the concept of cardiometabolic risk

Source: International Chair on Cardiometabolic Riskwww.cardiometabolic-risk.org

Illustrations relevant to The Concept of CMR section


FACTORS CONTRIBUTING TO CARDIOMETABOLIC RISK

Adapted from Després JP and Lemieux I Nature 2006; 444: 881-7

Metabolicsyndrome?

Diabetes

LDL

HDL

Hypertension

Age

Smoking

Male gender

Other (genetic factors)

Diabetes

LDL

HDL

Hypertension

Age

Smoking

Male gender

Other (genetic factors)

Metabolicsyndrome?

A new CVD risk factor Global CVD risk from traditional

risk factorsGlobal cardiometabolic risk


From National Center for Health Statistics. Health, United States, 2003Reproduced with permission

0

10

20

30

40

50

60

70

OVERWEIGHT AND OBESITY BY AGE, UNITED STATES, 1960-2000

Overweight, 20-74 years

Overweight,12-19 yearsOverweight, 6-11 years

Obesity, 20-74 years

Per

cen

t

Year

1960-1962 1963-1965 1966-1970 1971-1974 1976-1980 1988-1994 1999-2000


REGIONAL ESTIMATES FOR DIABETES (20-79 AGE GROUP),2003 AND 2025

From Intemational Diabetes Federation (IDF)http://www.eatlas.idf.org/Prevalence/AlI_diabetes/Reproduced with permission

Population (20-79 group)

(million)

Population (20-79 group)

(million)

No. of people with

diabetes (million)

No. of people with

diabetes (million)

Prevalence (%)

Prevalence (%)

African Region

European Region

North American Region

Eastern Mediterranean and Middle East Region

South and Central American Region

Southeast Asian Region

Western Pacific Region

Total


WORLDWIDE PREVALENCE OF DIABETES IN 2000AND ESTIMATES FOR THE YEAR 2030 (IN MILLIONS)

19.7 33.9

2000

2030

20.7 42.3

31.7 79.4

28.3 37.4

13.3 33.0

20.0 52.8

7.1 18.6

0.9 1.7

22.3 58.1

148%148%

104%104%

161%161%

150%150%164%164%

32%32%

89%89%

162%162%

72%72%

United States and Canada

India

China

Southeast Asia

Middle EastEurope

Latin America and Carabbean

Sub-Saharan Africa

Australia

Adapted from Hossain P et al. N Engl J Med 2007; 356: 213-5


THE CONCEPT OF POSITIVE ENERGY BALANCE

Energy Intake Energy Expenditure

Calories consumed(eating)

Resting(e.g. sleeping)

Physical activity(including exercise)

Thermic effect of food


SUMMARY OF THE INTERACTIONS BETWEEN PERIPHERAL ORGANS, THE CENTRAL NERVOUS SYSTEM, AND BEHAVIOUR IN REGULATING FOOD INTAKE

Conceptual nervous system

Central nervous system

Nutrient stores

Absorption

Digestion

Ingestion

Eating

Food

Cultural, psychological, and physiologicalinfluences of food on energy intake

• Cognitions and beliefs• Moods• Subjective hunger, appetite, preference

• Neurotransmitters• Neuro modulators• CNS-PNS relays

Religious taboos, economic factors, cuisine life events, learned experience, education cognitive effects

• Physical structure• Nutritional composition

• Food and energy intake• Meal size and frequency• Nutrient selection

• Lean body mass• Fat stores• CHO stores

Adapted from Bray GA et al. Handbook of Obesity 1998 pp.427-460

Learned preferences

Aversions

Postingestional feedback

Specific nutrient

Energy fluxLiver


COMPONENTS OF TOTAL ENERGY EXPENDITURE IN AN INITIALLY SEDENTARY MAN EATING 2800 KCAL/DAY (A), WHO INCREASES PHYSICAL ACTIVITY (B); WHO ADDS DAILY PHYSICAL EXERCISE (C)

