The Open Medicinal Chemistry Journal




ISSN: 1874-1045 ― Volume 13, 2019
REVIEW ARTICLE

Inhibition of PPARγ by Natural Compounds as a Promising Strategy in Obesity and Diabetes



Alessandra Ammazzalorso*, Rosa Amoroso
Department of Pharmacy, University G. d’Annunzio, Via dei Vestini 31, 66100 Chieti, Italy

Abstract

A wide group of natural compounds (flavonoids, stilbenes, neolignans and others) has been identified as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, with a large variety of chemical structure and different activity versus the three PPAR subtypes. These receptors are transcription factors controlling metabolic pathways in the organism, involved in lipid and glucose metabolism, cell differentiation and energy homeostasis. Otherwise, very little is known about natural compounds able to inhibit PPARs. A number of studies demonstrate that PPARγ repression has a beneficial effect in reducing body weight and improving insulin sensitivity, suggesting a potential clinical role in obesity and type 2 diabetes. This review analyzes natural compounds able to repress PPAR activity and their potential use in metabolic disorders.

Keywords: PPAR antagonist, Natural compound, Antidiabetic, Adipocyte differentiation, Antiobesity, Metabolic disorders.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 7
Last Page: 15
Publisher Id: TOMCJ-13-7
DOI: 10.2174/1874104501913010007

Article History:

Received Date: 06/11/2018
Revision Received Date: 26/01/2019
Acceptance Date: 04/02/2019
Electronic publication date: 28/02/2019
Collection year: 2019

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© 2019 Ammazzalorso and Amoroso.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Correspondence: Address correspondence to this author at the Department of Pharmacy, University “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy; Tel: +39-0871-3554682; Fax: +39-0871-3554911;E-mail: alessandra.ammazzalorso@unich.it




1. INTRODUCTION

Obesity is considered one of the major metabolic disease in industrialized countries, being the number of obese always increasing worldwide. Sedentary life, incorrect lifestyles and high-fat diet contribute to the weight gain, in addition to hereditary and medical factors. This disease is strongly linked to concomitant medical situations, as dyslipidemia, hypertension, coronary heart disease, type 2 diabetes and metabolic syndrome. For these reasons, there is an urgent need for drugs able to contrast obesity and related metabolic disorders.

Peroxisome Proliferator-Activated Receptors (PPARs), members of the nuclear receptor superfamily, represent important transcription factors controlling different metabolic pathways in the organism [1Willson, T.M.; Brown, P.J.; Sternbach, D.D.; Henke, B.R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem., 2000, 43(4), 527-550.[http://dx.doi.org/10.1021/jm990554g] [PMID: 10691680] ]. They are involved in lipid and glucose metabolism, in cell differentiation and energy homeostasis [2Berger, J.; Moller, D.E. The mechanisms of action of PPARs. Annu. Rev. Med., 2002, 53, 409-435.[http://dx.doi.org/10.1146/annurev.med.53.082901.104018] [PMID: 11818483] ]. The three PPAR isoforms, PPARα, PPARγ, and PPARδ, encoded by distinct genes, present a different distribution, related to specific metabolic actions in liver, adipose tissue, skeletal muscle, kidney and heart [3Braissant, O.; Foufelle, F.; Scotto, C.; Dauça, M.; Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology, 1996, 137(1), 354-366.[http://dx.doi.org/10.1210/endo.137.1.8536636] [PMID: 8536636] ]. PPARα activation promotes the fatty acid catabolism, by lowering triglyceride levels and rising HDL cholesterol; it represents the molecular target of fibrates, hypolipidemic drugs, used in dyslipidemia and hypertriglyceridemias [4Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.; Leitersdorf, E.; Fruchart, J-C. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation, 1998, 98(19), 2088-2093.[http://dx.doi.org/10.1161/01.CIR.98.19.2088] [PMID: 9808609] ]. PPARγ is a key regulator of glucose homeostasis, promoting adipocyte differentiation, insulin sensitivity, and glucose utilization in tissues [5Spiegelman, B.M. PPAR-gamma: adipogenic regulator and thia-zolidinedione receptor. Diabetes, 1998, 47(4), 507-514.[http://dx.doi.org/10.2337/diabetes.47.4.507] [PMID: 9568680] ]. PPARδ, the most ubiquitous PPAR isoform, plays important metabolic roles by controlling the expression of genes involved in fatty acid uptake, β-oxidation and energy utilization [6Luquet, S.; Gaudel, C.; Holst, D.; Lopez-Soriano, J.; Jehl-Pietri, C.; Fredenrich, A.; Grimaldi, P.A. Roles of PPAR delta in lipid absorption and metabolism: A new target for the treatment of type 2 diabetes. Biochim. Biophys. Acta, 2005, 1740(2), 313-317.[http://dx.doi.org/10.1016/j.bbadis.2004.11.011] [PMID: 15949697] ].

