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

STARVATION Fuel Reserves Substrate Fluxes in FED in FASTING State in FASTING State Metabolic Responses to SHORT-TERM PROLONGED Starvation PROLONGED Starvation

OBESITY  Fat homeostasis in man  Criteria of obesity  Methods for estimating fat tissue clinically useful anthropometric methods

Body fat and age

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, body mass index  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Hypertrophic-hyperplastic  Central-peripheral  Pathogenesis of obesity

ENERGY RESERVES IN LEAN AND OBESE SUBJECTS (After Bray, 1976 ) Body weight Fat (triglyceride) Proteine (muscle) Glycogen kg kJ kg kJ Lean Obese

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, BMI (body mass index)  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Hypertrophic-hyperplastic  Central-peripheral  Pathogenesis of obesity

Definitions Body Mass Index (BMI) describes relative weight for height: weight (kg)/height (m 2 ) Overweight = 25–29.9 BMI Obesity = >30 BMI

Classification of Overweight and Obesity by BMI

CLASSIFICATION BMI (kg/m²)Risk of comorbidities Underweight<18.5Low (but risk of other clinical problems increased) Normal range Average Overweight>25 Pre-obese Increased Obese class I Moderate Obese Class II Severe Obese Class III>40.0 Very severe Classification of overweight in adults according to BMI. Obesity is classified as BMI>30 kg/m²

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, body mass index  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Hypertrophic-hyperplastic  Central-peripheral  Pathogenesis of obesity

Prevalence of Obesity Adults Worldwide 1998—World Health Organization 1998—Geneva, WHO

W.Samoa (urban) Kuwait East Germany USA Saudi Arabia W. Germany Czech Republic England Canada Netherlands Australia Brazil Japan China WomenMen % population Age range Year * * Most recent available data. Surveys conducted between 1988 and GLOBAL PREVALENCE OF OBESITY (defined as BMI>30)

Historic, current and projected obesity prevalence rates (BMI > 30) Kopelman, Nature 404:635, 2000

Background  Hypertension  Type 2 diabetes  Coronary heart disease  Gallbladder disease  Certain cancers  Dyslipidemia  Stroke  Osteoarthritis  Sleep apnea Approximately 108 million American adults are overweight or obese. Increased risk of: CDC/NCHS NHANES 1999

Obesity 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, 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, 2000 Mokdad A H, et al. J Am Med Assoc 2001; 286:10 (*BMI > 30, or ~ 30 lbs overweight for 5’4” woman)

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, body mass index  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Hypertrophic-hyperplastic  Central-peripheral  Pathogenesis of obesity

Relationship of BMI to Excess Mortality 300 Age at Issue Bray GA. Overweight is risking fate. Definition, classification, prevalence and risks. Ann NY Acad Sci 1987;499: Mortality Ratio Body Mass Index (kg/[m 2 ]) Low Risk 4035 High Risk Moderate Risk

BMI and relative risk (a=woman b=men) Kopelman, Nature 404:635, 2000

Obesity and Diabetes Risk BMI Levels Incidence of New Cases per 1,000 Person-Years Knowler WC et al. Am J Epidemiol 1981;113:

Hypertension BMI Percentage 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:

NHANES III Prevalence of Hypertension* According 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: Percent

BMI Percentage 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:

26 -Year Incidence of Coronary Heart Disease in Men Incidence/1,000 BMI Levels Adapted from Hubert HB et al. Circulation 1983;67: Metropolitan Relative Weight of 110 is a BMI of approximately 25.

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, body mass index  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Hypertrophic-hyperplastic  Central-peripheral  Pathogenesis of obesity

Mortality in obesity Cause Non- obese mortality=100 Men Women Diabetes mellitus Gallstones Post surgery Cardiovascular and kidney Accidents Malignant diseases Suicide Tuberculosis 21 35

Consequences of obesity  Cardiovascular system  Arteriosclerosis  Congestív heart failure, cor pulmonale  Venous disorders, thrombophlebitis  Hypertension  Diabetes mellitus  Alveolar hypoventilation (Pickwick-syndrome)  Gastrointestinal disorders (fatty liver,gallstones)  Kidney  Arthrosis  Endocrine system (reproductive and menstrual disorders, toxaemia)  Other (intertrigosus dermatosis, hiatus hernia, endometrial carcinoma)

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, body mass index  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Central-peripheral  Pathogenesis of obesity

IncreasedSubstantially 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 fat by 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 can be estimated by waist measurement Despres et al. BMJ 322:716,2001

Obesity  Definition of obesity: Increase of adipose tissue  Criteria of obesity, grade of severity  Broca-index, relatíve weight, ideal weight, body mass index  Frequency, geographical distribution, time-trends  Effects on mortality and morbidity  Consequences and complications  Classification of obesity  Hypertrophic-hyperplastic  Central-peripheral  Pathogenesis of obesity

 Pathogenesis of Obesity  „Pure” Overeating  Disturbances in Appetite Regulation  Disturbances in Intermediate Metabolism  Defective Thermogenesis  „Thrifty” Gen Expression  Treatments Available  Diet  Drug  Surgery

 Pathogenesis of Obesity  „Pure” Overeating  Disturbances in Appetite Regulation  Disturbances in Intermediate Metabolism  Defective Thermogenesis  „Thrifty” Gen Expression  Treatments Available  Diet  Drug  Surgery

 Pathogenesis of Obesity  „Pure” Overeating  Disturbances in Appetite Regulation  Imbalance in Energy Expenditure  Defective Thermogenesis  „Thrifty” Gen Expression  Treatments Available  Diet  Drug  Surgery

Energy intake and demand in developped countries in the XX. Century Energy intake Energia demand kcal

 Pathogenesis of Obesity  „Pure” Overeating  Disturbances in Appetite Regulation  Imbalance in Energy Expenditure  Defective Thermogenesis  „Thrifty” Gen Expression  Treatments Available  Diet  Drug  Surgery

Thermogenesis in men

„Thrifty” gen and obesity

Genes and environment in type 2 diabetes and atherosclerosis

Age (years) Thrifty genes Maycoba 50% have type 2 diabetes 75% are overweight or obese Traditional way of life Animal fat poor diet Physical activity Few people with type 2 diabetes or obesity Animal fat and glucides rich foods Sedentary life Arizona Type 2 diabetes prevalence (%) 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:S Pima Indians

 Pathogenesis of Obesity  „Pure” Overeating  Disturbances in Appetite Regulation  Imbalance in Energy Expenditure  Defective Thermogenesis  „Thrifty” Gen Expression  Leptin  Treatments Available  Diet  Drug  Surgery

Appetite regulating feed-back mechanismns

Role of leptin in obesity

Monogenic obesity in rodents  Spontaneous  Lack of leptin (ob/ob)  Leptin receptor defect (db/db)  Ectopic Agouti expressio (Ay)  „Fat rich” (fa/fa)  Genetically manipulated  Serotonin 2C-receptor KO  Melanocortin-4 receptor KO  Agouti related protein (AgRP) hyperexpressio  Neuropeptid Y (NPY) receptor KO  CRH hyperexpession  Bombesin B-3 receptor KO  Glut-4 hyperexpression

The ob/ob mouse and its normal counterpart

Serum leptin and body fat

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

Examination and treatment of obesity

Treatment of obesity

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