BMR and UCPs Basal metabolism rate (BMR), or the rate at which the body burns fuel to make ATP and heat, is evidently modulated by uncoupling proteins(UCP) UCPs are mitochondrial channels. When open they uncouple mitochondrial production of ATP, shunting the energy into production of body heat Norepi opens these channels Allowing hibernating animals to stay warm (enough) DIETING, THE (ADULT) AMERICAN WAY OF LIFE At any given time, 40% of adult Americans are trying to lose weight Losing weight is easy, I've done it hundreds of times! And in well over 95% of dieters, the lost weight is back, and more, in a year or less "SET POINTS" ARE REAL Body weights below set-point are accompanied by incessant, nagging hunger The only way to get rid of the hunger? EAT until you're back to set-point THE NEGATIVE CONSEQUENCES OF DIETING Dieting INCREASES weight Body responds to starvation (aka dieting) by: Long-term reductions in metabolism And actual INCREASES in set-point WEIGHT CONTROL: WHY PHARMACOLOGY MIGHT WORK MUST CHANGE SET POINTS NOT WEIGHT MODERN DIET PILLS: They come in two forms: Serotonin reuptake inhibitors (Fenfluramine) Norepi-like sympathomimetics (Phentermine) There are over 100 such compounds on the market THEY DON'T DO MUCH FOR PERMANENT WEIGHT LOSS Without dieting, they have little effect They help increase diet-induced weight loss, MODERATELY They help maintain weight loss Of course all the weight comes back when the pills stop! THEY CAN HAVE NASTY SIDE EFFECTS: The recent FEN/PHEN disaster: valvular heart disease serious enough to kill in some patients With up to 30 % showing some symptoms! Causing all forms of fenfluramine to be pulled from the US market Fenfluramine, like MDMA, is potentially toxic to serotonin neurons The sympathomimetics generally increase blood pressure Several weight-loss drugs cause up to a six-fold increase in the rare but fatal primary pulmonary hypertension syndrome SOME DRUGS USED FOR WEIGHT LOSS: Many uses are "off label"; not illegal, but not approved usage by FDA This includes ALL drug combos, such as Fen/phen Amphetamines: Adderall, Dexedrine, Desoxyn, methampex Very effective, due to a combination of peripheral sympathomimetic effects and central dopaminergic and serotonergic effects Such use is rare, always off-label, sometimes illegal Fenfluramines: Pondimin, Ponderal, Redux Used for over 20 yrs in Europe, recently withdrawn from US market - see above Peripheral sympathomimetics: Mostly work via Norepi effects on metabolism, UCPs Diethylpropion: Amfepramine, Tenuate - linked to rare pulmonary hypertension Phentermine: Adipex, Fastin, Ionamin, Oby- Cap, T-diet, Zantryl Phenylpropanolamine: Only OTC drugs available, sold as Acutrim, dexatrim, Phenoxine, Phenyldrine, Propagest, Rindecon Sibutramine, a new antidepressant, marketed as Meridia combined serotonin and norepi reuptake blocker Supposedly without abuse potential Not notably more efficacious than fenfluramine Maximally effective dose around 15 mg/day Weight loss at plateau 3-5 kg greater than placebo diet Reduces appetite while increasing expenditure and diminishing diet-induced decreases in thermogenesis Known side effects are modest, and related to norepi, including dry mouth, insomnia, increased heart rate Of course Prozac has similar effects THE HOPE OF BETTER DRUGS: THIS FIELD IS ADVANCING VERY RAPIDLY PREDICTION: THERE WILL BE A RELATIVELY SAFE DRUG OR DRUG COMBO WHICH REALLY WORKS (FOR THE WEALTHY, AS ALWAYS) IN THE NEXT DECADE CANDIDATES INCLUDE: The leptin pathway - looking VERY good in SOME animal models The Good News: to date, very modest side- effects In genetically obese mice, has a dyno effect, normalizing body weight, increasing thermogenesis The Bad News??? In a very recent study of diet-induced obesity in mice (the American style of obesity), oral administration had only short-term anti-obesity effects, with some form of tolerance setting in after several weeks Also, no one knows if rebound occurs Human trials to date are consistently negative à-MSH receptor agonists: In development NPY receptor antagonists: Problem: NPY is the most common peptide in the brain, so unless we get lucky with receptor sub-types, side effects could be prohibitive Metabolic stimulators such as the UCPs A FUNDAMENTAL PROBLEM WITH PHARMACOLOGY Will probably suppress not fix set points Meaning a lifetime on meds With a GOOD chance of rebounds when one goes off the medication IS THERE A CURE FOR OBESITY? THE JAPANESE MODEL: THE TRADITIONAL DIET IS LOW-FAT, HIGH FISH Obesity is uncommon in adults raised and maintained on this diet INDICATIONS ARE THAT OBESITY MAY RESULT FROM OVER-FEEDING CHILDREN CALORIE- DENSE, HIGH-FAT DIETS, STARTING IN INFANCY Mamas don't let your babies grow up to be fatties! Animal studies indicate that early over-feeding causes long-term increases in size of fat cells, especially in females Childhood diets often establish life-long food preferences and eating habits, again suggesting that early factors can be important PHARMACOLOGICAL TREATMENT OF OTHER EATING DISORDERS EATING DISORDERS ARE RESTRICTED TO HIGHER- SES ADOLESCENT/YOUNG ADULT FEMALES These young women are often over-achievers They have a preoccupation with body weight Linked to modern beauty standards set by emaciated models They are all dieters Their disorder takes one of two main forms: Bulimia Nervosa: Dieting, binge eating and purging Anorexia Nervosa: Starvation Bulimia: The "sorority sisters' disorder" Incidence is 1-2% of US females, and climbing Rises to 15% of women undergraduates And as much as 1/3rd of some sororities! These women diet, then fall off the wagon, binge- eat, then purge themselves The eating binges can be pretty impressive, but are seldom as severe as perceived by the women themselves + The binging is most common during bouts of low spirits/normal mild downward mood swings The most common form of purging is induction of vomiting, followed by laxatives and diuretics Side effects typically involve: + Gastric Acid: can damage teeth, esophagus + Potassium deficiencies can result in cardiovascular complications This disorder can be quite long-term, since it is an effective form of weight control! TREATMENT: Sometimes responds to antidepressants Help to reduce morbid preoccupation with body weight May reduce "blues" as trigger to binging ANOREXIA NERVOSA: A rare disorder, although this too is increasing Sufferers starve themselves, sometimes to death Why? Morbid preoccupation with body image, coupled with a weird over-estimate of their own weight Prolonged fasting paradoxically depresses appetite, increases finickiness AND there is an attention-getting aspect to the disorder + The British MD who first identified the syndrome in the 1870s successfully treated it by totally ignoring his anorexic institutionalized patients! To date, no successful drug treatment has been reported