Since some decades, the Thiazolidinediones (TZDs), PPARγ agonists, have been used as antidiabetic drugs, being able to improve insulin sensitivity [7Saltiel, A.R.; Olefsky, J.M. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes, 1996, 45(12), 1661-1669.[http://dx.doi.org/10.2337/diab.45.12.1661] [PMID: 8922349] ]. Despite their beneficial effects in the treatment of diabetic patients, major safety problems emerged during the treatment with TZDs, including hepatic dysfunction, hypoglycemia, weight gain, cardiovascular failure and edema; for these reasons, some compounds of this class were withdrawn from the pharmaceutical market or discontinued from clinical studies [8Watkins, P.B.; Whitcomb, R.W. Hepatic dysfunction associated with troglitazone. N. Engl. J. Med., 1998, 338(13), 916-917.[http://dx.doi.org/10.1056/NEJM199803263381314] [PMID: 9518 284] , 9Rubenstrunk, A.; Hanf, R.; Hum, D.W.; Fruchart, J-C.; Staels, B. Safety issues and prospects for future generations of PPAR modulators. Biochim. Biophys. Acta, 2007, 1771(8), 1065-1081.[http://dx.doi.org/10.1016/j.bbalip.2007.02.003] [PMID: 17428730] ]. Many research efforts have been made by researchers to discover novel and potent PPARγ agonists, in an attempt to maximize the efficacy and minimize side effects [10Cho, N.; Momose, Y. Peroxisome proliferator-activated receptor γ agonists as insulin sensitizers: from the discovery to recent progress. Curr. Top. Med. Chem., 2008, 8(17), 1483-1507.[http://dx.doi.org/10.2174/156802608786413474] [PMID: 19075761] , 11De Filippis, B.; Linciano, P.; Ammazzalorso, A.; Di Giovanni, C.; Fantacuzzi, M.; Giampietro, L.; Laghezza, A.; Maccallini, C.; Tortorella, P.; Lavecchia, A.; Loiodice, F.; Amoroso, R. Structural development studies of PPARs ligands based on tyrosine scaffold. Eur. J. Med. Chem., 2015, 89, 817-825.[http://dx.doi.org/10.1016/j.ejmech.2014.10.083] [PMID: 25462281] ].

An alternative strategy, developed in recent years, aims at obtaining a reduced activation of PPARs: in fact, some experimental studies showed reduced body weight and improved insulin sensitivity, suggesting a potential clinical role of PPARγ antagonists in obesity and type 2 diabetes [12Rieusset, J.; Touri, F.; Michalik, L.; Escher, P.; Desvergne, B.; Niesor, E.; Wahli, W. A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity. Mol. Endocrinol., 2002, 16(11), 2628-2644.[http://dx.doi.org/10.1210/me.2002-0036] [PMID: 12403851] -14Nakano, R.; Kurosaki, E.; Yoshida, S.; Yokono, M.; Shimaya, A.; Maruyama, T.; Shibasaki, M. Antagonism of peroxisome proliferator-activated receptor γ prevents high-fat diet-induced obesity in vivo. Biochem. Pharmacol., 2006, 72(1), 42-52.[http://dx.doi.org/10.1016/j.bcp.2006.03.023] [PMID: 16696951] ]. Likewise, promising biological effects were demonstrated by reduced activation of PPARα and PPARδ, mainly in different cancer models [15Ammazzalorso, A.; De Filippis, B.; Giampietro, L.; Amoroso, R. Blocking the peroxisome proliferator-activated receptor (PPAR): An overview. ChemMedChem, 2013, 8(10), 1609-1616.[PMID: 23939910] -21Ammazzalorso, A.; De Lellis, L.; Florio, R.; Bruno, I.; De Filippis, B.; Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Perconti, S.; Verginelli, F.; Cama, A.; Amoroso, R. Cytotoxic effect of a family of peroxisome proliferator-activated receptor antagonists in colorectal and pancreatic cancer cell lines. Chem. Biol. Drug Des., 2017, 90(5), 1029-1035.[http://dx.doi.org/10.1111/cbdd.13026] [PMID: 28544586] ].

