Life course variations in the associations between FTO and MC4R gene variants and body size

Hardy, Rebecca; Wills, Andrew K; Wong, Andrew; Elks, Cathy E.; Wareham, Nicholas J.; Loos, Ruth J.F.; Kuh, Diana; Ong, Ken K.

doi:10.1093/hmg/ddp504

Cited by 238 publications

(268 citation statements)

References 28 publications

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“…Although just one study found an association with obesity in this review, there are in previous studies a description of decreased response to satiety in children and adolescents when rs9939609 is present, confirmed in other studies [25][26][27][28] . As Cecil, Frayling et al also identified, rs9939609 carries an association with a higher Body Mass Index (BMI) in children and adults 29 .…”

Section: Discussionsupporting

confidence: 74%

The Role of Fat Mass and Obesity Associated Gene (Fto) in Satiety and Binge Eating Disorder

Castro¹,

Horvath²,

Kops³

et al. 2015

cbr

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Obesity is a major health problem and one of the biggest predictors of the development of chronic diseases. Variations in the Fat mass and obesity associated gene (FTO) have been shown to associate strongly with obesity. Among patients with severe obesity, there is a subpopulation that presents an eating disorder known as Binge Eating Disorder. Because of its expression in the hypothalamus, FTO could be associated with modulation of satiety and, perhaps, play a role in the genesis of BED, contributing to severe obesity. A search in PubMed was carried out with the following terms: Morbid Obesity AND FTO, FTO AND Satiety Response, Binge Eating Disorder AND FTO. No restriction on the date of publication, language or type of design was applied. Sixteen articles were found. Twelve were related to FTO and grade III obesity, and three were related to FTO and satiety. Ten studies were excluded. Thus, six articles were evaluated in this review. The scarce literature limits further conclusions about the potential impact of the associations with FTO in the treatment of obesity, but all articles included in this revision show association with at least one SNP of FTO. Further studies are required to clarify these associations, especially in relation to rs9939609 (A/T), because, up to this moment, it seems to be the one variant with greatest impact on obesity in humans. Keywords: Obesity; FTO; satietyObesity is one of the main health problems in the 21st Century. It is an established risk factor for conditions such as Type 2 diabetes mellitus, cardiovascular disease and cancer 1 .The prevalence of overweight and obesity has doubled in the last thirty years. In Brazil, a 2008/2009 survey of the Ministry of Health showed that 8.9% of the population is obese. In the South of the country, 10.1% of the male population and 15.1% of the female population is obese. Brazilian estimates point out that, in the year 2025, the country will have the fifth largest prevalence of obesity worldwide 2 . Clinically, obesity is diagnosed in the presence of a body mass index (BMI) equal to or higher than 30 kg/m 2 , in adults 3 .Recent studies show associations of BMI with body fat and with the the "Fat mass and obesity associated" (FTO) gene 4 , located in chromosome 16q12.2 5,6 . Variations in this gene (single-nucleotide polymorphisms -SNPs) were strongly associated with obesity and diabetes mellitus 7 . The association of FTO with human obesity has been shown in caucasian populations studies [8][9][10][11] . Besides the association with BMI and higher risk for overweight and obesity, SNPs in FTO have been associated with obesity and body weight 5,8,11 , leptin levels 11 , subcutaneous fat 5,8 , fat mass 5,8,11 and waist circumference 11 .The messenger RNA (mRNA) of FTO is expressed in the hypothalamus 12 , an area that is connected with appetite regulation; in rodents, FTO mRNA expression in the hypothalamus is modulated by acute food deprivation 13 . One recent study, in human adults, has found differences in the caloric intake, but...

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Section: Discussionsupporting

confidence: 74%

The Role of Fat Mass and Obesity Associated Gene (Fto) in Satiety and Binge Eating Disorder

Castro¹,

Horvath²,

Kops³

et al. 2015

cbr

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“…This observation agrees with former findings in mature subjects. Hardy et al (2010) described a weak association between FTO and BMI at the age of 50. Jacobsson et al (2011) suggested that the effect of FTO on corporal adiposity may decrease by age.…”

Section: Discussionmentioning

confidence: 99%

Lifestyle factors modify obesity risk linked to PPARG2 and FTO variants in an elderly population: a cross-sectional analysis in the SUN Project

