WhatIstheDiseaseofObesity?

ObesityPathophysiology

ObesityHasMultiplePathophysiologicOrigins

2Bray GA, et al. Lancet. 2016;387:1947-1956.

Obesity

Epigenetic

Genetic

Physiologic

Behavioral

Sociocultural

Environmental

GeneticandEpigeneticOrigins

ObesityPathophysiology

3

GeneticDeterminantsofObesitySupportedbyGenome-WideAssociationStudies

4den Hoed M, Loos RJF. In: Bray GA, Bouchard C, eds. Handbook of Obesity, Vol. 1, 3rd ed. Boca Raton, FL: CRC Press; 2014.105-119.

Gene Tissue expressed Geneproduct/roleinenergybalance

MC4R Adipocyte,hypothalamus,liver Melanocortin 4receptor/Appetite stimulation;monogeniccauseofobesity

ADRB3 Visceraladiposetissue β3-Adrenergic receptor/Regulateslipolysis

PCSK1 Neuroendocrinecells (brain,pituitaryandadrenalglands)

Proproteinconvertase1/Conversionofhormones(includinginsulin)intometabolically active forms

BDNF Hypothalamus Brain-derived neurotrophicfactor/Appetitestimulation;regulatedbyMC4Rsignalingandnutritional state

LCT Intestinalepithelial cells Lactase/Digestionoflactose

MTNR1B Nearlyubiquitous Melantonin receptor 1B/Regulationofcircadian rhythms

TLR4 Adipocyte,macrophage Toll-like receptor4/Lipolysis,inflammatory reactions

ENPP1 Nearlyubiquitous Ecotnucleotide pyrophosphatase/phosphodiesterase 1/Inhibitstyrosinekinaseactivityoftheinsulinreceptor,downregulating insulinsignalinganddecreasing insulin sensitivity

FGFR1 Adipose, hypothalamus Fibroblastgrowth factorreceptor1/Hypothalamic regulationoffoodintakeandphysicalactivity

LEP,LEPR Adipocyte Leptin, leptin receptor/Appetiteinhibition

EpigeneticPerturbationsofGenesAssociatedwithObesity

5*Homeostatic appetite increase partially offset by upregulation of ST8SIA4. †Folate, vitamin D, vitamin A. ‡BPA, fetal alcohol exposure, POPs. See notes view for abbreviations.Xue J, Ideraabdullah FY. J Nutr Biochem. 2016;30:1-13.

↓ HypothalamicPOMC(homeostaticappetiteinhibition*)

Genesaffected:POMC,ST8SIA4

AbnormaladipocytedifferentiationGenesaffected:CEBPA,PPARG,FASN

↓ LeptintranscriptionGenesaffected:CEBPA,PPARG,FASN

↓ POMCneuronalresponsetoleptin(homeostaticappetiteinhibition)

Genesaffected:POMC

Dysregulationofdopaminergicneuronalsignaling(hedonicappetitecontrol)

Genesaffected:TH,SLC6A3,CDKN1C

DecreasedenergyexpenditureGenesaffected:ODC,SSAT

Obesogenic(highfat)diet

↑ Foodintake

Nutrientdeficiency†

Environmentaltoxins‡

↑ Adiposity

MechanismsofEpigeneticRegulation

6†Folate, vitamin D, vitamin A. ‡BPA, fetal alcohol exposure, POPs. See notes view for abbreviations.Xue J, Ideraabdullah FY. J Nutr Biochem. 2016;30:1-13.

AbnormaladipogenesisoradipocytedifferentiationKnownepigeneticregulators:histonemethyltransferases,miR-27a,27b

LeptintranscriptionandaffectsonPOMC

Knownepigeneticregulators:DNMT1,MBD2,RNApolymeraseII,miR-132,-143,-145,200a,

200bPOMC

Knownepigeneticregulators:Dnmt1,Mecp2,histonemarks,KAT8,miR-103

Dysregulationofdopaminergicneuronalsignaling

Epigeneticregulator:Notdetermined

DecreasedenergyexpenditureGeneaffected:NNMT

Epigeneticregulator:Notdetermined

↑ Foodintake

↑ Adiposity

H3K4methylation

Histoneacetylation

DNAmethylation

Obesogenic(highfat)diet

Nutrientdeficiency†

Environmentaltoxins‡

DNAmethylation

PhysiologicOrigins:EnergyStorageandRelease

ObesityPathophysiology

7

EnergyHomeostasis

8

Energy intakeIngestionof:

• Proteins

• Fats

• Carbohydrates

Energyexpenditure• Physicalactivity

• Diet-inducedthermogenesis

• Basalmetabolicrate

BodyWeight

Increase Decrease

AdiposeTissueTypes

9Lee P, et al. Endocr Rev. 2013;34:413-438. Warner A, Mittag J. J Endocrinol. 2016;228:R19-R29. Gustafson B, Smith U. Atherosclerosis. 2015;241:27-35.