2800 kcal 3000 kcal 3200 kcal

30%840 kcal

10%280 kcal

60%1680 kcal

34.7%1040 kcal

9.3%280 kcal

56%1680 kcal

6.3%200 kcal

32.5%1040 kcal

8.7%280 kcal

52.5%1680 kcal

Resting Metabolic Rate

Physically active individual

who does not exerciseBBPhysically active

individual who does

exerciseCC

Thermic Effect of Food Physical Activity Exercise

Sedentary individualAA

% T

ota

l En

erg

y E

xp

end

itu

re

0

20

40

60

80

100


CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS

Systolic Blood Pressure Diastolic Blood Pressure

<120 mmHg <80 mmHg

120-139 mmHg 80-89 mmHg

140-159 mmHg 90-99 mmHg

≥160 mmHg ≥100 mmHg

“Normal” Stage

“Prehypertension” Stage

Stage 1

Stage 2


AGE-ADJUSTED PREVALENCE OF CORONARY HEART DISEASE (CHD) IN THE U.S. POPULATION OVER 50 YEARS OF AGE, CATEGORIZED BY PRESENCE OF METABOLIC SYNDROME (MS) AND TYPE 2 DIABETES

Copyright© 2003 American Diabetes AssociationFrom Diabetes®, Vol. 52, 2003; 1210-1214Reprinted with permission from The American Diabetes Association.

8.7%

19.2%

7.5%

13.9%

14.8%2.3%28.7%54.2%

No MS /No Type 2 Diabetes

MS /No Type 2 Diabetes

Type 2 Diabetes/ MS

Type 2 Diabetes/ No MS

CH

D P

rev

ale

nc

e (%

)


RESPECTIVE CONTRIBUTION OF TYPE 2 DIABETIC HYPERGLYCEMIA VERSUS THE CLUSTERING OF ABDOMINAL OBESITY-RELATED RISK FACTORS (METABOLIC SYNDROME) TO THE INCREASED CORONARY HEART DISEASE (CHD) RISK IN DIABETES

Abdominal Obesity

Insulin Resistance

Atherogenic Dyslipidemia

Impaired FibrinolysisPro-thrombotic State

Inflammation

Increased Blood Pressure

IGT

NGT

Time

Patient withAbdominal Obesityand Type 2 Diabetes

Gly

cem

ia

75g OGTT

MetabolicSyndrome

CHD RISK


NUMBER OF METABOLIC SYNDROME ABNORMALITIES BY NCEP-ATP III CLINICAL CRITERIA, DIABETES, AND PREVALENT CVD AND HAZARD RATIOS OF 10-YEAR RISK OF FATAL AND NON-FATAL CVD

Men Women

0 1 2 0 1 2NCEP-ATP III

Type 2

DiabetesCVD NCEP-

ATP IIIType 2

DiabetesCVD

From Dekker JM et al. Circulation 2005; 112: 666-73Reproduced with permission


0

1

2

3

4

5

6

RISK OF CORONARY HEART DISEASE (CHD) IN U.S. ADULTS ACCORDING TO SUBGROUPS OF METABOLIC SYNDROME (MS) COMPONENTS

Haz

ard

Rat

io

No MSRisk Factors

1-2 MSRisk Factors No Diabetes Diabetes

Metabolic Syndrome (all)

Adapted from Malik S et al. Circulation 2004; 110: 1245-50

1.0

2.10

2.87

5.02


OBESITY AS A MODIFIABLE CARDIOVASCULAR DISEASE (CVD) RISK FACTOR

Global CVD risk

HypertensionCholesterol

Diabetes Smoking

OthersObesityBMI

LDL HDL


OBESE INDIVIDUALS WITH A PREFERENTIAL ACCUMULATION OF INTRA-ABDOMINAL ADIPOSE TISSUE (AT): SUBGROUP AT HIGH CVD RISK

Gynoid Obesity Android Obesity

CVD RISK CVD RISK

- Low Trlglycerides- Normal HDL Cholesterol- Insulin Sensitive- Normal Glucose Tolerance- Normal lnflammatory and Thrombotic Profile

NO METABOLIC SYNDROME

- Hypertriglyceridemia- Low HDL Cholesterol- Insulin Resistance- Glucose Intolerance- Pro-inflammatory and Pro-thrombotic Profile

METABOLIC SYNDROME

Intra-abdominal AT

Subcutaneous AT Subcutaneous AT

Intra-abdominal AT

Same BMI>30 kg/m2

Normal Metabolic Profile Altered Metabolic Profile


BODY MASS INDEX AND RELATIVE RISK OF TYPE 2 DIABETES IN WOMEN FOLLOWED FOR 14 YEARS IN THE NURSES' HEALTH STUDY

Adapted from Colditz GA et al. Ann Intern Med 1995; 122: 481-6

Body Mass Index (kg/m2)

