Genes Do Play a Role in Obesity

Sedentary people who enjoy high-caloric diets—adults and children alike—are getting dangerously fat.1 Along with the increased weight comes complications. Take obesity, for example. It is a risk factor for Type 2 diabetes. Once considered a strictly adult disease, Type 2 diabetes is now diagnosed in both preadolescents and adolescents.2 Some researchers believe that the interaction between obesity-related genes and society's increasingly sedentary lifestyle and fat-filled diet is to blame. The questions of when and how the environmental triggers set off the genes have, as of yet, no answers. The first hint that obesity has a genetic rather than a totally behavioral basis came in 1994 when Rockefeller University researchers identified the obese gene and cloned the murine version of it.3 The mice were obese, suffered from Type 2 diabetes, and lacked the protein leptin which appears to act primarily on the hypothalamus, where it influences appetite and energy use. The discovery opened the genetic floodgates. "[It] was the paradigm shift that turned [obesity] into a tractable problem," remarks clinical endocrinologist Stephen O'Rahilly, University of Cambridge, who studies the genetics of childhood obesity. O'Rahilly's research had focused on severe insulin resistance in children; after the discovery, he shifted to investigating leptin deficiency in extremely obese youngsters and their families. "Among the first kids we looked at, we did find a pair of first cousins who were [leptin] deficient," says O'Rahilly. In total, they found three families with this deficit; the children had extremely large appetites. "It was the first demonstration that a human being could become severely obese on the basis of a simple genetic defect," he states.4 O'Rahilly points out that these children are not comparable to the average, overeating child in the United States or United Kingdom; the leptin-deficient children would become obese as long as food was available. But even more remarkable than the gene's discovery and its effect in people was the decreased appetites seen in these children when given leptin therapy. O'Rahilly is currently preparing this research for publication. Courtesy of Kathleen Graham and Rudolph LeibelObesity SNP Shot: Shown are sequence variants in the coding and noncoding regions of the human leptin gene. Other Causes of Obesity But leptin deficiency is not the only cause of morbid obesity, and O'Rahilly and colleagues are looking for other genetic causes. His group has found that a mutation in another gene, MC4R, for the melanocortin-4 receptor in the hypothalamus, also leads to morbid obesity in about 5% of children studied.5 Researchers are now screening for obesity-related genes using blood plasma and DNA samples collected from obese children and adults who were obese as children. Pediatric endocrinologist Rudolph Leibel, head of the division of molecular genetics at Columbia University, was involved in cloning the leptin gene and its receptor. "There are probably 30 or 40 genes that are expressed in the brain and other parts of the body ... [that] play some part in body weight," he says. These genes probably affect food intake, energy expenditure, and whether calories are stored as fat or lean tissue. Leibel and colleagues are using genomics tools to identify genes related to body weight using a large sample of obese and lean people. By analyzing the data, the team hopes to determine the most common and less common allelic variations of genes that may affect body weight. "If one believes, as I do, that there is strong genetic influence on this phenotype, children who become obese and stay obese early are more likely to have more powerful genetic influence than an adult who gradually becomes obese later in life," Leibel says. Among these increasingly fat children, two opportunities for research exist: to study those who develop obesity early and those who develop Type 2 diabetes early. "We haven't changed our genes in the last 30 years," O'Rahilly says. "The cause of the increase in the frequency of obesity over the last 20 to 30 years clearly cannot reside in our genes." But, he continues, genes will play a major role in determining susceptibility to obesity in populations in which lack of exercise is combined with intake of high-caloric foods. In genetic studies of childhood obesity, O'Rahilly's team is looking at children who fit into a number of criteria, including obesity before age 10 and a body mass index (BMI) 3.5 standard deviations above the age-related mean. But, he notes, these children are in the extremes. There is "still is not a clear definition of obesity in childhood," says Van S. Hubbard, director of the division of nutrition research coordination at the National Institute of Diabetes and Digestive and Kidney Diseases. "We are currently utilizing the 85th percentile BMI from the CDC/National Center for Health Statistics growth curve as a marker for at-risk for overweight and using the 95th percentile as a marker for overweight. We do not have a separate distinction for obese." The Diabetes Epidemic Up until 10 years or so ago, explains Leibel, Type 2 diabetes was found in adults. Now Type 2 accounts for about 