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 highenergy 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 “excuse” 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. The obesity epidemic. Obesity is a major risk factor for premature mortality from cardiovascular and metabolic diseases and certain cancers and for greatly increased morbidity from osteoarticular, gastrointestinal, reproductive, and other disorders (1). It carries an enormous burden of health care costs (2). Therefore, evidence that its prevalence has been increasing and continues to increase in most developed and developing countries (3,4) is a cause for major concern. Whereas much of the epidemiological data suggest that even moderate degrees of overweight are associated with adverse effects on morbidity and mortality at the population level, there is some controversy about the overall impacts on mortality of moderate weight gain (5). More severe degrees of obesity bring a considerable burden of ill health and social and economic discrimination (6) and have adverse impacts on well-being and psychological and social functioning (7). It is worth noting that the relative importance of particular etiological factors for obesity is likely to be different when considering mild overweight versus morbid obesity and that interventions that may make a clinically significant impact on the overweight may have negligible beneficial effects in a morbidly obese person. Given what we already know about the etiological heterogeneity of obesity, it is important to emphasize that different forms of intervention may be needed for people with different subtypes of this condition. The contributions of the various environmental factors that are driving increasing obesity rates are hard to quantitate precisely and are likely to differ in degree between populations. They are certainly likely to include factors that make the purchase and consumption of energydense food easier and the expenditure of physical activity as part of daily life more difficult. However, it is undoubtedly true that, except for some population isolates, even in geographical areas where obesity rates are highest, a substantial proportion of the population has remained lean (5). In our opinion, there are really only two basic explanations (and they are not necessarily mutually exclusive) for how these people have avoided the “toxic” effects of environment. The one that intuitively appeals to the mass media (and to many lean people) is that this group is largely made up of individuals who have made conscious choices about diet and exercise and have actively fought off the “toxic environment.” An alternative explanation, much less frequently cited in public debate, is that this group of subjects are somehow biologically different and achieve their leanness largely through unconscious mechanisms. In this review, we would like to explore this hypothesis in more detail. We will argue that the heritable (and therefore biological) influences on human adiposity are strong and remain so in the midst of the epidemic. We will also argue that while some of that hereditary influence is likely to affect processes such as energy expenditure and nutrient partitioning, what we have discovered thus far about the genes influencing human obesity strongly suggests that heritable differences in neurobehavioral traits influencing habitual eating behavior such as hunger, From the University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K. Corresponding author: Stephen O’Rahilly, [email protected]. Received and accepted 14 February 2008. DOI: 10.2337/db08-0210 © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying commentary, p. 2918. PERSPECTIVES IN DIABETES