Rel

ativ

e R

isk

of

Typ

e 2

Dia

bet

es

0

20

40

60

80

100

120

1.0 2.98.1

15.8

27.6

54.0

40.3

93.2

4.3 5.0


III

III

0

5

10

15

III II I

PERCENTAGE PROBABILITY OF DEVELOPING TYPE 2 DIABETES IN 792 MEN FOLLOWED FOR 13.5 YEARS, ACCORDING TO TERTILES OF BODY MASS INDEX (BMI) AND WAIST-TO-HIP RATIO (WHR)

Copyright© 1985 American Diabetes AssociationFrom Diabetes®, Vol. 34, 1985; 1055-1058Reprinted with permission from the American Diabetes Association

Per

cen

tag

e P

rob

abil

ity

of

Dev

elo

pin

gTy

pe

2 D

iab

ete

s

BMI Tertiles (kg/m2)

WHRTertiles

0.5 0.5 0.5

9.1 9.1

9.1

15.2

2.9

2.9


GENERAL STRUCTURE OF A LIPOPROTEIN

Polar surface envelope

Neural lipid core

Apolipoprotein

Free cholesterol

Phospholipid

Cholesteryl ester

Triglyceride


TRIGLYCERIDE TRANSPORT AND METABOLISM

Intestinallumen

Chylomicron

VLDL

Acetyl-CoA

Fatty acids

Triglycerides

Oxidation

Dietarytriglycerides

Fatty acids Triglycerides

Triglycerides

Fatty acids

Fatty acids

LPL

Albumin

Enterocyte

Adipose tissue

Muscle

Liver

Legend

LPL=lipoprotein lipase


CHOLESTEROL TRANSPORT AND METABOLISM

Intestinal

lumen

Dietary cholesterol

Chylomicron

Chylomicron remnant

Bile

Excretion

HDL

LDL

VLDL

VLDLremnant

Cholesterol

Cholesterol Cholesterol

Acetyl-CoA Acetyl-CoA

Enterocyte Tissues

Liver

Acetyl-CoABile saltsCholesterol

LPLCETP

LCAT

HTGL

LPL

Legend

CETP = cholesteryl ester transfer proteinHTGL = hepatic triglyceride lipaseLCAT = lecithin cholesterol acyltransferaseLPL = lipoprotein lipase


INTRAVASCULAR VLDL METABOLISM

Legend

LPL = lipoprotein lipase

Liver

Nascent VLDL

Mature VLDL

VLDL remnant

LDL

HDL

HDL

Fatty acids

Tissues(adipose, muscle)

Apo EApo CII, CIII

Apo CII, CIIIApo E

Phospholipids

Cholesterylesters

Apo B/Ereceptor

LPL


Uptake by hepatic LDL receptors (60%-70%)

VLDL REMNANT METABOLISM

Legend

HTGL = hepatic triglyceride lipase

VLDL remnants

Liver uptake(LDL receptor)

LDL

LDL formation

HTGL

Fatty acids

Apo C’s

Apo E’s

Apo B/E receptor

Hydrolysis by HTGL(30%-40%)


HDL METABOLISM: GENESIS (A) AND ROLE IN REVERSE CHOLESTEROL TRANSPORT (B)

A B

Legend

CETP = cholesteryl ester transfer proteinHTGL = hepatic triglyceride lipaseLCAT = lecithin cholesterol acyltransferaseTG = triglyceride

Liver

Liver Intestine

Nascent HDL

Apo AI Apo E

Apo AIIApo AI

HDL3

LCAT

• Uptake of free cholesterol (from cells

surface of TG-rlch lipoproteins)• Esterification of free cholesterol by LCAT • Migration from surface to core of

HDL

Direct liver uptake of cholesteryl esters by SR-B1 receptor

Transfer of cholesteryl esters to VLDL via CETP

VLDL

LDL

HDL

Remnant

Lipid-depletedapo AI is catabolizedmainly In the kidney

Acquisition of freecholesterol by HDL andesterification by LCAT

HTGL

SR-B1 receptor


CHYLOMICRON METABOLISM: THE FATE OF DIETARY FAT

Legend

LPL = lipoprotein lipase

HDL

HDLGut

LiverLPL

Apo E

Apo CII

Apo CIII

Cholesteryl ester

Apo AI

Triglyceride

Apo CIIApo CIIIApo E

Chylomicron

Tissues(adipose, muscle)

Chylomicron remnant

Apo AI, AIV

Apo CII, CIII

Fatty acids

Remnantreceptor (LRP)

