Natural Peroxisome Proliferator-Activated Receptor γ (PPARγ) Activators for Diabetes

Hossam M. Abdallah, PhD; Riham Salah El Dine, PhD; Gamal A. Mohamed, PhD; Sabrin R. M. Ibrahim, PhD; Ibrahim A. Shehata, PhD; Ali M. El-Halawany, PhD

 


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ABSTRACT

Context • Metabolic syndrome (MetS) represents a worldwide problem. Drugs used in MetS target different symptoms, like excessive body weight, insulin resistance, hyperglycemia, dyslipidemia, or hypertension. Peroxisome proliferator-activated receptors (PPAR) regulate the gene expression involved in lipid metabolism, inflammation, and adipogenesis. Activation of PPARγ has become a target of interest to counter hyperglycemia linked with MetS and type 2 diabetes (T2DM).

Objective • The current review intended to summarize reported research on medicinal plants, or their bioactive constituents, with PPARγ-activating potential.

Design • The research team searched the literature up to 2016 using electronic databases— ScienceDirect, PubMed, Google-Scholar, SpringerLink, Scopus, and Wiley—for publications on medicinal plants with promising PPARγ modulators using keywords diabetes mellitus, natural products, peroxisome proliferator-activated receptors, metabolic syndrome, adipogenesis.

Setting • This study was conducted in the Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia, Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt, and Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah, Al Munawwarah, Saudi Arabia.

Results • Several natural products were considered to be good ligands for PPARγ. The PPARγ agonistic activity of over 100 plants covered in this review was supported by experimental evidence. Some of the plants and their constituents had been studied for their possible mechanisms of action.

Conclusions • Findings discussed in this review highlighted PPARγ’s role as an organizer of lipid metabolism and glucose homeostasis, thus supporting its function as a target for antidiabetic agents. The discovery that some natural compounds and plants could activate PPARγ opens up the prospect for future development of strategies to take advantage of its therapeutic potential in diabetes. Therefore, the current review could provide significant information for biotechnological or pharmaceutical applications in targeted drug delivery and design. (Altern Ther Health Med. 2020;26(S2):28-44.)

 

Hossam M. Abdallah, PhD, Associate Professor, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia, and Associate Professor, Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Riham Salah El Dine, PhD, Associate Professor, and Ali M. El-Halawany, PhD, Associate Professor, Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Gamal A. Mohamed, PhD, Professor, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia, and Professor, Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt. Sabrin R.M. Ibrahim, PhD, Professor, Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah, Al Munawwarah, Saudi Arabia, and Professor, Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, Egypt. Ibrahim A. Shehata, PhD, Professor, Faculty of Pharmacy, Department of Natural Products and Alternative Medicine, King Abdulaziz University, Jeddah, Saudi Arabia, and Professor, Faculty of Pharmacy, Department of Pharmacognosy, Cairo University, Cairo, Egypt.

 


Corresponding author: Sabrin R. M. Ibrahim, PhD
E-mail address: [email protected]


  

Metabolic syndrome (MetS) represents a worldwide problem. In 1920, Kylin defined metabolic syndrome as a clustering of gout, hyperglycemia, and hypertension.1 Later, in 1947, the term upper body obesity in men was first introduced as an obesity type associated with cardiovascular diseases and diabetes.2 It is also known as insulin resistance syndrome, syndrome X, and deadly quarter.3-5 Finally, it could be described as an imbalance between storage and use of energy, resulting in abdominal obesity, insulin resistance, hyperglycemia, and hypercholesterolemia.6

MetS is distinguished by hypertension, hyperinsulinemia, abdominal obesity, and dyslipidemia. It affects more than a quarter of the world’s population, because of high-calorie nutrition and lack of physical activity.7 People influenced by MetS are at a high risk for the development of cardiovascular complications,8 due to the influence of oxidative stress and hyperglycemia on vascular biology.9

The management of MetS could be achieved either by modification of life style through reducing calorie intake and increasing energy expenditure or using available pharmaceutical preparations. Drugs used in MetS target different symptoms, like excessive body weight, insulin resistance, hyperglycemia, dyslipidemia, or hypertension. Type 2 diabetes (T2DM) is treated either with insulin and insulin analogs or oral hypoglycemics.10 Oral hypoglycemics perform their action through increasing insulin secretion using sulfonylureas11; increasing insulin sensitization using biguanides, eg, metformin; slowing starch digestion in the small intestine using alpha-glucosidase inhibitors; and using biguanides increasing secretion of insulin using meglitinides or DPP-4 inhibitors, dipeptidylpeptidase 4, or PPARγ agonists—thiazolidinediones.12 PPARγ, the molecular target of thiazolidinediones, is implicated in the regulation of storage of fatty acids, insulin sensitivity, and glucose metabolism, thus representing a target of interest that can modulate several aspects of MetS.13,14

 

Methods

Procedures

The research team searched the literature up to 2016 using electronic databases—such as ScienceDirect, PubMed, Google-Scholar, SpringerLink, Scopus, and Wiley—for publications on medicinal plants with promising PPARγ modulators. The following keywords were used; diabetes mellitus, natural products, peroxisome proliferator-activated receptors, metabolic syndrome, and adipogenesis. Searching Sci Finder, 354 articles relating to these keywords have been found. Studies including plant extract or active metabolite that act as PPARγ modulators have been chosen to be included in this review. The authors share the collected articles to decide which one is suitable to be included in this work. The criteria of selection depend on choosing plant extract which should be either standardized or one with identified constituents, in addition, studies that included testing bioactive known secondary metabolite were also selected.

Results

PPARγ in Regulation of Metabolism

PPARs constitute a subfamily within the nuclear receptor superfamily of ligand-inducible transcription factors.15 Three known subtypes of PPARs exist: α, β/δ, and γ.16,17 They regulate the gene expression concerned with the metabolism of lipids, adipogenesis, and inflammation.

