Obesity, FTO, and Type 2 Diabetes

Updated: Feb 10, 2016
  • Author: Ali Torkamani, PhD; Chief Editor: Keith K Vaux, MD  more...
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The first report linking the FTO (fat mass and obesity-associated) gene (synonyms KIAA1752, MGC5149, ALKBH9) and obesity came from a genomewide association study linking FTO variants with type 2 diabetes in a European population. [1] The connection between FTO and diabetes was lost after correcting for body-mass index, suggesting that FTO -mediated susceptibility to type 2 diabetes was driven through a relationship between FTO and obesity.

Numerous studies have since confirmed the association of FTO with obesity in European populations. [2, 3, 4, 5] Although the strength of this association in other ethnic populations is not as striking, ample evidence suggests that FTO variants are related to obesity in nonwhite populations as well. [6, 7, 8, 9, 10]

In white populations, people who are homozygous for the at-risk allele of rs9939609 have an approximately 1.7-fold increased risk of obesity and are about 3kg heavier than average. Although the average weight difference attributable to common FTO variants is relatively modest, FTO is among the strongest known common genetic risk factors for obesity.


Function of FTO

When FTO was first associated with obesity, its function was unknown; its mechanistic relationship with obesity still remains to be discovered. Bioinformatic analysis indicates that FTO is part of a family of enzymes involved in deoxyribonucleic acid (DNA) repair, fatty acid metabolism, and posttranslational modifications, and functional studies suggest that FTO is involved in nucleic acid demethylation. [11] However, it is unclear if and how nucleic acid demethylation is related to obesity.

Animal studies have demonstrated strong FTO expression in the hypothalamus, especially in the arcuate, paraventricular, dorsomedial, and ventromedial nuclei, all of which are key brain regions for the control of appetite. [11, 12] FTO -deficient mice display postnatal growth retardation, significant reduction in adipose tissue, and increased energy expenditure. [13] Conversely, mice who over-express FTO display increased adiposity and increased food intake, with no change in energy expenditure. [14]

In several human studies, individuals with at least 1 of the FTO obesity risk alleles reported increased food intake, especially of high-energy foods, as well as impaired satiety, [15, 16, 17, 18, 19, 20, 21] but changes in energy expenditure appear to be driven by changes in body mass. [22] Thus, while the exact biologic process linking FTO and obesity is unknown, it is clear that FTO variants mediate obesity by increasing energy input.


Clinical Implications and Genetic Testing

Before any clinical applications for genetic testing for FTO variants can be considered, the mechanistic link between FTO and obesity needs to be further clarified. One study showed that a loss-of-function FTO mutation in humans led to postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits, facial dysmorphism, and early lethality, [23] indicating that pharmacologic inhibition of FTO in an attempt to combat a predisposition to obesity could yield multiple adverse reactions.

Moreover, a clear link between FTO demethylase activity and obesity has yet to be made. It is possible that FTO plays a specialized role in the hypothalamus, perhaps as a transcriptional regulator, and mediates obesity in a manner independent of its catalytic activity, in which case pharmacologic inhibition would not be useful. On the other hand, it is also possible that the true in vivo effect of FTO has yet to be described.

The association of FTO variants with obesity certainly hints at a novel pathway to obesity and suggests ways in which genetic testing for FTO variants might play a role in potential clinical interventions down the road.

In the meantime, since diet and lifestyle changes seem to blunt the effects of a genetic predisposition toward obesity due to the presence of an FTO risk allele, [24] there may be a more immediate role for genetic testing in the clinic; such testing may provide a means of encouraging allele carriers to implement diet and lifestyle changes that discourage obesity and improve their overall health.