Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of...

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Disturbances of Energy Disturbances of Energy Metabolism Metabolism Obesity Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine Budapest, Hungary 2006/2007

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Page 1: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.

Disturbances of Energy MetabolismDisturbances of Energy MetabolismObesityObesity

Lajos Szollár

Professor of Pathophysiology

Institute of Pathophysiology

Semmelweis University, Faculty of Medicine

Budapest, Hungary

2006/2007

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STARVATIONSTARVATION

Fuel ReservesFuel Reserves

Substrate Fluxes Substrate Fluxes in FEDin FED

in FASTING in FASTING StateState

Metabolic Responses to Metabolic Responses to SHORT-TERMSHORT-TERM

PROLONGEDPROLONGED Starvation Starvation

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OBESITY

Fat homeostasis in manFat homeostasis in man Criteria of obesityCriteria of obesity Methods for estimating fat tissue Methods for estimating fat tissue

clinically useful anthropometric clinically useful anthropometric methodsmethods

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Body fat and ageBody fat and age

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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

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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

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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, Broca-index, relatíve weight, ideal weight, BMI (bodyBMI (body mass index 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

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DefinitionsDefinitions

Body Mass Index (BMI) describes relativeweight for height: weight (kg)/height (m2)

• Overweight = 25–29.9 BMI

• Obesity = >30 BMI

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Obesity Class BMI kg/m2

Underweight <18.5

Normal 18.5–24.9

Overweight 25–29.9

Obesity I 30.0–34.9

II 35.0–39.9

Extreme Obesity III 40.0

Classification of Overweight and Obesity by BMIClassification of Overweight and Obesity by BMI

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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

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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

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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)

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

Kopelman, Nature 404:635, 2000

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BackgroundBackground

HypertensionHypertension Type 2 diabetesType 2 diabetes Coronary heart diseaseCoronary heart disease Gallbladder diseaseGallbladder disease Certain cancersCertain cancers

DyslipidemiaDyslipidemia StrokeStroke OsteoarthritisOsteoarthritis Sleep apneaSleep apnea

Approximately 108 million American adults are overweight or obese.

Increased risk of:

CDC/NCHS NHANES 1999

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Obesity Trends* Among U.S. Adults: BRFSS, 1988Obesity Trends* Among U.S. Adults: BRFSS, 1988

Mokdad A.H., CDC

(*BMI > 30, or ~ 30 lbs overweight for 5’4” woman)

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Obesity Trends* Among U.S. Adults: BRFSS, 1994Obesity Trends* Among U.S. Adults: BRFSS, 1994

Mokdad A H, et al. J Am Med Assoc 1999; 282:16

(*BMI > 30, or ~ 30 lbs overweight for 5’4” woman)

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Obesity Trends Among* U.S. Adults: BRFSS, 2000Obesity Trends Among* U.S. Adults: BRFSS, 2000

Mokdad A H, et al. J Am Med Assoc 2001; 286:10

(*BMI > 30, or ~ 30 lbs overweight for 5’4” woman)

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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

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Relationship of BMI to Excess MortalityRelationship of BMI to Excess Mortality

300Age at Issue

Bray GA. Overweight is risking fate. Definition, classification, prevalence and risks. Ann NY Acad Sci 1987;499:14-28.

20-29250

Mo

rta

lity

Ra

tio

Body Mass Index (kg/[m2])

200

150

100

50

150

30-39

20 25 30

LowRisk

4035

High

Risk

Moderate

Risk

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BMI and relative risk (a=woman

b=men)Kopelman,

Nature 404:635, 2000

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Obesity and Diabetes RiskObesity and Diabetes Risk

0

20

40

60

80

100

<20 20-25 25-30 30-35 35-40 >40

BMI Levels

Inci

den

ce o

f N

ew C

ases

p

er 1

,000

Per

son

-Yea

rs

Knowler WC et al. Am J Epidemiol 1981;113:144-156.

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Hypertension

BMI

Pe

rce

nta

ge

20 25 30 35 40

20

10

30

50

40

60

Relationship between BMI and crude percentage of women reportingmedical problems, surgical procedures, symptoms, and health care utilization.

Brown WJ et al. Int J Obes 1998;22:520-528.

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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

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14.9 15.2

22.1

27.727

32.7

41.937.8

0

10

20

30

40

50

Men Women

BMI <25 BMI 25-<27 BMI 27-<30 BMI >30

NHANES III Prevalence of Hypertension* NHANES III Prevalence of Hypertension* According to BMIAccording to BMI

*Defined as mean systolic blood pressure 140 mm Hg, mean diastolic 90 mm Hg, or currently taking antihypertensive medication.

Brown C et al. Body Mass Index and the Prevalence of Hypertension and Dyslipidemia. Obes Res. 2000; 8:605-619.

Pe

rce

nt

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BMI

Pe

rce

nta

ge

20 25 30 35 40

5

10

15

25

20

Cholescystectomy

Relationship between BMI and crude percentage of women reporting medical problems, surgical procedures, symptoms, and health care utilization.

Brown WJ et al. Int J Obes 1998;22:520-528.

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26 -Year Incidence of Coronary Heart Disease in Men26 -Year Incidence of Coronary Heart Disease in Men

177

255

350333366

440

0

100

200

300

400

500

600

<25 25-<30 30+

<50 years 50+ years

Inci

den

ce/1

,000

BMI LevelsAdapted from Hubert HB et al. Circulation 1983;67:968-977. Metropolitan Relative Weight of 110 is a BMI of approximately 25.

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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

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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

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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

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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))

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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

Central-peripheralCentral-peripheral

Pathogenesis of obesityPathogenesis of obesity

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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

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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

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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

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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

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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

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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

Treatments AvailableTreatments Available

DietDiet DrugDrug SurgerySurgery

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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

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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

Treatments AvailableTreatments Available

DietDiet DrugDrug SurgerySurgery

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Thermogenesis in menThermogenesis in men

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„Thrifty” gen and obesity

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

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20-44 45-54 55-64 65-74Age (years)

Thrifty genesThrifty genes

MaycobaMaycoba

50%50% have type 2 diabeteshave type 2 diabetes

75%75% are overweight or obeseare overweight or obese

Traditional way of lifeTraditional way of lifeAnimal fat poor dietAnimal fat poor dietPhysical activityPhysical activity

Few peopleFew people with type 2 diabetes or obesitywith type 2 diabetes or obesity

Animal fat and glucides Animal fat and glucides rich foodsrich foodsSedentary lifeSedentary life

ArizonaArizona

Type 2 diabetes prevalence (%)100

80

60

40

20

0

Pimas men

Pimas woman

USA woman

USA men

Knowler WC et al Obesity in the Pimas Indians. It magnitude and relationship with diabetes. Am J Clin Nutr1991;53:S1543-51.

Pima Indians

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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

Treatments AvailableTreatments Available

DietDiet DrugDrug SurgerySurgery

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Appetite Appetite regulating regulating feed-back feed-back

mechanismnsmechanismns

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Role of leptin in obesityRole of leptin in obesity

Page 91: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.
Page 92: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.

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

Page 93: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.

The ob/ob mouse and its normal counterpart

Page 94: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.

Serum leptin and body fat

Page 95: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.

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

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Examination and treatment of obesityExamination and treatment of obesity

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Treatment of obesityTreatment of obesity

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

Page 99: Disturbances of Energy Metabolism Obesity Lajos Szollár Professor of Pathophysiology Institute of Pathophysiology Semmelweis University, Faculty of Medicine.