A new article sheds a little bit of light on the latest player in obesity: the FTO gene (the fat-mass and obesity-associated gene). FTO was implicated as a gene important in determining who is more likely to be obese and at risk for diabetes in two genome-wide association studies published in May [Frayling 2007 ] and June [Scott 2007 , see also Dina 2007 ] of this yearAs you closet geneticists may recall, genome wide association studies are all the rage these days due to technological advances that have finally made them practical. Basically, you take a few thousand people with the trait you’re studying (obesity in this case, but cancer, arthritis, and Chron's disease in other studies) and a couple of thousand controls cases, isolate their DNA, and scan their genomes for DNA variants that are statistically associated with the trait of interest. Typically, these scans evaluate each sample for about 250,000 - 500,000 common DNA variations (SNPs) evenly spaced across all the chromosomes. (The scope of these studies is pretty outrageous, and would have cost hundreds of millions of dollars just a couple of years ago, but is now economically feasible due to advances in technology.) The good thing about these studies is that they are unbiased. They just associate a gene with a trait, with no preconceived notion of why that gene is associated with the trait - so you end up detecting genes that you wouldn't have necessarily guessed were important in that biological process.
Such is the case with the FTO gene. When the gene was implicated as an obesity-related gene back in the spring, little was known about what it normally did, and how variants of the gene might promote obesity. In a new study published just recently in Science (Gerken et al.,The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate Dependent Nucleic Acid Demethylase. Science. 2007 Nov 8; [Epub ahead of print]), scientists are starting to at least understand what the gene does. They are still puzzled as to how it regulates weight, but the results are intriguing for Prader-Willi syndrome (PWS). FTO apparently makes a protein that is important in regulating the methylation of nucleic acid (DNA or RNA). Further, this gene is expressed at high levels in the "right" places to regulate appetite – key regions of the hypothalamus known to regulate feeding and control energy balance.
The link to obesity remains elusive. Does FTO normally regulate the expression of genes important in food intake/energy balance by altering the methylation status of those genes at the DNA level? That's possible, but methylation/demethylation is not usually a very quick way to regulate gene expression; as would be needed for genes that important in appetite. Might it work on the RNA (the "message" from the gene), rather than the DNA? Having an effect on the RNA would likely give a much more timely regulation of feeding-associated gene expression, but it's not been show in mammals (yet...) that RNA demethylation actually plays a physiological role in regulating how much protein is made. An intriguing (if poorly defined) link to PWS is that snoRNAs, such as those encoded in the PWS critical region, are RNA methylases. How or whether the snoRNAs and FTO methylate and demethylate the same RNAs remains to be explored.
Additionally, the authors also showed that the FTO protein is regulated by metabolites in the Kreb's cycle (the major energy producing metabolic cycle in the cells) - and suggest that disease states that alter these metabolites might also alter the ability of FTO to do its job. Alternatively, FTO is similar to other proteins known to play a role in repairing DNA damage, particularly in low oxygen conditions. I think it's safe to say the link between DNA damage and obesity is not necessarily obvious (although there are some studies suggesting that poor DNA repair is linked to altered body weight), but this does suggest that further study in this area is warranted.
What does all this mean for PWS? The nonbiased approach to identifying FTO as a new obesity-related gene may open up a whole new understanding of the mechanisms that regulate appetite and energy balance. As PWS is likely caused by misregulation of genes outside the PWS region, advances in understanding how FTO can regulate other appetite genes may be relevant to understanding how PWS-region genes go about regulating other genes. In the shorter term, natural variants in the FTO gene (located on chromosome 16) may underlie some of the variability seen in PWS with respect to propensity to obesity.
Theresa Strong
Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.
