obesity pathophysiology -...
TRANSCRIPT
ObesityHasMultiplePathophysiologicOrigins
2Bray GA, et al. Lancet. 2016;387:1947-1956.
Obesity
Epigenetic
Genetic
Physiologic
Behavioral
Sociocultural
Environmental
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
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.
11
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*
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.
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
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
ContributionsofAlteredGutMicrobiotatoObesityPathogenesis
32Boulangé CL, et al. Genome Med. 2016;8:42.
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)
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