White Beige/Brite Brown

Shape Round Round Polygonal

Size Larger Larger Smaller

LipiddropletsSingle,large Intermediate Numerous,small

NucleusPeripheral Peripheral Central

Mitochondria Few Numerous,well-developed Numerous,well-developed

Precursor Myf5(–) lineage,BMP4-stimulatedadipogenesis

Depot-specific origin:Myf5(–)orMyf11and/orother(?)

Myf5(+) lineage, ,BMP7-stimulatedadipogenesis

Bodylocation Subcutaneous,visceral Subcutaneous,visceral Neck,shoulders,spine

Function Energystorage Energyrelease, regulatedbymitochondrialUCP1

Energyrelease, regulatedbymitochondrialUCP1

10

WhiteAdiposeTissue

§Mainformofadiposetissue§ Importantendocrineorganthatinteractswithmostotherbodyorgans

§Normallyfoundinsubcutaneousadiposetissue§ ~50%adipocytes§ ~50%othercells

§ Stem/precursor cells§ Preadipocytes§ Vascular,neural,andimmunecells§ Leukocytes

SAT = subcutaneous adipose tissue.

Gustafson B, Smith U. Atherosclerosis. 2015;241:27-35.

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EctopicWhiteAdiposeTissue

§DuetolimitedSATexpandability,mayaccumulateinectopictissues§ Viscera§ Heart§ Liver§ Pancreas§ Skeletalmuscle

§ Ectopicaccumulationleadstoincreasedinsulinresistanceandmetaboliccomplications

Gustafson B, Smith U. Atherosclerosis. 2015;241:27-35.

ConsequencesofWATExpansion

12

FFA = free fatty acid; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; ROS = reactive oxygen species; SAT = subcutaneous adipose tissue; TG = triglyceride; TNF-α = tumor necrosis factor α; VAT = visceral adipose tissue; WAT = white adipose tissue.

Gustafson B, Smith U. Atherosclerosis. 2015;241:27-35.

Positiveenergybalance

WAT hypertrophyHealthy

SATWAT apoptosis,

macrophage infiltration, lipolysis,

and fibrosis

Lipid accumulation in ectopic tissues (visceral cavity, heart,

pancreas, liver, skeletal muscle)

Increasedphysicalstress,ROS,FFAs,chemokines,inflammatorycytokines

FFAFFA FFA

FFA

FFA

FFAFFA

MCP-1

MCP-1

MCP-1

MCP-1

MCP-1

MCP-1

MCP-1

FFA

FFA

FFA

TG

TG

TG

FFA

TG

VAT

FFA

TG

IL-6

MCP-1

MCP-1

TNF-α

Angptl2 = angiopoietin-like protein 2; CXCL14 = CXC motif chemokine ligand 14; MCP-1 = monocyte chemoattractant protein 1; TLR4 = Toll-like receptor 4; TNF-α = tumor necrosis factor α; TNF-R = tumor necrosis factor receptor.

Itoh M, et al. Int J Inflam. 2011;2011:720926. doi: 10.4061/2011/720926.

Increasingobesity

InflammationandAdiposeTissueRemodeling

13

14

BrownAdiposeTissue

§ FunctionalPETandhistologicalanalysesshowthatnearlyalladulthumanshaveUCP1-expressionBATdepositsinthecervicalandsuperclavicular(neck)regions

§ ThereisasignificantnegativecorrelationbetweenUCP1mRNAabundanceandBMI,accountingfor44%ofBMIvariance(P=0.004)

BAT = brown adipose tissue; BMI = body mass index; mRNA = messenger ribonucleic acid; UCP1 = uncoupling protein 1.

Lee P, et al. J Clin Endocrinol Metab. 2011;96:2450-2455.

BrownFatPrevalenceandActivityDecreaseWithIncreasingAgeandBMI

15

*BAT not discernable with function positron emission tomography.