PPARα is expressed in the heart, liver, muscles, and kidney. It is responsible for controlling lipid and lipoprotein metabolism.18,19 Fenofibrate and gemfibrozil, selective agonists for PPARα, are efficient in improving dyslipidemia but are not considered to be antidiabetic agents.20 PPARβ/δ is expressed throughout the body. It controls lipid metabolism in adipose tissue.21 PPARγ is present in 2 isoforms—1 and 2.19 PPARγ-1 is expressed in the large intestine, adipose tissue, liver, kidney, and muscles; meanwhile, PPARγ-2 is restricted to brown adipose tissue only.19,21,22

At the molecular level, PPAR is found bound to the retinoic acid receptor in a heterodimer form.23 The PPAR-retinoid X receptor (PPAR-RXR) heterodimer is normally bound to a co-repressor protein. Upon activation of the PPAR-RXR complex by specific ligands, a dissociation of the corepressor protein and recruitment of a co-activator one takes place (Figure 1).24 In addition, ligand binding results in the binding of PPAR to a specific DNA response element, which in turn transmits a transcriptional activation signal to the cell transcriptional machinery. Based on the ligand structure, different PPAR-ligand-complex conformations are attained resulting in a recruitment of various co-activators based on that conformation.24 The recruitment of a specific co-activator results in a pattern of ligand-specific gene regulation.23,24

 

PPARγ Role In Diabetes

PPARγ plays a significant role in glucose homeostasis and the metabolism of lipids.25 Moreover, it can stimulate various genes involved in the storage of lipids in adipocyte.26 Adipose tissue is responsible for the insulin-sensitizing effects of thiazolidinedione-type PPARγ ligands. In addition, PPARγ can affect insulin sensitivity through the expression of some factors from adipose tissue; adiponectin and leptin have positive effects on insulin sensitivity, while resistin and tumor necrosis factor-α showed negative effects.27 In addition, PPAR affects glucose homeostasis through upregulation of glucose transporter type 4 (Glut4).27,28

PPARγ agonist improves insulin sensitivity and glucose tolerance by increasing adiponectin levels, a significant adipocytokine related to insulin sensitivity in adipose tissue.29,30 PPARγ agonists are used therapeutically to withstand hyperglycemia linked with MetS and T2DM.29,30 Regardless of their efficiency in normalization of blood-glucose levels, the presently used thiazolidinedione-type PPARγ agonists have severe side effects, making the finding of new ligands extremely relevant.

Thiazolidinediones (TZDs) represent the only approved class of compounds acting as full PPARγ agonists in T2DM. The first drug approved from this group was troglitazone, which can activate both PPARα and γ.30,31 Troglitazone increases insulin sensitivity and glucose tolerance, but it was withdrawn due to fatal hepatotoxicity.31 Rosiglitazone and pioglitazone are other drugs that were developed after TZDs, and they are still in clinical use in spite of their side effects. Rosiglitazone is effective in reducing insulin resistance, but this effect is accompanied by an increase in the risk of myocardial infarctions and heart failure.32 Treatment of T2DM with pioglitazone has also been limited due to the side effects of weight gain, and probably, blood cancer.31,32

 

PPARγ Activation by Natural Products

The significant side effects of TZDs, including weight gain, edema, and hepatotoxicity resulted in their limited clinical use or withdrawal from the market.33 These proposed side effects were due to activation of the PPARγ, unlike the weak PPARγ endogenous agonists, such as prostanoids and fatty acids.33,34 Therefore, researchers are struggling to find selective PPARγ modulators that can decrease insulin resistance and glucose use with the least possible side effects.35

The most recently identified compound is N-acetylfarnesylcysteine, which has shown full and partial agonistic effects on PPARγ.36 For thousands of years, natural products have been used for treating disease, and currently, many active pure compounds from natural resources are serving as marketed drugs or represent promising drug leads. Natural products have historically been a favorable pool for obtaining various metabolites for drug discovery.6

The ethnopharmacological use of medicinal plants for the treatment of diabetes developed because they have few side effects, low cost, and easy availability. A considerable research effort has occurred to discover the PPARγ-activation capacity of various natural products, produced by dietary sources or medicinal plants.28,30

Finding plants with promising, selective PPARγ modulators (SPPARMs) could occur based on ethnopharmacological uses, normal screening, or virtual screening. The traditional uses of herbal products can often introduce powerful hints about the pharmacological potential of their components.6 A study surveying 119 plant-originated drugs that are in clinical use revealed that 74% of them have actually been used to find ailment indications relevant to the traditional uses of the plants from which the clinical constituents were separated.37 Numerous investigations have been conducted to explore the ability of natural products or their bioactive compounds to act as PPARγ modulators.38

The reported data in this review are presented in two parts; first part includes pure secondary metabolites1-41 that inspected for their PPARγ-activation capacity where their structures are presented in Figures 2-4, compunds 1 to 42 the second part includes standardized plant extract or one with identified major constituents and examined for its PPARγ activity, which is presented in Table 1, and structure of its major constituents are displayed in Figure 2-4, compunds 43 to 95.

 


Table 1. List of Plants Evaluated for Peroxisome Proliferator-activated Receptor-γ (PPAR γ) Agonistic Activity.

 

Plant Name (Family) Active Compound (Class) Cell Line/ Model/Assay Activity/Mechanism
A
Alnus japonica Siebold & Zucc.

(Betulaceae)82

4-hydroxy-alnus-3,5-dione (42) (Diarylheptanoid) 3T3-L1 cells Found anti-adipogenic effect via downregulation of PPARγ, C/EBPα, and SREBP1c signaling.
Amorpha fruticosa L.

(Fabaceae)71

Amorfrutins

(Isoprenoid-substituted benzoic acid derivative)

  Amorfrutins bonded to and activated PPARγ, which resulted in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs.
Astragalus membranaceus Moench (Fabaceae)20 Formononetin (43) (Isoflavonoid) Chimeric PPARα/γ reporter-gene bioassay Found potent activators of PPARα/PPARγ receptors (EC50 1-4 μM/L) with PPARα/PPARγ activity ratios of 1:3 in the chimeric and almost 1:1 in the full-length assay, comparable to those observed for synthetic dual PPAR-activating compounds under pharmaceutical development.
Alnus incana (L.) Moench (Betulaceae)83   3T3-L1 cell model Found Alnus incana extracts acted as partial agonists toward PPARg activity.
Akebia quinate (Thunb. Ex Hout.) Decne. (Lardizabalaceae)84   3T3-L1 adipocytes Found reduced expression of genes related to adipogenesis and increased expression of PPARα acetyl-CoA oxidase and adiponectin in the epididymal adipose tissue.
Artemisia scoparia Waldst. Kit.

Artemisia santolinifolia Turcz. ex Besser (Asteraceae)85

  Mouse model of
diet-induced obesity
Activated PPARγ, promoted adipogenesis, and enhanced insulin sensitivity in adipose tissue of obese mice.
Aegle marmelos L. Corrêa (Rutaceae)86

 

(3,3-Dimethylallyl) Hfn (44) T3-L1 adipocytes

High-fat and fructose-diet-induced obese C57/BL6J mice

Hfn decreased the expression of PPARγ and CEBPα and increased the expression of SREBP-1c, PPARα, adiponectin and GLUT4 compared to the HFD group.
Aristolochia manshuriensis Kom.(Aristolochiaceae)87

 

Aristolochic acid (45)

(Alkaloid)

3T3-L1 cells

HFD-induced obesity mouse model

Inhibited lipid accumulation by the downregulation  of the major transcription factors of the adipogensis pathway, including PPARγ and C/EBPα through regulation of the Akt pathway and ERK 1/2 pathway in 3T3-L1 adipocytes and HFD-induced obesity mice, and AA may be main act in inhibitory effects of AMK during adipocyte differentiation.
Acorus calamus L.