Apo B48


TRIGLYCERIDE AND HDL CHOLESTEROL LEVELS IN NON-OBESE WOMEN AND IN OBESE WOMEN WITH LOW OR HIGH LEVELS OF INTRA-ABDOMINAL ADIPOSE TISSUE

HDL cholesterol (mmol/l) Triglycerides (mmol/l)

Non-obese (N=25)

Obese with low levels of intra-abdominal fat

(N=10)

Obese with high levels of intra-abdominal fat

(N=10)

Non-obese (N=25)

Obese with low levels of intra-abdominal fat

(N=10)

Obese with high levels of intra-abdominal fat

(N=10)

Adapted from Després JP et al. Arteriosclerosis 1990; 10: 497·511

Legend

* Significantly different from non-obese women† Significantly different from obese women with low levels of intra-abdominal fat, p<0.05


THE DYSLIPIDEMIA OF INTRA-ABDOMINAL OBESITY AND THE METABOLIC SYNDROME

NORMAL

INSULINRESISTANCE

VLDL LDL HDL

↑ VLDL triglycerides↑ VLDL apo B↑ Number↑ Size

= LDL cholesterol↑ LDL apo B↑ LDL apo B/LDL↑ Number↓ Size (small, dense)

↓ HDL2 cholesterol↓ Number↓ Size (small, dense)


THE MANY FUNCTIONS OF INSULIN IN LIPID METABOLISM

Legend

The arrows indicate whether insulinincreases (upward green) or decreases(downward red) the corresponding process under normal conditions of insulin sensitivity. The red Xs indicate the insulin actions that are lost in the insulin resistant state. In this condition, liver lipid synthesis is the sole insulin action maintained and is therefore exacerbated by hyperinsulinemia.

LPL = lipoprotein lipaseCETP = cholesteryl ester transfer protein

Insulin resistance

Adipose LPL (triglyceride clearance)Lipolysis (VLDL-triglyceride precursors)

Muscle LPL (triglyceride clearance)

De novo lipid synthesisApo B degradationLDL-receptor expressionVLDL assemblyVLDL secretionApo CIII expression

Intravascular CETP-mediated lipid transfer


HOW INSULIN RESISTANCE AND DYSLIPIDEMIA ARE LINKED

CETP

CETP

HTGL

HTGL

Adipose tissue* Liver* Blood Kidney

Legend

CE = cholesteryl esterCETP = cholesteryl ester transfer proteinHTGL = hepatic triglyceride lipaseTG = triglyceride

* Insulin resistance

Hypertriglyceridemia

Shorter HDL Half-life

Small HDL

Small LDL

CE

CE

TG

TGApo AI

TGApo BVLDL

Fatty acids Adipokines

VLDL HDL

LDL LDL


LINK BETWEEN HYPERTRIGLYCERIDEMIA AND SMALL, DENSE LDL AND LOW HDL

Legend

CETP = cholesteryl ester transfer proteinHTGL = hepatic triglyceride lipaseLPL = lipoprotein lipase

Efficient triglyceride metabolism

Inefficient triglyceride metabolism

Atherogenic remnant

Remnant uptake

LPL

HTGL HTGL

CETP

CETP

LPL

LDL HDL

Chylomicrons VLDL

Fatty acids

Atherogenic Short ½ life

Triglycerides

Cholesterol


GLUCOSE TRANSPORTERS (GLUT)

Inside

Outside

Step 1

Step 2

Step 3

Step 4

Organ TransporterD-Glucose

Blood-brainbarrier

Brain

Intestine

Liver

Adipose tissue

Muscle

Pancreas

GLUT 1

GLUT 3

GLUT 5

GLUT 2

GLUT 2

GLUT 4*(GLUT 1)

GLUT 4*(GLUT 1)

*Insulin-sensitive


SIMPLIFIED SCHEME OF INSULIN ACTION ON GLUCOSE TRANSPORT

LegendAkt = protein kinase PI3K= phosphatidylinositol [3,4,5) kinaseAS160 = Akt substrate of 160 kDa PKC = protein kinase CGLUT = glucose transporter pS/T = serine/threonine phosphorylationIRS = insulin receptor substrate-1/2 pT = threonine phosphorylationPDK = phosphoinositide-dependent protein kinase pY = tyrosine phosphorylationPIP3 = phosphatidylinositol 3 triphosphate

