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IntroductionInthepresentscenario,obesityisthemajorpublichealthproblemwithabout1.9billionadults(18yearsandolder)worldwideareoverweight and about 600million of themare clinically obese[1].Obesityischaracterizedbyincreaseinadiposecellsizewhichisdeterminedbyamountoffataccumulatedinthecytoplasmofadipocytes[2].Thischangeinthemetabolismintheadipocytesis regulated by various enzymes such as fatty acid synthase,lipoproteinlipaseandadipocytefattyacid-bindingprotein[3].
Obesity results from an imbalance between energy intake andexpenditure. It is caused by altered lipid metabolic processesincludinglipogenesisandlipolysis[4].Lipogenesisistheprocessthat stores free fatty acids in the form of triglyceride (TG)[5]; similarly, lipolysis is the process whereby the TG storedis metabolized to free fatty acids and glycerol [6]. Obesityaccompaniedbyhyperlipidemiawhichisindicatedbyabnormallyhighconcentrationof lipids inblood[7].Theadiposetissue,anendocrineorgan,hasamajorroleintheregulationofmetabolismand homeostasis, through the secretion of several biologicallyactiveadipokines[8].Duringadiposetissuedevelopment,three
major transcription factors, peroxisome proliferator-activatedreceptor(PPAR)γ,CCAAT/enhancerbindingprotein(C/EBP)α,andsterol regulatory element-binding protein (SREBP) 1c, regulatetheexpressionoftheselipid-metabolizingenzymes[9].5'AMP-activatedproteinkinase(AMPK)playsamajorroleinglucoseandlipidmetabolismbyinactivatingacetyl-CoAcarboxylase(ACC)andstimulatesfattyacidoxidationbyup-regulatingtheexpressionofcarnitinepalmitoyltransferase-1(CPT-1),PPARα,anduncouplingprotein[10].
Nowadays,changesinhumanlifestyleandhighenergydiethaveincreasedtheincidenceofobesityandevenhavebecomeariskfactor to the population of children [11,12]. There are severalpharmacologicsubstancesavailableasantiobesitydrugs,howeverthey have hazardous side effects and hence natural productshavebeenusedfortreatingobesityinmanyAsiancountries[13].Thepotentialofnaturalproductsforthetreatmentofobesityisstilllargelyunexploredandcanbeanexcellentalternativeforthesafeandeffectivedevelopmentofantiobesitydrugs[14].
Review of Medicinal Plants for Anti-Obesity Activity
AbstractObesityisacomplexhealthissuetoaddress,itisaseriousandchronicdiseasethatcanhaveanegativeeffectonmanysystemsinyourbody.Overweightandobesitymayincreasetheriskofmanyhealthproblems,includingdiabetes,heartdisease,osteoarthritis and certain cancers. Obesity is increasing at an alarming ratethroughouttheworld.Todayitisestimatedthattherearemorethan300millionobesepeopleworld-wide.Obesity isregardedasadisorderof lipidmetabolismand the enzymes involved in this process could be targeted selectively for thedevelopmentofantiobesitydrugs.However,mostoftheanti-obesitydrugsthatwereapprovedandmarketedhavenowbeenwithdrawnduetoseriousadverseeffects. The naturopathic treatment for obesity has been explored extensivelysinceancienttimesandgainingmomentuminthepresentscenario.Traditionalmedicinal plants and their active phytoconstituents have been used for thetreatmentofobesityandtheirassociatedsecondarycomplications.Someactivemedicinalplantsand their respectivebioactivecompoundswerealso testedbyclinicaltrialsandareeffectiveintraemnetofobesity.Thisreviewfocusonnaturalphytoextractswiththeirmechanismofactionandtheirpreclinicalexperimentalmodelforfurtherscientificresearch.
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reduces fat absorption through inhibition of pancreatic lipaseandthesecondissubutraminewhichisananorecticorappetitesuppressant.Bothdrugshaveadverseeffectsincludingincreasedbloodpressure,headache,drymouth,insomnia,andconstipation[15,16]. In 1990 Fenfluramine and Dexfenfluramine werewithdrawnfromthemarketbecauseofheartvalvedamage[17].TheUSFDAin1997approvedsubutraminedrugasatreatmentforobesity.But later inOctober2010 thedrugwaswithdrawnfrom the market due to increased cardiovascular events andstrokes[18,19]. InFebruary2011theUSFDArejectedapprovalofcontrivewhichisacombinationofbupropion/naltrexoneduetoconcernsoverpotentialcardiovascularrisks[20].Certaindrugshavepotentialforabusesuchasphentermineanddiethylpropionandhenceareapprovedforshorttermuse[21].
