The Obesity Gene, FTO, Is of Ancient Origin, Up-Regulated during Food Deprivation and Expressed in Neurons of Feeding-Related Nuclei of the Brain

Abstract

lem. There are about one billion adults that are overweight with a body mass index (BMI) over 25, and 300 million are obese with a BMI over 30 (http://www.who.int). Today there are more people overweight than underweight. It causes costly health problems, reduces life expectancy, and is associated with stigma and discrimination, which has a major effect on the quality of life. Obesity and overweight substantially increase the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, and coronary heart disease. Obesity is also important for the development of obstructive sleep apnea and respiratory problems, gallbladder disease, osteoarthritis, and nonalcoholic fatty liver disease as well as endometrial, breast, prostate, and colon cancers.There are several genes associated with obesity on the human obesity map (1) such as the melanocortin 4 receptor (MC4R), leptin and the leptin receptor. However, the contribution of each specific gene to obesity is low, being highest for the MC4R gene ranging from 1-6% (2). The overall inheritability of BMI is estimated to be about 50 -60%. Recently, three reports have shown a strong association of a singlenucleotide polymorphism (SNP) in a gene called FTO with both childhood and adult obesity. Frayling and colleagues (3) performed a genome-wide association study for about 490,000 autosomal SNPs in a type 2 diabetes population in the United Kingdom. They found that SNP rs9939609 in the FTO gene was strongly associated with type 2 diabetes, but this allele was also strongly associated with an increased BMI. The association between this FTO SNP and type 2 diabetes was abolished by adjustment for the BMI, suggesting that it was due to the increased BMI. The association of this variant with the BMI was replicated in 13 cohorts with over 38,000 individuals. Interestingly, 16% of the adults who were homozygous for this SNP weighed about 3 kg more and had 1.67-fold increased odds of obesity. This association was observed from age 7 yr upward, and it reflects a specific increase in fat mass (3). Independently, Dina et al. (4) found another SNP, rs1121980, in the first intron of the FTO gene, that was strongly associated with severe (BMI Ͼ 40) adult obesity with odds ratio of 1.55 in a population of French individuals of European ancestry). Further genotyping showed a similarly strong association of several SNPs in a cohort of about 900 severely obese adults and 2700 nonobese French controls. Three of the four most significantly associated SNPs (rs17817449, rs3751812, and rs1421085) are puta-

Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway

“…Fto was significantly upregulated in the hypothalamus of food-deprived mice (p = 0.0012) in good agreement with previously published findings [18,19]. Several FTO network interaction candidates were also regulated in these mice (Figure 2).…”

“…Hypothalamic FTO is highly regulated in mouse and rat feeding models [18,19]. However, our knowledge of the molecular and physiological functions of FTO is still very limited.…”

Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents

“…Thus, this FTO gene variant associates with other phenotypes when compared with previously studied FTO variants where the associations are almost exclusively mediated by differences in BMI. 6,8,9 The FTO gene encodes a probable 2-oxoglutarate-dependent nucleic acid demethylase 19 and is expressed in multiple peripheral and central tissues, 3,20 which is characteristic for a gene that may display a pleiotropic character influencing several systems simultaneously. This suggests that FTO and polymorphism, such as c.896 þ 223A4G and rs9939609, that are not in linkage disequilibrium with each other may have different molecular effects on metabolic conditions and phenotypes.…”

Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans

“…Studies in rodents provide evidence supporting a central role for Fto in the regulation of energy balance. [18][19][20] These studies suggest that FtoFlike the majority of genetic defects associated with obesityFhas its principal impact on the function of the hypothalamus, although the results are inconsistent. In a 48-h deprivation model performed in mice Fto mRNA levels in arcuate nucleusFwhich is of critical importance for the control of energy balanceFwere reduced by B60% in fasted compared with freely feeding mice.…”

“…A similar effect of starvation on hypothalamic Fto expression was seen in another mouse study, 20 whereas the opposite effect was found in rats. 18 It is of potential importance to identify individuals with a genetic pattern that influences the response to weight reduction therapy, but it is still unclear if variants in FTO affect weight loss in obese individuals. Two studies are published with findings of no association between FTO variants (rs8050136 and rs9939609, respectively) and weight loss.…”