et al. 2012

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Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are relevant obesogenes. Our aim was to explore the effect of Pro12Ala (rs1801282) of PPARG2 and rs9939609 of FTO on obesity risk and to examine their interaction with lifestyle factors in an elderly population. Subjects (n = 978; aged 69 ± 6) were recruited from the SUN (Seguimiento Universidad de Navarra) Project. DNA was obtained from saliva, and lifestyle and dietary data were collected by validated self-reported questionnaires. Genotyping was assessed by RT-PCR plus allele discrimination. Subjects carrying the Ala allele of PPARG2 gene had a significantly increased obesity risk compared to non-carrier (Pro12Pro) subjects (OR, 1.66; 95 % CI, 1.01-2.74; p = 0.045). Greater obesity risk was also found in inactive or high carbohydrate intake subjects with the Ala12 allele of PPARG2 gene. Interestingly, subjects carrying the Ala allele of the PPARG2 gene and with a high CHO ([246 g/ day) intake had an increased obesity risk compared to Pro12Pro subjects (OR, 2.67; 95 % CI, 1.3-5.46; p = 0.007; p for [CHO 9 PPARG2] interaction = 0.046). Moreover, in subjects with a high CHO intake, the co-presence of the Ala allele of PPARG2 gene and one minor A allele (rs9939609) of FTO gene did increase obesity risk (OR, 3.26; 95 % CI,; p = 0.021) when compared to non-carrier (Pro12Pro/TT) subjects. In conclusion, it appears that lifestyle factors may act as effect modifiers for obesity risk linked to Ala12 allele of the PPARG2 gene and the minor A allele of FTO gene in an elderly population.

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“…We found that the effect of FTO on BMI gradually diminished in men and women with advancing age, an observation shared by others. 3,[22][23][24] Jacobsson et al found no association between FTO and BMI when they analysed a cohort of 1115 men, who were repeatedly examined each decade starting from the age of 50 years. 23 Similarly, Hardy et al reported that the association between FTO and BMI increased during childhood and adolescence, peaked at around 20 years, diminished gradually with advanced age and levelled off by the age of 53 years.…”

Section: Introductionmentioning

confidence: 99%

“…23 Similarly, Hardy et al reported that the association between FTO and BMI increased during childhood and adolescence, peaked at around 20 years, diminished gradually with advanced age and levelled off by the age of 53 years. 22 Given the age-dependent reduction of growth hormone (GH) and insulin-like growth factor-I (IGF-I), 25 we hypothesized that the risk alleles of FTO were associated with the GH-IGF-I axis. Biological evidence is based on the abundant expression of FTO in the hypothalamus and pituitary gland, both key organs for the GH-IGF-I axis and also for weight control.…”

Section: Introductionmentioning

confidence: 99%

The growth hormone—IGF-I axis as a mediator for the association between FTO variants and body mass index: results of the Study of Health in Pomerania

Rosskopf

Schwahn²,

Neumann

et al. 2010

Int J Obes

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Context: Risk alleles of the fat mass-and obesity-associated gene (FTO) are related not only to increased body mass index (BMI) values but also to mortality. It was speculated that cellular effects of the FTO gene affect most organs, especially their ability to maintain or regenerate proper function when afflicted by various diseases. FTO is highly expressed in the hypothalamus and also in the pituitary gland. The decrease in growth hormone (GH) secretion is known to cause a decrease in lean body mass in older subjects. Objective: We hypothesized an association of rs9926289 with insulin-like growth factor (IGF)-I. Design and setting: Cross-sectional data from the Study of Health in Pomerania, a population-based study in the northeastern part of Germany, were used. Participants: For the final analyses, 3882 subjects aged 20-79 years were available. Main outcome measures: Continuous IGF-I, low IGF-I according to clinically meaningful age-and gender-specific reference values, and BMI were used as outcome measures. Results: Over all age groups, a statistically significant relationship between FTO and IGF-I was found. In subjects younger than 55 years of age, homozygous carriers of the FTO risk allele exhibited lower serum IGF-I levels adjusted for 5-year age groups, gender and IGF-I binding protein 3 levels (linear regression, coefficient ± s.e. for FTO AA genotype:À8.6 ± 2.8; P ¼ 0.002). Further adjustments for obesity and diabetes did not suspend this association (coefficient:-7.8; P ¼ 0.005). As expected, the FTO AA genotype effect on BMI was reduced from 0.76 to 0.62 kg m À2 by including IGF-I. No relationship between FTO and IGF-I levels was found in subjects aged 55 years or older (À2.7±2.4; P ¼ 0.260 for FTO AA genotype adjusted for age, gender and IGF-I binding protein 3 levels). Conclusion: We propose that the GHFIGF-I axis is a mediator for the relationship between FTO and BMI.

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Life course variations in the associations between FTO and MC4R gene variants and body size

Cited by 238 publications

References 28 publications

The Role of Fat Mass and Obesity Associated Gene (Fto) in Satiety and Binge Eating Disorder

The Role of Fat Mass and Obesity Associated Gene (Fto) in Satiety and Binge Eating Disorder

Lifestyle factors modify obesity risk linked to PPARG2 and FTO variants in an elderly population: a cross-sectional analysis in the SUN Project

The growth hormone—IGF-I axis as a mediator for the association between FTO variants and body mass index: results of the Study of Health in Pomerania

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