Human genomics and obesity: finding appropriate drug targets

The increasing prevalence of obesity worldwide has prompted the World Health Organization (WHO) to classify it as a global epidemic. Around the globe, more than a half billion people are overweight, and the chronic disease of obesity represents a major threat to health care systems in developed and developing countries. The major health hazards associated with obesity are the risks of developing diabetes, cardiovascular disease, stroke, osteoarthritis and some forms of cancer. In this paper, we review the prevalence of obesity and its cost to health care systems and present the relative contribution of environmental conditions and genetic makeup to the development of obesity in people. We also discuss the concept of "essential" obesity in an "obesigenic" environment. Though weight gain results from a sustained imbalance between energy intake and energy expenditure, it is only recently that studies have identified important new mechanisms involved in the regulation of body weight. The etiology of the disease is presented as a feedback model in which afferent signals inform the central controllers in the brain as to the state of the external and internal environment and elicit responses related to the regulation of food intake and energy metabolism. Pharmaceutical agents may intervene at different levels of this feedback model, i.e., reinforce the afferent signals from the periphery, target the central pathways involved in the regulation of food intake and energy expenditure, and increase peripheral energy expenditure and fat oxidation directly. Since obesity results from genetic predisposition, combined with the proactive environmental situation, we discuss mew potential targets for generation of drugs that may assist people in gaining control over appetite as well as increasing total energy expenditure and fat oxidation. (C) 2000 Elsevier Science B.V. All rights reserved.