INSULIN

ss

ss ss

GLUCOSE

GLUT 4

pY pY

pY pY

pY pY

Akt

Akt

PI3K

PIP3

PIP3pY

pT

pS/T

PKC-ξ/λIRS IRS

PDK

AS160

Y


IMPACT OF INTRA-ABDOMINAL FAT ON PLASMA GLUCOSE-INSULIN HOMEOSTASIS

Legend

1 different from non-obese subjects (p<0.05)2 different from obese subjects with low intra-abdominal fat (p<0.05)

Copyright© 1992 American Diabetes AssociationFrom Diabetes®, vol. 41, 1992; 826-834Reprinted with permission from the American Diabetes Association

Glucose (mmol/l) Insulin (pmol/l)

Glucose area Insulin area

Time (minutes) Time (minutes)

Non-obese Obese with low intra-abdominal fat accumulation

Obese with high intra-abdominal fat accumulation


MODEL FOR ADIPOSE TISSUE MACROPHAGE POLARIZATION AND ITS FUNCTION IN ADIPOSE TISSUE WITH PROGRESSIVE OBESITY

LegendATM = adipose tissue macrophageCLS = crownlike structuresDIO = diet-induced obesityFFA = free fatty acidsIL = interleukiniNOS = inducible nitric oxide synthaseJNK = C-jun N-terminal kinaseMCP-1 = monocyte chemoattractant protein-1NF-κB = nuclear factor-кBNO = nitric oxideTNF-α = tumor necrosis factor-α

DIO DIO

Leanness Insulin-sensitive

Mild Obesity Insulin-sensitive

Severe Obesity Insulin-resistant

Adapted from Lumeng CN et al. J Clin Invest 2007; 117: 175-84Reproduced with permission

FFAInflammatoryadipo-cytokinesArginase: less NO production

IL-10: anti-inflammatory

M2 ATMCX3CR1highCCR2-

M1 ATMCX3CR1lowCCR2+

Tissue repairLess NO production

Pro-inflammatoryMore NO production

↑Arginase↑ IL-10

↑Arginase↑ IL-10

CCR2+ MCP-1

Insulinresistance

CLS

JNKNF-κB

↑ iNOS↑ TNF-α↑ IL-6↓ IL-10 ↑↑ iNOS

↑↑ TNF-α↑↑ IL-6


MECHANISM OF FATTY ACID-INDUCED INSULIN RESISTANCE IN SKELETAL MUSCLE

LegendAkt = protein kinase BDAG = diacylglycerolFATPs = fatty acid transport proteinsG6P = glucose 6-phosphateGLUT = glucose transporterGS = glycogen synthase

GSK3 = glycogen synthase kinase-3IRS-1 = insulin receptor substrate-1LCCoA = long-chain acylcoenzyme APDK = phosphoinositide-dependent protein kinasePKC = protein kinase CPI3K = phosphatidylinositol [3,4,5] kinase

PIP3 = phosphatidylinositol 3 triphosphatepS = serine phosphorylationpS/T = serine/threonine phosphorylationpY = tyrosine phosphorylationSer/Thr = serine/threonineUDP = uridine diphosphate glucose

Adapted from Savage DB et al. Physiol Rev 2007; 87: 507-20

Insulin Receptor

Fatty AcidGLUCOSE

pY

pY

pY

pY

pYpS

pS

pSpS/T

pS/TPDK Akt

Akt

FATPs

PI3K

PIP3

IRS-1

GLUT 4

GSK3

Glucose

DAG

G6P

GS activity

GlycogenSynthesis

UDP-glucose

Tran

sloc

atio

n

PKC-θSer/Thr kinase

LCCoA

β-oxidation

MitochondrialDensity


MECHANISM OF FATTY ACID-INDUCED INSULIN RESISTANCE IN LIVER

LegendAkt = protein kinase BDAG = diacylglycerolFATPs = fatty acid transport proteinsFOXO = forkhead box protein OG6P = glucose 6-phosphateGLUT = glucose transporter

GSK3 = glycogen synthase kinase-3IRS-2 = insulin receptor substrate-2LCCoA = long-chain acylcoenzyme APDK = phosphoinositide-dependent protein kinasePKC = protein kinase CPEPCK = phosphoenolpyruvate carboxykinase

PI3K = phosphatidynositol [3,4,5] kinasePIP3 = phosphatidylinositol 3 triphosphatepS/T = serine/threonine phosphorylationpY = tyrosine phosphorylationSer/Thr = serine/threonlne

Adapted from Savage DB et al. Physiol Rev 2007; 87: 507-20

Fatty Acid

Insulin ReceptorGLUCOSE

GLUT 2

IRS-2

Gluconeogenesis

FOXO

FOXO PEPCK

G6Pase

pS/T

pS/T

pS/T

pY

pY

pY

pY

pY

pY PDK

PIP3

PI3KAkt

Akt

GSK3

Glycogen Synthesis

PKC-εSer/Thr kinase

β-oxidation?

