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Second genetic link to weight and obesity
Date:5/4/2008

ration can bring about new findings that can be missed when researchers work in isolation," explains Dr Ins Barroso, Investigator at the Wellcome Trust Sanger Institute and one of the senior authors on the study. "The precise role in obesity of genetic variants in FTO and near MC4R remains to be discovered, but we can now begin to understand the biological consequences of these variants. This is where this research will make a difference."

MC4R protein plays a pivotal role in many aspects of physiology, including regulation of appetite and energy expenditure. The severe form of MC4R-related obesity is a consequence of alterations in the gene sequence, resulting in an inactive or less active MC4R protein.

By contrast, the new variants lie some distance from the MC4R gene. The team suspect that the sequence variant changes activity of the MC4R gene, perhaps by disrupting DNA regions required for normal activity of MC4R.

"Through this new and powerful genetic approach we are increasingly finding that the genes known to play a role in severe - but rare - diseases are also implicated in much more common disease," explains Professor Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford, UK. "The common variants we are uncovering do not have such a dramatic effect on the normal functioning of the gene as do the rare mutations in MC4R that can cause rare examples of very serious, early onset obesity."

Dramatically, in a study of almost 6000 children, they found that the effects were almost double those seen in adults. Between the ages of four and seven, this additional increase in weight was the result, almost exclusively, of gain of fat tissue, and not due to gain in muscle or other solid tissues.

This more dramatic effect in young children reflects the more extreme consequences seen with rare variants of MC4R that severely disrupt its activity, suggesting that the novel variants do indeed exert their
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Contact: Don Powell
don@sanger.ac.uk
44-012-234-96928
Wellcome Trust Sanger Institute
Source:Eurekalert

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