The rising interest in the moderate activation of PPARs was directed by researchers also in the natural compound field: the nature historically offers a wide range of precious active ingredients, utilized by traditional medicine. Literature surveys describe a very large number of natural compounds able to activate PPARs, mainly PPARγ subtype: stilbenes, flavonoids, neolignans, sesquiterpenes, amorfrutins, coumarins and several others (Fig. 1) [22Wang, L.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Blunder, M.; Liu, X.; Malainer, C.; Blazevic, T.; Schwaiger, S.; Rollinger, J.M.; Heiss, E.H.; Schuster, D.; Kopp, B.; Bauer, R.; Stuppner, H.; Dirsch, V.M.; Atanasov, A.G. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): A review. Biochem. Pharmacol., 2014, 92(1), 73-89.[http://dx.doi.org/10.1016/j.bcp.2014.07.018] [PMID: 25083916] , 23De Filippis, B.; Ammazzalorso, A.; Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Amoroso, R. Anticancer activity of stilbene-based derivatives. ChemMedChem, 2017, 12(8), 558-570.[http://dx.doi.org/10.1002/cmdc.201700045] [PMID: 28266812] ]. In addition, the incorporation of different natural scaffolds, such as stilbenes and chalcones, afforded novel synthetic molecules endowed with a PPAR agonist activity [24Li, W.; He, X.; Shi, W.; Jia, H.; Zhong, B. Pan-PPAR agonists based on the resveratrol scaffold: biological evaluation and docking studies. ChemMedChem, 2010, 5(12), 1977-1982.[http://dx.doi.org/10.1002/cmdc.201000360] [PMID: 20973122] -27Giampietro, L.; D’Angelo, A.; Giancristofaro, A.; Ammazzalorso, A.; De Filippis, B.; Di Matteo, M.; Fantacuzzi, M.; Linciano, P.; Maccallini, C.; Amoroso, R. Effect of stilbene and chalcone scaffolds incorporation in clofibric acid on PPARα agonistic activity. Med. Chem., 2014, 10(1), 59-65.[http://dx.doi.org/10.2174/157340641001131226123613] [PMID: 234 32317] ].

Fig. (1)
Natural compounds found PPAR agonists.


Fig. (2)
Chemical structures of 7-chloroarctinone-b (1) and protopanaxatriol (2).


Compared to agonists, only few natural compounds have been identified with antagonistic activity on PPARs: in particular, to the best of our knowledge, natural PPARα and PPARδ antagonists are not mentioned in literature, while a short group of PPARγ antagonists has been recently reported.

PPARγ antagonists from natural sources will be the focus of this review, with special attention to their promising activities as antiobesity and antidiabetic agents.

Fig. (3)
Chemical structures of tanshinone IIA (3) and betulinic acid (4).


2. PPARγ ANTAGONISTS FROM NATURAL SOURCES

Several natural compounds have been identified as PPAR activators, with a large variety of chemical structure and different activity versus the three PPAR subtypes. Many of them are PPARγ agonists, generally showing activity in the low micromolar range. From the structural point of view, there is a great variability, with flavonoids, stilbenes, neolignans, polyacetylenes, amorfrutins and others. Otherwise, very little is known about natural compounds able to inhibit PPARs. Compounds mentioned in the literature show a repressive effect on PPARγ, whereas no data are available on selective PPARα and PPARδ natural antagonists.

In the next paragraphs, natural PPARγ antagonists will be analyzed, focusing on their promising antiobesity and antidiabetic properties.

2.1. 7-Chloroarctinone-b

7-Chloroarctinone-b, isolated from the roots of Rhaponticum uniflorum (Asteraceae family), is an ethynyl-thiophene derivative able to inhibit PPARγ activation (Fig. 2) [28Liu, H-L.; Guo, Y-W. Three new thiophene acetylenes from Rhaponticumuniflorum (L.) DC. Helv. Chim. Acta, 2008, 91, 130-135.[http://dx.doi.org/10.1002/hlca.200890003] ]. This plant is widely distributed in China and has been long used in traditional medicine for the treatment of fever and intoxications. Several pharmacological effects were described for ethynyl-thiophenes, including antitumor, antifungal and antiviral activities.

7-Chloroarctinone-b is a selective PPARγ antagonist, capable of inhibiting rosiglitazone-induced transcriptional activity in a dose-dependent way (IC50 5.61 µM) [29Li, Y.T.; Li, L.; Chen, J.; Hu, T.C.; Huang, J.; Guo, Y.W.; Jiang, H.L.; Shen, X. 7-Chloroarctinone-b as a new selective PPARgamma antagonist potently blocks adipocyte differentiation. Acta Pharmacol. Sin., 2009, 30(9), 1351-1358.[http://dx.doi.org/10.1038/aps.2009.113] [PMID: 19684608] ]. After binding to PPARγ, 7-chloroarctinone-b antagonizes the heterodimerization PPAR/RXR, necessary to start the transcription machinery. Additionally, the same study demonstrates the ability of 7-chloroarctinone-b to inhibit the recruitment of the PPARγ coactivator CBP (cAMP response element binding protein). This compound significantly blocked the differentiation of adipocytes 3T3-L1 in a dose-dependent manner [29Li, Y.T.; Li, L.; Chen, J.; Hu, T.C.; Huang, J.; Guo, Y.W.; Jiang, H.L.; Shen, X. 7-Chloroarctinone-b as a new selective PPARgamma antagonist potently blocks adipocyte differentiation. Acta Pharmacol. Sin., 2009, 30(9), 1351-1358.[http://dx.doi.org/10.1038/aps.2009.113] [PMID: 19684608] ].