(Acoraceae)88

Asarone (46)

(2,4,5-trimethoxyphenyl-2-propene)

3T3-L1 adipocytes Asarone inhibited adipogenesis by downregulation of PPARg and C/EBPα and reduced lipid accumulation by stimulation of lipolysis through an increase in hormone-sensitive lipase activity.
B      
Bixa orellana L.

(Bixaceae)89

Bixin (47)

Norbixin (48) (Apocarotenoid)

3T3-L1 adipocytes Activated PPARγ by luciferase reporter assay using GAL4-PPAR chimera proteins and regulated mRNA expression involved in adipogenesis and enhanced insulin sensitivity in 3T3-L1 adipocytes through PPARγ activation.
C      
Carduus crispus L.

(Asteraceae)90

Apigenin (40)

(Flavonoid)

3T3-L1 adipocytes Inhibited lipid accumulation as well as C/EBPα and PPARg protein expression levels.
Camellia sinensis (L.) Kuntze

(Theaceae)55

(-)-Catechin (14)

(Flavonoid)

Human bone marrow mesenchymal stem cells (hBM-MSCs) Catechin promoted adipocyte differentiation and increased sensitivity to insulin, in part by direct activation of PPARγ.
Cannabis sativa L. (Cannabaceae)91 D9-Tetrahydrocannabinol (49)   THC is a PPARγ ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.
Chromolaena odorata (L.) R.M. King & H. Rob. (Asteraceae)92 (9S,13R)-12-Oxo-phytodienoic acid (50)

Odoratin (51)

(Isoflavonoid)

   
Coix lacrymajobi var. mayuen (Rom. Caill.) Stapf ex Hook. f. (Poaceae)93 Hydroxy unsaturated fatty acids PPARγ luciferase reporter assay Natural PPARγ agonists are produced in various mammalian cells.
Commiphora mukul (Hook. ex Stocks) Engl. (Burseraceae)41

 

Commipheric acid (1) (guggulipid) Lepob/Lepob mice

COS-7 cells

3T3 L1 preadipocytes

Both guggulipid- (EC50 0.82 μg/mL) and commipheric-acid- (EC50 0.26 μg/mL) activated human PPARα in COS-7 cells transiently transfected with the receptor and a reporter gene construct. Similarly, both guggulipid (EC50 2.3 μg/mL) and commipheric acid (EC50 0.3 μg/mL) activated PPARγ, and both promoted the differentiation of 3T3 L1 preadipocytes to adipocytes.
Cymbopogon citratus (DC.) Stapf (Poaceae)94 Citral (52) (Monoterpene)   Citral activated PPARα and γ and regulated COX-2 expression.
Curcuma longa

(Zingiberaceae)95

Curcumin (53) (Diarylheptanoid) db/db mice Curcumin regulated the expression of AMPK, PPARg, and NF-κB.
Cynanchum paniculatum (Bung) Kitag. ex H. Hara (Asclepiadaceae)96 Antofine (54)

(Alkaloid)

  Antofine exerted potent anti-adipogenic effects via direct suppression of PPARg protein expression, with consequent downregulation of adipogenic gene expression.
Cirsium japonicum DC.

(Asteraceae)97

Silydianin (55) (Flavonolignan) 3T3-L1 cells Chloroform fraction suppressed the expression of genes such as PPARγ, C/EBPα, adiponectin, lipoprotein lipase, and fatty acid synthetase involved in adipogenesis.
Cornus alternifolia L.f.

(Cornaceae)98

Kaempferol-3-O-b-glucopyranoside (56) (Flavonoid)   Exhibited potent agonistic activities for PPARα, PPARγ, and LXR with EC50 values of 0.62, 3.0, and 1.8 mM, respectively.
Cassia fistula L. (Caesalpiniaceae)99 (-)-Catechin (14) (Flavonoid) Streptozotocin-induced diabetic male albino Wistar rats Catechin possesses a potential agonistic characteristic that is capable of activating insulin receptor and PPARγ.
Cistus salvifolius

(Cistaceae)100

Trans-cinnamic acid derivative 3T3-L1 adipocytes Stimulated PPARγ and inactivated PPARα.
Cinnamomum cassia (L.) J. Presl

(Lauraceae)101

  3T3-L1 murine preadipocytes cells Significantly reduced lipid accumulation and down-regulated the expression of PPARg, C/EBPα, and SREBP-1c in 3T3-L1 adipocytes. CR extract also suppressed the expression of FAS, acyl-CoA synthase, and perilipin.
Cornus kousa Buerger ex Miquel

(Cornaceae)102

  3T3-L1 cells Increased PPARg ligand-binding activity in a
dose-dependent manner. Enhanced adipogenesis and the expression of PPARg and target proteins, including GLUT4 and adiponectin as well as proteins involved in adipogenesis, including PPARγ and C/EBPα in 3T3-L1 adipocytes.
D      
Harpagophytum procumbens DC. (Pedaliaceae)103 Harpagoside (57)

(Iridoid glycoside)

3T3-L1 Pretreatment with harpagoside activated PPARγ.
E      
Echinacea purpurea (L.) Moench

(Asteaceae)104,48

Isomeric C12-alkamides 3T3-L1 adipocytes Activated PPARγ to increase basal and insulin-dependent glucose uptake in adipocytes in a dose-dependent manner and exhibited characteristics of a PPARγ partial agonist.
  Alkamides   Activated PPARγ with no concurrent stimulation of adipocytic differentiation.
Eclipta prostrate L.

(Asteraceae)105

Wedelolactone (58) (Coumestan) Human adipose tissue-derived mesenchymal stem cells

(hAMSCs)

Wedelolactone reduced the formation of lipid droplets and the expression of adipogenesis-related proteins, such as C/EBPα, PPARγ LPL, and aP2.
Elaeis guineensis Jacq. (Arecaceae)106 Tocotrienols   Both α- and γ-tocotrienol activated PPARα, while δ-tocotrienol activated PPARα, PPARγ, and PPARδ in reporter-based assays. Tocotrienols enhanced the interaction between the purified ligand-binding domains of PPARα with the receptor-interacting motif of coactivator PPARγ coactivator-1α.
Elephantopus scaber L. (Asteraceae)107 Deoxyelephantopin (31) (Sesquiterpene lactone)   ESD functioned as a partial agonist of PPARγ by adopting a distinct mode of binding to PPARγ compared with rosiglitazone. The inhibition of ESD against cancer-cell proliferation is more possibly through the PPARγ-independent pathway.
Epimedium elatum C. Morren & Decne. (Berberidaceae)108 Acylated flavonol glycosides GAL-4-PPAR-γ chimera assay system Showed high PPAR-γ binding activity.
Euonymus alatus (Thunb.) Siebold (Celastraceae)54 Kaempferol (12)

Quercetin (11)

(Flavonoid)

3T3-L1 adipocytes Kaempferol and quercetin could significantly improve insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes and served as weak partial agonists in PPARγ reporter gene assay.
Eugenia jambolana Lam.