BAT = brown adipose tissue; BMI = body mass index; SUVmax = maximal standardized uptake value.

Yoneshiro T, et al. Obesity (Silver Spring). 2011;19:1755-1760.

ProspectiveCross-sectionalHumanStudy(N=162)

0

10

20

30

40

50

60

70

20s 30s 40s 50s ≥60s

(44/83)

(15/38)

(7/26)

(1/8)

(0/7)

P<0.01

Age (years)

AdiposityincreaseswithageinBAT-negativeindividualsbutnotinBAT-positiveindividuals

Inci

denc

e of

BAT

(%)

0

5

10

15

20

25

30

35

20-29 30-39 40-49Age (years)

050

100150200250300350400

20-29 30-39 40-49Age (years)

Abd

omin

al fa

t (cm

2 )

Bod

y fa

t (%

)

P<0.01 P<0.05

BAT-positive BAT-negative*

PhysiologicOrigins:AdiposeTissueInflammationandAdiposeDysfunction

ObesityPathophysiology

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EctopicFatDepositsAssociatedWithMetabolicDisorders

17FFA = free fatty acid; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; RAS = renin angiotensin system; TG = triglyceride; TNF-α = tumor necrosis factor α; VLDL = very low density lipoprotein;Gustafson B, Smith U. Atherosclerosis. 2015;241:27-35.

SystemiceffectsIncreasedmetabolicriskfactors

LocaleffectsIncreasedriskforvasculardiseases

Pancreaticfat

Intramuscularfat

Fattyliver

Visceralfat

PerivascularfatEpi/pericardial fat

Myocardialsteatosis

Renalsinusfat

β-celldysfunction,insulinresistance, impairedglucosemetabolism,inflammation, lipotoxicity

Hepatic insulinresistance,oxidativestress,inflammation,↑ lipogenic transcriptionfactors,↑

VLDL-TG

Inflammation,macrophageinfiltration,insulinresistance,alteredreleaseofadipokines,alteredFFAmetabolites, RASactivation,oxidativestress

Inflammation,↑ TNF-α, IL-6,leptin,MCP-1,celladhesionmolecules, calcification,decreased

diastolicfunction,coagulationdefects

Hypertension,vascularresistance,glumerosclerosis,proteinuria,↑ intra-renal

pressure

Systemicandintramuscularinsulinresistance,mitochondrialdysfunction,impairedlipidand

glucosemetabolism

Metabolic

syndrome

Cardiovasculardisease,type2diabetes

PathogenesisoftheMetabolicSyndromeTraitComplex

18

CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IL-6 = interleukin 6; LDL = low-density lipoprotein; PAI-1 = plasminogen activator inhibitor 1; TNF-α = tumor necrosis factor α; VLDL = very-low-density lipoprotein.

WT Garvey, 2013.

Central AdiposityDyslipidemia

Increased largeVLDLIncreasedsmallLDLDecreased largeHDL

Endothelial DysfunctionVascularreactivityDysfibrinolysisInflammation

Foamcellproliferation

InsulinResistanceGlucose intolerance

MetabolicConsequences

SecretedAdipocyteFactors

• Adiponectin• Leptin• Resistin• Freefattyacids• PAI-1• IL-6• TNFα• Angiotensinogen• CETP

Insulin Sensitive

Insulin Resistant

CT scans courtesy of Wilfred Y. Fujimoto, MD.

Carey DG, et al. Diabetes. 1996;45:633–638.

AssociationBetweenVisceralFatandInsulinResistance

19

Insu

lin S

ensi

tivity

(µm

ol/m

in p

er k

g le

an m

ass)

% Visceral Abdominal Fat

20

110

25 30 35 40 45 50

100

90

80

70

60

50

40

30

20

BMI <25 kg/m2

BMI ≥25 kg/m2

FactorsSecretedbyAdiposeTissueUnderInflammatoryConditions

20

Adiponectin Unknown factors

Bone morphogenic protein

Resistin

AdipsinEstrogen

ANG-II

Angiotensin ASP LeptinPAI-1

Retinol

CRP

Fatty acidsLysophospholipids

LactateAdenosine

ProstaglandinsGlutamine

Interleukins (IL-6, IL-8)TGF-βFGFEGF

IGF-1IGFBP

ADMATNF-α

AdiposeTissue

Adipocyte

Macrophage

T-cell

ADMA = asymmetric dimethyl-arginine; ANG-II = angiotensin II; ASP = acylation-stimulating protein; CRP = C-reactive protein; EGF = epidermal growth factor; FGF = fibroblast growth factor; IGF-1 = insulin-like growth factor 1; IGFBP = insulin-like growth factor binding protein; PAI-1 = plasminogen activator inhibitor 1; TGF-β = transforming growth factor β; TNF-α = tumor necrosis factor α.

