Human Obesity: A Heritable Neurobehavioral Disorder That Is Highly Sensitive to Environmental Conditions

The recent increase in the worldwide prevalence of obesity has understandably focused attention on the environmental determinants of this epidemic. Whereas identifying the relative contributions of the factors underlying this recent trend is critical, a comprehensive understanding of the causes of obesity will need to explain why, even in high-risk populations, many people remain lean. Contemporary studies indicate that the heritability of adiposity remains high, even in the face of a strongly obesogenic environment. Whereas the role of inheritance has long been appreciated, only recently have we begun to develop a genuine understanding of the critical role of specific molecules in sensing the state of nutrient storage and regulating food intake and energy expenditure. Notably, a number of single gene disorders resulting in human obesity have been uncovered and, strikingly, all of these defects impair the central control of food intake. Early indications are that common genetic variants influencing adiposity on a population level affect the same processes. While the rising prevalence of obesity is related to increasing ease of access to high-energy palatable food combined with diminishing requirement for physical activity, differences in inter-individual susceptibility to obesity are likely to be related to inherited variation in the efficiency of central control mechanisms influencing eating behavior. Such a construct understandably courts unpopularity, since it can appear to diminish the importance of human free will and is perceived by some as representing a counsel of despair and an ﾓexcuseﾔ for otherwise controllable behavior. We argue that a view of obesity that emphasizes the profound biological basis for inter-individual differences in responding to the challenges of achieving a healthy control of nutrient intake should result in a more enlightened attitude toward people with obesity with a consequent reduction in their experience of social and economic discrimination. In the longer term, this may also lead to more efficacious individually targeted approaches to the treatment and prevention of obesity.