2.2. Protopanaxatriol

Ginseng has been largely used as food and tonic herb for the treatment of various pathological conditions, including obesity and diabetes, mainly in Asiatic countries [30Attele, A.S.; Wu, J.A.; Yuan, C.S. Ginseng pharmacology: multiple constituents and multiple actions. Biochem. Pharmacol., 1999, 58(11), 1685-1693.[http://dx.doi.org/10.1016/S0006-2952(99)00212-9] [PMID: 10571 242] ]. The reduction of body weight induced by ginseng and its constituents in obese animal models makes this plant a promising candidate for metabolic diseases; however, molecular mechanisms involved in these therapeutic effects remain unclear to date [31Sotaniemi, E.A.; Haapakoski, E.; Rautio, A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care, 1995, 18(10), 1373-1375.[http://dx.doi.org/10.2337/diacare.18.10.1373] [PMID: 8721940] , 32Lee, M.R.; Kim, B.C.; Kim, R.; Oh, H.I.; Kim, H.K.; Choi, K.J.; Sung, C.K. Anti-obesity effects of black ginseng extract in high fat diet-fed mice. J. Ginseng Res., 2013, 37(3), 308-349.[http://dx.doi.org/10.5142/jgr.2013.37.308] [PMID: 24198656] ].

Protopanaxatriol (PPT, Fig. 2), extracted from roots of Panax ginseng, is a major constituent of this plant, and it shows anti-carcinogenic effects in in vitro and in vivo models [33Shibata, S. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J. Korean Med. Sci., 2001, 16(Suppl.), S28-S37.[http://dx.doi.org/10.3346/jkms.2001.16.S.S28] [PMID: 11748374] ]. A recent study identified the protopanaxatriol as a PPARγ antagonist with moderate binding affinity [34Zhang, Y.; Yu, L.; Cai, W.; Fan, S.; Feng, L.; Ji, G.; Huang, C. Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice. Sci. Rep., 2014, 4, 7375.[http://dx.doi.org/10.1038/srep07375] [PMID: 25487878] ]. In a competitive binding assay using TR-FRET, PPT induced a selective antagonism on PPARγ (IC50 11.75 µM), showing no activity versus other nuclear receptors controlling metabolic functions, as PPARα, PPARδ and LXR. PPT induced a significant inhibition of adipocyte differentiation (3T3-L1) and a repressive effect on genes involved in adipogenesis, as PPARγ, adipose fatty acid-binding protein 2 (aP2), Cluster of Differentiation 36 (CD36), Lipoprotein Lipase (LPL) and Fatty Acid Synthase (FAS) [34Zhang, Y.; Yu, L.; Cai, W.; Fan, S.; Feng, L.; Ji, G.; Huang, C. Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice. Sci. Rep., 2014, 4, 7375.[http://dx.doi.org/10.1038/srep07375] [PMID: 25487878] ]. In vivo experiments on C57BL/6 obese mice confirmed previous results: PPT treatment ameliorates metabolic disorders, reducing body weight and fasting blood glucose levels, and improving insulin resistance [34Zhang, Y.; Yu, L.; Cai, W.; Fan, S.; Feng, L.; Ji, G.; Huang, C. Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice. Sci. Rep., 2014, 4, 7375.[http://dx.doi.org/10.1038/srep07375] [PMID: 25487878] ]. These scientific evidences suggest the potential use of protopanaxatriol as a dietary supplement for the treatment of obesity.

Fig. (4)
Chemical structure of astaxanthin.


2.3. Tanshinone IIA

Tanshinone IIA represents one of the most abundant constituents of the roots of Salvia miltiorrhiza (danshen), a plant distributed in Asiatic countries, widely used in Chinese traditional medicine to treat cardiovascular and cerebrovascular diseases [35Zhou, L.; Zuo, Z.; Chow, M.S. Danshen: An overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J. Clin. Pharmacol., 2005, 45(12), 1345-1359.[http://dx.doi.org/10.1177/0091270005282630] [PMID: 16291709] ]. Tanshinone IIA, a lipophilic diterpene (Fig. 3), is available as sulfonate salt for use in angina, stroke, cardiovascular disorders and ischemic attacks. The therapeutic effects of danshen have been attributed to the antioxidant and anti-inflammatory activity of tanshinone IIA. In addition, recently, it has been reported a beneficial effect of this natural compound in weight suppression and adipocyte differentiation [36Park, Y.K.; Obiang-Obounou, B.W.; Lee, J.; Lee, T.Y.; Bae, M.A.; Hwang, K.S.; Lee, K.B.; Choi, J.S.; Jang, B.C. Anti-adipogeniceffects on 3T3-L1 cells and zebrafish by Tanshinone IIA. Int. J. Mol. Sci., 2017, 18(10), E2065.[http://dx.doi.org/10.3390/ijms18102065] [PMID: 28953247] ].

