Combating genetic predisposition to obesity

20 April 2010

The FTO gene is known to be associated with the risk of increased body mass index (BMI) and obesity (see previous news); obesity is a serious public health problem. The aim of research into the genetic basis of disease is to understand how conditions arise, and to identify the best opportunities for prevention and treatment.
 
The FTO gene encodes a DNA / RNA demethylase enzyme that preferentially binds to 3-methylthymidine (3-meT) residues in single-stranded DNA or 3-methyluracil (3-meU) residues in single-stranded RNA. FTO is known to be involved in the regulation of energy homeostasis and body metabolism Now, scientists have generated a high resolution crystal structure of the FTO protein bound to a 3-meT [Han Z et al. (2010) Nature doi:10.1038/nature08921].
 
The structure (combined with biochemical assays) reveals that the protein has two main domains separated by a fold, and that interaction between these two regions is crucial for the enzymatic activity of FTO. It also shows the region of the protein crucial for selective binding of substrate residues in DNA. The potential application of these findings is that it may allow the design of new drugs to inhibit the FTO protein – by blocking ability to bind to DNA / RNA or interfering with enzymatic function – that could serve as effective new anti-obesity treatments.

Comment: This research from China provides only a starting point for rational drug design, but is nevertheless a promising development following relatively quickly after the identification of the FTO gene as a significant player in obesity. In the UK recently there has been criticism of government attitudes to obesity  and their effects on the medical profession; National Obesity Forum chair Dr David Haslam reportedly praised recent initiatives to prevent and reduce obesity levels by encouraging healthier lifestyles, but that too few resources were available for the treatment of those who were already obese, such as drugs or surgery [White C. BMJ (2010) 340:c1716. doi: 10.1136/bmj.c1716]

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