Fettsucht Lajos Szollár Semmelweis Universität Fakultät für Medizin Institut für Pathophysiologie 2006

FettsuchtFettsucht

Lajos Lajos SzollárSzollárSemmelweis Semmelweis Universität Universität

Fakultät für MedizinFakultät für MedizinInstitut für PathophysiologieInstitut für Pathophysiologie

20020066

ObesityObesity

Definition of obesity: Increase of adipose tissueDefinition of obesity: Increase of adipose tissue Criteria of obesity, grade of severityCriteria of obesity, grade of severity

Broca-index, relatíve weight, ideal weight, body mass indexBroca-index, relatíve weight, ideal weight, body mass index

Frequency, geographical distribution, time-trendsFrequency, geographical distribution, time-trends Effects on mortality and morbidityEffects on mortality and morbidity Consequences and complicationsConsequences and complications Classification of obesityClassification of obesity

Hypertrophic-hyperplasticHypertrophic-hyperplastic Central-peripheralCentral-peripheral

Pathogenesis of obesityPathogenesis of obesity

Body fat in obesityBody fat in obesity

ENERGY RESERVES IN LEAN AND OBESE ENERGY RESERVES IN LEAN AND OBESE SUBJECTSSUBJECTS

((After After BrayBray,, 1976 1976 ))

Body weight 70 100 Fat (triglyceride) 15 564.840 40 1.506.240Proteine (muscle) 6 100.416 7 117.152Glycogen 0.07 1.170 0.07 1.170

kg kJ kg kJ

Lean Obese

ObesityObesity






Clinically useful anthropometric Clinically useful anthropometric methodsmethods

Broca-index: ideal weight=body height (cm)-100Broca-index: ideal weight=body height (cm)-100

Modified Broca-index: ideal weight=((body height (cm)-100))-10 %Modified Broca-index: ideal weight=((body height (cm)-100))-10 %

Relatíve weight: actual weight / ideal weight x 100 obese > 120Relatíve weight: actual weight / ideal weight x 100 obese > 120

BMI (BMI (BBody ody MMass ass IIndex), Quetelet-index:ndex), Quetelet-index:

body weight (kg) / body heightbody weight (kg) / body height2 2 (m(m22))

desirable < 25, overweight 27-30, obese >30desirable < 25, overweight 27-30, obese >30

BMI (body mass BMI (body mass index)index)

CLASSIFICATIONBMI (kg/m²) Risk of comorbidities

Underweight <18.5 Low (but risk of other clinical problems increased)

Normal range 18.5-24.9 Average

Overweight >25

Pre-obese 25.0-29.9 Increased

Obese class I 30.0-34.9 Moderate

Obese Class II 35.0-39.9 Severe

Obese Class III >40.0 Very severe

Classification of overweight in adults according to

BMI. Obesity is classified as BMI >30 kg/m²

ObesityObesity






Prevalence of Overweight in Girls and Boys by Race Prevalence of Overweight in Girls and Boys by Race and Ageand Age

11.5 11.29.2

11.6

22.219.6

12.4

26.6

19.4

0

5

10

15

20

25

30

White Black Mexican American

Prev

alen

ce %

Ages 2-5 Ages 6-11 Ages 12-19

Ogden CL, et al. JAMA 2002;288:1730

8.85.9

1312

17.1

27.3

12.8

20.7

27.5

0

5

10

15

20

25

30

White Black Mexican American

Pre

vale

nce

%Ages 2-5 Ages 6-11 Ages 12-19

W.Samoa (urban)

Kuwait

East Germany

USA

Saudi Arabia

W. Germany

Czech Republic

England

Canada

Netherlands

Australia

Brazil

Japan

China

Women Men

80 70 60 50 40 30 20 10 0 10 20 30 40 50 60 70 80

% population

Age rangeYear *

* Most recent available data. Surveys conducted between 1988 and 1994.

