UNDERSTANDING OBESITY AS A DISEASE€¦ · UNDERSTANDING OBESITY AS A DISEASE CARLOS JORDAN, M.D ....
Transcript of UNDERSTANDING OBESITY AS A DISEASE€¦ · UNDERSTANDING OBESITY AS A DISEASE CARLOS JORDAN, M.D ....
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UNDERSTANDINGOBESITYASADISEASE
CARLOSJORDAN,M.D.
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DisclosuresAppdeveloper:“GuÍa interactiva paraperder peso”
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The patient is a 48 y.o woman with history of type 2 DM sinceage 35. Currently her hemoglobin A1c is 9.6 and she is beingtreated with a combination of metformin, glyburide andpioglitazone; she takes metoprolol for HTN and, last year, shewas started on gabapentin for bilateral neuropathy. She followsa 1800 cal ADA, exercises 1 hour 5x Week, combining Zumbaand other aerobic routines. She is showing progressivehypomenorrhea and her weight, currently 155 lbs, is increasing.She is 5 feet tall, BMI 30.3
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Whatwouldyoudonext?
a) startinsulintherapytogetherHba1catgoal.b) discontinueglyburide,gabapentin,pioglitazoneandmetoprolol.
c) referhertoaweightlossspecialist.d) tellhertochangeherdietto1500calandchangeherexerciseprogramto2hoursinsteadof1.
e) referhertoSurgeryforgastricbypass.
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Whatisobesity?
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Truestatementsaboutobesityincludeallofthefollowing,except:
1.Bodymassindex>30.2.Increaseinbodyfatthatismakingthepersonsick.3.Excessivefatthatcauseshormonal,mechanicalandpsychologicalillness.4.Chronic,inflammatory,relapsingmultifactorialdisease.
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Beforethisobesitywasconsideredabehavioraldisorder,wherethepatientwasovereatingan
Missinglastpartofstatement
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ObesityMedicineAssociation
“Obesityisdefinedasachronic,relapsing,multi-factorial,neurobehavioraldisease whereinanincreaseinbodyfatpromotesadiposetissuedysfunctionandabnormalfatmassphysicalforcesresultinginadversemetabolic,biomechanical,andpsychosocialhealthconsequences.”
http://obesitymedicine.org/obesity-algorithm/
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Disease
ØIncorrectfunctionoforgan,part,structureorsystemofthebody.ØResultsfromgenetic,developmentalerrors,infection,poisons,nutritionaldeficiencyorimbalance,toxicityorunfavorableenvironmentalfactors.ØManifestsasillness,sickness.
www.dictionary.com
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Howisadiposityaccuratelymeasured?
a)Bodymassindex.b)Bioelectricimpedance.c) Underwaterbodyweight.d)DEXAscan.
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Indirectmethods
BodyMassIndex•Adolphe Quetelet,1832.•Indirectwaytomeasureadiposity.•Lowcost.•Reproducible.•Nogenderorracialdistinction.
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IndirectMethods
Anthropometricmeasures•Waistcircumference.•Waist/hipratio.•Neckcircumference.•Arereproducible,lowcost,considergenderdifferences.
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IndirectMethods
Bioelectricimpedance• Smallelectriccurrenttravelsthroughbodyandcalculatesamountoffat.• Relativelowcost.• Accuracydependsonlevelofhydration.
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DirectMethods
Dexa,CTorMRIscans
• veryaccurate.• expensive,limits ituse.
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Functionsoftheadipocyte are?
A)fatstorage.B)thermogenesis.C)appetiteregulation,glucoseandlipidmetabolism.D)AandB.E)alloftheabove.
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Typesofadipocytes
• Whiteadiposetissue(WAT)(visceral)• fatstorage•hormonesecretion
• Brownadiposetissue(BAT)•highinmitochondria• thermogenesis (UCP1-thermogenin)
• BeigePeirce V,CarobbioS,Vidal-Puig A.Nature.2014 Jun 5;510(7503):76-83.doi:10.1038/nature13477.Review.