DAGLCCoA

de novo lipid synthesis

NUCLEUS

FATPs


POTENTIAL CELLULAR MECHANISMS FOR ACTIVATING INFLAMMATORY SIGNALING

Legend

AP-1 = activator protein-1ER = endoplasmic reticulumIKK = IкB kinaseIL-1 R = interleukin-1 receptorINOS = inducible nitric oxide synthaseIRS-1 = insulin receptor substrate-1JNK = C-jun N-terminal kinaseNF = nuclear factorPKC = novel protein kinaseRAGE = receptor of advanced glycation endproductsROS = reactive oxygen speciesTLR = toll-like receptorTNFR = tumor necrosis factor receptorTZD = thiazolidinediones

Adapted from Shoelson SE et al. J Clin Invest 2006; 116: 1793-1801

TNFR, RAGE TLRs, IL-1R

Plasma Membrane

Insulin ResistanceNucleus

ROS

IRS-1

PKCs

ER stress

Ceramide

AP-1

?

JNK IKKα IKKβ

IKKγ

IκBα

p65 p50

p50p65

NF-κB

NF-кB

Salicylates, TZDs, and

statins

iNOS and other inflammatory

mediators

pS

pS


SUMMARY OF THE EFFECTS OF INSULIN ON GLUCOSE AND LIPID METABOLISM IN VARIOUS TISSUES AND THE COMPONENTS AFFECTED BY INSULIN RESISTANCE

Insulin action is reduced in obesity

Glucose Lipids

Legend

Green upward arrow = stimulation by insulinRed downward arrow = inhibition by insulin

Red x mark = loss of insulin action in insulin resistance

Uptake Uptake from blood triglyceridesGlucose → Glycerol → TriglyceridesGlucose → Fatty acids → TriglyceridesRelease (anti-lipolytic)

UptakeStorage (glycogen)Oxidation

Oxidation

Glucose → Fatty acids → TriglyceridesVLDL secretion

Storage (glycogen)OxidationGluconeogenesisSecretion

Hyperglycemia, Delayed triglyceride clearance, Increased fatty acid output

Lesser use of glucose

Hyperglycemia, Hypertriglyceridemia


POTENTIAL MECHANISMS FOR OBESITY-INDUCED INFLAMMATION

Nutrient excess

Lean

Obese

Expansion of fat mass

Adipocyte production of cytokines and chemokines

Endothelial cell expressionof adhesion molecules

Monocyte recruitmentand differentiation

Macrophage infiltrationand cytokine production

Insulin resistance

Pro-inflammatory andpost-atherogenic mediators

Atherosclerosis


ADIPOSE TISSUE AS AN ENDOCRINE ORGAN

LegendASP= Acylation-stimulating proteinFFA= Free fatty acidFIAF= Fasting-induced adipose factorHGF= Hepatocyte growth factorIGF-1 = Insulin-like growth factor-1IL= Interleukin

MCP-1= Monocyte chemoattractant protein-1MIF= Macrophage migration inhibitory factorNGF= Nerve growth factorPAI-1= Plasminogen activator inhibitor-1PGE2= Prostaglandin E2

PGF2α= 8-iso-prostaglandin F2α

PGI2= Prostaglandin I2

RAS= Renin-angiotensin systemTF= Tissue factorTGF-β= Transforming growth factor-βTNF-α= Tumor necrosis factor-αVEGF= Vascular endothelial growth factor

Adiponectin FFA

AdiposeTissue

Leptin Adipsin/ASPPAI-1

Complement factorsIL-6

TNF-α

Visfatin, ResistinSeveral soluble receptor

Sex hormonesGlucocorticoids

Retinol-blinding protein

PGI2/PGF2α/PGE2

HaptoglobulinSerum amyloid A

IL-1βIL-8

IL-10IGF-1

TGF-βMCP-1

MIFVEGF

HGFFIAFApolipoprotein ETF

NGFAgiotensin 2/RAS

Agouti


Macrophage

INFLAMMATION: THE LINK BETWEEN ABDOMINAL OBESITYAND GLOBAL CARDIOMETABOLIC RISK (CVD RISK)

Legend

FFA: Free Fatty Acids

Apo B: Apolipoprotein B

CRP: C-Reactive Protein

IL: Interleukln

TNF-α : Tumor Necrosis Factor -α

Adiponectin

IL-6 CRP

TNF-α

Inflammation

Abdominal Obesity

Atherogenic, insulinresistant dysmetabolicmilieu

Risk of CVD

Adapled from Després JP Int J Obes Metab Disord 2003; 27: 5224

AdiposeTissue

TriglyceridesInsulin

Glucose

Apo B

FFA

(-)

(-)

?

