The genetics of human body fat content (obesity) are clearly complex. Genetic and physiological analysis of rodents have helped enormously in pointing to critical molecules and cells in central nervous system and "peripheral" pathways mediating the requisite fine control over the defense of body fat (3). A vast body of research exists to demonstrate that obesity is a complex disorder with a strong genetic basis and a multifactorial etiology. Yet despite the overwhelming evidence that genes play an important role in the development of obesity, many people argue that the increasing prevalence of obesity is simply due to an abundance of palatable food and a dearth of opportunities for physical exercise (1).
According to one recent reviewed the literature indicating that natural alleles influence a substantial percentage of responses to nutrition and exercise in both humans and animal models (2). While activity and eating behaviors contribute substantially to the development of obesity, considering these to be the only etiologic factors is directly contradictory to what is now known about how eating and energy balance are regulated (1).
Human and animal studies are consistent with inferences from evolutionary considerations that the strengths of defenses against fat loss are greater than those against gain. Many of the genes participating in these pathways have reciprocal effects on both energy intake and expenditure, though different genes may have primary roles in respective responses to weight gain or loss. Such distinctions have important consequences for both research and treatment strategies (3). There is also a substantial amount of evidence that treatment responses to exercise and diet strategies may also be regulated by genes. Understanding gene-response relationships is the key to developing more efficacious intervention and prevention programs for obesity (1).
Gene-nutrient and gene-physical activity summary-genetics viewpoint.
The advent of high-density genome-wide scans in large numbers of human subjects for association analysis will revolutionize the study of the genetics of complex traits such as obesity by generating substantial numbers of powerful linkage signals from smaller genetic intervals (3).
Human genetic studies provide evidence that body weight response to over- and underfeeding and to exercise is associated with specific genes. Studies in animal models, primarily rodents, prove the genetic control of responsiveness to diet and exercise and provide the tools to examine specific mechanisms (2). Many of the genes implicated will not have been previously related to energy homeostasis (e.g., recent experience with FTO/FTM as described below), and will have relatively small effects on the associated phenotype(s). The mouse will again prove useful in determining the relevant physiology of these new genes (3).
Phenotypes related to energy intake and expenditure-which clearly are the major determinants of net adipose tissue storage-are not salient when individuals are in energy balance (weight stable); measurements obtained during weight perturbation studies are likely to provide more revealing phenotypes for genetic analysis (3).
New analytic tools will have to be developed to permit the necessary analysis of the gene x gene interactions that must ultimately convey aggregate genetic effects on adiposity. The body mass index (BMI) is a useful gross indicator of adiposity, but more refined measurements of body composition and energy homeostasis will be required to understand the functional consequences of allelic variation in genes of interest (3).
Gene-physical activity interactions: overview of human studies.
Physical activity level is an important component of the total daily energy expenditure and as such contributes to body weight regulation. A body of data indicates that the level of physical activity plays a role in the risk of excessive weight gain, in weight loss programs, and particularly in the prevention of weight regain.
Our understanding of the molecular processes controlling eating behavior, in particular, has accelerated exponentially in the last 10 years, and this is one area in which obesity genetics has made great progress. Our challenge is to understand more fully how genetic variation may interact with behavioral factors to influence the regulation of body weight and adiposity. Although exercise and diet strategies are used routinely for obesity treatment, there is a huge variability in how individuals respond to these interventions (1). Most studies dealing with potential gene-physical activity interaction effects use an exercise and fitness or performance model as opposed to an obesity-driven model. From these studies, it is clear that there are considerable individual differences in the response to an exercise regimen and that there is a substantial familial aggregation component to the observed heterogeneity (4).
Few studies have focused on the role of specific genes in accounting for the highly prevalent gene-exercise interaction effects. Results for specific genes have been inconsistent with few exceptions. Progress is likely to come when studies will be designed to truly address gene-exercise or physical activity interaction issues and with sample sizes that will provide adequate statistical power (4). Genetics has a substantial impact on responses to both diet and exercise. However, current knowledge does not allow individual diet and exercise recommendations. New resources and technologies, including cost-effective phenotyping for humans and whole genome sequencing in both humans and rodents, are needed (2).
1. Bray MS; Obesity (2008) 16, S72-S78; doi:10.1038/oby.2008.522.
2. Warden CH, Fisler JS; Obesity (2008) 16, S55-S59; doi:10.1038/oby.2008.519.
3. Chung WK, Leibel RL;Obesity (2008) 16, S33-S39; doi:10.1038/oby.2008.514.
4.Rankinen T, Bouchard C;Obesity (2008) 16, S47-S50; doi:10.1038/oby.2008.516.