxycalabaxanthone, garcinone E, 1,5-dihydroxy-3-methoxy-2-(3-methylbuten-1-yl)-9H-xanthen-9-one, 1,3,7-trihydroxyxanthone, 2,4,6,7tetrahydroxyxanthone, 3,4,5,3′-tetrahydroxybenzophenone, 2,4,6,3′,5′-pentahydroxybenzophenone, neosmitilbin, epicatechin, and egonol.74 In an experiment done by Quan et al., it was discovered that among the 13 phenolic compounds isolated,74 α-mangostin induced apoptosis and suppressed differentiation of 3T3-L1 cells through inhibition of fatty acid synthase (FAS). Further

Oil Red O staining tests showed that it was able to prevent the intracellular lipid accumulation of the differentiating adipocytes and that it stimulated fat cell breakdown in the mature adipocytes.18 Loftus et al. highlighted how central inhibition of FAS suppressed food intake and led to dramatic weight loss in mice.75 It is believed that natural sources of nutraceuticals that are capable of reducing FAS activity or expression levels may be useful for the supplementary treatment of obesity. Among the 13 phenolic compounds present in the hulls of G. mangostana (Figure 2), it was found that phenolic constituents containing the conjugated system of phenyl and carbonyl, especially xanthones and benzophenones, particularly α-mangostin, γmangostin, garcinone E, and 2,4,6,3′,5′-pentahydroxybenzophenone, exhibited the strongest inhibitory activity of FAS.74 These series of findings suggesting the ability of isolated components extracted from the hulls of mangosteen fruit, namely, α-mangostin, to induce apoptosis of 3T3-L1 preadipocytes that consequently suppressed lipid accumulation as well as α-mangostin, γ-mangostin, garcinone E, and 2,4,6,3′,5′-pentahydroxybenzophenone exhibiting strong inhibitory activity of FAS, certainly highlights the great potential of this fruit component to be exploited and used to treat obesity. Citrus Genus Peel (C. sunki, C. reticulata, C. grandis, C. aurantifolia). Over the past years, a series of studies have been done on the Citrus family. Whereas the flesh itself has been widely known to contain antioxidants and weight -loss properties,76 the peels of a few species were recently discovered to exhibit a wide range of biological activities, including antioxidative, antihypertension, antihyperglycemia, and antiobesity effects.77−79 Among the species identified include the peels of C. sunki, C. ichangenesis, and C. grandis. These potentially health-promoting effects observed from the citrus components have been ascribed to the bioactive compounds present such as flavanoids, coumarins, polyphenols, limonoids, and alkaloids. The immature C. sunki peel extract as recently discussed by Kang et al. was found to exhibit antiobesity effects by βoxidation and lipolysis in adipose tissue.77 The study was based on an in vivo experimental model of which controlled dosage of C. sunki extract was administered to high fat diet-induced obese mice, and their respective liver, epididymal tissue, and perirenal adipose tissue were regularly monitored. Protein expressions of the related pathways were then investigated by obtaining the total RNA from the respective adipose tissue of mice and in vitro 3T3-L1 adipocyte cells, via reverse transcription polymerase chain reaction (RT-PCR). The collective data were sufficient for the author to conclude that the peel of C. sunki had an antiobesity effect. However, although no phytochemicals were isolated in the study, polymethoxyflavonones (PMFs), namely, tangeretin and nobiletin, were identified in the extract and deduced to be the possible bioactive compounds that mediate the antiobesity effect.77,80 In a research study done by Ding et al., they made a similar observation in C. grandis, more commonly known as the pomelo, peels. Using an in vivo experimental model of obese C57BL/6 mice induced with a high-fat diet (HFD), they found that the peel crude extract was able to block the body weight gain and lower the blood glucose level, serum total cholesterol, liver lipid levels, and serum insulin levels as well as improve glucose tolerance and insulin resistance. Further effects of the extract on various gene expressions were also investigated using quantitative RT-PCR via extraction of total RNA from mouse tissues. Interestingly, despite the lack of identification of 3512



