Obesity and Medicine in the 21st Century

1. Obesity and Medicine in the 21st Century Bosch, Gluttony, from The Table of the Seven Deadly Sins, c. 1480

2. One of the myths of the modern world is that health is largely determined by individual choice. — Barry R. Bloom (2000) Director of the Harvard School of Public Health

3. Body Mass Index (BMI): Medically Significant Adiposity BMI = 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.

4. Adipocyte Hypertrophy and/or Hyperplasia Subcutaneous Intra-abdominal (independent morbidity risk factor) 3. Muscles (particularly in older people)

5. Health Risks Associated with Obesity • Type 2 Diabetes (NIDDM) 2. Cardiovascular Disease a. Hypertension b. Dyslipidemia (high total cholesterol, low HDL, high LDL, high triglycerides) • Sleep-Breathing Abnormalities a. difficulty breathing b. obstructive apnea • Gallstones • Menstrual irregularity, difficulty getting pregnant • Osteoarthritis • Cancer (colon, endometrial, breast) • Mice lacking insulin receptors in adipose tissue live longer! Science299: 572-4 (2003)

6. Magnitude of Risk 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% in US women. • Framingham study estimates BMI < 25 would reduce coronary heart disease by 25% and strokes and congestive heart failure by 35%.

7. 1997 1998 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1985 1986 <10% 10-15% >15% Prevalence of Obesity among U.S. Adults, BRFSS

9. Trends in Prevalence Worldwide

10. Genes 50%-90% of variation in BMI in twin studies Monogenic syndromes Susceptibility genes (many genes, each with small effect) OBESITY Physical activity Food intake Environment/Lifestyle

11. “Obesogenic” Environment Eat more: Increased food availability calories/person/day has increased 15% since 1970 % of food $ spent outside the home has doubled since 1970 Increased portion size in the 1950’s a 12 oz soda at McDonalds was king-sized; now it’s child size Increased energy density (kcal/g) high fat foods; low fat/low cal foods Do less: Increased sedentary leisure time activities TV, computers, video games; cutbacks in mandatory PE Decreased occupational physical activity Increased use of automobiles

12. Energy Balance Basal 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.

13. Energy Homeostasis • There are very effective mechanisms to defend against body weight loss but less effective 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 compensatory decrease in energy expenditure. • Therapeutic Consequences: • Current interventions target energy balance and fat, not the set point. • Treatment plateaus: treating obesity results in ~10% weight loss. • Recurrence when treatment stops.

14. 3 weeks normal mouse: 12 g ob/ob mouse: 16 g 10 months normal mouse: 29 g ob/ob mouse: 90 g Ingalls et al., J. Hered.41:317-8 (1950) Early-onset obesity, hyperphagia, decreased energy expenditure, hyperglycemia, hyperinsulinemia. Increased fat stores result from adipocyte hyperplasia (rare).

15. Parabiosis Experiments ob/ob + normal: weight gain of ob/ob mouse suppressed. db/db + normal: normal mouse slowly loses weight and dies of apparent starvation. db/db + ob/ob : ob/ob mouse rapidly loses weight and dies of apparent starvation. Interpretation: Circulating factor involved in energy balance regulation. Defects in ob/ob and db/db mice may be in signal and the receptor for that signal, respectively. In 1994, the leptin gene was positionally cloned from the ob mouse; the leptin receptor was subsequently cloned from the db mouse.

16. Leptin: Anti-obesity or Energy Sufficiency Signal • 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 of overfeeding 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 (decreased thyroid and gonadal hormones, increased glucocorticoids, decreased body temperature, increased eating).

17. Profusion of Peripheral Signals DVC: Dorsal Vagal Complex

18. Gutkines

19. Adipokines and Pancreakines

20. The Agouti Ag Obese Mouse Maturity-onset obesity, yellow coat color, hyperphagia, hyperglycemia in males, hyperinsulinemia. Increased fat stores result from adipocyte hypertrophy.