Itoh M, et al. Int J Inflam. 2011;2011:720926. doi: 10.4061/2011/720926. Epub 2011 Jul 7. Dixit VD. J Leukoc Biol. 2008;84:882-892.

PhysiologicOrigins:PeripheralandCentralSignalsControllingEnergyIntake

ObesityPathophysiology

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PeripheralandCentralRegulationofEnergyIntake

22Bray GA, et al. Lancet. 2016;387:1947-1956.

AdaptationstoWeightLoss:ObesityProtectsObesity

23

CCK = cholecystokinin ; GLP-1 = glucacon like peptide 1; NREE = nonresting energy expenditure; PYY = peptide YY; SNS = sympathetic nervous system; REE = resting energy expenditure; T4 = thyroxine; TEE = total energy expenditure.

Sumithran P, Proietto J. Clin Sci (Lond). 2013;124:231-241.

MetabolismChanges↓ Fatoxidation,↑ cortisol

NervousSystemChanges↓ SNSactivity,increasedmesolimbic rewardcenter

activity

↓ AnorexigenicHormonesLeptin,PYY,CCK,GLP-1,

amylin,insulin

↑ Orexigenic HormonesGhrelin

EatingBehaviorChanges↑ Hunger,preferencefor

caloriedensefoods

↓ EnergyExpenditure↓ TEE,↓ REE,↓ NREE,↓ T4

BodyWeight

Obesity-RelatedImpairmentsinHormonalRegulationofAppetiteandEnergyBalance

24Sumithran P, Proietto J. Clin Sci (Lond). 2013;124:231-241.

KeyHormone ChangesAssociatedwithWeightGainandRegainHormone Source Normalfunction Alteration

Cholecystokinin(CCK)

Duodenum Suppressappetite Levels decreaseduringdietingandweightloss

Glucose-dependentinsulinotropicpolypeptide (GIP)

Duodenum,jejunum

Energystorage Levels increaseduring dietingandweightloss

Ghrelin Gastricfundus

Stimulateappetite,particularly forhigh-fat, high-sugarfoods

Levels increaseduringdietingandweightloss

Glucagon-likepeptide1(GLP-1)

Ileum Suppress appetiteandincreasesatiety

Decreased functionality

Insulin Pancreas RegulateenergybalanceSignalsatietytobrain

InsulinresistanceinobesepersonsReducedinsulinlevelsafterdieting

Leptin Adipocytes RegulateenergybalanceSuppressappetite

Levelsdecreaseduringweightloss

PeptideYY(PYY) Distalsmallintestine

Suppressappetite Levelsdecreased inobesepersons

HormonalChangesAfterDiet-InducedWeightLossMayContributetoRegain

25

P values shown in graphs are for mean postprandial period at 10 and 62 weeks vs baseline, except for amylin, which was not significantly different from baseline at 62 weeks.

Sumithran P, et al. N Engl J Med. 2011;365:1597-1604.

Baseline

ChangefromBL

Week10 Week 62

Weight (kg) 95.4±13.5 −13.5±0.5 −7.9±1.1

ProspectiveObservationalStudy(N=50)

P<0.001

P<0.001

P<0.001P=0.008

P<0.001

P<0.001

PhysiologicOrigins:MetabolicConsequencesofAging

ObesityPathophysiology

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Age-RelatedChangesinBodyComposition

27Stenholm S, et al. Curr Opin Clin Nutr Metab Care. 2008;11:693-700.

10 20 30 40 50 60 70 80

Mas

s

Age (years)

Muscle mass

Fat mass

Age-RelatedSarcopeniaandSarcopenicObesity

Characteristics

§ SpecifictypeIImuscle fiberatrophy,fibernecrosis,andfiber-typegrouping

§ Reducedsatellite cellproliferationanddifferentiationmaycontributetoage-dependentdecreases inmuscle regenerativecapacity

§ Lipidinfiltrationintomuscle tissueandincrease insatellitecellswithadipocyticphenotype

EtiologicFactors

§ Decreased physicalactivity

§ Alterednutritional intake

§ Oxidativestress

§ Hormonalchanges

§ Disruptionofpositive regulators(eg,Aktandserumresponsefactor)

28Sakuma K, Yamaguchi A. Int J Endocrinol. 2013;2013:204164. doi: 10.1155/2013/204164. Epub 2013 Apr 11.