(Myrtaceae)52

Flavonoid rich fraction   Caused insulin release in vitro from pancreatic islets, decreased levels of LDL and triglycerides, and increased HDL level through dual upregulation of both PPARα and PPARγ up to 3-4-fold. Flavonoid-rich fractions have both hypoglycemic and hypolipidemic effects in the management of diabetes.
G      
Ganoderma atrum (PSG-1) (Ganodermataceae)109 Polysaccharides Liver function in type 2 diabetic rats Improved liver function through antioxidant effects, short-chain fatty acid excretion in the colon from PSG-1; upregulated mRNA expression of PPARγ and hepatic glucose uptake by inducing GLUT4 translocation through PI3K/Akt signaling pathways.
Glycyrrhiza glabra L. (Fabaceae)110,111 Glabridin (59)

(Isoflavonoid)

  Glabridin bonded to and activate PPARγ. It activated PPARγ-regulated gene expression in human hepatoma cells similar to known PPARγ ligands, and the expression was blocked by a PPARγ-specific antagonist.
Glycyrrhiza uralensis Fisch. ex DC. (Fabaceae)111 Dehydroglyasperins C (60)

D (61)

Glabridin (59)

Glyasperins B (62) & D (63)

Glycyrin (64)

(Flavonoid)

Glycycoumarin (65)

(Coumarin)

  The extract activated PPARγ. The isolated compounds had significant PPARγ ligand-binding activity. Moreover, glycerin decreased blood-glucose levels of genetically diabetic KK-Ay mice.
Grewia hirsuta (Korth.) Kochummen (Tiliaceae)112 (4Z,12Z)-Cyclopentadeca-4, 12-dienone (66)   The docking studies of (4Z, 12Z)-cyclopentadeca-4, 12-dienone with 7 target proteins showed that it docked well with various targets related to diabetes mellitus as PPARγ.
Glycine max (L.) Merr. (Fabaceae)58 Genistein (18)

(Isoflavonoid)

   
Glycyrrhiza foetida Desf. (Fabaceae)71 Amorfrutins (2022)

(Isoprenoid-substituted benzoic acid derivative)

   
Glycyrrhiza inflata Batalin (Fabaceae)113 Licochalcone E (66)

(Flavonoid)

   
H      
Hibiscus sabdariffa L.

(Malvaceae)114

  3T3-L1 preadipocytes Hibiscus extract inhibited significantly the lipid-droplet accumulation by MDI in a dose-dependent manner. It attenuated dramatically the expressions of adipogenic transcriptional factors, C/EBPα, and PPARγ during adipogenesis.
L      
Lysimachia foenum-graecum Hance (Primulaceae)115   3T3-L1 Possessed anti-adipogenic and antilipogenic effects due to inhibition of PPARg and C/EBPα expression.
Limnocitrus littoralis (Miq.) Swingle (Rutaceae)116 Meranzin (67)

(Coumarin)

In-silico biological profiling software

 

Meranzin acted as COX1, COX2, and PPARγ-modulator.
Lycium chinense Mill. (Solanaceae)42 Fatty acids   Fatty acids were identified as the major plant constituent responsible for the PPARγ activation. Structure-activity relationship analysis suggested that the NF-κB inhibitory activity of trans-N-caffeoyltyramine can be attributed to its Michael acceptor-type structure (α,β-unsaturated carbonyl group).
M      
Magnolia officinalis Rehder & E.H.Wilson (Magnoliaceae)117 Magnolol (2)

Honokiol (3)

Mixture of both

(Lignan)

High-fat-diet-induced obese mice Both compounds individually and in combination significantly increased Akt phosphorylation and GLUT4 protein expression in white adipose tissue. Honokiol and magnolol improved dyslipidemia and hyperglycemia and acted synergistically when used in combination.
Momordica charantia L. (Cucurbitaceae)118   C57BL/6J mice Activated PPARα and PPARγ signaling pathway in vivo.
Melampyrum pratense L. (Orobanchaceae)119 Lunularin (68)

(Bibenzyl)

Fatty acids

  Were the only PPARα and PPARγ ligands that were identified in the plant extracts.
N      
Nelumbo nucifera Gaertn.

(Nelumbonaceae)120

  Rats fed a high-fat diet Exhibited an anti-adipogenic effect in human pre-adipocytes and anti-obesity and anti-oxidant effects through attenuating expression of PPARγ.
Notopterygium incisum C.T. Ting ex H.T. Chang (Apiaceae)67 Falcarindiol-type polyacetylenes   Polyacetylenes displayed properties of selective partial PPARγ agonists in the luciferase reporter model.
Nymphaea nouchali Burm. f.

(Nymphaeaceae)121

  3T3-L1 cells The extract promoted adipocyte differentiation and glucose consumption by inducing PPARγ activation.
Nigella sativa L.

(Ranunculaceae)122

  C2C12 cells and H4IIE hepatocytes

3T3-L1 cells

Acted as an agonist of PPARγ. The data supported the ethnobotanical use of N. sativa seed oil as a treatment for diabetes and suggested potential uses of the product or compounds derived from it against obesity and metabolic syndrome.
O      
Oroxylum indicum L. Benth. ex Kurz (Bignoniaceae)123 Oroxylin A (69)

(Flavonoid)

3T3-L1 adipocytes Decreased the nuclear translocation of PPARγ and mRNA expression of its downstream genes (FAS and LPL), together with adiponectin secretion.
Origanum vulgare L. (Lamiaceae)57 Biochanin A (23)

(Isoflavonoid)

Chimeric PPARα/γ reporter-gene bioassays Biochanin A was a potent activator of both PPAR receptors (EC50 1-4 μM/L) with PPARα/PPARγ activity ratios of 1:3 in the chimeric and almost 1:1 in the full-length assay, comparable to those observed for synthetic dual PPAR-activating compounds under pharmaceutical development.
P      
Diospyros kaki Thunb (PL)

(Ebenaceae)124

  Type 2 diabetic mice PL improved type 2 diabetes accompanied by dyslipidemia and hepatic steatosis. It also led to a decrease in lipogenic transcriptional factor PPARγ as well as in gene expression and the activity of enzymes involved in lipogenesis.
Pinellia ternata (Thunb.) Ten. ex Breitenb. (Araceae)74 Fatty acids including:

