Motivation and the Regulation of Internal States Obesity Anorexia and bulemia Other eating disorders

1. Motivation and the Regulation of Internal States Obesity Anorexia and bulemia Other eating disorders

2. Obesity • According to the National Health and Nutrition Examination Surveys, • the adult obesity rate in the U.S. has doubled since 1980. • Obesity rate for children ages 2-5 has doubled • Obesity rate for children 6-12 has tripled • Obesity is most important because of its health risks. • incidence of a variety of diseases goes up: • Diabetes • heart disease • high blood pressure • stroke • colon cancer. • Obesity is also linked to cognitive decline and risk of Alzheimer’s disease.

3. Obesity • BMI (body mass index) • calculated by dividing the person’s weight in kilograms by the squared height in meters. • BMI of 25-29 is overweight • Higher than 29 is considered obese • Hereditary? • adoption studies and twin studies demonstrate the influence of heredity on body weight. • Adopted children show a moderate relationship with their biological parents’ weights and BMIs, but little or no similarity with their adoptive parents. • Several potential genes linked to obesity, but rarely • Obesity gene on chromosome 6 • Diabetes gene on chromosome 4 • Some genetic factor, but environment is the biggest factor

5. Obesity: reset set point • basalmetabolism: • the energy required to fuel the brain and other organs and to maintain body temperature • Appear to be differences in basal metabolism in obese vs. normal weight individuals • In the average sedentary adult, about 75% of daily energy expenditure goes into resting or basal metabolism • The remainder is spent about equally in physical activity and in digesting food. • In normal weight individuals- amount of energy devoted to resting/basal metabolism is much lower

6. Obesity: reset set point • Resetting the basal metabolism • Altering dietary intake and increasing exercise should reset basal set point • Problem: remember step-down reflex from drug abuse? • Body reacts to reduction in intake/increase in exercise • Sudden decrease in intake • Sudden increase in exercise • Body will attempt to increase fat/glucose storage to compensate • Thus, must “trick” body into slowly and permanently resetting the basal set point. • This is why programs like weight watchers works better than extreme diet/exercise programs

7. Treatment of Obesity • Dietary restrictions • The standard treatment for obesity • Increase exercise • Dieters who exercise lose more weight than dieters who do not exercise. • Medication. • Not a particularly promising alternative. • Lack of effectiveness • drugs manipulate metabolic and other important systems, they often have adverse side effects.

8. Medication and Obesity • The approval of dexfenfluramine in 1996 was the first by the FDA in 20 years. • just a year later, both it and the older fenfluramine were withdrawn from the market by the manufacturer • Many reports that these drugs caused heart valve leakage. • In June 2007: the FDA denied approval of rimonabant • blocks the endogenous cannabinoid receptors that are responsible for the “marijuana munchies” and produces five percent weight losses. • The panel was concerned by reports linking the drug to increased psychiatric problems, including suicide.

9. Weight loss drug setbacks • Weight-loss drug setbacks • 1997: American Home Products pulls Redux and Pondimin, components of "fen-phen," off the market on concerns they cause heart valves to leak. • 2007: Sanofi-Aventis withdraws application to sell Acomplia in the U.S. after an FDA panel rejected the drug because it was linked to depression and suicidal thinking. • 2008: Merck halts development of experimental antiobesity drug taranabant because of side effects including psychiatric events.

10. Weight loss drug setbacks 2010: Abbott Laboratories removes Meridia from the U.S. market amid concerns it is linked to heart attack and stroke. FDA also rejects Qnexa by Vivus on the grounds it needs more information about possible cardiovascular effects and rejects lorcaserin by Arena Pharmaceuticals. 2011: FDA rejects Contrave from Orexigen Therapeutics and Takeda Pharmaceutical and asks for another clinical trial on long-term heart risk.

