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UNDERSTANDINGOBESITYASADISEASE
CARLOSJORDAN,M.D.
DisclosuresAppdeveloper:“GuÍa interactiva paraperder peso”
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
Whatwouldyoudonext?
a) startinsulintherapytogetherHba1catgoal.b) discontinueglyburide,gabapentin,pioglitazoneandmetoprolol.
c) referhertoaweightlossspecialist.d) tellhertochangeherdietto1500calandchangeherexerciseprogramto2hoursinsteadof1.
e) referhertoSurgeryforgastricbypass.
Whatisobesity?
Truestatementsaboutobesityincludeallofthefollowing,except:
1.Bodymassindex>30.2.Increaseinbodyfatthatismakingthepersonsick.3.Excessivefatthatcauseshormonal,mechanicalandpsychologicalillness.4.Chronic,inflammatory,relapsingmultifactorialdisease.
Beforethisobesitywasconsideredabehavioraldisorder,wherethepatientwasovereatingan
Missinglastpartofstatement
ObesityMedicineAssociation
“Obesityisdefinedasachronic,relapsing,multi-factorial,neurobehavioraldisease whereinanincreaseinbodyfatpromotesadiposetissuedysfunctionandabnormalfatmassphysicalforcesresultinginadversemetabolic,biomechanical,andpsychosocialhealthconsequences.”
http://obesitymedicine.org/obesity-algorithm/
Disease
ØIncorrectfunctionoforgan,part,structureorsystemofthebody.ØResultsfromgenetic,developmentalerrors,infection,poisons,nutritionaldeficiencyorimbalance,toxicityorunfavorableenvironmentalfactors.ØManifestsasillness,sickness.
www.dictionary.com
Howisadiposityaccuratelymeasured?
a)Bodymassindex.b)Bioelectricimpedance.c) Underwaterbodyweight.d)DEXAscan.
Indirectmethods
BodyMassIndex•Adolphe Quetelet,1832.•Indirectwaytomeasureadiposity.•Lowcost.•Reproducible.•Nogenderorracialdistinction.
IndirectMethods
Anthropometricmeasures•Waistcircumference.•Waist/hipratio.•Neckcircumference.•Arereproducible,lowcost,considergenderdifferences.
IndirectMethods
Bioelectricimpedance• Smallelectriccurrenttravelsthroughbodyandcalculatesamountoffat.• Relativelowcost.• Accuracydependsonlevelofhydration.
DirectMethods
Dexa,CTorMRIscans
• veryaccurate.• expensive,limits ituse.
Functionsoftheadipocyte are?
A)fatstorage.B)thermogenesis.C)appetiteregulation,glucoseandlipidmetabolism.D)AandB.E)alloftheabove.
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.
Whatcausesobesity?
“Amindislikeaparachute.Itdoesn'tworkunlessitisopen.”
FrankZappa
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.
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.
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
HormonalImbalances
• Insulin•Cortisol•TSH•Melatonin•Leptin•GLP-1•Androgens•Estrogen/Progesterone
Insulin
•Masterhormoneoffatstorage.•Stimulateslipogenesis.• Inhibitslipolysis.•Stimulatesproteinsynthesis.•Stimulatesglycogenformation.
Insulin
•Bothcarbohydratesandproteinsstimulatereleaseofinsulin.
•Fathaslessimpactoninsulinrelease.
InsulinResistance
•Definedclinicallyastheinabilityofaknownquantityofexogenousorendogenousinsulintoincreaseglucoseuptakeandutilizationinanindividualascomparedtoanormalpopulation
Exp Clin Endocrinol Diabetes2001;109(Suppl 2):S135-S148DOI:10.1055/s-2001-18576
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;
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.
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
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.
Circadianrhythmalterations• Shiftworkersarepredisposedtometabolicdisordersandcancers.• Circadianregulationofhormones,cortisol andmelatoninbalance.• Bluelightsuppressesmelatoninrelease.
AnthonyHTsang,JournalofMolecularEndocrinology (2014),52,R1–R16
Endocrinedisruptingchemicals(EDCs)
•Exogenouschemicalsubstancesthatmaybindtoendocrinereceptorsandcanstimulate,inhibitorpreventthebindingofthenaturalhormone.
•Alsocalledobesogens.•Mayincreasethenumberorsizeofadipocytes.
•MaylowerBMR.
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)
Glyphosate
•Mineralchelation (Cu,Zn,Mn,Mg).
•Toxictosoilmicroorganisms.
•Decreasesbeneficialbacteriainsoil.• Increasesfusariumsp.andpathogenicbacteria,includingsalmonellasp.,C.botulinum,pseudomonassp.
•Decreasesrhizobia,enterococci.
ErratuminJAgric FoodChem.2013Dec26;61
Fructose:the“devil”
• Hasalowglycemic index.
• Canonlybemetabolizedbytheliver.
• CouldleadtofattyliverandNASH.
• Highlyaddictive.
• FFAswillleadtofurtherinsulinresistance.
• Increasesuricacidproduction,increasingBPcontributingtothemetabolicsyndrome.
