THE PHARMACOLOGY OF DIET AND EATING DISORDERS OBESITY AND LONGEVITY: Eat, Eat, Die, Die LIFE-SPAN AND CALORIC INTAKE: Animal Studies Rodents maintained on 2/3rds ad lib. diet for a lifetime live as much as 50% longer than ad lib. controls! Kidney failure, cardiovascular disease and most forms of cancer are reduced by this dietary restriction Dietary restriction increases life span in fruit fly and nematode as well as rodents Long-term studies now underway in dogs and monkeys suggest the same is true of these species CALORIC INTAKE AND DISEASE IN HUMANS Numerous diseases are associated with overweight: Cardiovascular disease Diabetes High blood pressure Common cancers, especially of the breast, colon and prostate Measuring Obesity: BMI: {weight in kg} / {height in meters}2 + Average for the US is around 26 + Generally advised to stay < 25 + See table Waist/hip ratio also good, recognizes the greater risk of upper abdominal fat Nurses' Health Study (115,000 US nurses): Compared to very skinny nurses (BMI<19), mortality risk was: BMI INCREASED MORTALITY RISK: 19-24.9 +20% 27-28.9 +60% > 29 +100% OBESITY IN THESE UNITED STATES: Americans are among the world's fattest folks Graph - obesity in the USA Table - Comparisons between nations Prevalence of obesity is sky-rocketing, in the US and throughout the world - graph + Clinically obese - BMI > 30, went from 14.5% of the US population in 1980, to 22.5 % in 1996! + Children affected as well as adults + The poor, Hispanics, Blacks and Native Americans have obesity rates substantially higher than the national average Popular to speak of an epidemic of obesity in the US PROBABLE CAUSES OF THE EPIDEMIC: Eating too much! Fat, carbos both culprits Exercising too little! Factors include: Low physical activity in the workplace Modern transportation Television Extermination of large predators THE BIOLOGY OF BODY WEIGHT REGULATION THERE IS BOTH SHORT AND LONG-TERM REGULATION OF FOOD INTAKE Short-term regulation is partially linked to glucose, and meals are stopped by a variety of gut and brain satiety factors These factors include Bombesin and CCK from the gut Such satiety factors act at the level of the lower brainstem, including the area postrema This lower brainstem region controls taste and eating And, for example, makes food taste less yummy when satiety signals are received + This is the satiety mechanism in the fly Long-term regulation is linked to body fat, and is not altered by any of the above Hence messages must pass between body fat stores and brain, allowing long-term control of adiposity It has long been known that such signals are blood-borne It is thought that the body has a "set point", an ideal degree of fatness, which it "defends" by increasing or decreasing long-term intake LIPOSTATIC BLOOD-BORNE SATIETY FACTORS Two are known One is leptin, a hormone released from adipocytes The other is insulin, released from the pancreas Blood levels of both are proportional to adiposity Infusion of either directly into the brain reduces food intake The reduction is almost all in fat intake and fat stores, and is NOT accompanied by reduced metabolism! Mice with dysfunctional leptin receptors are obese CNS CONTROL OF LIPOSTASIS Regions in the hypothalamus and lower brainstem (area postrema and related regions, also involved in emesis) are involved Within the hypothalamus, specific systems both increase and decrease long-term food intake First demonstrated with lesion experiments in rats VMH rats - damage to a very small area of the ventro-medial hypothalamus causes immense obesity + Such animals are GOURMANDS - pig out on goodies, refuse to eat nasty food + Hence live to eat, not eat to live Lateral hypothalamus - lesions here cause rats to starve to death without special intervention Hypothalamic systems which promote eating Medial hypothalamic regions have large amounts of neuropeptide Y (NPY) Infusion of NPY into the hypothalamus triggers ravenous eating, reduced metabolism and increased lipogenesis, leading to obesity in a matter of days! NPY levels increase with fasting Leptin and insulin suppress hypothalamic NPY Leptin and insulin potentiate the effects of the gut satiety factors A number of other neurotransmitters in the hypothalamus also increase eating, although not as readily as NPY. These include norepi and the endorphins, among others Hypothalamic systems which suppress eating à-melanocyte stimulating hormone (à-MSH) in the hypothalamus potently suppresses eating + Leptin stimulates à-MSH release A second hormone, Corticotropin-releasing Hormone (CRH, the hormone that tells the pituitary to tell the adrenals to make cortisol) also potently inhibits eating when injected into the hypothalamus A number of other neurotransmitters in the hypothalamus, including serotonin, have a lesser inhibitory effect on appetite 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) Individual differences in UCPs may explain why some gain weight on diets causing others to lose weight Activity and caloric consumption: Recent study shows that people who FAIL to gain weight on a high-calorie diet FIDGET off the extra calories And long known that obese people and animals show low levels of physical activity