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Whatcausesobesity?
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“Amindislikeaparachute.Itdoesn'tworkunlessitisopen.”
FrankZappa
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Theenergybalancetheory
• Lawofconservationofenergy:• Inanclosedsystem,energycannotbecreatedordestroyed.
• Caloriesincaloriesout.
• Doesnotfullyexplainwhyisocaloricdietshavedifferentoutcomes.• Caloriesarenottheonlyvariable.
Obesity and energy balance: isthe tail wagging thedog?WellsJC,Siervo M.Eur JClin Nutr.2011Nov;65(11):1173-89.doi:10.1038/ejcn.2011.132.Epub2011Jul20.Review.
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ComparisonofisocaloricVLCarb,VLFandHUFonbodycompositionandcardiovascular risk
ConclusionIsocaloricVLCARBresultsinsimilarfatlossthandietslowinsaturatedfat,butaremoreeffectiveinimprovingTG,HDL-C,fastingandpostprandialglucoseandinsulinconcentrations.
Noakes M,FosterPR,KeoghJB,JamesAP,Mamo JC,CliftonPM.Comparisonofisocaloricverylowcarbohydrate/highsaturatedfatandhighcarbohydrate/lowsaturatedfatdietsonbodycompositionandcardiovascularrisk.Nutrition&Metabolism.2006;3:7.doi:10.1186/1743-7075-3-7.
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Energyexpenditure
•Basicmetabolicrate(BMR)65-70%•Thermic effectoffood(TEF)5-10%•Nonexerciseactivitythermogenesis (NEAT)10-15%•Exercise(E)5-10%
Nonexercise activitythermogenesis--liberatingthelife-force.JInternMed. 2007Sep;262(3):273-87
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HormonalImbalances
• Insulin•Cortisol•TSH•Melatonin•Leptin•GLP-1•Androgens•Estrogen/Progesterone
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Insulin
•Masterhormoneoffatstorage.•Stimulateslipogenesis.• Inhibitslipolysis.•Stimulatesproteinsynthesis.•Stimulatesglycogenformation.
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Insulin
•Bothcarbohydratesandproteinsstimulatereleaseofinsulin.
•Fathaslessimpactoninsulinrelease.
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InsulinResistance
•Definedclinicallyastheinabilityofaknownquantityofexogenousorendogenousinsulintoincreaseglucoseuptakeandutilizationinanindividualascomparedtoanormalpopulation
Exp Clin Endocrinol Diabetes2001;109(Suppl 2):S135-S148DOI:10.1055/s-2001-18576
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Advanceglycation endproducts(AGEs)
•Proteinsorlipidsthatbecomeglycatedasaresultofexposuretosugars.
•HyperglycemiacausesAGEseveninnondiabetics.
•Alsocanbegeneratedbyhightemperaturecooking(enhancesflavor).
•Cancomefromingestedfood.
•TheygenerateROSandinduceinflammation.
•ReceptorforAGE(RAGEs)(PRR)
Proteins/Lipids CHO
AGEs
RAGEs
NFKBInflammation
Vlassara,H.&Striker,G.�E.Nat.Rev.Endocrinol. 7,526–539 (2011);publishedonline24May2011;
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Foodcancauseinflammation•Patternrecognitionreceptors(PRRs)
• Tolllikereceptors(TLR).• NODlikereceptor(NLR).• Retinoidacidinduciblegene(RIG)likereceptor.
• CTypeLecithinReceptors(CLRs).• Absenceinmelanoma2likereceptors(ALRs)
•Pathogen-associatedmolecularpatterns(PAMPs)LPS-mannose.
•Damage-associatedmolecularpatterns(DAMPs)Amylin,Glucose,FFAs.
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Cortisol
• Stresshormone.• Increasesbloodglucose(gluconeogenesis).