21. Agouti in Obesity • • The agouti locus was positionally cloned in 1992. • It encodes the secreted 131 residue agouti protein that normally antagonizes the melanocortin 1 receptor in peripheral hair follicles to control pigmentation. • The obesity of A mice results from ectopic expression of agouti in the CNS, which antagonizes the melanocortin-4 receptor in the hypothalamus. • Deletion of the MCR4 phenocopies A Huszar et al., Cell88:131-40 (1997). • Mutation of the MCR4 receptor is the most commonly occurring monogenic cause of inherited morbid obesity in human beings (~4% of the patient population).

22. Brain Lesioning Studies • Profound obesity from destruction of hypothalamic: • Paraventricular nucleus (PVN) • Ventromedial nucleus (VMN) • Dorsomedial nucleus (DMN) • Anorexia/weight loss from destruction of: • Lateral hypothalamic area (LHA)

23. Brain Centers in Energy Homeostasis ARC: arcuate nucleus, PVN: paraventricular nucleus, PFA: perfornical area, FX: fornix, LHA: lateral hypothalamic area, VMN: ventromedial nucleus, DMN: dorsomedial nucleus, AM: amygdala, CC: corpus callosum, OC: optic chiasm, SE: septum, TH: thalamus, 3V: third ventricle

24. Overview of the Setpoint Circuit DVC

25. Dominant Inputs to Primary Neurons

26. Inputs

27. Signals Produced by Primary Neurons

28. Primary Neurons

29. Outputs to Body and Higher Brain

30. Endocrine Efferent Outputs

31. Dopamine and Outputs to Striatum (motor activity) (motivation/reward) SNPC: substantia nigra pars compacta VTA: ventral tegmental area Opioids and amphetamines remove a GABAnergic block on dopamine production. These drugs suppress appetite, and were initially used to treat obesity. In humans, BMI is anti-correlated with #D2 receptors in the striatum.

32. Bias Toward Weight Gain Arc destruction causes weight gain. Response to weight loss bidirectional; weight gain unidirectional. DMc4r=> weight gain whereas Dnpy=>no weight loss. AgRP/Npy neurons are more sensitive to adiposity signals than Pomc/Cart neurons. HOWEVER: Anabolic pathways are required for intact responses to negative energy balance (IDDM causes negative energy balance in Npy-/- mice). Anabolic pathways are required for response to decreased leptin (Npy-/- over ob/ob mice show reduced hyperphagia).

33. Currently Approved Therapies Orlistat (interferes with fatty acid hydrolysis); => moderate clinical effects; side effects include gas/diaharrea. Sibutramine (central norepinephrine/serotonin RI); => moderate clinical effects; side effects include tachycardia and hypertension. Roux-en-Y gastric bypass (absorption and hormonal). 4. Rimonabant (Acomplia; CR1 endocannabinoid antagonsist).

34. Next Line Therapies SNAP-7941 (potent MCH receptor antagonist) SNAP-7941 Synaptic Pharmaceutical Corporation. Filled Squares: Control Open Diamonds: Fenfen Filled Circles: SNAP-7941 Borowsky et al., Nat. Med. 8:825-30 (2002)

35. Further Out 6. Exendin-4 (Gila Monster DPP-IV resistant GLP-1) 7. Pramlintide (amylin analog, anti-obesity for diabetics) 8. PYY analogs (small molecule mimics lacking) 9. Ghrelin (treatment of anorexia) SOCS-3 KO (combat insulin/leptin resistance) pro-Apoptotic peptides linked to peptides that target prohibitin in adipocytes ("magic bullets that melt fat"), Kolonin et al., Nat. Med. 10:625-632 (2004).

36. The Next Blockbuster Drug? Van Gaal LF, et al. (2005) “RIO-Europe Study Group… Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study." Lancet 365(9468):1389-97. 2. Luquet et al. (2005). "NPY/AgRP Neurons are essential for feeding in adult mice but can be ablated in neonates." Science310: 683-5.