Krishna Pabba FTO Gene: The Shadow of Obesity

As defined by the World Health Organization, obesity is a medical condition is which excess body fat has accumulated to the extent hat it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems [1]. In relation to the body mass index (BMI), which is a mathematical relationship between a persons weight and height, an over weight person has an average BMI between 25 to 30 kg/m2. An obese person has a BMI over 30 kg/m2. In 2005, the World Health Organization estimated that 1.6 billion adults (aged 15 years and over) were overweight and 400 million were obese [2]. In 2015, it is predicted that 2.3 billion adults will be overweight and 700 million will be obese. Even though the main causes of obesity are from excessive food intake and a lack of physical exercise, new research suggests that genetic factors play a tremendous role in the increasing BMI of the population. Most of the current research done on genetic causes of obesity is focused on a gene called FTO. The FTO gene was first found in mice due to a deletion on chromosome 8, which is responsible for the Fused toe (Ft) phenotype [3]. Mice that were homozygous for the deletion died early, had several physical malformations, and central nervous system damage. Heterozygotes were observed to have toes that were fused together and an enlarged thymus. In fact, obesity was never even reported in these mice. However, a human patient with a phenotype similar to the one found in the Ft mice carried a small duplication on 16q12.2, a region that includes the FTO gene [4].

Krishna Pabba The function of the FTO gene was still a mystery until in silico analyses were done because the FTO sequence was not found to have any homology in the public databases. The analysis showed that the FTO base pair sequence is homologous to the sequences found in other vertebrates and marine algae. The analysis also showed that the FTO protein has similar function to Fe (II) and 2-oxoglutarate oxygenases, which catalyze oxidative reactions on multiple substrates using a non-heme iron as a cofactor [5,6]. However, FTO was found to be most similar to Escherichia coli enzyme AlkB [7]. This enzymes function is to repair DNA damage due to improper methylation. This would mean that FTO also might act as a demethylase. In vitro studies were done to prove this hypothesis and confirm that FTO acts as an oxygenase that catalyzes nucleic acid demethylation. This demethylation activity of FTO acts as the basis for the regulation of the expression of genes that are involved in metabolism and regulation of bodily processes that might lead to obesity. To observe FTO expression, earlier in vivo studies were done on fed, fasted, and obese rodents [6]. During fasting, mice were observed to have a significant reduction in hypothalamic FTO mRNA expression when compared to the fed controls. These studies were shown to be independent on how much leptin, an anti-starvation hormone, were given to the starving mice. This would suggest that FTO is down regulated during fasting and upregulated during feeding. These changes in FTO expression could provide a signal in which feeding and obesity occur. In contrast, FTO expression was upregulated during fasting and downregulated during feeding for rats. The differences between the rodents FTO expression was hypothesized to be due to the sensitivity that each rodent has to starvation and different times in which the studies were actually done. However, recent

Krishna Pabba studies in rats have shown to show the same FTO expression as in the mice [7]. This expression was observed to have relations with changes in obesity. In six mouse models of obesity, hypothalamic FTO expression did not differ significantly than the wild type fed mice. Nevertheless, when compared to the fasted mice, FTO gene expression was shown to be down regulated in the obese mice. This would suggest that obese mice mimic the fasted mice and this might contribute to over eating. However, these differences and similarities between fed and fasted mice are inconclusive to determine whether they are the cause or consequence of obesity. Further investigations were done to determine whether changing FTO gene expression and function would cause a change in fat mass. Two different mouse models were found to have some type of deficiency in FTO expression [8, 9]. One was caused by a null mutation that results in an absence of FTO expression and another caused by a point mutation that results in a change of the amino acid sequence from isoleucine to phenylalanine at position 367 (1376F). The point mutation at position 367 caused a partial loss of function in FTO expression. Both mutations were found to result in loss of fat and reduced body weight. The mice with the null mutation were found to have low weight at birth while the mice with the point mutation were found to have reduced body weight during maturity. Also, the mice with the null mutation had a 30-40% weight reduction compared to the wild type, while the mice with the point mutation had only a 10% reduction in body weight. Even on a high fat diet, both models of mice were seen to have reduced body weight and this would suggest that disrupting FTO activity can be useful for obesity induced by a diet. The results of the experiment are summarized below [8,9].

