Genetics and Obesity

A new research shows that an entire network of genes in the body is disrupted by overeating and this not only causes obesity, but also diabetes and heart disease.

In two related studies, scientists at Merck Research Laboratories (MRL) and their collaborators used large-scale analyses of data on DNA variations, gene expression patterns in disease-relevant tissues and clinical data to identify molecular networks underlying metabolic disorders.

The first study, involving Merck researchers and colleagues from the University of California at Los Angeles, used liver and fat tissue samples from mice to identify genetic variations associated with obesity, diabetes and atherosclerosis. Then, the authors constructed gene networks and identified core groups of genes in these networks that caused the diseases. Based on various analyses, the authors identified and experimentally validated three novel genes causally related to obesity-associated traits: Lpl, Pmpll and Lactb. All of them provide new targets for anti obesity drugs because they seem key players in the genetic network that control girth.

The second study by researchers from Merck, the Icelandic company deCODE Genetics and the National University, Iceland involved more than 1,000 people known to be susceptible to obesity and then used a powerful computer to match data on genetic makeup, gene use and obesity to identify networks of gene interactions altered in individual susceptible to obesity. A gene expression network constructed from human fat tissue contained a similar core group of genes found to be causally related to obesity in the mouse study.

“What the new methods we’ve developed deliver is the complex web (network) of interacting genes in disease relevant tissues that actually lead to disease. These studies strongly support the theory that common diseases such as obesity result from genetic and environmental disturbances in entire networks of genes rather than in a handful of genes. If diseases like obesity are the result of complex networks of genes, the accurate reconstruction of these networks will be critical to identifying the best therapeutic targets,” Dr. Eric Schadt, executive director of Genetics at Merck Research Laboratories and senior author wrote in the studies.

Dr. Schadt also said a good diet and exercise remain the best ways to prevent the onset of obesity.

"If you are not going to alter your lifestyle, we can identify what network is going to be most significantly altered. Then we can bring that network more into a state to where it looks like when you are on a normal diet."

Schadt suggests the diseases of obesity seem to originate in the immune system and the network is enriched for genes that are involved in macrophages.

"In a normal state these things are keeping you free of infection and fighting off things that want to harm your body. This network is also significantly changed when you are on a high-fat diet," he added.

The results of the studies appeared in the journal Nature.

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