Palmitic (24)

Linoleic acids (25)

  Dose-dependently activated PPARα and PPARγ.
Pueraria thomsonii Benth. (Fabaceae)20 Daidzein (70)

(Isoflavonoid)

Chimeric PPARα/γ reporter-gene bioassay  
Pistacia lentiscus L. var. Chia

(Anacardiaceae)39,125

Methyl oleanonate (71)

Oleanolic acid (72)

Pharmacophore model based on partial agonists of PPARg. Was a PPARγ agonist.
Zanthoxylum schinifolium (Sieb. and Zucc) (Rutaceae)126  

 

Adipocytic differentiation of OP9 cells Decreased the expression of the adipogenesis-related transcription factor and PPARγ and PPARγ-target genes, such as aP2, FAS, and other adipocyte markers.
Piper chaba Hunter (Piperaceae)127 Piperlonguminine (7)

(Alkaloid amide)

Nuclear receptor cofactor assay Piperlonguminine increased mRNA levels of PPARγ2. Unlike troglitazone, piperlonguminine did not activate PPARg directly.
Populus balsamifera L.

(Salicaceae)83

    Populus balsamifera extracts exerted antagonist PPARg activity.
Pseudolarix kaempferi Gordon

(Pinaceae)128

Pseudolaric acid B (73)

(Diterpene acid)

CV-1 and H4IIEC3 cells. Pseudolaric acid B activated PPARα, γ and δ isoforms.
Panax ginseng C.A. Mey. (Araliaceae)129 Protopanaxatriol (74)

(Triterpene)

Mice consuming a high-fat diet

3T3-L1 adipocytes

Genetically obese ob/ob mice.

Inhibited rosiglitazone-supported adipocyte differentiation of 3T3-L1 cells by repressing the expression of lipogenesis-related gene expression. It is a novel PPARγ antagonist. The inhibition of PPARγ activity could be a promising therapy for obesity and steatosis.
Panax ginseng C.A. Mey. (Araliaceae)130 Ginsenosides

(Triterpenoidal glycosides)

Mononuclear macrophage PPARg mRNA expression Ginsenosides improved PPARγ expression and lipid metabolism Thus, ginsenosides can be applied as an adjuvant for treating type 2 diabetes.
R      
Rubus idaeus Thunb.

(Rosaceae)131

Raspberry ketone (75)

(Phenolic compound)

3T3-L1 adipocytes Suppressed the expression of major genes involved in the adipogenesis pathway including PPARγ and C/EBPα, which led to further downregulation of aP2.
Rhus verniciflua Stokes

(Anacardiaceae)70

Butein (76)

(Flavonoid)

  Butein inhibited adipocyte differentiation through the TGF-β pathway, followed by STAT3 and PPARγ signaling.
Rhizoma polygonati falcatum

(Asparagaceae)132

Kaempferol (12)

(Flavonoid)

3T3-L1 cells Reduced adipogenesis and balanced lipid homeostasis partly through the downregulation of PPARγ.
Renealmia thyrsoidea Poepp. & Endl. (Zingiberaceae)133 Diarylheptanoids CD36, MR

Dectin-1 mRNA expression on human monocytes-derived macrophages

Diarylheptanoids bearing a Michael acceptor moiety strongly increased the expression of PPARγ target genes, such as CD36, Dectin-1, and MR.
Robinia pseudoacacia var. umbraculifer DC. Fabaceae)68,134 Amorphastilbol (20)

(Trans-stilbene)

In vitro 3T3-L1 adipocyte systems

In vivo db/db mice model

Selectively stimulated the transcriptional activities of both PPARα and PPARγ, which were able to enhance fatty acid oxidation and glucose utilization.
Rosmarinus officinalis L. (Lamiaceae)135 Carnosic acid (78)

Carnosol (79)

(Abietane diterpene)

Fusion receptor of the yeast Gal4-DNA-binding domain joined to the hinge region and ligand-binding domain of the human PPARγ,  in combination with a Gal4-driven luciferase reporter gene, cotransfected into Cos7 cells Glucose-lowering effect reported recently for rosemary may be attributed to PPARγ activation.
S      
Solanum xanthocarpum Schrad.

(Solanaceae)136

  L6 cell lines Produced an upregulation of both GLUT-4 and PPARγ gene expression.
Sasa borealis Makino & Shibata (Poaceae)113   3T3-L1 cells Inhibited intracellular accumulation of lipid droplets in 3T3-L1 cells through downregulation of PPARγ and C/EBPα (key adipogenic transcription factors).
Sclerotia of Poria cocos

(Polyporaceae)137

Dehydrotrametenolic acid (80)

(Triterpene)

Obese hyperglycemic db/db mice Induced adipose conversion, activated PPARγ in vitro. Also, reduced hyperglycemia in animal models of NIDDM. Dehydrotrametenolic acid is a promising candidate for a new type of insulin-sensitizing drug.
 Salacia reticulata Wight

(Celastraceae)138

  3T3-L1 adipocytes Downregulated the mRNA expressions of lipogenesis factors (PPARγ, lipoprotein lipase, CD36, and fatty acid binding protein 4).
Serenoa repens (W. Bartram)

(Arecaceae)139

    Attenuated the protein expressions of C-EBPα and PPARγ.
Selaginella tamariscina (P. Beauv.) (Selaginellaceae)140 Flavonoids Diabetic rats induced by high fat diet and low dose STZ Total flavonoids of S. tamariscina exerted beneficial effects on hyperglycosemia and hyperlipoidemia in diabetic rats, possibly through regulating the levels of PPARγ in adipose tissue and IRS-1 in hepatic and skeletal muscle tissues.
Swietenia mahagony

(Meliaceae)141

  Diabetic db/db mice Showed agonistic activity to PPARγ and can ameliorate the blood-glucose levels of diabetic
db/db mice. SmE can be thus used as a potential agent for diabetes therapy.
Saururus chinensis (Lour.)

Baill. (Saururaceae)142

Saurufurans A (81)

B (82)

(Furanoditerpenes)

  Saurufuran A is effective on the activation of PPARγ, with an EC50 value of 16.7 mM. Saurufuran B, with an EC50 value of >100 mM, weakly activated the PPARγ.
Salvia officinalis L. (Lamiaceae)143 Carnosic acid (78)

Carnosol (79)

12-O-methyl carnosic acid (83) (Abietane diterpene)

α-linolenic acid

PPARγ transactivation assay Significantly activated PPARγ.
Sambucus nigra L. (Adoxaceae)144 α-Linolenic acid (84)

Linoleic acid (25)

(Fatty acids)

Naringenin (85)

(flavonoid)

T3-L1 cells Naringenin activated PPARγ without stimulating adipocyte differentiation.
Silybum marianum L. Gaertn. (Asteraceae)145 Isosilybin A (86)

(Flavonolignans)

  Isosilybin A caused transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner.
T      
Terminalia bellerica Roxb. (Combretaceae)46 Gallotannins Luciferase assay

HepG2 cells

3T3-L1 cells

Acted as enhancers of both PPARα and PPARγ signaling, increasing insulin-stimulated glucose uptake without inducing adipogenesis.
Thymus vulgaris L. (Lamiaceae)146 Carvacrol (87)

(Monoterpene)

Human macrophage-like U937 cells Carvacrol regulated COX-2 expression through its agonistic effect on PPARγ.
Trifolium pratense L. (Fabaceae)47 Isoflavones    
 Tripterygium wilfordii Hook.f.