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bioactive compounds81 presented in their study, Ding et al. brought up several differences in bioactivity of C. grandis originating from different cultivars.82 This observation, therefore, illustrated an important fact as to how agronomic factors, such as environmental factors and varied conditions, may affect the overall bioactivity and antioxidant capacity of the fruit. Mango Peel (Mangifera indica L.). M. indica L. is a tropical fruit that is rich in a diverse array of bioactive phytochemicals. There is a growing body of evidence that links phytochemicals with the inhibition of adipogenesis and protection against obesity. In particular, Taing et al. carried out an experiment demonstrating not only the effect of the mango peel extract on adipogenesis in 3T3-L1 cells but also how the differences in phytochemical quantity and composition between species of the same fruit can exhibit different adipogenesis inhibition efficiencies.19 Methanol extracts of peel and flesh from three archetypal mango cultivars, Irwin, Nam Doc Mai, and Kensington Pride, were assessed for their effects on the 3T3-L1 preadipocyte cell line model of adipogenesis, respectively. Whereas the flesh from all three cultivars was ineffective, two of the peel extracts, namely, Irwin and Nam Doc Mai, inhibited adipogenesis. This observation was further analyzed, and it was concluded that differences in phytochemical composition between mango cultivars may influence their effectiveness in inhibiting adipogenesis and that specific components within the phenolic content make a major contribution to its overall antiadipogenic effects. The studies further showed that the inhibition of adipogenesis occurred possibly through the inhibition of mitotic clonal expansion, mediated by pathways similar to those of the red grape component resveratrol.83 Essentially, regardless of the different efficiencies, the ability of M. indica L. to promote positive inhibition effects toward adipogenesis puts forth another fruit waste component as a potential tropical fruit source to treat obesity. In general, several studies of various tropical fruit components and their respective observed biological activities have certainly highlighted the potential benefits that may result when they are used as supplements for the treatment of obesity, along with its related diseases such as diabetes. The study of mango peels originating from various cultivars, as discussed by Taing et al., exhibiting varied effects on the overall biological activity suggests that the chemical composition present in fruits may differ, even if they are from the same species. The environmental factor, weather conditions, amount of nutrition, and the overall agricultural technique used to grow these fruits will essentially determine the primary composition of the fruit components. Ideally, then, before the agronomic approaches can be developed to alter the agricultural conditions leading to an effective yield of fruit components consisting of highly bioactive phytochemicals, the actual bioactive phytochemicals have to first be determined. This would therefore require further isolation and elucidation of the active compounds responsible for the overall respective antihyperlipidemic, antiinflammatory, hypoglycemic, and antiobesity effects as addressed previously. Although the isolation and effective separation process of various chemicals from the fruit waste components may be time-consuming, it is absolutely necessary for the effective development of this field. The presence of more advanced analytical devices such as the prep-HPLC, supercritical fluid extraction technique, and LC-MS, for instance, will definitely help to facilitate this research. The subsequent steps would

therefore require further elucidation of chemical structure for the novel bioactive phytochemicals. As for the existing/current bioactive chemicals identified, further investigation is required so that absolute confirmation of its respective bioactive capacity proposed can be done.

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PHYTOCHEMICALS RESPONSIBLE FOR THE RESPECTIVE BIOACTIVITY Polyphenols are often associated as the component responsible for antioxidant effects commonly observed in natural products.84,85 Therefore, this would also suggest that if a fruit component exhibits high antioxidant capacity, it effectively means that there is a high presence of polyphenols in the fruit component. In addition to this, polyphenols have also been found in several studies to be responsible for the positive antiobesity effect as established by Wang et al.86 In relation to the commonly suggested “high antioxidant capacity in natural components reflecting higher potential to treat disease” phenomenon, a comparative study recently published by AlMansoub et al. on antihyperlipidemic and antioxidant effects of Garcinia atroviridis showed an interesting observation that suggests otherwise. In their study, they revealed that the aqueous extract was observed to contain fewer polyphenols than the methanolic extract but reflected a stronger bioactivity (antihyperlipidemic effect). This finding further suggested that there were other compounds besides polyphenols that were involved, leading to the overall efficacy of the bioactivity observed.87 From the collection of major compounds identified in the series of studies as summarized in Table 1, we have found that the bioactive phytochemicals recommended were not necessarily polyphenols. In promegranate flowers, for instance, the major compounds identified were oleanolic acid and ursolic acid,41 whereas in the bishop’s weed, the main components identified as exhibiting antiobesity activities were the furocoumarins. Among some of the other nonpolyphenols were the polymethoxyflavonones (PMFs) found in C. sunki and flavonoids in C. grandis and H. umbellata.31,77,82 Therefore, the independent role of polyphenols in inducing positive antiobesity effects was questioned. How these phytochemicals were proposed in the studies to effectively result in the reduction of lipid accumulation at the adipocytes, a characteristic of antiobesity properties, differed from one component to another. Could it be a combinatorial effect with other compounds mentioned? Do they share a similar lipid accumulation inhibition mechanism as polyphenols? Although the exact role of the bioactive compounds in the overall inhibition of lipid accumulation has yet to be determined, various studies have shown the different possible mechanisms that these compounds may play. On the basis of the mechanistic analysis of how the respective major bioactive compounds identified play a role in the overall positive antiobesity effect, it was observed that each compound reacts differently from one another, regardless of its class (i.e., polyphenols or flavonoids or PMFs). Typically, this boils down to the different set of genetic expressions that these compounds affect, which gradually leads to the overall antiobesity effect observed in the end. Between the polyphenols identified in olive leaves and mango leaves, for instance, the oleuropein and hydroxtyrosol in olives were found to prevent 3T3-L1 adipocyte differentiation via the inhibition of the mitotic clonal expansion and down-regulation of the adipogenesis-related genes, namely, PPARγ, C/EBPα, and SREBP-1c,16 whereas the 3513