?


ADIPOSE TISSUE AND SOME OF THE ADIPOKINES/FACTORS INVOLVED IN THE PRO-THROMBOTIC STATE OF INTRA-ABDOMINAL OBESITY

Adipose Tissue

Adiponectin

Leptin PAI-1

IL-6Tissuefactor

Factor VIIand VIII

Fibrinogen

TNF-α

Liver

Oxidative Stress

Hypercoagulability

Initiation of coagulation cascade

Nitric oxide

Pro-thromboticand

HypofibrinolyticState Fibrin formation

Platelet aggregation

Plasma viscosityThrombotic events

(-)

Hyperactivity of platelets Hypofibrinolysis

Inhibitor of fibrinolysisPlatelet aggregation

CRP

Inflammation

Endothelial dysfunction


TRADITIONAL RISK FACTORS AND EMERGING MARKERS CONTRIBUTING TO CARDIOMETABOLIC RISK

((

((

CardiometabolicRisk

Emerging Markers

Traditional RiskFactors

BLOODPRESSUREAge

GenderType 2 Diabetes(hyperglycemia) Smoking

Lipid Profile

AtherogenicDyslipidemia

InsulinResistance

AbdominalObesity

Pro-thromboticProfile

InflammatoryState


TEN-YEAR RISK OF CORONARY HEART DISEASE (CHD) BY SYSTOLIC BLOOD PRESSURE (SBP) AND PRESENCE OF OTHER RISK FACTORS

10-Y

ear

Ris

k o

f C

HD

(%

)

From Chobanian AV et al. Hypertension 2003; 42: 1206-52Reproduced with permission

*Left Ventricular Hypertrophy

Cholesterol

HDL

Smoking

Diabetes

LVH*

180

50

No

No

No

No

No

No

No

No

No

No

No No

Yes

Yes

Yes Yes

Yes

Yes

240 240 240 240 240

50 35 35 35 35

SBP 120 SBP 180


CHANGES IN BLOOD PRESSURE WITH AGE

Men Women

From Burt VL et al. Hypertension 1995; 25: 305-13Reproduced with permission

Non-Hispanic black Non-Hispanic white Mexican American

Systolic blood pressure Systolic blood pressure

Diastolic blood pressure Diastolic blood pressure

Age Age


LINKS BETWEEN HYPERTENSION AND CARDIOVASCULAR DISEASE IN INSULIN RESISTANCE AND OBESITY

Genetic Factors Environmental Factors

Abdominal Obesity

Cardiovascular Risk

Impact on the Heart, Kidneyand Vasculature

Insulin Resistance /Hyperinsulinemia

Abnormal LipidProfile

Vasoconstriction Cardiac Output

Blood Pressure


ADIPOSE TISSUE DISTRIBUTION IN MEN AND WOMEN

Android Obesity Gynoid Obesity

Adapted from Vague J Presse Med 1947; 30: 339-40


AGE-RELATED CHANGES IN INTRA-ABDOMINAL ADIPOSE TISSUE DISTRIBUTION IN (a) MEN AND (b) WOMEN

(a)

(b)

Rel

ativ

e se

gm

enta

l fat

vo

lum

e (%

)

From Kotani K et al. Int J Obes 1994; 18: 207-12Reproduced with permission

Head

Forearm

Upper arm

Chest

Age (years)

Age (years)

Head

Forearm

Upper arm

Chest

Thigh

Calf

Thigh

Calf

Abdomen(subcutaneous)

Abdomen(subcutaneous)

Abdomen(intra-abdominal)

Abdomen(intra-abdominal)


FOUR-YEAR CHANGES IN INTRA-ABDOMINAL ADIPOSE TISSUEIN WHITE VS. AFRICAN-AMERICAN WOMEN

Intr

a-ab

do

min

al a

dip

ose

tis

sue

(cm

2)