ResistanceTrainingImprovesBodyCompositioninElderly,ObesePatients

29

Adults,BMI25-39kg/m2,Age60-75Years(N=27)

*P<0.05, **P<0.001 vs baseline.

DASH = Dietary Approaches to Stop Hypertension; IMAT = intermuscular adipose tissue; LDM = low density muscle; NDM = normal density muscle; SAT = subcutaneous adipose tissue; TAT = total thigh adipose tissue; TMA = total thigh muscle area.

Avila JJ, et al. Eur J Appl Physiol. 2010;109:517-525.

Change inWeight Change inFatandMuscle

-6-5-4-3-2-1012

Cha

nge

(kg)

DASH diet DASH + resistance training

P=0.005

P=0.002

***

**

*

-25-20-15-10-505

101520

Cha

nge

in C

SA (c

m2 )

DASH diet DASH + resistance training

**

**

**

**

***

P=0.013

P=0.019

PhysiologicOrigins:GutMicrobiota

ObesityPathophysiology

30

GutMicrobiotaandMetabolicHealth

31Boulangé CL, et al. Genome Med. 2016;8:42.

ContributionsofAlteredGutMicrobiotatoObesityPathogenesis

32Boulangé CL, et al. Genome Med. 2016;8:42.

Behavioral,Sociocultural,andEnvironmentalOrigins

ObesityPathophysiology

33

SocioculturalandEnvironmentalContributorstoObesity

Sociocultural

§ Preference forfoodshighinfatand/orcarbohydrates

§ Largeportionsizes(valuemeals)

§ Work-life circumstances§ Sedentaryoccupations andleisure activities

§ Heavytime commitments towork,social,andfamilyobligations

§ Sleepdeprivation

Environmental

§ Communitydesignandinfrastructure notconducive tophysicalactivity

§ Lackofsafe,convenientareasforoutdooractivities

§ Distances betweenhomes andwork/shopstoofarforwalking

§ Lackofpublictransportation§ Ubiquityofescalators,elevators,etc

34Keith SW, et al. Int J Obes (Lond). 2006;30:1585-1594.

EffectsofAlcohol,SleepDeprivation,andTVWatchingonFoodIntake

35

Effectsize (95%CI) Pvalue

No.studies/subjects

Alcohol 1.03(0.66,1.4) <0.001 14/278

Sleep deprivation 0.49(0.11,0.88) 0.01 5/78

TVwatching 0.20(0.04,0.37) 0.02 15/363

-0.50 0.00 0.50 1.00 1.50

Food intake higher

LifestyleEffectsMeta-analysis

Chapman CD, et al. Am J Clin Nutr. 2012;96:492-497.

PossibleNeurobehavioralMechanismsUnderlyingDevelopmentofObesity

36Chapman CD, et al. Am J Clin Nutr. 2012;96:492-497.

Inhibitorycontrol

Conditionedmemory

Rewardsignals

Drivetoeat

Inhibitorycontrol

Conditionedmemory

Rewardsignals Drivetoeat

Normal

Chronicexposure toobesity-promoting behaviors(eg,alcoholabuse, sleepdeprivation, TV)

SummaryObesityPathophysiology

37

38

Summary

§ Obesityhasageneticbasisaswellasenvironmentalandbehavioralorigins

§ Agecontributestoshiftinbalancebetweenfatandmusclemass

§ Variousnegativefeedbackloopscontributetoobesity§ Increased caloricintakeandreducedphysicalactivity

§ Altersenergyhomeostasis→reducedmetabolic rate§ Altersneurohormonal signals→increasedappetite

§ Increased visceraladiposity§ Promotes insulin resistance§ Promotes inflammation

§ Worsens insulinresistance§ Leadstomacrophagemobilizationintoadiposetissue,whichworsens

inflammation§ Together, inflammation andinsulin resistancecontribute todevelopment of

cardiovasculardisease,type2diabetes,cancer,andotherpooroutcomes