11. New Drug: Qnexa • Qnexa® (phentermine and topiramate) • Made by Vivas • Extended-release Capsules • investigational, once-per-day, weight-loss therapy that combines low doses of two agents approved by the Food and Drug Administration (FDA), phentermine and topiramate, in a controlled-release formulation. • Phentermine: (Adipex) • psychostimulant drug of the phenethylamine class • with pharmacology similar to amphetamine. • Topiramate: Topamax: antiepileptic and antimigraine • blockage of voltage-dependent sodium channels, • augmentation of gamma-aminobutyrate acid activity at some subtypes of the GABA- A receptors, • antagonism of AMPA/kainate subtype of the glutamate receptor • inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV .

12. Obesity • Even the two approved drugs have their problems: • Orlistat (Xenical) causes cramping and severe diarrhea because it blocks water absorption. • Sibutramine (Meridia) has been linking to a number of deaths due to cardiovascular problems (similar in form to fenfluramine) • Sibutramine blocks norepinephrine and serotonin reuptake and acts as an appetite suppressant. • Drugs that block serotonin reuptake reduce carbohydrate intake. • The experimental drug C75 reduces fat storage by oxidizing fatty acids. • At the same time, it reduces appetite by interfering with NPY production.

13. An obese control mouse and a formerly obese mouse treated with C75. Microscopic views of fatty tissue in the livers of the mice.

14. Anorexia and Bulimia • Anorexia nervosa • the “starving disease” • individual restricts food intake to maintain weight at a level so low that it is threatening to health. • There are two subgroups of anorexics. • Restrictors rely only on reducing food intake to control their weight. • Purgers restrict their calorie intake as well, but they also resort to purging, by vomiting or using laxatives. • The anorexic individual’s unwillingness to eat does not necessarily imply lack of hunger. • NPY levels are high • leptin levels are low. • Is voluntary: overpower and ignore feelings of hunger

15. Anorexia and Bulimia • Bulimia nervosa • Also a means of weight control • behavior is limited to bingeing and purging. • If the bulimic restricts food intake, it is only for a few days at a time, • restricting takes a backseat to bingeing and purging. • Interesting physiological changes: • Ghrelin levels between meals are a third higher than in controls • Ghrelin decrease is less following a meal. • also, PYY levels do not rise as much following a meal. • Suggests that the lack of digestion induces significant brain changes • Bulimia upsets the homeostatic balance of eating

16. Brain changes and Anorexia and Bulimia • What changes produce these conditions? Serotonin may be important • Critical role of serotonin in eating and in obesity • Also critical changes in serotonin in depression • Many anorexics and bulimics also show symptoms of depression • Thus. Researchers suspected that anorexics and bulimics have lower than normal serotonin activity. • Bulimics do have reduced CSF levels of the serotonin metabolic by-product 5-HIAA. • Besides depression, bulimics also likely to show: • increased rate of anxiety • alcoholism, and other drug abuse • impulsive behavior, including stealing and sexual activity. • All these characteristics are associated with low serotonin activity.

17. Societal influences • Changes in serotonin may be effect, not cause • Anorexics and bulimics show preoccupation with weight and body shape • More often a woman’s disease • This is changing somewhat • Interesting cultural differences: • higher rates in Western cultures, western European/white American women than African American women or Pacific Islanders • Influence of “ideal women” cross culturally • More exposure to TV/magazines seems to increase rates of disorder • By age 3 young children choose “skinny” girl over more normal size girl; boys choose “muscle” man over typical man. • How change? Change society

18. treatment • Medication: antidepressants may help • Alter serotonin levels • Alleviate underlying depression • Must change cognition/behavior • Alter perception of self, body weight • Alter ideal weight perception • Must relearn to eat: reshape the brain. • Recognize appropriate hunger/satiety signals • Learn appropriate nutrition • May never enjoy food again • Can most certainly be fatal: • Starvation, physical effects from bulimia can induce permanent physiological changes • Brain changes • Heart, circulatory system changes • Karen Carpenter!