•Promotesinsulinresistance.• Increasesadipocytedifferentiation.
• Increasesvisceralfat.
Selective inhibition of 11 -hydroxysteroiddehydrogenase type 1 as a novel treatment for the metabolic syndromeTomlinson Nature Clinical Practice Endocrinology & Metabolism(2005) 1, 92-99
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Circadianrhythmalterations
Decreasedamountofsleepandalteredday/nightcyclesareassociatedwith:
• ElevatedGhrelin(hunger).• Leptin………• IL-6(inflammation).• Foodcravings(especiallyCHO).• Increasedpostprandial glucose.• Insulinresistance.
Taheri S,ShortSleepDurationIsAssociatedwithReducedLeptin,ElevatedGhrelin,andIncreasedBodyMass Index.Froguel P,ed. PLoSMedicine.2004;1(3):e62.
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Circadianrhythmalterations• Shiftworkersarepredisposedtometabolicdisordersandcancers.• Circadianregulationofhormones,cortisol andmelatoninbalance.• Bluelightsuppressesmelatoninrelease.
AnthonyHTsang,JournalofMolecularEndocrinology (2014),52,R1–R16
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Endocrinedisruptingchemicals(EDCs)
•Exogenouschemicalsubstancesthatmaybindtoendocrinereceptorsandcanstimulate,inhibitorpreventthebindingofthenaturalhormone.
•Alsocalledobesogens.•Mayincreasethenumberorsizeofadipocytes.
•MaylowerBMR.
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Endocrinedisruptingchemicals(EDCs)
EDCs Effect
Tobacco Increases IR(50%Obesityinoffspring)
Polycyclic AromaticHydrocarbons (PAHs) Increases visceralfat/Inflammation
Tributyltin (TBT) IncreaseAdipogenesis (PPAR-y)
BisphenolA(BPA) Estrogenic/Dopamine addictivebehavior
FlameRetardants IncreaseAdipogenesisInsulinresistance/ThyroidDysfunction
PolychlorinatedBiphenyls(PCBs) DisruptThyroid Function
Phthalates IncreaseAdipogenesis
Perfluorinated Chemicals(PFCs) IncreasesInsulinandLeptinlevels
Glyphosate Disruption ofGutBacteria(dysbiosis)
Heindel,J. J.et al.Nat.Rev.Endocrinol.11,653–661(2015)
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Glyphosate
•Mineralchelation (Cu,Zn,Mn,Mg).
•Toxictosoilmicroorganisms.
•Decreasesbeneficialbacteriainsoil.• Increasesfusariumsp.andpathogenicbacteria,includingsalmonellasp.,C.botulinum,pseudomonassp.
•Decreasesrhizobia,enterococci.
ErratuminJAgric FoodChem.2013Dec26;61
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Fructose:the“devil”
• Hasalowglycemic index.
• Canonlybemetabolizedbytheliver.
• CouldleadtofattyliverandNASH.
• Highlyaddictive.
• FFAswillleadtofurtherinsulinresistance.
• Increasesuricacidproduction,increasingBPcontributingtothemetabolicsyndrome.
• ?????????Correctlastpoint.
Metabolicsyndrome;CostasANature502, 181–182 (10October2013)
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Fructose:itis“alcoholwithoutthebuzz”
RobertLustig MD,AmericanSocietyforNutrition.Adv.Nutr.4:226–235,2013;
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Artificialsweetenersandfoodadditives
• Artificialsweetenersarelikelytocauseweightgain(adiposity).
• Mayincreaseriskoftype2DM,promotinginsulinresistance.
• Effectsarelikelyrelatedtothealterationinthemicrobiota.
• Foodemulsifiersalsodisruptthemicrobiota (soylecithin).
• Monosodiumglutamate(MSG)increasesinsulinsecretion.
