Obesity and Medicine in the 21st CenturyBosch, Gluttony, from The Table of the Seven Deadly Sins, c. 1480One of the myths of the modern world is that health islargely determined by individual choice.— Barry R. Bloom (2000)Director of the Harvard School of Public HealthBMI = weight [kg]/(height [m])2• At a given BMI, women, on average, have more body fat.• Morbidity and mortality increase with BMI similarly for men and women.• Risk at a given BMI can vary between populations.Body Mass Index (BMI): Medically Significant AdiposityAdipocyte Hypertrophy and/or Hyperplasia1. Subcutaneous2. Intra-abdominal (independent morbidity risk factor)3. Muscles (particularly in older people)Health Risks Associated with Obesity1. Type 2 Diabetes (NIDDM)2. Cardiovascular Disease a. Hypertension b. Dyslipidemia (high total cholesterol, low HDL, high LDL, high triglycerides)3. Sleep-Breathing Abnormalitiesa. difficulty breathingb. obstructive apnea4. Gallstones5. Menstrual irregularity, difficulty getting pregnant6. Osteoarthritis7. Cancer (colon, endometrial, breast)8. Mice lacking insulin receptors in adipose tissue live longer!Science 299: 572-4 (2003)Women: RR is 18.1 for BMI ≥ 31 Men: RR is 50.7 for BMI ≥ 35• WHO estimates BMI < 25 would prevent 64% of Type 2 DM in US men and 74% inUS women.• Framingham study estimates BMI < 25 would reduce coronary heart disease by 25%and strokes and congestive heart failure by 35%.Magnitude of RiskPrevalence of Obesity among U.S. Adults, BRFSSPrevalence of Obesity among U.S. Adults, BRFSS <10%<10% 10-15% >15% 10-15% >15% 1985198519861986198719871988198819891989199019901991199119921992199319931994199419951995199619961997199719981998Trends in Prevalence WorldwideOBESITYGenesMonogenic syndromesSusceptibility genes(many genes, each with small effect)Physical activity Food intakeEnvironment/Lifestyle50%-90% of variation in BMI in twin studiesA. Eat more:Increased food availabilitycalories/person/day has increased 15% since 1970% of food $ spent outside the home has doubled since 1970Increased portion size in the 1950’s a 12 oz soda at McDonalds was king-sized; now it’s child sizeIncreased energy density (kcal/g)high fat foods; low fat/low cal foodsB. Do less:Increased sedentary leisure time activitiesTV, computers, video games; cutbacks in mandatory PEDecreased occupational physical activityIncreased use of automobiles“Obesogenic” EnvironmentEnergy BalanceBasal metabolism: energy expenditure of a subject relaxed and at rest, at thermoneutrality,8–12 hours after last food ingestion.Adaptive thermogenesis: energy dissipated as heat in response to environmental changes.• There are very effective mechanisms to defend against body weight loss but lesseffective mechanisms to defend against body weight gain.• Energy stores (adipose mass) are maintained at a set point.• Weight loss leads to compensatory response: decreased energy expenditure,hyperphagia, and eventual restoration of body weight.• A formerly obese person requires about 15% fewer calories to maintain a “normal’weight than someone who has not been obese because of the compensatorydecrease in energy expenditure.Energy Homeostasis (FatStat)Therapeutic Consequences:1. Current interventions target energy balance and fat, not the set point.2. Treatment plateaus: treating obesity results in ~10% weight loss.3. Recurrence when treatment stops.mutant strains of mice …10 monthsnormal mouse: 29 gob/ob mouse: 90 g3 weeksnormal mouse: 12 gob/ob mouse: 16 gEarly-onset obesity, hyperphagia, decreased energy expenditure, hyperglycemia,hyperinsulinemia. Increased fat stores result from adipocyte hyperplasia (rare).Ingalls et al., J. Hered. 41:317-8 (1950)ob/ob + normal: weight gain of ob/ob mouse suppressed.db/db + normal: normal mouse slowly loses weight and diesof apparent starvation.db/db + ob/ob : ob/ob mouse rapidly loses weight and diesof apparent starvation.Interpretation:1. Circulating factor involved in energy balance regulation.2. Defects in ob/ob and db/db mice may be in signal and the receptor forthat signal, respectively.3. In 1994, the leptin gene was positionally cloned from the ob mouse; theleptin receptor was subsequently cloned from the db mouse. Leptinreceptors are found predominantly in the arcuate nucleus of thehypothalamus.Parabiosis Experiments• Leptin is secreted by fat cells.• Circulating levels of leptin correlate with fat stores.• Leptin receptors are abundant on neurons in the arcuate nucleus of the hypothalamus.• Leptin levels increase within hours after a meal in rodents and after several days ofoverfeeding in humans.• Administration of leptin to rodents decreases food intake increases energy expenditure,and results in weight loss due to loss of adipose tissue.• Obese people have high leptin levels.• Leptin levels decrease rapidly with food restriction.• Administration of leptin during a fast prevents the starvation response (decreasedthyroid and gonadal hormones, increased glucocorticoids, decreased body temperature,increased eating).Leptin: Anti-obesity or Energy Sufficiency SignalThe Agouti Aγ Obese MouseMaturity-onset obesity, yellow coat color, hyperphagia, hyperglycemia in males,hyperinsulinemia. Increased fat stores result from adipocyte hypertrophy.Agouti in Obesity• The agouti locus was positionally cloned in 1992.• It encodes the secreted 131 residue agouti protein that normally antagonizes themelanocortin 1 receptor in peripheral hair follicles to control pigmentation.• The obesity of Aγ mice results from ectopic expression of agouti in the CNS, whichantagonizes the melanocortin-4 receptor in the hypothalamus.• Deletion of the MCR4 phenocopies Aγ, Huszar et al., Cell 88:131-40 (1997).• Mutation of the MCR4 receptor is the most commonly occurring monogenic cause ofinherited morbid obesity in human beings (~4% of the patient population).brain lesioning experiments …Brain Lesioning StudiesProfound obesity from destruction of hypothalamic:1. Paraventricular nucleus (PVN)2. Ventromedial nucleus (VMN)3. Dorsomedial nucleus (DMN)Anorexia/weight loss from destruction of:4. Lateral hypothalamic area (LHA)Genetic lesioning:5. PVN-specific restoration of Mcr4 in KO mouse correctshyperphagia but not energy expenditure6. Cholera toxin ablation of Agrp/NPY neurons; neonates adapt butadults starve to death.Other:7. Severing the fore-brain to hind-brain connection blocks theeffects of