Tanshinone IIA has been identified as a PPARγ antagonist through a competitive binding assay: it was able to displace radiolabeled rosiglitazone, showing a moderate binding affinity (IC50 3.897 µM) [37Gong, Z.; Huang, C.; Sheng, X.; Zhang, Y.; Li, Q.; Wang, M.W.; Peng, L.; Zang, Y.Q. The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism. Endocrinology, 2009, 150(1), 104-113.[http://dx.doi.org/10.1210/en.2008-0322] [PMID: 18818299] ]. In in vitro experiments tanshinone IIA strongly inhibited adipocyte differentiation (3T3-L1) in a dose-dependent manner; in obese mice, it decreased adipose mass and body weight, improved glucose tolerance and positively affected serum lipid levels. These beneficial properties make this natural compound potentially useful in obesity and related metabolic disorders.

2.4. Betulinic Acid

Betulinic acid (3β-Hydroxy-lup-20(29)-en-28-oic acid) (Fig. 3), a pentacyclic triterpene found in the bark of several plants, shows a wide range of biological activities, including antiviral, anti-inflammatory, antimalarial and antitumor [38Yogeeswari, P.; Sriram, D. Betulinic acid and its derivatives: A review on their biological properties. Curr. Med. Chem., 2005, 12(6), 657-666.[http://dx.doi.org/10.2174/0929867053202214] [PMID: 15790304] , 39Cichewicz, R.H.; Kouzi, S.A. Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Med. Res. Rev., 2004, 24(1), 90-114.[http://dx.doi.org/10.1002/med.10053] [PMID: 14595673] ]. In a murine model of obesity, this compound inhibited adipogenesis, preventing abdominal fat accumulation: this result suggests an antiobesity potential for betulinic acid [40de Melo, C.L.; Queiroz, M.G.; Arruda Filho, A.C.; Rodrigues, A.M.; de Sousa, D.F.; Almeida, J.G.; Pessoa, O.D.; Silveira, E.R.; Menezes, D.B.; Melo, T.S.; Santos, F.A.; Rao, V.S. Betulinic acid, a natural pentacyclic triterpenoid, prevents abdominal fat accumulation in mice fed a high-fat diet. J. Agric. Food Chem., 2009, 57(19), 8776-8781.[http://dx.doi.org/10.1021/jf900768w] [PMID: 19754196] ]. In a recent work by Brusotti et al betulinic acid, extracted from the African plant Diospyros bipindensis, was identified as PPARγ and PPARα antagonist [41Brusotti, G.; Montanari, R.; Capelli, D.; Cattaneo, G.; Laghezza, A.; Tortorella, P.; Loiodice, F.; Peiretti, F.; Bonardo, B.; Paiardini, A.; Calleri, E.; Pochetti, G. Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis. Sci. Rep., 2017, 7(1), 5777.[http://dx.doi.org/10.1038/s41598-017-05666-6] [PMID: 28720829] ]. It was able to displace rosiglitazone from PPARγ (IC50 3.1 µM) and Wy-14643 from PPARα (IC507.4 µM) in a luciferase-based transactivation assay. The crystal structure of the complex PPARγ-betulinic acid was obtained, showing a unique binding mode, accounting for antagonistic properties of the ligand. In vitro studies on adipocytes (3T3-L1) and osteoblasts (MC3T3-E1) showed a marked decrease of adipogenesis, a promotion of osteogenesis and an improvement of glucose uptake [41Brusotti, G.; Montanari, R.; Capelli, D.; Cattaneo, G.; Laghezza, A.; Tortorella, P.; Loiodice, F.; Peiretti, F.; Bonardo, B.; Paiardini, A.; Calleri, E.; Pochetti, G. Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis. Sci. Rep., 2017, 7(1), 5777.[http://dx.doi.org/10.1038/s41598-017-05666-6] [PMID: 28720829] ]. These preliminary results are of great interest and confirm the pharmacological potential of betulinic acid in different pathologies.