• ?????????Correctlastpoint.
Metabolicsyndrome;CostasANature502, 181–182 (10October2013)
Fructose:itis“alcoholwithoutthebuzz”
RobertLustig MD,AmericanSocietyforNutrition.Adv.Nutr.4:226–235,2013;
Artificialsweetenersandfoodadditives
• Artificialsweetenersarelikelytocauseweightgain(adiposity).
• Mayincreaseriskoftype2DM,promotinginsulinresistance.
• Effectsarelikelyrelatedtothealterationinthemicrobiota.
• Foodemulsifiersalsodisruptthemicrobiota (soylecithin).
• Monosodiumglutamate(MSG)increasesinsulinsecretion.
Jotham Suez,Nature 514,181–186(09October2014)
Nutritionaldeficiency
•Obesityisachronicinflammatorydisorderthatdepletesthebodyofnutrients,causingmalnutrition.•Thelackofnutrientsfurtherimpairsinsulinsignalingandpredisposestotype2DM.
ViaM.TheMalnutritionofObesity:MicronutrientDeficienciesThatPromoteDiabetes.ISRNEndocrinology.2012;2012:103472. doi:10.5402/2012/103472.
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.
MitochondrialDysfunction
•MitochondriasconvertnutrientsintoATP.
•Mitochondriasdeclinewithage.(infunction,numberorboth?)
•Fataccumulationincreaseswithageduetodecreasedfatoxidation.
•GlucoseoxidationincreasesROS.•FatOxidationdecreasesROS.•Propernutritionisrequiredfornormalfunction.
•Firststatementisincorrect.
Howdoyouincreasethenumberofmitochondrias ?
AMPKupregulation
•Fasting.•Muscularstrengthexercises.•Lowglucosediet.•Hypoxia.•Coldexposure.•Near-infraredlight.
Isobesityiatrogenic?
Thefollowingmedicationsareassociatedwithweightgain,except:a) Insulin.b) Sulfonylureas.c) Betablockers.d) Antihistaminics.e) Exenatide .f) SSRIs.
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
Medicationsthatcauseorworsenfataccumulation
Drug Possiblemechanism
TCAsAmitriptyline, Doxepin,NortriptylineMirtazapine
Unknown
AntipsychoticsLithium,Haloperidol, risperidone,olanzapine
Unknown
H1antagonistsCetirizine, Fexofenadine
Unknown
MAOiSelegiline,Phenelzine
Unknown
AntiepilepticdrugsValproic Acid,Carbamazepine,Gabapentin,
Unknown
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.
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
EpigeneticsofObesity
• Inheritableandreversiblephenomenathataffectgeneexpressionwithoutalteringtheunderlyingbasepairsequenceresultingfromenvironmentalinfluence.
• DNAmethylation,histonemodificationandchromatinremodelingareinfluencedbydiet.
• Intrauterinemalnutritionpredisposestoobesityanddiabetesintheoffspring(transgenerational).
Areyourgutbacteriamaking
youfat?
Microbiota andobesity
• 100trillionbacteria.
• >1000species.
• 90%firmicutes andBateriodetes (?????)• Actinobacteria
• Dietaltersthemicrobiome.
• Prebiotics (foodforthemicrobiota)fiber–RS.
• Probiotics (alivemicroorganisms).
• Symbiotics (preandprobiotics).
• Braingutaxis,gut-liveraxis.
Microbiota andObesity•Modulationoftheinflammatoryresponse.
•Fiber➡️ SCFA➡️ GLP-1/Inflammation.•Formationofsecondarybileacids
• lipidmetabolism
•GLP-2I\intestinalpermeability/endotoxemia.
•Endocannabinoid system.•Fasting-inducedadiposefactor(ANGPTL4)• InhibitsLPL(hypertriglyceridemia)
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
Whatwouldyoudonext?
a) startinsulintherapytogetherHba1catgoal,discontinueglyburide,gabapentin,pioglitazoneandmetoprolol.
b) referhertoaweightlossspecialist.c) tellhertolowerherdietto1500calandmakeherexercise2hoursinsteadof1.
d) referhertoSurgeryforgastricbypass.
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.
TheHorizon…..Thefoodandbeverageindustryspendsapproximately$2billionperyearmarketingtochildren.
Thefastfoodindustryspendsmorethan$5millioneverydaymarketingunhealthyfoodstochildren.
Nearly40%ofchildren’sdietscomefromaddedsugarsandunhealthyfats.
Kidswatchanaverageofovertenfood-relatedadseveryday(nearly4,000/year).
http://www.preventioninstitute.org
Takehomepoints
• Itisdetrimentalforpatientcaretoassumethatpatientseattoomuchandlackthewillpowertoexercise.
•Wearebarelybeginningtounderstandthecomplexityofthehumanbodyanditsinteractionwiththeatoxicenvironment,includingthemicrobiome.
• Iatrogenicobesityplaysabigroleinthepersistenceofthedisease.
• Getmotivated,learnmoreaboutobesity.
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