Atpresent,becauseofhighcostandpotentiallyhazardoussideeffects, the need for natural products against obesity is underexplorationwhichmaybeanalternativestrategyfordevelopingeffective, safeantiobesitydrugs [22]. In2000,MoroandBasilereportedtheuseofcertainwellknownmedicinalplantsthathadclaimedtobeuseful intreatingobesity.Theantiobesityeffectsofnaturalproductsfrommorediversesources[23].Theaimofthepresentreviewwastoupdatedataonpotentialantiobesityherbalplants.
MethodsDatabases used for this study to search include PubMed,Scopus, Google Scholar, Web of Science, and IranMedex withinformationreportedbetweenSeptember2,2006toSeptember22,2014.Searchofliteratureswasfocusedonhumanoranimalsinvestigatingthebenefitsandharmsofherbalmedicinestotreatobesity.Thesearchtermswere“obesity”and(“herbalmedicine”or“plant”,“plantmedicinal”or“medicinetraditional”)withoutnarrowingorlimitingsearchitems.Publicationswithabstractfromthementioneddatabaseswereusedtopreparethisreview.Themainoutcomemeasuresweredefinedasbodyweight,bodyfat,includingfatmass/fatweightorfatpercentage/visceraladiposetissueweight,waistorhipcircumference,tricepsthicknessandappetite, and the amount of food/energy intake. Abstracts of
publicationsonplantsused toevaluate theactivityonhuman,animals,celllinesstudieswiththemainoutcomeasmentionedabovewereincluded.Invitrostudies,reviewarticlesandletterstotheeditorwereexcluded.Tworeviewersreviewedthearticlesforabstractsandtitle.Duetoourinclusionandexclusioncriteria,the duplicate articles were eliminated. The review includesactivecomponentsandmechanismofactionagainstobesity inanimalsandpresentedinTable 1.SomeoftheplantsaretestedfortheiractivityagainstobesityincelllineslistedinTable 2 and plantsthatweretestedonhumanvolunteersorclinicaltrailsarelistedinTable 3.Insomeinstancesscientisthaveevaluatedtheanti-obesity activity in isolated cell organelles, isolated cellularenzymesspecificallypancreaticlipasearelistedinTables 3 and 4 respectively.Table 4presenttheplantwhichwasstudiedforitsactivityagainstobesityinanin silicomodel.
DiscussionInthisreview,wehavereporttheantiobesityeffectsofdifferentherbal plants or compounds containing minerals or chemicalextractsofplants.PlantshavingreportedantiobesityeffectsarelistedinTable 1withinformationabouttheiractivecomponentsand theireffects. From the review itwas suggested that,plantshowing anti-obesity potential mainly belongs to the familyLeguminoseae,Lamiaceae,Liliaceae,Cucurbitaceae,Asteraceae,Moraceae, Rosaceae and Araliaceae. Majority of the studiesindicatesdecreaseinbodyweightorbodyweightgaininanimalsand humans with or without changes in body fat indicatingantiobesityeffects.Theantiobesityeffectssuchasbodyweightreduction,decreaseinthelevelsoftriglycerides,totalcholesterol,and low density lipoprotein cholesterol with simultaneousincreaseinhighdensitylipoproteincholesterolwasobservedintheanimalstreatedwiththeplants[1,15,29,31,39,54,60,78,79,83,85,98,100,101,133,145,152,165,190,196,201].Inonestudy[41],ithasbeenreportedthatacompoundchakasaponinII,suppressedmRNAlevelsofneuropeptideY(NPY)andenhancedthereleaseof serotonin (5-HT) that suppressed theappetite signals in thehypothalamus of the mice. Clinical trials were conducted onhumans for various plant extracts [45,49,135]which showed asignificantdecreaseinbodyweightandbodyfatreduction.There
Table 1. Anti-obesityeffectofnaturaloccurringplantswithmechanismofactionstudiedonanimalmodelsPlant name Part(s) Mechanism Experimental model Reference
Rhizome It inhibitshumanpancreaticlipase.Anewpolyacetylene,syn-(5E,11E)-3-acetoxy-4-O-(3-methylbutanoyl)-1,5,11-tridecatriene-7,9-diyne-3,4-diolhasbeenisolatedandidentifiedandexhibitslipaseinhibitoryactivity.
Roots B. grandifloraexertsanti-obesityactivitybydecreasingintheplasma-triglyceridelevels.
MiceoftheC57B1/6strainwithhypercaloricdiet.
[54]
27 Calanus finmarchicus(Calanidae)
Wax C. finmarchicusreducesmacrophageinfiltrationanddownregulatesexpressionofproinflammatorygenesincludingtumornecrosisfactor-α,interleukin–6,andmonocytechemoattractantprotein–1,whereasup-regulatesadiponectinexpression.
