Dietary Intake, FTO Genetic Variants, and Adiposity

A Combined Analysis of Over 16,000 Children and Adolescents

Qibin Qi; Mary K. Downer; Tuomas O. Kilpeläinen; H. Rob Taal; Sheila J. Barton; Ioanna Ntalla; Marie Standl; Vesna Boraska; Ville Huikari; Jessica C. Kiefte-de Jong; Antje Körner; Timo A. Lakka; Gaifen Liu; Jessica Magnusson; Masayuki Okuda; Olli Raitakari; Rebecca Richmond; Robert A. Scott; Mark E.S. Bailey; Kathrin Scheuermann; John W. Holloway; Hazel Inskip; Carmen R. Isasi; Yasmin Mossavar-Rahmani; Vincent W.V. Jaddoe; Jaana Laitinen; Virpi Lindi; Erik Melén; Yannis Pitsiladis; Niina Pitkänen; Harold Snieder; Joachim Heinrich; Nicholas J. Timpson; Tao Wang; Hinoda Yuji; Eleftheria Zeggini; George V. Dedoussis; Robert C. Kaplan; Judith Wylie-Rosett; Ruth J.F. Loos; Frank B. Hu; Lu Qi

Disclosures

Diabetes. 2015;64(7):2467-2476. 

In This Article

Discussion

We confirmed the association between an index SNP in the FTO gene, rs9939609 (or its proxy), and BMI in white children and adolescents and in all participants combined, but did not detect significant association in African American or Asian children and adolescents. This might be due to the relatively small sample size used by studies of African Americans or Asians included in the current analysis and/or to different linkage disequilibrium patterns across FTO intron 1 between different ethnic groups, particularly in populations of African ancestry.[4,51] Other index SNPs within FTO locus might be needed in future studies of African American children and adolescents.

Although studies of FTO association with dietary intake in adults have been more numerous and often better powered with larger sample sizes than similar studies conducted in children and adolescents, the reported results have been inconsistent.[16–20,25–34] Our and other studies even observed an inverse association between FTO variant and total energy intake in adults, which might be partly due to under-reporting of total energy intake among individuals with a higher BMI.[19,20,39] In the current analysis, we demonstrated an association between the BMI-increasing allele of the FTO variant and higher total energy intake. However, we did not observe a significant association between FTO variants and percentages of energy derived from protein, which has been observed in adults,[39] or other macronutrients.

An apparently stronger, and more consistently reported, effect of FTO on total energy intake in children and adolescents could have several explanations. The influence of social desirability bias and the under-reporting issues are smaller in children than in adults.[52–54] It is possible that the effect of FTO variation on appetite may be stronger in children and adolescents than in adults. Consistent with this hypothesis and with the idea that FTO genetic effects might vary over the life course, previous studies[49,55–60] have reported an increasing effect of FTO variants on BMI from early childhood to adolescence, with a subsequently decreasing effect throughout adulthood. Our result is also consistent with this, as we observed a stronger association between FTO variant and total energy intake in studies of older children than in studies of younger children.

Several lines of evidence from animal and in vitro studies are consistent with the observed association between FTO variant and total energy intake in humans. It has been reported that overexpression of Fto in mice led to increased food intake,[5] and Fto expression in hypothalamus was regulated by feeding, fasting, and energy restriction.[61–67] Further studies showed that glucose and amino acid deprivation decreases Fto expression, suggesting a role of FTO in cellular nutrient sensing,[68,69] possibly acting via hypothalamic mammalian target of rapamycin pathways known to regulate food intake.[70] A recent study[71] suggested a link among FTO, ghrelin (a key mediator of ingestive behavior), and impaired brain food-cue responsivity in both animals and humans. Interestingly, a recent study[9] has challenged the established view of FTO as the major gene associated with BMI and risk of obesity, reporting that the region of FTO intron 1 harboring the BMI-associated variants are strongly associated with IRX3 gene (500 kbp downstream of FTO intron 1) expression in cerebellar brain samples. However, it has been pointed out that the cerebellum is not primarily involved in food intake or appetite regulation and FTO expression may function in a site-dependent manner.[72] In addition, another study[10] suggested that RPGRIP1L, located >100 bp 5' in the opposite transcriptional orientation of FTO, may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.

One novel finding of our study is the interaction between the FTO variant and dietary protein intake on BMI. The effect size of FTO variant on BMI in children with a low–protein intake was much smaller than in children with a high–protein intake, suggesting that low–protein intake may attenuate the influence of FTO variation on BMI. A study of 354 Spanish children and adolescents reported a significant interaction between the FTO-rs9939609 variant and dietary saturated fat intake on BMI,[38] and several adult studies also found interactions between the FTO variant and total fat or saturated fat intake on BMI and obesity risk,[20,26,34] while no significant interaction between the FTO variant and dietary intake was observed in our meta-analysis of adult data.[39] In addition, we previously found that dietary protein intake might modify the effects of FTO variants on changes in body composition, fat distribution, and appetite in a 2-year weight-loss trial.[73,74] A recent mouse study[6] showed that loss of Fto gene altered protein utilization and body composition; and consistently, other studies[68,69] also suggest that FTO may influence body composition through cellular sensing of amino acids. Given the increasing evidence supporting the role of FTO in protein metabolism and body composition, future investigations on this topic might help to clarify the mechanisms underlying the observed interaction between the FTO variant and protein intake, and its effect on BMI.

Major strengths of our study include a large sample size of >16,000 children and adolescents from 14 studies, a wide range of studies with data from early childhood to late adolescence, and the standardized analytical plan across studies. There are some limitations in our study. Our analysis was conducted based on cross-sectional data. Measurement errors in dietary assessment are inevitable since self-reported data on dietary intake are all subject to bias. We only included dietary data on total energy and macronutrient intake, but no data on specific foods or more specific types of fatty acids or micronutrients, which may potentially interact with the FTO variant as suggested previously.[26,34,38] We were unable to examine other adiposity proxies, but were limited to the consideration of BMI, which cannot distinguish body composition and does not give any indication about body fat distribution. To the best of our knowledge, this is to date the largest analysis of FTO variant and dietary intake in children and adolescents, though more data are needed to further confirm our results. In particular, most of the children and adolescents included in our analysis are individuals of European ancestry (95% of all samples), and it is unknown whether our results can be generalized to other ethnic groups.

In summary, we demonstrated an association between the BMI-increasing allele of FTO variant and total energy intake based on data from 16,094 children and adolescents. Our data also show that dietary protein intake may modify the influence of FTO variants on BMI, offering new insight into the interrelationships between FTO genetic variants, dietary intake, and obesity.

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