Baseline Year 1 Year 2 Year 4Year 3

From Lara-Castro C et al. Obes Res 2002; 10: 868-74Reproduced with permission

White women

African-Americanwomen

p<0.01 for time effect

p<0.001 for race effect

(n): Number of subjects


SEVEN-YEAR CHANGES IN BMI (a), WAIST CIRCUMFERENCE (b) AND INTRA-ABDOMINAL ADIPOSE TISSUE (c) IN PRE-MENOPAUSAL WOMEN (N=32)

Adapted from Lemieux S et al. Diabetes Care 1996; 19: 983-91

a) BMI (kg/m2) b) Waist circumference (cm)

c) Intra-abdominal adipose tissue (cm2)

NS p<0.05 p<0.01

15

20

25

30

35

Baseline Follow-up

30.531.8

60

70

80

90

100

Baseline Follow-up60

80

100

120

140

160

Baseline Follow-up

134.5

102.7

93.0

88.9


60

80

100

120

140

Pre-menopausal women Post-menopausal women300

310

320

330

340

350

Pre-menopausal women Post-menopausal women

10

20

30

Pre-menopausal women Post-menopausal women10

20

30


INCREASE IN INTRA-ABDOMINAL ADIPOSE TISSUE (AT) ACCUMULATION ASSOCIATED WITH MENOPAUSE

NS

NS

NS

p=0.04

Adapted from Tchernof A et al. J Clin Endocrinol Metab 2004; 89: 3425·30

a) BMI (kg/m2) b) Body fat mass (kg)

c) Subcutaneous AT (cm2) d) Intra-abdominal AT (cm2)


DEVELOPMENT OF AN ATHEROGENIC PROFILE ASSOCIATED WITH MENOPAUSE-RELATED GAIN IN INTRA-ABDOMINAL ADIPOSITY

Menopause

CHD risk


Insulin resistance

Apolipoprotein B

Triglycerides

HDL cholesterol

LDL size


EVIDENCE FOR A GREATER RELATIVE ACCUMULATION OF INTRA-ABDOMINAL ADIPOSE TISSUE (AT) IN JAPANESE THAN IN CAUCASIAN AMERICANS

Caucasian (N=177) Japanese (N=239)

Intra-abdominal adipose tissue (cm2) Intra-abdominal / subcutaneous AT ratio

Adapted from Kadowaki T et al. Int J Obes 2006; 30: 1163-5

Waist girth quartiles (cm) Waist girth quartiles (cm)

p=0.001

p<0.001p<0.001

p<0.001

p=0.001

p=0.026


RELATIVE ACCUMULATION OF INTRA-ABDOMINAL VS. SUBCUTANEOUS DEPOT ACCORDING TO ETHNICITY

Caucasians Blacks Asians

Intra-abdominaldepot

Subcutaneousdepot


LIPID OVERFLOW HYPOTHESIS FOR THE PATHOGENESIS OF LIVER FAT

Positive Energy Balance

Metabolic Abnormalities

Caloric Intake Energy Expenditureand/or

Buffering of excessenergy in healthy

adipose tissue

Exhaustion ofbuffering capacity of

adipose tissue

Lipid overflow into liver,muscle or epicardium


COMPUTED TOMOGRAPHY IMAGING OF A NORMAL AND FATTY LIVER

The normal liver is free of lipid storage, denser and therefore has a higher Hounsfield unit (HU)and appears bright in contrast. On the other hand, lipid infiltration as seen in the fatty liverreduces the density of the liver tissue, thus the HU is lower and the image appears darker.

Normal liver Fatty liver

CT Liver (CTL) = 79.44 HU CT Liver (CTL) = 14.82 HU


SIMPLIFIED MODEL OF THE "PORTAL" THEORY

Release of free fatty acids (FFA) froman expanded, and highlyactive intra-abdominaladipose tissue depot

Products released from theintra-abdominal depot aredrained via the portal vein,

leading directly tothe liver

Increased exposure to FFAleads to hepatic insulin

resistance, fat deposition,lipotoxicity and metabolic

derangements

FFA FFA


INDEPENDENT ASSOCIATIONS BETWEEN LIVER FAT, INTRA-ABDOMINAL FAT AND CARDIOMETABOLIC RISK

Cardiometabolic Risk

Increased liver fatdeposition

Expanded intra-abdominalfat depot

?PositiveEnergyBalance


www.cardiometabolic-risk.org

the concept of cardiometabolic risk

Health & Medicine

international chair

cardiometabolic riskadapted

cardiometabolic riskhttp

groupwith diabetes

age group

active individual

united stateseast

years10 overweight