(Celastraceae)147

Celastrol (88)

(Triterpene)

3T3-L1 adipocytes Inhibited adipocyte differentiation and increased lipolysis, which are controlled by PPARγ and
C/EBPα signaling pathways.
Triticum aestivum L. sprout

(Poaceae)148

  HFD-induced obese mice Decreased PPARγ and FAS expression.
Tadehagi triquetrum LH. Ohashi

(Fabaceae)149

Tadehaginoside (89)

(Phenylpropanoid glucosides)

HepG2 cells Stimulated glucose consumption by HepG2 cells and glucose uptake by C2C12 myotubes, by the upregulation of PPARγ.
Terminalia chebula Retz Combretaceae150 Chebulagic acid (90) 3T3-L1 adipocytes Behaved like partial PPARγ agonist, which could be exploited for phytoceutical development against T2DM.
Trigonella foenum-graecum L.

(Fabaceae)151

Trigonelline (91)

(Alkaloid)

3T3-L1 cells Trigonelline inhibited adipogenesis by its influence on the expression of PPARγ, which led to subsequent downregulation of the PPARγ-mediated pathway during adipogenesis.
Tetrapanax papyriferus (Hook) K. Koch (Araliaceae)152   3T3-L1 preadipocytes Showed anti-obesity effects by modulating C/EBPα, C/EBPb, and PPARγ gene and protein expressions.
Tinospora cordifolia Miers

(Menispermaceae)153

  L6 myotubes Showed antidiabetic effect due to expression of

Glut-4 and modulation of the expression of PPARα and γ.

 Tacca plantaginea (Hance) Drenth (Taccaceae)154 Plantagineosides (Diarylheptanoid glycosides)

 

  Plantagineosides significantly enhanced the transcriptional activity of PPARβ(δ), with EC50 values in a range of 11.0-30.1 μM..
V      
Vitis vinifera L. (Vitaceae)155 Ellagic acid (92)

(Tannin)

Epicatechin gallate (93) (Flavonoid)

   
W      
Withania somnifera L. Dunal

(Solanaceae)156

Withaferin A (94)

(Steroidal lactone)

3T3-L1 adipocytes Withaferin A decreased lipid accumulation in a dose-dependent manner and decreased the expression of PPARγ, C/EBPα, and aP2.
Wolfiporia extensa (Peck) Ginns (published as Poria cocos F.A. Wolf) (Polyporaceae)137 Dehydrotrametenolic acid (80)

(Triterpene)

Obese hyperglycemic db/db mice Induced adipose conversion, activated PPAR γ in vitro, and reduced hyperglycemia in animal models of NIDDM.
Z      
Zizyphus jujuba (Rhamnaceae)77   3T3-L1 adipocytes Blocked adipogenesis, at least in part, by decreasing the expression of PPARγ, C/EBPδ, and C/EBPβ.
 Zanthoxylum schinifolium, Siebold & Zucc. (Rutaceae)157   3T3-L1 cells Inhibited lipid accumulation by downregulating the major transcription factors involved in the pathway of adipogenesis, including PPARγ, C/EBPδ, and C/EBPβ, via regulation of the ERK and PI3K/Akt signaling pathways in 3T3-L1 adipocyte differentiation.
    3T3-L1 pre-adipocytes Suppressed intracellular lipid accumulation which was associated with the downregulation of several adipocyte-specific transcription factors, including PPARγ, C/EBPα, and C/EBPβ.
Zingiber officinale Roscoe (Zingiberaceae)158 6-Shogaol (S6) (95) 3T3-L1 adipocytes 6-shogaol (6S) significantly inhibited the tumor necrosis factor-α (TNF-α)-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes. 6S functioned as a PPARγ agonist with its inhibitory mechanism due to the PPARγ transactivation.

 

Abbreviations: AA, aristolochic acid; Akt, RAC-alpha serine/threonine-protein kinase; AMPK, 5’ adenosine monophosphate-activated protein kinase; aP2, adipocyte-specific fatty acid-binding protein; CCAAT, cytidinecytidine-adenosine-adenosine-thymidine; CD36, cluster of differentiation 36; C/EBPα, CCAAT enhancer binding proteinα; CoA, coenzyme A; COX-2, cyclooxygenase-2;  DNA, deoxyribonucleic acid; ERK, extracellular signal-regulated kinase; ESD, deoxyelephantopin; FAS, fatty acid synthase; GAL4, galactose-responsive transcription factor; GLUT4, glucose transporter protein 4; HDL, high-density lipoprotein; HFD, high-fat diet; Hfn, halfordinol; IRS1, insulin receptor substrate 1; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LXR, Liver X receptor; MDI, methylisobutylxanthine, dexamethasone and insulin; MR, mannose receptor; mRNA, messenger ribonucleic acid; NIDDM, non-insulin-dependent diabetes mellitus; NF-κB, nuclear factor kappa-B; SmE, Swietenia mahagony extract; SREBP1c, sterol regulatory element-binding transcription factor-1c; T2DM, Type 2 diabetes; TGF-β, transforming growth factor beta; HC, D9-Tetrahydrocannabinol.


