Study Identifies Genes Key to the Regulation of Body Weight

Preliminary findings deepen understanding of factors leading to obesity – point to genetic risk variant in women.

A new Joslin Diabetes Center-led study has further illuminated the role of genes in regulating body weight and fat distribution. Because obesity is a major risk factor for type 2 diabetes, identifying genes that affect this condition holds promise for the detection of individuals at risk, as well as for potential prevention and treatment methods. The study, presented on June 25, was among almost 80 presented by Joslin scientists and clinicians at the American Diabetes Association’s (ADA) 67th Annual Scientific Sessions in Chicago.This study is a continuation of prior research (published in the Proceedings of the National Academy of Sciences in 2006, 103:6676-6681), led by C. Ronald Kahn, M.D., head of the Joslin section on Obesity and Hormone Action, which observed differences between fat cells from different parts of the body in the expression of 10 genes involved in cell growth and development. Fat cells from different parts of the body are believed to have different functions and metabolism. Three of these genes (T-box 15, Glypican 4, Hox A5) showed changes in expression that correlated with body weight and waist:hip ratio. Genes “express” themselves by translating encoded information into proteins, enabling visible characteristics, such as weight, to manifest. Only a fraction of the genes located on the genome are expressed in a given cell type. “We were interested in exploring the genetic characteristics that might be responsible for differences in body weight and distribution,” said Alessandro Doria, M.D., Ph.D., Investigator in the Section on Genetics and Epidemiology at Joslin Diabetes Center, who led the study.The study examined DNA from a representative sample of healthy, Caucasian subjects who had no symptoms of diabetes. Genetic variants (known as polymorphisms) are sites along the genes where the DNA sequence varies among people. In the 10 identified genes, researchers identified 120 single nucleotide polymorphisms (SNPs) that were representative of all other common variants in those genes. They then tested the association of these SNPs with the subjects’ body weight and waist measurement.An SNP in one particular gene, T-box 15, which regulates the development of cells and cellular growth in fat tissue, showed a strong correlation with both higher body weight and bigger waistlines. While this effect was observed in the entire sample of individuals, it was much stronger in women. The women with the risk variant were three times more likely to be overweight than women who did not have the variant. “We don’t know why this is the case but body fat regulation and distribution are different in women than men. So, it is not surprising that a genetic variant has different effects on body weight in the two genders,” says Doria.The next step is replicating the results in other populations in follow-up studies. Doria reports that there are already researchers interested in pursuing this line of research.If the results are confirmed, researchers would then seek to identify the specific pathway or cellular mechanisms that regulate body weight and are under the control of T-box 15. Unlocking how this process works could lead to ideas for new pharmaceutical treatments or screening tests, according to Doria. Early detection could help people with the genetic predisposition take preventive measures to avoid gaining weight. “Staying active and making smart food choices are part of a healthy lifestyle, but if you are genetically predisposed to obesity, you should be extra careful about what you do,” said Dr. Doria.Reducing the incidence of obesity could reduce the prevalence of type 2 diabetes. However, there are several other risk factors for type 2 diabetes including family history, high cholesterol, high blood pressure and physical inactivity. In type 2 diabetes, insulin-producing cells are still intact and functioning, but either they are not producing enough insulin to meet the body’s needs, or the body’s cells cannot react appropriately to the insulin being produced to convert food into energy. Diabetes now affects more than 20 million Americans, and yet one third are not aware that they have the disease. Funding for the study was provided by the National Institutes of Health.Other researchers participating in this study include: Christine Powers, M.S., Lucia Gottardo, M.D., Grzegorz Placha, M.D., Stephane Gesta, Ph.D., and C. Ronald Kahn, M.D., of Joslin Diabetes Center; and Angelo Avogaro, M.D. of the University of Padova, Italy.(Source: American Diabetes Association’s 67th Annual Scientific Sessions : Joslin Diabetes Center : August 2007)