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FUTURE OF TROPICAL FRUIT WASTE COMPONENTS Tropical fruit waste components, as discussed in this review, have various bioactive components with health benefits. The combination of these effects rendered by the reported tropical fruit “waste components” is crucial to prevent the development of complex pathophysiology of obesity and diabetes. The extraction of these components and in-depth study of their effects on the various genetic expression using in vitro and in vivo test models, as addressed in this paper, have shown clear evidence of the positive effects that these bioactive phytochemicals possess. This essentially suggests the potential use of such components as future therapies to further supplement antiobesity treatments. In addition, as these components originate from natural sources, the likelihood of these extracts being toxic and detrimental is decreased.9 Further studies involving the isolation of bioactive compounds from tropical fruit waste components and the elaboration of a mechanistic approach toward the overall lipid regulation in cells is, however, still necessary for further advances in the development of these waste components. The exact structural roles of the bioactive phytochemicals in the overall antiobesity mechanism have to be further looked into, of which some of the studies may encompass the need for chemical crystallization and computer modeling. In addition, further large-scale defined basic and clinical studies are critical to determine optimal dietary regimens to achieve the desired beneficial health effects. Ultimately, only with enough positive and reliable relevant data can the commercial use of these tropical fruit waste components as future therapeutics be advocated.

foliamangiferoside A, iriflophenone-3-C-β-glucoside, and mangiferin found in mango leaves were found to result in the same effect but via the down-regulation or inhibition of the FAS and hormone-sensitive lipase (HSL) gene expression.54 In C. sunki peel extract, where the major compounds identified were mainly flavonoids, it was found that the observed antiobesity effect proceeded via elevated β-oxidation and lipolysis in adipose tissue. This was deduced from a series of results that included the crude extract’s ability to increase AMPK and ACC phosphorylation in mature 3T3-L1 adipocytes.77 We therefore conclude that there is indeed no one mechanism that is used to find the cure to obesity. Many scientists used different models in identifying antiobesity capacity, some of which use the in vivo experimental model, whereas others use the in vitro assay, typically 3T3-L1 adipocyte cells. There is, however, no specific right or wrong answer to this phenomenon. The mechanisms by which these bioactive compounds proceed to sequentially result in an overall positive antiobesity effect vary from one fruit component to another. The roles of the specific bioactive phytochemicals, mainly the polyphenols, flavonoids, and furocoumarins, in the overall mechanism have yet to be established. More research, particularly in the area of isolation, identification, and elucidation of bioactive compounds, has to be done. Subsequently, crystallization of these compounds can then proceed, in order for computational modeling to be generated to further investigate how these respective bioactive compounds play an essential role in the overall mechanism (such as adipogenesis), that leads to the positive antiobesity effect, initially observed in vivo. Following this, only then can the in vivo as well as clinical studies, using the isolated bioactive phytochemicals, be facilitated to support the therapeutic roles of fruit waste components in the overall effect of obesity treatment. Such results may then push for further development of new agronomic approaches, implementing new technological innovation to cultivate tropical fruit parts enriched in a specifically desired composition of phytochemicals and, at the same time, an effective large-scale processing technique of specific tropical fruit wastes can be strategized.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Author Contributions ∥

K.L. and H.L.T. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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DEVELOPMENT OF EFFECTIVE FRUIT WASTE PROCESSING/RECYCLING TECHNIQUES AND AGRONOMIC ADVANCES In the pursuit of finding an alternative means to combat obesity using natural sources, studies of fruit waste components have been done, and they have appeared to be prospective sources of remedy due to their high bioactivity and lesser tendency of inducing detrimental side effects. Although more elaborate studies have to be done specifically on the isolation and elucidation of compounds responsible for their respective bioactivity, as addressed earlier in the review, there are a few other challenges that have to be dealt with. To effectively tap the maximum potential of tropical fruit waste components as future therapeutics, an effective large-scale processing technique for these waste components has to be designed. Other relevant factors include finding the right places and equipment to store these components to prevent them from decaying, intricate engineering of large-scale extraction techniques to take up only the desired materials, and implementing necessary agronomic advances to utilize and develop new technological innovations to cultivate crops containing high useful phytochemical compositions.

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