 

It has been found that numerous food sources can be considered to be good ligands for PPARγ, including soybeans (Glycine max), tea (Camellia sinensis), grapes and wine (Vitis vinifera), palm oil (Elaeis guineensis), and ginger (Zingiber officinale).6 In addition, a number of culinary spices and herbs—such as Rosmarinus officinalis, Origanum vulgare, Thymus vulgaris, and Salvia officinalis—have been found to exhibit affinity to PPARγ.Moreover, studies have found that many other plants show an affinity toward the PPARγ receptor, namely: [1] Echinacea purpurea due to the presence of alkamide contents,39,40 [2] Commiphora mukul due to commipheric acid (1),41 [3] Lycium chinense attributed to its fatty acids,42 [4] Momordica charantia due to cucurbitane-type triterpene glycosides,43 [5] Magnolia officinalis ascribed to magnolol (2), and honokiol (3),44,45 [6] Pistacia lentiscus due to oleanonic acid (4),39 [7] Terminalia bellerica attributed to gallotannins (in the fruits),46 and [8] Trifolium pratense due to isoflavones (in red clover extracts).47

The EtOH extracts of 263 plant species from 94 families were evaluated for PPARα– and PPARγ-activating capacities using a reporter gene assay.8 The extracts activated PPARγ; however, 22 extracts activated PPARα. Five extracts—Illicium anisatum (I. anisatum), Daphne gnidium (D. gnidium), Terminalia chebula (T. chebula), Juniperus virginiana (J. virginiana), and Thymelaea hirsuta (T. hirsuta)—activated PPARα and PPARγ and increased cellular-glucose uptake. The T. hirsuta and D. gnidium extracts remarkably raised PPARγ/α protein expression. Of the 5 dual agonists, T. hirsuta and T. chebula did not display any increase in differentiation of 3T3-L1 preadipocytes, but I. anisatum increased adipogenesis. While J. virginiana and D. gnidium had toxic effects for adipocytes, T. hirsuta and T. chebula antagonized the adipogenic effect of rosiglitazone.

It was deduced that T. hirsuta and T. chebula elevated the uptake of glucose as PPARγ/α dual agonists, without the side effects of adipogenesis. This revealed the glucose
uptake-enhancing effect and PPARγ/α dual-agonistic activity of T. chebula and T. hirsuta.38 Moreover, to identify the plants with potentially PPAR agonistic potential, Christensen et al40 examined 133 known medicinal and food-plant extracts using a series of bioassays, including tests for differentiation of adipocytes; PPARα, γ, and δ transactivation; and glucose uptake stimulated by insulin. The results revealed that 22 of the tested extracts increased glucose uptake stimulated by insulin; 18 extracts activated PPARγ; 3 activated PPARα and γ; 6 activated PPARγ and δ; and 9 activated PPARα, γ, and δ. Among the tested plant species, 50% were shown to have constituents able to activate PPARγ and to stimulate insulin-dependent uptake of glucose with little or no effects on differentiation of adipocytes, allowing further investigation and characterization.48

In addition, the H2O extracts of the Artemisia iwayomogi plant and the Curcuma longa radix mixture were examined on fat-rich, diet-induced MetS, using C57BL/6N male mice. The mixture normalized synthesis of lipids associated with gene expressions of fatty acid synthase (FAS), PPARγ and α, and sterol regulatory element-binding transcription factor-1c (SREBP-1c)). The results suggested that this mixture has a pharmaceutical capacity in the reduction of metabolic abnormalities in an animal model.49

Hydrangenol (5) and hydrangeic acid (6) from processed leaves, piperlonguminine (7) and retrofractamide A (8) of H. macrophylla var. thunbergii, separated from P. chaba fruit, encouraged 3T3-L1 cells adipogenesis.30 They also raised the levels of messenger ribonucleic acid (mRNA) in adiponectin and Glut4-like troglitazone, but unlike troglitazone, they had less agonistic activity for PPARγ. Farnesol (9) and geranylgeraniol (10), typical isoprenoids in fruits and herbs, activated both human PPARg and PPARα in CV1 cells, using the chimera assay.50 Moreover, they regulated the expression of some PPARα and PPARγ, lipid metabolic target genes in HepG2 hepatocytes and3T3-L1 adipocytes, respectively.

 

Secondary metabolites with PPARγ-activity

Flavonoids. They are compounds known for their health-boosting properties due to their powerful antioxidant potential.51 Flavonoids have been characterized as excellent free-radical scavengers.52 Quercetin (11)53 and Kaempferol (12), as multitargeting compounds, not only activated PPARγ but also inhibited inflammatory signaling, resulting in satisfactory amelioration of hyperglycemia and lesser adverse effects.54 In addition, luteolin (13),53 (-)-catechin (14),55 and 2`-hydroxy chalcone (15) are examples of flavonoids with PPARγ agonistic activity. Myricetin (16) downregulated the protein and mRNA levels of cytidinecytidine-adenosine-adenosine-thymidine (CCAAT) enhancer-binding protein α (C/EBPα), and PPAR-γ.56

Biochanin A (17) and genistein (18), major examples of isoflavones, can activate PPAR-α and PPAR-γ.56-58 Signaling activation of isoflavonoid-dependent PPAR-α and -γ provides a clue to understanding how these metabolites affect diverse pathophysiological processes.58 It is noteworthy that a study using virtual screening based on structures and fit-locking analyses for the identification of new PPARγ ligands showed that isoflavones were the most favorable PPARγ ligands out of the natural-products library, containing 200 compounds. It has been stated that modification of isoflavonoids by chlorination and/or nitration, which may take place in vivo, produces novel products with different PPARγ activating capacities.59,60

Additionally, a study of the structure-activity relationship revealed that the 7-hydroxybenzopyran-4-one moiety, which represents the isoflavonoids/flavonoids core, is essential for PPAR activation.61 Selective modification of this moiety can produce molecules with dual PPAR-γ- and PPAR-α-ligand-binding capacity.61 So, isoflavonoids and their metabolites may supply the model for generation of PPAR agonists.

Saponins. One study found that Platycodi radix saponins improved the homeostasis of glucose in individuals with T2DM, partly via enhancing adipocytic and hepatic insulin sensitivity, which is accomplished by PPAR-γ activation.62 Activators of PPAR-γ are insulin-sensitizing agents that typically facilitate accumulation of triacylglycerides in adipocytes and increase the glucose uptake stimulated by insulin.63 Moreover, ginseng saponins can promote adipogenesis by increasing PPARγ expression64 and targeting genes as lipoprotein lipase (LPL), adipocyte-specific, fatty-acid-binding protein (aP2), and phosphoenolpyruvate carboxykinase (PEPCK).65

Phytoestrogens. They are a varied class of nonsteroidal metabolites that have an affinity for PPAR, α and β estrogen, and aryl hydrocarbon receptors. Many phytoestrogens oppose the cellular derailments that account for the development of MetS. They can assist in the prevention of MetS. Phytoestrogen-rich extracts can be used as complementary conventional or alternative treatments for diseases associated with MetS.66

The mechanism of action in MetS depends on 5 principles or pillars. First, phytoestrogens increase PPARγ-mediated, reverse cholesterol transport. Second, they are implicated in the downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), by inhibition of nuclear factor kappa-B (NF-κB) inhibitor α (IκB) activation and activation of PPAR. Third, they possess antioxidant capacities by activation of antioxidant genes through Kelch-like ECH-associated protein (KEAP). Fourth, they increase PPARα-mediated insulin sensitivity. Fifth, they increase expenditure of energy by influencing adenosine monophosphate (AMP)-activated-kinase signaling cascades, which account for adipogenesis inhibition. In addition, they activate endothelial nitric oxide synthase (eNOS). Extracts from red clover, soya or licorice are described as panPPAR activators. They can be used for treating polycystic ovary syndrome, a disease related to obesity and hyperandrogenism.