2.5. Astaxanthin

Astaxanthin is a natural carotenoid, found in a great variety of red-colored aquatic organisms, as salmon, crustaceans and microalgae (Fig. 4) [42Higuera-Ciapara, I.; Félix-Valenzuela, L.; Goycoolea, F.M. Astaxanthin: A review of its chemistry and applications. Crit. Rev. Food Sci. Nutr., 2006, 46(2), 185-196.[http://dx.doi.org/10.1080/10408690590957188] [PMID: 16431409] ]. It is structurally similar to beta-carotene, but it does not work as a precursor of vitamin A in the human organism. Thanks to its antioxidant activity, it is mainly used as a dietary supplement for human consumption, but also as a food colorant. Astaxanthin protects against lipid peroxidation and contrasts the oxidative damage of cells and tissues; its antiatherogenic effects were studied in animal models of cardiovascular diseases [43Pashkow, F.J.; Watumull, D.G.; Campbell, C.L. Astaxanthin: A novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am. J. Cardiol., 2008, 101(10A), 58D-68D.[http://dx.doi.org/10.1016/j.amjcard.2008.02.010] [PMID: 18474276] ]. Additional beneficial activity of astaxanthin has been described in different studies, where it demonstrated hypolipidemic and antiatherogenic effects [44Hussein, G.; Nakagawa, T.; Goto, H.; Shimada, Y.; Matsumoto, K.; Sankawa, U.; Watanabe, H. Astaxanthin ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sci., 2007, 80(6), 522-529.[http://dx.doi.org/10.1016/j.lfs.2006.09.041] [PMID: 17074368] , 45Kumar, R.; Salwe, K.J.; Kumarappan, M. Evaluation of antioxidant, hypolipidemic, and antiatherogenicproperty of lycopene and astaxanthin in atherosclerosis-induced rats. Pharmacognosy Res., 2017, 9(2), 161-167.[PMID: 28539740] ]. In high cholesterol diet fed rats, astaxanthin induced a marked decrease of total cholesterol, Low-density Lipoprotein Cholesterol (LDL-C), Very Low-density Lipoprotein Cholesterol (VLDL-C) and triglycerides, and increased High-density Lipoprotein Cholesterol (HDL-C). A significant reduction in atherosclerotic lesions was observed on aorta of high cholesterol-fed rats, after treatment with astaxanthin [45Kumar, R.; Salwe, K.J.; Kumarappan, M. Evaluation of antioxidant, hypolipidemic, and antiatherogenicproperty of lycopene and astaxanthin in atherosclerosis-induced rats. Pharmacognosy Res., 2017, 9(2), 161-167.[PMID: 28539740] ]. The effects of astaxanthin on serum lipids prompted researchers to investigate about a possible mechanism of action involving PPAR receptors; the study by Jia and coworkers showed that astaxanthin works as moderate PPARα agonist (EC50 3.9 µM) and PPARγ antagonist (IC50 607.8 µM), whereas it is inactive versus PPARδ [46Jia, Y.; Kim, J.Y.; Jun, H.J.; Kim, S.J.; Lee, J.H.; Hoang, M.H.; Hwang, K.Y.; Um, S.J.; Chang, H.I.; Lee, S.J. The natural carotenoid astaxanthin, a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes. Mol. Nutr. Food Res., 2012, 56(6), 878-888.[http://dx.doi.org/10.1002/mnfr.201100798] [PMID: 22707263] ]. These findings were confirmed analyzing the expression profile of specific target genes for PPARα and PPARγ. In lipid-loaded hepatocytes, the treatment with astaxanthin produced a strong reduction of cellular lipid accumulation: these data support the potential of astaxanthin as nutritional prevention of obesity and metabolic disorders.