25-6918+

25-6420-74

15+25-6920-6516-6418-7420-5920-6915-6425-64

20+20-45

GLOBAL PREVALENCE OF OBESITY (defined as BMI >30)

Total Prevalence of Obesity in the U.S.: Total Prevalence of Obesity in the U.S.: Men and Women (Ages 20-74 years)Men and Women (Ages 20-74 years)

10.712.1 12.7

20.6

27.7

15.8 16.6 17

25.9

34

0

5

10

15

20

25

30

35

40

1960-62 1971-74 1976-80 1988-94 1999-00

Men

Women

Pre

vale

nce

%

Flegal KM, et al. JAMA 2002;288:1724

1978 19910

10

20

30

40

50

60

70

80

Pre

va

len

ce

of

ob

esit

y (

%)

W. Samoa (Urban)

25-69 yrs

1978 19910

10

20

30

40

50

60

70

80

Pre

va

len

ce o

f o

besit

y (

%)

19821987

1993 19751989 1980

1986/871991

1995 19731978

1991 19851989

19920

10

20

YEAR

Pre

vale

nc

e o

f o

bes

ity

(%)

19821987

1993 19751989 1980

1986/871991

1995 19731978

1991 19851989

19920

10

20

YEAR

Pre

vale

nce o

f o

besit

y (%

)THE GROWING EPIDEMIC OF OBESITY

Women

Japan20+ yrs.

Brazil 25-64 yrs.

England16-64 yrs.

USA20-74 yrs.

Former E. Germany25-65 yrs.

Men

Historic, current and projected obesity prevalence rates (BMI > 30)

Kopelman, Nature 404:635, 2000

ObesityObesity






BMI and mortalityBMI and mortality

ObesityObesity






Mortality in obesityMortality in obesity

CauseNon- obese

mortality=100

Men Women

Diabetes mellitus 383 372Gallstones 206 284Post surgery 200 300Cardiovascular and kidney 149 177Accidents 111 135Malignant diseases 97 100Suicide 79 73Tuberculosis 21 35

Health Consequences of Obesity

• Cardiovascular disease

• Dyslipidemia

• Type II diabetes mellitus

• Hypertension

• Cancer, some common types

• Degenerative joint disease

• Gallstones

• Gynecologic irregularities

• Sleep apnea syndrome

Data from British Regional Heart Survey.

18 20 22 24 26 28 30 32 341.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

6.6

6.2

5.8

Total cholesterol

Triglycerides

HDL cholesterol

Body Mass Index (kg/m²)

0

10

20

30

40

50

60

SBP

Obesity: cardiovascular risk

26 -Year Incidence/10,000 of Coronary Heart Disease in Women and Men by BMI26 -Year Incidence/10,000 of Coronary Heart Disease in Women and Men by BMI

76119

179223

268292

0

100

200

300

400

500

<25 25-<30 30+

<50 years 50+ years

BMI Levels

Hubert HB et al. Circulation 1983;67:968-977.

177

255

350333366

440

0

100

200

300

400

500

600

<25 25-<30 30+

<50 years 50+ years

BMI and relative risk (a=woman

b=men)Kopelman,

Nature 404:635, 2000

DCEM/2001DCEM/2001

OBESITY

volumeoverload

pressureoverload

ARTERIALHYPERTENSION

sympatheticactivity

vascularhypertrophy

Na+

retention

peripheralinsulin-resistance

abdominal fat

insulin secretion

release of Free Fatty Acids

type 2diabetes

dyslipidemiahyperinsulinemiahyperinsulinemia

Type 2Type 2 diabetes and obesity diabetes and obesity

The risk of diabetes in relation to weight and weight change.

BMI at 21 years

Weight change since age 21

0

5

10

15

20

25

<5 kg 5-10 kg 11+ kg

<22

22-23

24+

1.0

1.0

2.1

2.5

3.6

5.3

6.3

9.1

21.1

From: Chan et al. 1994, Diabetes Care, 17: 961.

Osteoarthrosis and obesityOsteoarthrosis and obesity

Infertility and obesityInfertility and obesity

Gout and Gout and obesityobesity

Obesity and ovarian cancerObesity and ovarian cancer

Consequences of obesityConsequences of obesity

CardiovascularCardiovascular system system

ArteriosclerosisArteriosclerosis

CongestCongestíív v heart failure, cheart failure, cor pulmonor pulmonaleale

VVenous disordersenous disorders, thrombophlebitis, thrombophlebitis

HHyypertenpertensionsion

Diabetes mellitusDiabetes mellitus

AlAlveolveolarar h hyypoventilpoventilationation (Pickwick-s(Pickwick-syndromeyndrome))

Gastrointestinal disorders Gastrointestinal disorders (fatty liver,gallstones)(fatty liver,gallstones)

