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.