2.6. Foenumoside B

Lysimachia foenum-graecum is an herbal plant, used as a spice and insect repellent. In traditional oriental medicine, the extract of this plant has been used for the treatment of various disorders, as cold, headache, toothache, discomforts of the digestive system. Different triterpene saponins, named foenumoside A-E, have been identified as active ingredients, and a wide panel of biological effects have been described, including antioxidant, anti-inflammatory, and antiadipogenic [47Li, H.Y.; Hao, Z.B.; Wang, X.L.; Huang, L.; Li, J.P. Antioxidant activities of extracts and fractions from Lysimachia foenum-graecum Hance. Bioresour. Technol., 2009, 100(2), 970-974.[http://dx.doi.org/10.1016/j.biortech.2008.07.021] [PMID: 18793841] , 48Seo, J.B.; Choe, S.S.; Jeong, H.W.; Park, S.W.; Shin, H.J.; Choi, S.M.; Park, J.Y.; Choi, E.W.; Kim, J.B.; Seen, D.S.; Jeong, J.Y.; Lee, T.G. Anti-obesity effects of Lysimachia foenum-graecum characterized by decreased adipogenesis and regulated lipid metabolism. Exp. Mol. Med., 2011, 43(4), 205-215.[http://dx.doi.org/10.3858/emm.2011.43.4.025] [PMID: 21389766] ]. The antiadipogenic effect was attributed to Foenumoside B (Fig. 5), but the mechanism of action at the molecular level was not determined [49Seo, J.B.; Park, S.W.; Choe, S.S.; Jeong, H.W.; Park, J.Y.; Choi, E.W.; Seen, D.S.; Jeong, J.Y.; Lee, T.G. Foenumoside B from Lysimachia foenum-graecum inhibits adipocyte differentiation and obesity induced by high-fat diet. Biochem. Biophys. Res. Commun., 2012, 417(2), 800-806.[http://dx.doi.org/10.1016/j.bbrc.2011.12.039] [PMID: 22197824] ]. A recent study examined a possible connection between Foenumoside B and Lysimachia foenum-graecum extract with PPARγ, a master regulator of adipocyte differentiation [50Kwak, H.J.; Choi, H.E.; Jang, J.; Park, S.K.; Cho, B.H.; Kim, S.K.; Lee, S.; Kang, N.S.; Cheon, H.G. Suppression of adipocyte differentiation by foenumoside B from Lysimachia foenum-graecum is mediated by PPARγ antagonism. PLoS One, 2016, 11(5), e0155432.[http://dx.doi.org/10.1371/journal.pone.0155432] [PMID: 27176632] ]. In transactivation assays, both Foenumoside B and Lysimachia foenum-graecum extract showed a selective antagonism on PPARγ, with IC50 7.63 and 22.5 µg/mL, respectively. They strongly affected adipocyte differentiation induced by PPARγ agonists, and reduced expression of lipogenic genes. In vivo administration of Lysimachia foenum-graecum extract in ob/ob and KKAy mice induced beneficial effects on body weight, insulin resistance and glucose tolerance, offering novel therapeutic strategies in the treatment of obesity, insulin resistance and metabolic disorders.

Fig. (5)
Chemical structure of Foenumoside B.


Fig. (6)
Chemical structures of PPARγ inhibitors berberine (5) and isoflavonoids (6-8) from Crotalaria albida.


3. PPARγ INHIBITORS FROM NATURAL SOURCES

A number of natural compounds affect PPAR activity, inducing beneficial effects in adipocyte differentiation, insulin sensitivity and glucose and lipid homeostasis. However, sometimes the inhibition of PPAR is not related to an antagonistic effect, but it may be induced by multiple mechanisms affecting PPAR levels and activity. Some compounds were reported as PPAR inhibitors, but it was not effectively demonstrated their binding to the receptor. The observed repression of PPAR could be ascribed to a gene downregulation of PPAR expression, not related to a classical antagonism on the receptor. Berberine and isoprenyl dihydrofuran isoflavonoids are example of compounds inhibiting PPARγ, but not acting as antagonists.

Berberine is an active alkaloid extracted from Berberis vulgaris, found also in other plants as Cortidis rhizome. Given the multiple pharmacological actions of berberine, it was used in Chinese traditional medicine to treat diarrhea, dysentery, stomatitis, hepatitis [51Imanshahidi, M.; Hosseinzadeh, H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother. Res., 2008, 22(8), 999-1012.[http://dx.doi.org/10.1002/ptr.2399] [PMID: 18618524] ]. From a structural point of view, berberine belongs to the class of protoberberines, showing an isoquinoline core (Fig. 6). Multiple beneficial effects of berberine attracted the attention of scientists, and several studies were carried out to clarify its pharmacological and therapeutic effects. Berberine has shown antihyperlipidemic and antihyperglycemic effects, increased insulin secretion and sensitivity, suggesting a potential application in the prevention or treat-ment of diabetes [52Lee, Y.S.; Kim, W.S.; Kim, K.H.; Yoon, M.J.; Cho, H.J.; Shen, Y.; Ye, J-M.; Lee, C.H.; Oh, W.K.; Kim, C.T.; Hohnen-Behrens, C.; Gosby, A.; Kraegen, E.W.; James, D.E.; Kim, J.B. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes, 2006, 55(8), 2256-2264.[http://dx.doi.org/10.2337/db06-0006] [PMID: 16873688] , 53Zhang, Y.; Li, X.; Zou, D.; Liu, W.; Yang, J.; Zhu, N.; Huo, L.; Wang, M.; Hong, J.; Wu, P.; Ren, G.; Ning, G. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J. Clin. Endocrinol. Metab., 2008, 93(7), 2559-2565.[http://dx.doi.org/10.1210/jc.2007-2404] [PMID: 18397984] ]; anti-inflammatory and antitumor effects were also described [54Kuo, C-L.; Chi, C-W.; Liu, T-Y. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett., 2004, 203(2), 127-137.[http://dx.doi.org/10.1016/j.canlet.2003.09.002] [PMID: 14732220] , 55Mantena, S.K.; Sharma, S.D.; Katiyar, S.K. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol. Cancer Ther., 2006, 5(2), 296-308.[http://dx.doi.org/10.1158/1535-7163.MCT-05-0448] [PMID: 1650 5103] ]. Given the multiple meta-bolic effects played by berberine, its PPAR activity was investigated: results confirmed that metabolic actions of berberine are mediated by PPARs [56Huang, C.; Zhang, Y.; Gong, Z.; Sheng, X.; Li, Z.; Zhang, W.; Qin, Y. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway. Biochem. Biophys. Res. Commun., 2006, 348(2), 571-578.[http://dx.doi.org/10.1016/j.bbrc.2006.07.095] [PMID: 16890192] ]. Berberine showed inhibitor activity on PPARγ and PPARα, but it did not induce transcriptional activity changes: these data indicate that berberine does not act as an antagonist, and the PPAR inhibition is probably a consequence of the reduction of PPAR protein levels. Moreover, berberine inhibited adipocyte differentiation and proliferation, acting also on target genes involved in adipocyte differentiation [56Huang, C.; Zhang, Y.; Gong, Z.; Sheng, X.; Li, Z.; Zhang, W.; Qin, Y. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway. Biochem. Biophys. Res. Commun., 2006, 348(2), 571-578.[http://dx.doi.org/10.1016/j.bbrc.2006.07.095] [PMID: 16890192] ].