Neolignans are exemplified by magnolol (2) and honokiol (3), which are dual agonists of PPARγ and RXR,67,68 bonded to human PPARγ with Ki 22.9 and 2 µM, respectively44,67 and which activate expression of PPARγ-dependent reporter genes as partial agonists with EC50 3.9 and 1.6 µM, respectively.44,67 Moreover, stilbene-like resveratrol (19)69 and amorphastilbol (20)70 as well as amorfrutins (21-23)71 are other examples of phytoestrogens. Resveratrol (19) can attenuate accumulation of lipids in human cultured macrophages by affecting transport of cholesterol. Mechanistically, its effects depend on adenosine 2A and PPAR-γ receptor pathways.72

On the other hand, amorfrutins (21-23) separated from Amorpha fruticosa and Glycyrrhiza foetida are powerful antidiabetics with unique effects. They can bond to and activate PPARγ, leading to selective expression of genes and physiological profiles obviously different from the synthetic-PPARγ drug activation. In diet-induced obese and db/db mice, treatment with amorfrutins strongly ameliorated insulin resistance and other inflammatory and metabolic parameters without increased storage of fat or other undesired side effects such as hepatoxicity.71 These findings proved that selective activation of PPARγ by diet-derived molecules may comprise a prominent approach to counteract metabolic disease.

Fatty acids. Peroxisome proliferators include fatty acids and fibrates, which activate PPAR transcriptional activity. Derivatives of prostaglandin J2 have been known as PPARγ-subtype natural ligands that also bind thiazolidinediones with high affinity.73 Some fatty acids are known as PPAR-agonists, including palmitic acid (24), linoleic acid (25), oleic acid (26), and stearic acid (27).74

Miscellaneous. In one study, 90 natural marine products were screened for active compounds that are able to increase transcriptional activity of PPARγ/α.75 Two active metabolites activated PPARα/γ: sargaquinoic acid (SQA) (28) and sargahydroquinoic acid (SHQA) (29), isolated from Sargassum yezoense. Also, they stimulated differentiation of adipocytes via increasing expression of the adipogenic gene, which provided a logical basis for development of SHQA and SQA for treating metabolic disorders.

In addition, one study showed that some compounds belonging to different classes showed promise as selective PPARγ modulators, such as falcarindiol (30), deoxyelephantopin (31), and some alkaloids.76 In addition, the study found that boldine (32) interacted with the response element of PPAR and could likely modulate responsive genes of PPAR and could be valuable in cardiovascular disease related to obesity.

Berberine (33) prevented 3T3-L1-cell differentiation via a downregulation of C/EBPα and PPARγ expression.77 Finally, it is noteworthy that the plurality of identified metabolites were SPPARMs that transactivated the PPARγ-dependent reporter gene expression as partial agonists. Those PPARγ natural ligands had different receptor-binding modes compared to the thiazolidinedione agonists. Sometimes, they also activated PPARα—such as biochanin A (17), sargaquinoic acid (28), sargahydroquinoic acid (29), resveratrol (19), amorphastilbol (20), and genistein (18) or PPARγ dimer partner retinoid X receptor (RXR), eg, 2 and 3.77

In vivo studies suggested honokiol (3), amorphastilbol (20), amorfrutin 1 (21), and amorfrutin B (23) were natural PPARγ activators, improving metabolic parameters, partly with minimal side effects compared to thiazolidinedione agonists in diabetic animal models.6 The dietary use as well as bioactivity pattern of the identified metabolites and plant extracts justify future research concerning their therapeutic effects and the possibility of modifying activation of PPARγ by food supplements or dietary interventions.

In addition to examining the extracts and bioguided approaches, virtual screening was found to be an efficient strategy for discovering novel natural PPARγ ligands. Rupp et al used Gaussian process regression to look for PPARγ agonists, relying on the published data set of 144 PPARγ ligands.78 The researchers used a combination of manual inspection, and prediction models of the hit list afforded 15 compounds, which were assessed experimentally for activation of PPARγ and PPARα. Eight compounds displayed agonistic effects against one of these receptors or both. A truxillic-acid derivative was the most active one, showing a PPARα selective agonistic effect (EC50 10 mM).

Petersen et al carried out virtual screening based on a pharmacophore for over 57 000 constituents of traditional Chinese medicine.39 That study revealed that oleanonic acid (34) was a moderate PPARγ partial agonist. Fakhrudin et al reported that magnolol (2), dieugenol (35), and tetrahydrodieugenol (36) had partial PPARγ agonistic activity.44 Those researchers found that magnolol (2), dieugenol (35), and tetrahydrodieugenol (36) stimulated 3T3-L1-adipocyte differentiation with EC50s in the micromolar or submicromolar range.

Lewis et al found that α-eleostearic acid (37) exhibited activity in the cell-based reporter and PPARγ-binding assays and in an irritable bowel syndrome, in vivo mouse model.79 Salam et al used a multistep docking strategy for screening a small in-house natural product library.80 From the 200 docked compounds, the researchers chose 29 hits for experimental analysis in a PPARγ activity assay. The results showed that biochanin A (17), genistein (18), psi-baptigenin (38), hesperidin (39), apigenin (40), and chrysin (41) showed EC50 in the low micromolar range.

Finally, Tanrikulu et al reported that 2 α-santonin derivatives were PPARγ activators, while α-santonin was inactive.81

In summary, various 3D and 2D virtual screening approaches have discovered structurally varied, natural PPARγ activators, thereby revealing natural products as a large pool for new PPARγ agonists.

 

CONCLUSIONs

The prevalence of diabetes mellitus and/or metabolic syndrome is growing worldwide. Medicinal plants play a promising role in healthcare. They are widely prescribed because of their lower side effects, effectiveness, relatively low cost, and a broad range of action. They have been proven to be a large pool of substances for the invention of novel PPARg ligands. Recently, numerous structurally varied agonists of PPARg have been reported from natural sources. Many medicinal plant extracts, such as PPARg agonists, so far have not been fully investigated. Thus, the identification of their active metabolites may supply further interesting ligands and offer valuable information for rational drug design in the future.

Also, the identified natural constituents in this review have the same or lower potential for activation of PPARg as the synthetic PPARg ligands; this needs to be proven on the basis of clinical trials. Some the identified natural compounds possess dual agonistic activity; they are able to activate both PPARg and PPARα.

In conclusion, natural compounds and their related derivatives are attracting attention as leads for developments of new treatments against T2DM and MetS.

 

AUTHOR DISCLOSURE STATEMENT

The authors declare that they have no conflict of interests related to the study.

 

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