Jotham Suez,Nature 514,181–186(09October2014)
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Nutritionaldeficiency
•Obesityisachronicinflammatorydisorderthatdepletesthebodyofnutrients,causingmalnutrition.•Thelackofnutrientsfurtherimpairsinsulinsignalingandpredisposestotype2DM.
ViaM.TheMalnutritionofObesity:MicronutrientDeficienciesThatPromoteDiabetes.ISRNEndocrinology.2012;2012:103472. doi:10.5402/2012/103472.
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Nutrient Effect
VitaminD B Cellfunction/IR
Chromium Enhancesinsulin signal /IR
Biotin Hexokinase,hepaticuptakeofglucose/IR
Thiamine Glycolysis, TCA/def increaseAGEs
Magnesium EnhancesinsulinSignal/IR
Selenium Insulinmimeticeffect
Zinc Insulinmimeticeffect– Celldivision
ViaM.TheMalnutritionofObesity:MicronutrientDeficienciesThatPromoteDiabetes.ISRNEndocrinology.2012;2012:103472. doi:10.5402/2012/103472.
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MitochondrialDysfunction
•MitochondriasconvertnutrientsintoATP.
•Mitochondriasdeclinewithage.(infunction,numberorboth?)
•Fataccumulationincreaseswithageduetodecreasedfatoxidation.
•GlucoseoxidationincreasesROS.•FatOxidationdecreasesROS.•Propernutritionisrequiredfornormalfunction.
•Firststatementisincorrect.
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Howdoyouincreasethenumberofmitochondrias ?
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AMPKupregulation
•Fasting.•Muscularstrengthexercises.•Lowglucosediet.•Hypoxia.•Coldexposure.•Near-infraredlight.
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Isobesityiatrogenic?
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Thefollowingmedicationsareassociatedwithweightgain,except:a) Insulin.b) Sulfonylureas.c) Betablockers.d) Antihistaminics.e) Exenatide .f) SSRIs.
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Medicationsthatcauseorworsenfataccumulation
Drug Possiblemechanism
Insulin Worsensinsulin resistance
Sulfonylureas Increasestherelease ofinsulin
TZDs PPARY,increases Lipogenesis
Betablockers B3R, decreasesBMR10%
SSRIs,Fluoxetine, Paroxetine, Unknown
Steroids Increasesblood sugars
Xenoestregen’s andProgestin's Hormonal disruption
Statins Insulin Resistance
PPIs Alterationonthemicrobiome
THC Increases appetite
HCTZ InsulinResistance
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Medicationsthatcauseorworsenfataccumulation
Drug Possiblemechanism
TCAsAmitriptyline, Doxepin,NortriptylineMirtazapine
Unknown
AntipsychoticsLithium,Haloperidol, risperidone,olanzapine
Unknown
H1antagonistsCetirizine, Fexofenadine
Unknown
MAOiSelegiline,Phenelzine
Unknown
AntiepilepticdrugsValproic Acid,Carbamazepine,Gabapentin,
Unknown
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Appetiteregulationandweightgain
•Hypothalamic(ARC)controlofappetite.
•Orexigenicpathway(Hunger-POMC).
•Anorexigenicpathway(Satiety-NPY-AgRP).
•Multiplesystemsinvolved:pancreas,gut,brain.
•Systemfeedbackmechanisminhibitedbyfood:• fat(CCK)• carbs (Insulin/Leptin)• proteins(GLP1/PP)
PerryB,WangY.Appetiteregulationandweightcontrol:theroleofguthormones. Nutrition&Diabetes.2012;2(1):e26-.doi:10.1038/nutd.2011.21.
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GeneticsofObesity5%ofobesityisattributabletogeneticdefects
◦ mostcommongeneticabnormalityisadefectonthemelanocortin receptor4(MCR4).
◦ leptin andleptin receptordefects.◦ POMCmutations.◦ Prader-Willysyndrome(hypotonia-hyperphagia).
