SPECIAL REPORT Conference Report-Obesity zyx : New Directions, June 27-29, 1998, Charleston, South Carolina z Donna H. Ryan, George A. Bray, Stephen Rossner, and George zyxw J. Galasso Introduction zyxwvu Obesity: New Directions, an international conference held June 27-29, 1998 that drew together leading authori- ties in a variety of areas related to obesity, was organized because the world is experiencing its first epidemic of obe- sity (1). Now upwards of 25% of the population in some countries are obese (1,2) as defined by a body mass index above 30 kg/m2. This has occurred despite an enormous industry that caters to the public’s desire for diet and exer- cise remedies, the growth of behavioral therapy techniques, and a gradual reduction of the intake of dietary fat in most western countries. The conference pulled together research- ers who reviewed the state of obesity research and treatment and identified promising areas for further research. The meeting was organized and convened by The Macrae Group NY, New York.* This report will highlight some of the meeting’s discussion and potential avenues which may be fruitful in coping with this epidemic. Genesis of the Problem: Genetic and Environmental Components of the Obesity Epidemic In an overview of genetic advances, Claude Bouchard estimated the genetic contribution to obesity runs from 25- 40% of the variance in body mass index (BMI) (3). Despite the fact 250 million individuals world-wide have a BMI >30 kg/m2, there have been only about 10 individuals identified who possess a single gene defect contributing to obesity (abnormality of leptin, leptin receptor, prohormone conver- tase, carboxypeptidase E or proopiomelanocortin) (4). Furthermore, not one candidate gene has been consis- Received for review August zyxwvutsrqpo 24, 1998. Accepted for publication in final form November 18, 1998. Reprint requests to Dr. Donna Ryan, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail: RYANDH@MHS.PBRC.EDU *This meeting was co-sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Foundation for Biomedical Research. Educa- tional grants were provided by Amgen, Inc., Amylin Pharmaceuticals, Inc., F. Hoff- man-LaRoche. Ltd., Glaxo Wellcome, Inc., and Merck Research Laboratories. Copyright zyxwvutsrqponm 0 1999 NAASO. tently associated with BMI when studies of likely genes are evaluated in population studies! This suggests several things. First, our current knowledge of key genes involved in food intake and energy regulation may be incomplete. Second, there may be great diversity in the types of genetic abnormalities that produce obesity. Or, third, there may be difficulty in selecting appropriate phenotypes. Identifying new candidate genes that are located in ar- eas where genetic transmission seems to be focused through quantitative trait loci (QTL) evaluation has yielded some insights but considerable contradiction. Rodent models would lead us to expect about 25 loci associated with obe- sity in humans. From the six ongoing family studies looking for human QTL, results to date are disappointing (3). Even when the entire genome is sequenced and we have all of the individual units of heredity in hand, the problem of predict- ing which combinations will produce obesity on which background will still be difficult, if not impossible. It is similar to predicting the properties of organic molecules from the atomic structure of carbon, hydrogen, oxygen, ni- trogen, and sulfur: Genes rarely act alone. The number of phenotypes of obesity identified accidentally from studies with transgenic animals points up the many unknowns in the phenotype of human obesity. The obesity phenotype is very plastic. Twin studies show that for the same genetics, the BMI spread is fairly wide. The mean difference in weight gain for twins in one overfeeding study was 14 kg (5). Furthemore, when there are multiple genes involved influencing body fat and mul- tiple environmental factors, i.e., dietary fat or energy intake, for example, we must know all genes and all environmental aspects to develop adequate models for study. Clearly, obe- sity is more than simply a gene-environment interaction. It is influenced by gene-gene, environment-environment in- teractions along with gene-environment interactions. Un- raveling these factors in the polygenic problem posed by obesity will take time and imagination. Overeating and physical inactivity are the most impor- tant environmental factors in the development of obesity. Stephan Rossner noted that Scandinavian and other Western countries differ in recreational physical activity ( 1). We OBESITY RESEARCH Vol. zyx 7 zyx No. 3 May 1999 303