KidneyKidney

AArthrosisrthrosis

EndoEndocrine system crine system (reproductive and menstrual disorders,(reproductive and menstrual disorders, toxaemia toxaemia))

Other Other (i(intertrigosusntertrigosus dermatosisdermatosis, hiatus hernia, e, hiatus hernia, endometrindometrial al carcinomacarcinoma))

Diabetes

Gall bladder disease

Hypertension

Dyslipidaemia

Insulin resistance

Breathlessness

Sleep apnoea

Greatly increased(relative risk >>3)

Coronary heart disease

Osteoarthritis (knees)

Hyperuricaemia and gout

Moderately increased(relative risk

ca 2-3)

Cancer (breast cancer in postmenopausal women, endometrial cancer, colon cancer)

Reproductive hormone abnormalities

Polycystic ovary syndrome

Impaired fertility

Low back pain

Increased anaesthetic risk

Foetal defects arising from maternal obesity

Slightly increased(relative risk

ca 1-2)

Relative risk of health problems associated with

obesity in developed countries.

ObesityObesity






Increased Substantially increased

Men >94 cm (37 inches) >102 cm (40 inches)

Women >80 cm (32 inches) >88 cm (35 inches)

Sex-specific waist circumferences that denote "increased risk" and "substantially increased risk" of metabolic

complications associated with obesity in Caucasians.

Risk of obesity associated metabolic complications

Assessment of accumulation of abdominal fatby measurement of waist at mid-distance between bottom of rib cage and iliac crest. Amount of visceral adipose tissue that can be assessed by CT canbe estimated by waist measurementDespres et al. BMJ 322:716,2001

The Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk Factors

Insulin Resistance

AtherosclerosisAtherosclerosis

Endothelial Dysfunction

Hypertension

Abdominal obesity

Hyperinsulinaemia

Dyslipidaemia• high TGs

• small dense LDL• low HDL-C

Diabetes

Hypercoagulability

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

HBP Inflam-mation Insulin Diabetes TG

Dense LDL-C

Low HDL-C Coag.

Interrelationships Between Insulin Resistance and Interrelationships Between Insulin Resistance and AtherosclerosisAtherosclerosis

Insulin Resistance

Endothelial dysfunction

Atherosclerosis

Obesity

ObesityObesity






Pathogenesis of ObesityPathogenesis of Obesity „„Pure” OvereatingPure” Overeating Disturbances in Appetite RegulationDisturbances in Appetite Regulation Disturbances in Intermediate MetabolismDisturbances in Intermediate Metabolism Defective Thermogenesis Defective Thermogenesis „„Thrifty” Gen ExpressionThrifty” Gen Expression

Treatments AvailableTreatments Available

DietDiet DrugDrug SurgerySurgery

Energy intake and demand in developped countries in Energy intake and demand in developped countries in the XX. Centurythe XX. Century

2800

2900

3000

3100

3200

3300

3400

1882 1925 1950 1970

Energy intake

Energia demand

kcal

Prevalence of overweight and intake of fatPrevalence of overweight and intake of fat

U.S.A.

India

Cuba

AustrailaBrazil

Malaysia

China

Kyrgyzstan

Mauritius

Phillipines

Saudi Arabia

S. Africa

Tunisia

CongoMali

Russian Fed

Italy

Morocco

Kuwait

New Caledonia

0

10

20

30

40

50

60

70

80

15 20 25 30 35 40

Percentage of energy from fat

Pe

rce

nt

ov

erw

eig

ht

actual obesity predicted obesity

Ludwig

Energy intake and demand in developped countries in Energy intake and demand in developped countries in the XX. Centurythe XX. Century

2800

2900

3000

3100

3200

3300

3400

1882 1925 1950 1970

Energy intake

Energia demand

kcal

Obesity and lifestyleObesity and lifestyle

Percent of Adults Physically InactivePercent of Adults Physically Inactive

0

10

20

30

40

50

60

70

Women Men

18-2425-4445-6465-7475+

Age-Groups

Percent

Source—Advance Data from Vital and Health Statistics. #325, April 7, 2002

Ages 45-54 Ages 55-Ages 45-54 Ages 55-6464

Percent of Adults Percent of Adults with Diabeteswith Diabetes

Pathogenesis of ObesityPathogenesis of Obesity „„Pure” OvereatingPure” Overeating Disturbances in Appetite RegulationDisturbances in Appetite Regulation Imbalance in Energy ExpenditureImbalance in Energy Expenditure Defective Thermogenesis Defective Thermogenesis „„Thrifty” Gen ExpressionThrifty” Gen Expression