25% or more of all diabetes cases diagnosed in children. Type 1 diabetes is a childhood autoimmune disease. Although their comorbidities and results are similar, these two diseases have very different etiologies. Certainly, evidence exists that Type 2 diabetes in children can be genetically mediated. Cardiologist Gerald Berenson of Tulane University, who directs the Bogalusa Heart Study, says his team has found that at least 30% to 40% of Caucasian children who have a diabetic parent have a high glucose tolerance curve and are apt to become diabetic in 10 to 20 years. The study is a continuing, 30-year project that is following participants from childhood into adulthood, looking at risk factors and the development of heart disease. "Increasing obesity is becoming expressed in diabetes," he says. In a glucose tolerance test, a high tolerance curve indicates that blood glucose levels are not going down quickly enough after receiving a glucose challenge. This means that there is insufficient insulin present or, more likely, that cells are resistant to insulin's effects. Berenson notes that African American children do not show this abnormal glucose tolerance curve. But in African Americans, obesity and insulin resistance begin to develop in the third decade of life, explains Berenson. Leibel notes that children diagnosed with early Type 2 diabetes also probably have genetic loading that predisposes then to the disease's development. "And it's very likely that the genes are not the same in all ethnic groups or environments," he adds. There "may be different sets of genes involved in different ethnic groups, and different environments may bring out these genes." Obesity Genes Unlike O'Rahilly's team, which is looking at rare obesity types, Nancy Butte, professor of pediatrics at Baylor College of Medicine, and colleagues are looking at more common obesities. Butte is studying genetic and phenotypic characteristics related to obesity in Hispanic children, with her group carrying out a genomic scan, studying about 1,600 children and parents in 300 families. "There are several genes involved in common obesities," says Butte. The team is identifying specific regions on given chromosomes associated with obesity and then homing in to describe responsible genes. At the same time, they are taking copious data on the children's phenotype by studying body composition, measuring energy expenditure, testing serum biochemistries, determining fitness levels, assessing diet and physical activity. "We know genetics are certainly involved, but we know that diet and physical activity also must contribute to the obese phenotype," remarks Butte. Courtesy of Sonia CaprioSonia Caprio Others are studying physiological factors in obesity. Sonia Caprio, associate professor of pediatric endocrinology at Yale University, and colleagues are studying the link between obesity and insulin resistance. Most children with Type 2 diabetes develop it around puberty; few cases arise in preadolescents, Caprio explains. "In addition to obesity, the adolescent is at high risk for developing Type 2 diabetes because of the additive effects of the natural presence of insulin resistance of puberty and the genetic predisposition to diabetes," she says. With these risk factors, obese adolescents might first develop impaired glucose tolerance, then overt diabetes. The group is studying the mechanisms leading to the development of impaired glucose tolerance in obese children and adolescents. "We need to have better ideas of how to prevent type 2 diabetes in the pediatric population," she says. Using nuclear magnetic resonance imaging, Caprio is measuring the amount of fat within the myocite, or muscle cell. She says that she found a positive relationship between the quantity of this fat and insulin resistance. "The alteration of muscle metabolism may be critical to development of Type 2 diabetes, not only in adults, but also in the pediatric population," Caprio says. Until more genetic and biochemical information is uncovered on the causes of childhood obesity, comprehensive health instruction programs, such as those carried out as part of the Bogalusa Heart Study, may be effective for most children. While Berenson says there's "nothing wrong with looking at the computer or television, [children] have got to be active." If society does not do something about obesity, high blood pressure and diabetes, Berenson warns, there are "60 million kids in the country who will become our next generation of heart attacks." Myrna E. Watanabe is a freelance writer in Patterson, NY. References 1. www.cdc.gov/nchs/products/pubs/pubd/hestats/overwght99.htm 2. S. Caprio and W. V. Tamborlane, "Metabolic impact of obesity in childhood," Pediatric Endocrinology 28:731-47, 1999. 3. Y. Zhang et al., "Positional cloning of the mouse obese gene and its human homologue," Nature, 372:425-32, 1994. 4. C. T. Montague et al., "Congenital leptin deficiency is associated with severe early-onset obesity in humans," Nature, 387:903-8, 1997. 5. G.S.H. Yeo et al., "A frameshift mutation in MC4R associated with dominantly inherited human obesity," Nature Genetics, 20:111-2, 1998.

Genes Do Play a Role in Obesity

Interested in reading more?

Become a Member of