Weight and Physical Health - The Genetics Of Body Weight And Obesity

Genetics, the study of single genes and their effects, explains how and why such traits as hair color and blood types run in families. In the early twenty-first century the scientific community agrees that body shape and body weight also are regulated traits, that genes govern much of this regulation, and that altering genetically predetermined set points for body weight is often difficult. "Geno-mics," a discipline that emerged during the 1980s, is the study of more than single genes; it considers the functions and interactions of all the genes in the genome. In terms of understanding genetics as a risk factor for obesity, genomics has broader applicability than does genetics because it is likely that humans carry dozens of genes that are directly related to body size, and most obesity is multi-factorial—resulting from the complex interactions of multiple genes and environmental factors.

Since genomics is a relatively new discipline, many questions are still unanswered about how genes influence the ability to balance energy input and energy expenditure, and why individuals vary in their abilities to perform this critical body function. Table 2.5 summarizes what is known and what remains to be learned about variations in body weight, energy metabolism, and inherited obesity syndromes.

Single Mutant Genes Cause Obesity

While the majority of obesity in humans is not due to mutations (alterations or changes) in single genes, there are obesity syndromes caused by variations in single genes, and these account for approximately 5% of all obesity. In rare cases of severe obesity that begin during childhood, a single gene has a major effect in determining the occurrence of obesity, with environmental factors playing a lesser role. The mutations occur in genes that encode proteins related to the regulation of food intake. One example is mutations of the leptin gene (on chromosome 7) and its receptor. The circulating hormone leptin (leptos means thin) sends the brain a satiety signal to decrease appetite. Obese mice of the ob/ob strain produce no leptin and tend to overeat; when given leptin, the mice stop eating and lose weight. Unfortunately, experiments have failed to replicate these findings in humans. Blood concentrations of leptin are usually elevated in obese humans, suggesting that they may be insensitive or resistant to leptin, rather than leptin deficient. The majority of obese individuals appear to have normal genetic sequences for leptin and its receptor, although humans with a demonstrable genetic leptin deficiency suffer from extreme obesity.

Melanocortin 4 receptor (MC4R) deficiency is the most commonly occurring monogenic (single gene) form of obesity. Nearly 6% of people with severe obesity commencing in childhood have this mutation. Inheriting one copy of certain variants of the gene causes obesity in some families. Researcher I. Sadaf Farooqi and his colleagues screened 500 subjects with severe, early-onset obesity for mutations in MC4R and conducted clinical studies of those with mutations. The investigators conducted body composition studies, measured subjects' resting metabolic rates (calories expended at rest), performed metabolic and endocrine testing, and assessed eating behaviors. In "Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene" (New England Journal of Medicine, vol. 348, no. 12, March 2003), the investigators reported that mutations in MC4R produced a distinct obesity syndrome that is inherited. They also concluded that these mutant receptors played a pivotal role in the control of eating behavior—that regulation of body weight in humans is sensitive to variations in the amount of functional MC4R.

Multiple Gene Variants Involved in Body Weight and Obesity

It has long been known that heredity affects health. Heritability studies, which seek to determine the proportion of variance of a particular trait that is attributable to genetic factors and the proportion that is attributable to environmental factors, indicate that genetic factors may account for as much as 75% of the variability in human body weight and approximately one-third of the variation in the overall body mass index (BMI; body weight in kilograms divided by the height in meters squared). Genetic factors affect the variations in resting metabolic rate, body fat distribution, and weight gain related to overfeeding, which explains in part why some individuals are more susceptible than others are to weight gain or weight loss. To ensure survival in times of scarce food supplies, the human body has evolved to resist any loss of body fat. This biological drive to maintain weight is coordinated through central nervous system pathways, with the involvement of many neuropeptides. (Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones outside of the nervous system.) Evidence from twin, adoption, and family studies reveals that biological relatives exhibit similarities in maintenance of body weight. First-degree relatives of moderately obese people are at three to four times the risk of obesity relative to the general population. First-degree relatives of severely obese people are at five times greater risk. Genetic predisposition to obesity does not mean that developing the condition is inevitable; however, research indicates that inherited genetic variation is an important risk factor for obesity.

Genetic factors have been implicated in the development of such eating disorders as anorexia and bulimia and appear to be involved in the extent to which diet and exercise are effective strategies for weight reduction. Further, genetic variations among individuals may promote different food preferences and eating patterns that interact with environmental conditions to maintain healthy body weight or promote obesity.

These genetic risk factors tend to be familial but are not inherited in a simple manner; they may reflect many genetic variations, and each variation may contribute a small amount of risk and may interact with environmental elements to produce obesity. By 2005 the eleventh update of the human obesity gene map contained more than 600 genes, markers, and chromosomal regions had been associated or linked with human obesity. In addition to offering direction for future efforts to prevent and treat obesity, mounting genetic evidence offers a compelling argument that obesity is not a personal failing, and that in the majority of cases, obesity involves multiple genetic and environmental components that affect endocrine, metabolic, and regulatory mechanisms.

Genetic Susceptibility and Environmental Influences

Although genetics may largely predetermine adult body weight absent specific environmental triggers or influences, genetic destiny in terms of body weight may not necessarily be realized. For example, an individual with a strong genetic predisposition for obesity will not become obese in the absence of sufficient food (caloric) intake. Similarly, when people genetically predisposed to normal body weight consume a largely high-fat diet, they may become overweight or obese because they may be more inclined to overeat. This is in part because the brain has difficulty conveying the satiety signal—the message to stop eating—when fatty foods are being consumed.

In addition to caloric intake and physical activity, both of which are able to modify body weight, environmental influences before birth also significantly influence adult health and body weight. Research has demonstrated that the pregnant mother's nutritional status affects the metabolism of her unborn child. Women who are severely malnourished during pregnancy stimulate the fetus to modify its metabolism to conserve and store energy, a survival practice that can promote overweight when the food supply is ample.

Societal and cultural norms also can cause such environmental influences as lifestyle and behavior to override genetic programming. For example, in the United States many young women with genetic predisposition to normal body weight or even overweight sharply limit their caloric intake and exercise vigorously in order to achieve "model thin" bodies. Similarly, in cultures where overweight is perceived as an indication of prosperity and is admired and coveted, people may override genetic tendencies to be normal weight by increasing caloric intake in an effort to achieve the culturally established ideal.

FIGURE 2.3 Age-adjusted prevalence of high blood cholesterol* according to BMI "Figure 3. NHANES III Age-Adjusted Prevalence of High Blood Cholesterol according to Body Mass Index," Guidelines on Overweight and Obesity: Electronic Textbook, National Heart, Lung, and Blood Institute in cooperation with the National Institute of Diabetes and Digestive and Kidney Diseases, September 1998, http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf (accessed January 9, 2006)