A new technique for analyzing DNA has provided a team of researchers from Merck with a more comprehensive view of the genetic factors that may underly obesity. Rather than looking for genes that are more common in obese individuals than in controls, the researchers, led by Dr. Eric Schadt, assessed variations in the functional actions of genes, or gene expression, that could form what the researchers describe as gene "networks." Their findings, published in two studies appearing in the journal Nature, suggest that a network of hundreds of genes may be involved in obesity and could predispose obese individuals to certain diseases.
Initially, using liver and fat tissue samples from mice fed with a diet high in fat, the researchers studied variations in gene functioning in mice of varying weight. They identified hundreds of genetic variations that were associated both with obesity and to obesity-related disease in the mice, including heart disease and diabetes. Additionally, their work led to the discovery of three novel genes, Lpl, Ppm1l, and Lactb, that appear to be involved in obesity.
To further investigate the effect of variations in gene expression on disease, the researchers utilized a database of Icelandic volunteers. With over 1,000 blood samples and close to 700 tissue samples from these subjects, they analyzed the expression of over 23,000 genes while also considering the subjects' overall genetic makeups. They observed a distinct pattern of gene expression evident in tissue samples from individuals with high BMIs, and this key group of genes was similar to the gene network seen in overweight mice. These patterns of gene expression were not seen in blood samples, however, and the researcher surmise that simple genetic tests are not sufficient to identify these gene networks.
Both studies hint at the role played by the immune system in obesity, as the researchers observed that in mice and in humans many genes involved in the gene network associated with obesity were also associated with inflammation. Normally, these genes would be involved in keeping the body healthy and fighting infection, the researchers explained. But a diet high in fat creates changes in gene expression within the network that could then increase an individual's susceptibility to some diseases, such as heart disease, diabetes, and metabolic syndrome, a cluster of symptoms that includes high blood pressure, high blood sugar, and insulin resistance. The researchers suggest that different individuals are vulnerable to different obesity-related health conditions, depending upon the patterns that comprise their gene networks.
These findings support the theory of obesity as resulting from complex interactions between networks of genes and environmental factors, and continued research on gene networks may allow researchers and physicians the ability to determine the health conditions to which an obese individual will be most vulnerable. While this research will also be used in the search for medications to treat overweight and obese individuals, the researchers also stress the crucial role of diet and exercise in losing weight. More research is needed to better clarify our understanding of obesity and the disorders associated with it, and they emphasize the importance of seeing genes as a network full of interactions and studying these networks rather than just the role of individual genes.
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