Hypothalamic areas implicated in eating behaviour

Pathogenesis of ObesityPathogenesis of Obesity „„Pure” OvereatingPure” Overeating Disturbances in Appetite RegulationDisturbances in Appetite Regulation Imbalance in Energy ExpenditureImbalance in Energy Expenditure Defective Thermogenesis Defective Thermogenesis „„Thrifty” Gen ExpressionThrifty” Gen Expression



„Thrifty” gen and obesity

Genes and environment in type 2 diabetesGenes and environment in type 2 diabetesand atherosclerosisand atherosclerosis

Pima IndiansPima Indians T Thrifty geneshrifty genes

Thermogenesis in menThermogenesis in men

Pathogenesis of ObesityPathogenesis of Obesity „„Pure” OvereatingPure” Overeating Disturbances in Appetite RegulationDisturbances in Appetite Regulation Imbalance in Energy ExpenditureImbalance in Energy Expenditure Defective Thermogenesis Defective Thermogenesis „„Thrifty” Gen ExpressionThrifty” Gen Expression LeptinLeptin



Monogenic obesity in rodentsMonogenic obesity in rodents

SpontaneousSpontaneous Lack of leptin (ob/ob)Lack of leptin (ob/ob) Leptin receptor defect Leptin receptor defect

(db/db)(db/db) Ectopic Agouti expressio Ectopic Agouti expressio

(Ay)(Ay) „„Fat rich” (fa/fa)Fat rich” (fa/fa)

Genetically manipulatedGenetically manipulated Serotonin 2C-receptor KOSerotonin 2C-receptor KO Melanocortin-4 receptor KOMelanocortin-4 receptor KO Agouti related protein (AgRP) Agouti related protein (AgRP)

hyperexpressiohyperexpressio Neuropeptid Y (NPY) receptor KONeuropeptid Y (NPY) receptor KO CRH hyperexpessionCRH hyperexpession Bombesin B-3 receptor KOBombesin B-3 receptor KO Glut-4 hyperexpressionGlut-4 hyperexpression

The ob/ob mouse and its normal counterpart

Serum leptin and body fat

Soluble leptin receptors, immunoreactive leptin and BMIShimizu et al., Nutrition 18:309 (2002)

Hypothetical risk of obesityHypothetical risk of obesityHill et al., Science 280:1371 (1998)Hill et al., Science 280:1371 (1998)

A systematic approach to management based on BMI and other risk factors

Assess overall health risk from BMI and other risk factors, e.g. waist circumference

MANAGEMENT STRATEGIES

OVERALL HEALTH RISK

NO

Additional risk factors ?

YES

BMI

Refer to specialist for separate management and consideration of surgery if conventional treatment fails. Aim for 20-30% weight reduction.

Use ful therapy including drugs to achieve >10% weight loss.

Goal for diet, exercise, behaviour: primarily geared to risk management. Weight loss needed if risk not reduced substantially within 3 months, then aim for 5-10 kg over 24 weeks by mild energy deficit. If not achieving this weight reduction at 24 weeks and risks persist, test usefulness of drug to reduce risk by weight management.

Weight maintenance, healthy diet, exercise.

Elevated waist circumference: institute weight management.Family history of obesity: prevent weight gain >3 kg.Smoking: stop with dietary advice.Lipids high: dietary advice.Hypertensive: diet, exercise, weight maintenance.Glucose intolerance: exercise, diet, weight maintenance.

Healthy diet and advice on preventing weight gain.

Goal of 5-10% weight loss without risk appropriate.

Consider very low calorie diet and drug therapy if diet, exercise and lifestyle programme unsuccessful after 12 weeks in reducing all risk factors.

Average

Increased

Moderate

Severe

Verysevere

Very severe

Moderate

Severe

Increased

BMI18.5 -24.9

BMI>40

BMI25 - 29.9

BMI30 - 34.9

BMI35 - 39.9

Documents

Fettsucht Lajos Szollár Semmelweis Universität Fakultät für Medizin Institut für Pathophysiologie 2006