Genes and Obesity: Is There Reason To Change Our Behaviors?

Several major factorsenergy requirements, nutrient partitioning, dietary intake, and physical activityinteract to contribute to the development of obesity. Each factor is influenced by our genotypes. For example, cross-sectional and longitudinal studies show familial resemblance in adiposity, and adoption and twin studies offer clear evidence of a genetic component in human obesity (1-3). It is estimated that 40% to 70% of the within-population variation in obesity is heritable (4). Unfortunately, readers too often mistakenly interpret such reports of high heritability estimates as an indication that genes play a deterministic role in causing obesity, independent of the environment and of behaviors. In contrast, behavioral geneticists have provided mathematical expressions indicating the important role of environmental and behavioral factors in determining body weight despite the fairly high heritability of relative body weight (5). Our genes can create an energy imbalance and influence weight gain in two primary ways: by contributing to our susceptibility for overeating despite normal energy requirements and by contributing to low energy requirements despite a normal drive to eat. In the first possibility, genetic factors might influence appetite and regulate food intake through many pathways (6). However, cases of genetic syndromes of obesity due to lack of appetite control, such as the Prader-Willi syndrome or leptin deficiency, are rare. Only five cases of leptin deficiency have been reported, two of which were in young cousins from a consanguineous family who had a homozygous frame-shift mutation in the leptin gene (7). These unusual cases of obesity shed light on important pathways by which genotypes might influence more common forms of obesity. Nevertheless, recent studies suggest that obese persons probably have normal appetite responses to circulating leptin levels and that strong environmental cues may override their normal inherited responses and result in eating, even in the presence of excess energy reserves (8, 9). A second way in which genes can influence obesity is by contributing to low energy requirements. Normal variations in body composition-adjusted resting energy expenditure can be expected to affect daily energy requirements. Collectively, however, the evidence suggests that variations in resting energy expenditure and in fuel partitioning have, at best, only a small effect on one's tendency to gain weight over the long term (10). In contrast to resting energy requirements, genetic factors might influence physical activity-related energy expenditure to a greater degree. The propensity to be physically inactive seems to be at least partly determined by genotype (11), and preliminary data obtained from young pairs of siblings suggest that nonresting energy expenditure is significantly correlated among siblings and hence may have a genetic basis (12). It is well known that muscle fiber types and muscle metabolic characteristics vary among individual persons; this variation is not totally explained by differences in exercise training and may have inherent (that is, genetic) features (13). Persons with greater proportions of the less aerobic type II fibers may have reduced oxidative capacity and greater difficulty in exercise. These persons may therefore be genetically predisposed to engage in less spontaneous physical activity and to have relatively low energy requirements (14). Given an environment that is less physically demanding, as is typically found in the United States, persons who are genetically prone to accept a sedentary lifestyle might then gain weight. If someone is genetically predisposed to be spontaneously physically inactive, is he or she predestined to become obese? An article in this issue by Samaras and colleagues (15) contributes to our understanding by examining the relation of physical activity and dietary behaviors to adiposity, controlling for genetic influences. The strength of their study lies in the use of a co-twin casecontrol design, in which the investigators assumed that monozygotic twins have essentially 100% concordance in their genetic make-up. Within twin pairs, they found that the twin who reported being more physically active was generally less obese than the more sedentary sibling. Furthermore, the investigators identified persons who were genetically prone to obesity on the basis of having an overweight identical twin. Even in this group of genetically high-risk, obesity-prone persons, greater physical activity levels were associated with lesser degrees of obesity. One cannot deduce from this cross-sectional study whether greater physical activity caused the lower body weight or whether having a lower body weight was conducive to being more physically active, because obesity-prone persons seem to become more spontaneously active after they lose weight (16). However, an important implication of Samaras and colleagues' study is that physical activity is likely to help prevent obesity regardless of one's genetic predisposition. The power of the environment to affect our behaviors is evident in a recent study of obesity development in Pima Indians. In remote areas of Mexico, Pima Indians are lean and have metabolic and body mass characteristics similar to those of non-Pima Mexicans living in the same physically demanding environment (17). However, their Pima cousins, who live in Arizona under conditions conducive to positive energy balance, are among the most obese populations in the world. From an evolutionary standpoint, one could argue that innate drives to conserve energy by preferentially selecting energy-dense foods and favoring sedentary activity would be genetic traits favoring survival for all of us; that is, such traits might be considered normal, not abnormal (18). Whereas these genetic traits may have previously favored health and longevity, in our modern society, they may be playing permissive roles for the development of obesity and ill health. It is noteworthy that population studies conducted in the United States, Great Britain, and France have suggested that the rapidly increasing prevalence of obesity in recent several decades may be largely due to increasing sedentary behaviors, perhaps even to a greater extent than dietary excesses (10). These increases in obesity prevalence are almost certainly not explained by evolutionary changes in our gene pool. The findings of Samaras and colleagues (15) and Poehlman and associates (19) suggest that within our current population, physical inactivity may have a stronger influence than dietary intake patterns on variations in adiposity. Furthermore, a 5-year prospective study of more than 12 000 Finnish adults indicated that sedentary persons were almost twice as likely as those who were physically active to experience substantial weight gain and that the relation of physical inactivity to weight gain was more consistent than the relation of excess energy intake to weight gain (20). In summary, modern society may offer the perfect environment for expression of genetic proclivities for physical inactivity; it makes it easy to be sedentary, especially when one is predisposed to such behavior. It may well be that genetic variants that were previously important for survival but were phenotypically silent in terms of obesity may now, in the presence of a permissive environment, contribute to illness. The combination of our genetic makeup and the current environment poses a challenge for us to control our body weight. In fact, subsistence in modern societies requires adaptations in dietary and physical activity behaviors that most people find difficult to achieve. However, whether we stay lean or become obese is ultimately determined not by our genes or our environment but by our behaviors.