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Disturbances of Energy MetabolismDisturbances of Energy MetabolismObesityObesity
Lajos Szollár
Professor of Pathophysiology
Institute of Pathophysiology
Semmelweis University, Faculty of Medicine
Budapest, Hungary
2006/2007
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
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
Body fat and ageBody fat and age
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
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
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
DefinitionsDefinitions
Body Mass Index (BMI) describes relativeweight for height: weight (kg)/height (m2)
• Overweight = 25–29.9 BMI
• Obesity = >30 BMI
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
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
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
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)
Historic, current and projected obesity prevalence rates (BMI > 30)
Kopelman, Nature 404:635, 2000
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
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)
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)
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)
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
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
BMI and relative risk (a=woman
b=men)Kopelman,
Nature 404:635, 2000
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.
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.
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
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
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.
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.
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
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
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
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))
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
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
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
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
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
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
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
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
Thermogenesis in menThermogenesis in men
„Thrifty” gen and obesity
Genes and environment in type 2 diabetesGenes and environment in type 2 diabetesand atherosclerosisand atherosclerosis
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
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
Appetite Appetite regulating regulating feed-back feed-back
mechanismnsmechanismns
Role of leptin in obesityRole of leptin in obesity
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)
Examination and treatment of obesityExamination and treatment of obesity
Treatment of obesityTreatment of obesity
Hypothetical risk of obesityHypothetical risk of obesityHill et al., Science 280:1371 (1998)Hill et al., Science 280:1371 (1998)