◦ Bardet–Biedl syndrome(RP-polydactyly)
Youngage,hyperphagiaFarooqi IS (2006) The severely obese patient—a genetic work-up
Nat Clin Pract Endocrino Metabol 2: 172–177 doi:10.1038/ncpendmet0137
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EpigeneticsofObesity
• Inheritableandreversiblephenomenathataffectgeneexpressionwithoutalteringtheunderlyingbasepairsequenceresultingfromenvironmentalinfluence.
• DNAmethylation,histonemodificationandchromatinremodelingareinfluencedbydiet.
• Intrauterinemalnutritionpredisposestoobesityanddiabetesintheoffspring(transgenerational).
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Areyourgutbacteriamaking
youfat?
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Microbiota andobesity
• 100trillionbacteria.
• >1000species.
• 90%firmicutes andBateriodetes (?????)• Actinobacteria
• Dietaltersthemicrobiome.
• Prebiotics (foodforthemicrobiota)fiber–RS.
• Probiotics (alivemicroorganisms).
• Symbiotics (preandprobiotics).
• Braingutaxis,gut-liveraxis.
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Microbiota andObesity•Modulationoftheinflammatoryresponse.
•Fiber➡️ SCFA➡️ GLP-1/Inflammation.•Formationofsecondarybileacids
• lipidmetabolism
•GLP-2I\intestinalpermeability/endotoxemia.
•Endocannabinoid system.•Fasting-inducedadiposefactor(ANGPTL4)• InhibitsLPL(hypertriglyceridemia)
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LeanGutMicrobiota ObeseGut Mibrobiota
NormalratioofFirmicutes/BacteriodetesMoreDiversity
Increased FirmicutesLessDiversity
Normal Satiety(⬆GLP-1-PYY) LessSatiety(⬇GLP-1-PYY)
Decreasedfecal SCFA IncreasedfecalSCFAs(Propionate)
⬆AMPK/ FatOxidationIncreasedFIAF
⬇ AMPK/FatOxidationDecreasedFIAF(Lipogenesis)
⬆ Insulin Sensitivity ⬇ Insulinsensitivity
⬇ Inflammation(LPS) ⬆ Inflammation(LPS)
⬆ ButyricAcid ⬇ ButyricAcid
Front.Endocrinol., 07April2014|http://dx.doi.org/10.3389/fendo.2014.00047
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Whatwouldyoudonext?
a) startinsulintherapytogetherHba1catgoal,discontinueglyburide,gabapentin,pioglitazoneandmetoprolol.
b) referhertoaweightlossspecialist.c) tellhertolowerherdietto1500calandmakeherexercise2hoursinsteadof1.
d) referhertoSurgeryforgastricbypass.
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This patient has a chronic inflammatory process that iscausing her to store fat while she is unable to use fat thatshe has already stored. It is also causing her moreinflammation, likely from a disrupted microbiome due topoor dietary choices, lack of sleep, hormonaldysregulation and epigenetic mediated factors.
Changing her medications would likely help her to looseweight.
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TheHorizon…..Thefoodandbeverageindustryspendsapproximately$2billionperyearmarketingtochildren.
Thefastfoodindustryspendsmorethan$5millioneverydaymarketingunhealthyfoodstochildren.
Nearly40%ofchildren’sdietscomefromaddedsugarsandunhealthyfats.
Kidswatchanaverageofovertenfood-relatedadseveryday(nearly4,000/year).
http://www.preventioninstitute.org
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Takehomepoints
• Itisdetrimentalforpatientcaretoassumethatpatientseattoomuchandlackthewillpowertoexercise.
•Wearebarelybeginningtounderstandthecomplexityofthehumanbodyanditsinteractionwiththeatoxicenvironment,includingthemicrobiome.
• Iatrogenicobesityplaysabigroleinthepersistenceofthedisease.
• Getmotivated,learnmoreaboutobesity.