C57BL/6Jmicewithhigh-fat diet
[55]
28 Camellia japonica L.(Theaceae)
Leaves C. japonicacontrolinsulinwhichisamodulatoroflipidsynthesisviasterolregulatoryelementbindingprotein-1c(SREBP-1c),decreasedlevelsofinsulinaffectshepatictriglyceridesynthesis.
HighfatdietinducedSprague−Dawleyrats
[56]
29 Camellia oleifera Abel(Theaceae)
Fruithull Serum levels of total cholesterol and triacylglycerols are decreased but high-density lipoprotein cholesterol increased.Activity of fatty acid in animal liver is lowered by.
MaleICRmicewerefedaHFD
[57]
30 Camellia sinensis (L.)Kuntze(Theaceae)
Leaves,twigsandstems,flowerbuds
C. sinesisattenuatesthegeneexpressionof(SREBP-1c),fattyacidsynthaseandCCAAT/enhancerbindingproteinα.ExtractfoundtoreducesICAM-1releasefollowedbynonpharmacologicalHGTEsupplementationindb/dbmicecausingnoadiponectin-inducingorantiadipogeniceffects,reducedsICAM-1release.ChakasaponinIIfromflowerbud,suppressesmRNAlevelsofneuropeptideY(NPY).ThemRNAlevelsofadipogenicgenessuchasPPAR-γ,C/EBP-α,SREBP-1c,adipocytefattyacid-bindingprotein,lipoproteinlipaseandfattyacidsynthasearedecreased in C. Sinensistreatedanimals.
Seeds C. quinoaextractattenuatemRNAlevelsofseveralinflammationmarkersincludingmonocytechemotacticprotein-1,CD68andinsulinresistanceosteopontin,plasminogenactivatorinhibitor-1anditalsoreversestheeffectsofHF-induceddownregulationoftheuncouplingprotein(s)mRNAlevelsinmuscle.
Micefedwithstandardlow-fatorahigh-fatdiet
[66]
33 Cirsium brevicaule A. Gray (Compositae)
Leaves C. brevicauleinhibitsfattyacidsynthaseandsuppressthedifferentiationandlipidaccumulationandaffectingtranscriptionfactorssuchasSREBP-1c,C/EBPα,andPPARγknowntocontrolthefattyacidsynthaseexpression.
Seed C. arabicadietsupplementationcanimpairglucosetolerance,hypertension,cardiovascularremodeling,andnonalcoholicfattyliverdisease.
High-carbohydrate,high-fatdiet-fedWistarmalerats
[73]
40 Coleus forskohlii (Willd.)Briq.(Lamiaceae).
Root C. forskohliiactasanti-obesisitydrugbyinhibitingdyslipidemia.
Diet-inducedobesityinrats [74,75]
41 Corchorus olitorius L.(Malvaceae)
Leaves Livertissuegeneexpressionofgp91phox(NOX2)involvedinoxidativestressisdown-regulatedbyC. olitorius and genesrelatedtotheactivationofβ-oxidationlikePPARαandCPT1Aareup-regulatedbytheplant.
Fruit Reducesanimalbodyweightsofthefatinwhiteadiposetissues,glucose,totalcholesterol,triglycerides,andLDL-candinsulinbloodlevels.AnincreaseinHDL-clevelsalsoseen.
Fruit IncreasesCPT-1expressionanddecreasesFAS,ACC,andSREBP-1cintheliverandquadricepsmusclestoresultinginreducingtriglycerideaccumulation.ItalsoimprovesinsulinsensitivityinOVXratsandpreventstheimpairmentofenergy,lipid,andglucosemetabolismbyOVXthroughpotentiatinghypothalamicleptinandinsulinsignaling.
Fruit AMP-activatedproteinkinaseandacetyl-CoAcarboxylasephosphorylationinliveriselevated,andHMG-CoAreductaseexpressionisdecreased.ItstronglydecreasesexpressionofperoxisomePPAR-γ,CCAAT/enhancer-bindingproteinalphaandperilipinintheadiposetissue.
Fruit Itreducesweightgain,whiteadiposetissuemass,andserumtriglycerideandcholesterollevels.ItalsodecreasedlipidaccumulationandPPARγ,C/EBPα,SREBP-1,andFASproteinandmRNAlevelsintheliver.
Root Lipolysis-relatedgenesincludingβ3-adrenergicreceptor,hormone-sensitivelipase,adiposetriglyceridelipase,anduncouplingproteinareinducedinwhiteadipocytesofanimalstreatedwithextract of B. campestris.ActivationofcyclicAMPK,HSL,andextracellularsignal-regulatedkinaseareinducedinEBR-treated3T3-L1cells.