In analogy to berberine, some isoprenyl dihydrofuran isoflavonoids (Fig. 6) extracted from Crotalaria albida have been identified as adipocyte differentiation inhibitors through downregulation of PPARγ activity [57Sun, Q.; Chou, G. Isoflavonoids from Crotalaria albidainhibit adipocyte differentiation and lipid accumulation in 3T3-L1 cells via suppression of PPAR-γ pathway. PLoS One, 2015, 10(8), e0135893.[http://dx.doi.org/10.1371/journal.pone.0135893] [PMID: 26285147] ]. In transactivation assays, these compounds strongly inhibited rosiglitazone-induced PPARγ activity. They induced suppression of adipocyte differentiation and adipogenesis, probably mediated by PPARγ. However, there is no real evidence about the binding of these compounds with PPARγ; for this reason, they have been indicated as PPARγ inhibitors, and not as antagonists.

CONCLUSION AND PERSPECTIVES

Since centuries ago and still to date, plants have been offered to humans precious ingredients with various pharmacological properties. The use of plants in traditional medicine accounts for the wide panel of beneficial effects they can induce in humans. Natural compounds identified in the past were used in medicine or served as lead compounds, useful for the discovery of novel synthetic drugs.

Among the great variety of pharmacological effects, many plants show antiobesity and antidiabetic effects, suppressing adipocyte differentiation and adipogenesis. In light of these evidences, many researchers studied the mechanisms involved in these activities: in particular, the role of PPARγ was explored, being this receptor a key regulator of metabolic functions in the cells. For a number of plants, it was demonstrated that these effects were effectively linked to a reduction of PPARγ activity.

This review has been focused on natural compounds showing an antagonistic behavior on PPARγ, and their potential as antiobesity and antidiabetic drugs. Moreover, if a great number of PPAR agonists have been obtained from natural sources, very little is known about natural PPAR antagonists. Compounds analyzed in this review showed the ability to inhibit adipocyte differentiation and proliferation, reduce the weight gain, improve the insulin sensitivity and glucose tolerance. Indeed, results obtained in in vitro and in vivo experiments are really encouraging, but they require further studies to clarify a possible utilization in humans for the treatment of obesity, diabetes and related metabolic disorders. Some of these natural compounds are currently used as dietary supplement, given their general safety and the lacking of important side effects.

Whereas some natural compounds were demonstrated PPARγ antagonists, for some compounds a PPAR repression was reported, but it was not effectively demonstrated the binding to the receptor. The observed repression of PPAR could be ascribed to a gene downregulation of PPAR protein expression, also if the compound does not produce an antagonism on the receptor. Compounds acting in this way, as berberine and some isoflavonoids, were reported as PPAR inhibitors, and not as PPAR antagonists.

To the best of our knowledge, natural compounds able to selectively inhibit PPARα and PPARδ have not been identified to date.

LIST OF ABBREVIATIONS

PPARs = Peroxisome Proliferator-Activated Receptors
TZDs = Thiazolidinediones
RXR = Retinoid X Receptor
CBP = cAMP response element binding protein
PPT = Protopanaxatriol
TR-FRET = Time-resolved Fluorescence Resonance Energy Transfer
LXR = Liver X Receptor
aP2 = Adipose fatty acid-binding Protein 2
CD36 = Cluster of Differentiation 36
LPL = Lipoprotein Lipase
FAS = Fatty Acid Synthase
LDL-C = Low Density Lipoprotein Cholesterol
VLDL-C = Very Low Density Lipoprotein Cholesterol
HDL-C = High Density Lipoprotein Cholesterol

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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