Krishna Pabba

Krishna Pabba Even though these animal models are useful for investigating how genes function, they do not reflect what happens in humans. However, new studies have been done on different populations across the world to see the effect of variation on the FTO gene. In Korea, Hye-Ja Lee and co. of the National Institute of Health studied two different FTO gene variants (SNP 9939609T and SNP rs993973G) and their association with BMI on dietary intake and physical activity in Koreans [10]. The group studied two different populations: a children population of 711 seven to ten year old children and a population of adults aged forty to sixty nine. All the study subjects were observed in the morning after an overnight fast. Height, weight, circumference of waist and hips and blood pressure was measured. Blood samples were taken for biochemical measurements such as fasting serum glucose, total cholesterol, triglycerides and etc. A questionnaire was given to each population to determine dietary intake and physical activity. Genotyping was done using Illumina Golden Gate genotyping system and data was assessed using duplicate DNA samples. The results are shown on Tables 2 and 4 [10].

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The results showed that SNP rs9939609 showed a significant association with BMI, bodyweight, and waist conference in children. The children that carried the homozygous minor allele (AA) of rs9939609 had a higher BMI compared to carrying the homozygous major allele (TT) and heterozygous (AT). Also, children carrying the minor allele of rs9939973 showed an overall trend in the risk of being overweight when compared to the children carrying the major allele of that SNP. The children with rs9939609 genotype AA took in more total fat than the children with the genotype TA with the same SNP. There

Krishna Pabba was no direct relationship between physical activity and FTO genotypes in either the children or adults. In adults, there were significant associations between rs9939973 and BMI, waist circumference, fasting serum insulin, and HOMA-IR. The study by Lee and co. had limitations: the dietary record method observed was on a short term period and a small children population. However, the conclusions made are valid for the study of the FTO genotype. Their analyses showed that FTO influences childhood weight and adulthood BMI. The (A) allele of rs9939609 SNP was observed to make Koreans more susceptible to being overweight. Also, the FTO variants might have a greater influence in children with a diet higher in fat content and with a low level of physical activity then in children with low fat diet and high physical activity. Even though the study done be Lee and co. provided a nice statistical analysis on how FTO variants affects BMI and physical activity, there needs to be an investigation on FTO SNPs/expression and neuropeptide levels in human hypothalamus might therefore provide a mechanism for the modulatory effect of FTO SNPs on appetite. Also, presently, the strongest associations between FTO SNPs and BMI belong to intronic SNPs [11]. It also important to map out the other variants that can shed light on how FTO functions. Moreover, it has been seen that FTO SNPs do not influence the expression of the FTO gene but influence its neighboring gene, RPGRIPLL. Therefore, more studies studying the joint effects via FTO and RPGRIPLL are needed to truly understand what is happening at the genetic level. Ultimately, by studying the gene function of FTO, novel genes and molecules can be made to target FTO for therapeutics. The studies above detailed a loss or partial loss in FTO function which lead to a decrease in obesity in the subjects. However, a complete loss of FTO function can lead to serious physical and neurological effects [12].

Krishna Pabba Therefore, it is important to find drugs and genes that reduce the expression of FTO but not completely nullify it. Thus, this will alleviate obesity with minimal harm done to the human.

Krishna Pabba References

1. Kopelman P. Health risks associated with overweight and obesity. Obes. Rev. 2007;8:1317. [PubMed: 17316295] 2. Hjelmborg J.B. Genetic influences on growth traits of BMI: a longitudinal study of adult twins. Obesity 2008;16:847852. [PubMed: 18239571] 3. van der Hoeven F. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 1994;120:26012607. [PubMed: 7956835] 4. Stratakis C.A. Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503). J. Clin. Endocrinol. Metab. 2000;85:33963401. [PubMed: 10999840] 5. Gerken T. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007;318:14691472. [PubMed: 17991826] 6. Sanchez-Pulido L. Andrade-Navarro M.A. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily. BMC Biochem. 2007;8:23. [PubMed: 17996046] 7. Trewick S.C. Methylation: lost in hydroxylation? EMBO Rep. 2005;6:315320. [PubMed: 15809658] 8. Fischer J. Inactivation of the Fto gene protects from obesity. Nature 2009;458:894898. [PubMed:19234441] 9. Church C. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet. 2009;5:e1000599. [PubMed: 19680540] 10. Hye-Ja Lee, In kyoung Kim, Jae Heon Kang, Younjhin Ahn, Bok-Ghee Han, Jong-Young Lee, Jihyun Song, Effects of Common FTO gene variants associated with BMI on dietary intake and physical activity in Koreans. Clinica Chemica Acta. 2010. 11. Ragvin A. Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proc. Natl. Acad. Sci. 2010;107:775780. [PubMed: 20080751] 12. Boissel S. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 2009;85:106111. [PubMed: 19559399]