Stem Flavonoid,phloretin-3′,5′-di-C-glucosideinhibitsintracellulartriglycerideanddownregulatesPPAR2expression and in in vitro conditionitcaninhibitadipogenesis.
Fruit Suppresseslipidaccumulationandglycerol-3-phosphatedehydrogenase.Elicitsthemostinhibitoryeffectwithattenuationoftheexpressionofkeyadipogenictranscriptionfactors,includingPPAR-γandCCAATenhancerbindingproteins(C/EBPs)attheproteinlevel.
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wasanincreaseinmetabolicrateandenergyexpenditure.Itwasalsoreportedthattheclinicaltrialsperformedonhumansfortheplant extracts [151,165,226] showed an excess fat elimination,body mass index, fat percentage and blood glucose loweringeffects. In another clinical trial study [148] the fenugreek seed
extractdecreasedthefatconsumptionandalso insulin/glucoseratio.Theessentialoilfromtheplants[124,227]suppressedfataccumulation, intracellular triglyceride and decrease in bodyweight. Ginseng which is a popular Chinese herbal medicinesignificantly decreased the weight gain and improved glucose
Fruit Theextractsuppresseslipidaccumulationandglycerol-3-phosphatedehydrogenase.Z. jujubaextractelicitsthemostinhibitoryeffectwithattenuationoftheexpressionofkeyadipogenictranscriptionfactors,includingPPAR-γandCCAATenhancerbindingproteins(C/EBPs)attheproteinlevel.
Aerialparts 4β-cinnamoyloxy,1β,3α-dihydroxyeudesm-7,8-eneistheactiveconstituentpresent in V. persicifoliainducesbioenergeticcollapseinratlivermitochondria,demonstratingtypicaluncouplingagent.ItactsasamilduncouplerdropingΔψandincreasesrespiratorystate4.Theenergycollapse,milduncoupling,andthe fact that V. persicifoliaislargelyusedinfolkmedicines,thisplantmaybeviewedasapotentiallyeffectiveanti-obesitydrug.
tolerance [115,120].P. granatum exhibits potential antiobesitymechanismincludinginhibitionofpancreaticlipaseactivityandsuppression of energy intake. Its effect on energy intake wassimilartosubutraminebutwithadifferentmechanism.
A study reported that Green tea possessed higher antioxidantactivitythanantiobesityactivityduetoitshighconcentrationofcatechins, includingepicatechins,ECGandEGCG. Itwasprovedthatantiobesityactivityofcatechinsresultedfromthecombinedactions of appetite reduction, greater lipolytic activity, energyexpenditureandadipocytedifferentiation.
TheactivecompoundsumbelliferoneandesculetinfromtheplantAegle marmeloshaveshownmarkedeffectbydepletingthelipidcontentintheadipocytesandbydecreasingthehyperlipidemia.Similarly,galanginacompoundfromAlpinia galangal showedasignificantdecreaseinserumlipids,liverweight,lipidperoxidationandaccumulationofhepaticTriglycerides.Decursinacompoundfrom Angelica gigas significantly improved glucose toleranceandreducedthesecretionofHFD-inducedadipocytokines.Thephytoconstituent compound sitosterol found in Boerhaavia diffusa is structurally similar tocholesterolhasbeensuggestedto reduce cholesterol by lowering the level of LDL-cholesterol.p-synephrinecompoundfromtheplantCitrus aurantiumshowedincreased metabolic rate, energy expenditure and increasein weight loss. In Nelumbo nucifera flavonoids showed mildinhibitoryeffectonbothadipocytedifferentiationandpancreatic
lipase activity.Among theflavonoids, flavoneswithout glucoseinhibited pancreatic lipase activity, whereas flavone glycosidesdidnotshowinhibition.Thepresenceofephedrineandpseudo-ephedrine in the plant Sida rhomboidea induced appetitesuppressionthatinhibitsbodyweightgain.
ConclusionNatural products identified from traditional medicinal plantshave always paved the way for development of new types oftherapeutics. Generally most of the compounds were isolatedfrom natural sources despite which orlistat a semi-syntheticderivativeof lipstatinhavebeenapprovedby theUS foodanddrug administration for the treatment of obesity. Orlistat is apotent inhibitor of pancreatic lipase (PL) which is a lipolyticenzymewhichhydrolysesdietary fats in the initial stepof lipidmetabolism. There have been many reports on other effectssuchasanti-oxidativestresseffectswhichmaybe important inthemanagementofotherdiseases like cardiovasculardiseasesand diabetes. The antiobesity drugs are generally preferredbasedonhighefficacyandeffectiveness.Theactiveexplorationof natural sources has provided new developments based onthe understanding of complex and redundant physiologicalmechanisms. Such explorationwill lead to a safe and effectivepharmacologicaltreatment.
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