The FTO gene rs9939609 obesity-risk allele and loss of control over eating.
ABSTRACT Children with rs9939609 FTO variant alleles (homozygous = AA and heterozygous = AT) are predisposed to greater adiposity than are those with 2 wild-type alleles (TT).
Because FTO is highly expressed in hypothalamic regions that are important for appetite, FTO genotype may affect energy balance by influencing eating behavior. Loss of control (LOC) eating, a behavior commonly reported by overweight youth, predicts excessive weight gain in children. However, the relation between FTO genotype and LOC eating has not been previously examined.
Two-hundred eighty-nine youth aged 6-19 y were genotyped for rs9939609, underwent body-composition measurements, and were interviewed to determine the presence or absence of LOC eating. A subset (n = 190) participated in a lunch buffet test meal designed to model an LOC eating episode. Subjects with AA and AT genotypes were grouped together for comparison with wild-type TT subjects.
Subjects with at least one A allele (67.7%) had significantly greater body mass indexes, body mass index z scores (P < 0.01), and fat mass (P < 0.05). Of the AA/AT subjects, 34.7% reported LOC compared with 18.2% of the TT subjects (P = 0.002). Although total energy intake at the test meal did not differ significantly by genotype (P = 0.61), AA/AT subjects consumed a greater percentage of energy from fat than did the TT subjects (P < 0.01).
Children and adolescents with 1 or 2 FTO rs9939609 obesity-risk alleles report more frequent LOC eating episodes and select foods higher in fat at a buffet meal. Both LOC eating and more frequent selection of energy-dense, palatable foods may be mechanisms through which variant FTO alleles lead to excess body weight.
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ABSTRACT: Background: The fat mass and obesity-associated (FTO) single nucleotide polymorphisms (SNPs; rs1421085, rs17817449, rs9939609, rs8050136) and macronutrient intake (carbohydrate, protein, fat, total calories) are associated with body mass index (BMI). However, the mechanism for this relationship has not been fully elucidated. Objective: This study examined whether macronutrient intake mediates the association between FTO SNPs and BMI. Design: Baseline cross-sectional data from the Atherosclerosis Risk in Communities (ARIC) study of whites (n = 10,176) and African Americans (n = 3641) aged 45 to 64 years were analyzed. Results: In linear regression models with BMI as the dependent variable, FTO SNPs were significantly associated with higher BMI after adjusting for covariates. The addition of energy-adjusted macronutrients attenuated the FTO effect estimates, indicating partial mediation. In whites, β ranged from 0.40 (95% confidence interval [CI], 0.20, 0.60) for rs17817449 heterozygous carriers to 0.93 (95% CI, 0.64, 122) for rs8050136 homozygous carriers; for African Americans rs17817449 homozygous carriers β was 0.65 (95% CI, 0.03, 1.27). In models with macronutrient intake as the dependent variable, all FTO SNPs were associated with higher protein intake for homozygous carriers after adjusting for BMI and other covariates. Among whites, β ranged from 1.44 (95% CI, 0.51, 2.37) for rs8050136 to 1.73 (95% CI, 0.85, 2.61) for rs17817449; among African American rs8050136 homozygous carriers β was 2.46 (95% CI, 0.77, 4.14). In mediation analysis, in whites only, FTO high-risk alleles were associated with higher BMI partly through their small effects on carbohydrate and protein intake. Conclusions: These findings suggest that in adults, the relationship between FTO variants and BMI is not primarily through mediation of food intake.Journal of the American College of Nutrition 08/2014; · 1.68 Impact Factor
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ABSTRACT: FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake, and body mass index (BMI) are complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154,439 whites, 5,776 African Americans, and 17,115 Asians) from 40 studies to examine: 1) the association between the FTO-rs9939609 variant (or a proxy SNP) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in whites (effect per allele =0.34 [0.31, 0.37] kg/m(2), P=1.9×10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P=3.6×10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele =0.08[0.06, 0.10]%, P=2.4×10(-16)), and relative weak associations with lower total energy intake (-6.4[-10.1, -2.6] kcal/day, P=0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02]%, P=0.004). The associations with protein (P=7.5×10(-9)) and total energy (P =0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate, or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.Human Molecular Genetics 08/2014; · 6.68 Impact Factor
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ABSTRACT: The fat mass and obesity-associated (FTO) gene is currently recognized as the most robust predictor of polygenic obesity. We investigated associations between the FTO rs1421085 and rs17817449 polymorphisms and the FTO rs1421085-rs17817449 haplotype and dietary intake, eating behavior, physical activity, and psychological health, as well as the effect of these associations on BMI. N = 133 treatment seeking overweight/obese Caucasian adults participated in this study. Genotyping was performed from whole blood samples. Weight and height was measured and a non-quantified food frequency questionnaire was completed to assess food group intake. Validated questionnaires were completed to assess physical activity (Baecke questionnaire), psychological health (General Health questionnaire, Rosenburg self-esteem scale and Beck Depression Inventory), and eating behavior (Three Factor Eating questionnaire). The risk alleles of the FTO polymorphisms were associated with poorer eating behaviors (higher hunger, internal locus for hunger, and emotional disinhibition scores), a higher intake of high fat foods and refined starches and more depressive symptoms. The modeled results indicate that interactions between the FTO polymorphisms or haplotypes and eating behavior, psychological health, and physical activity levels may be associated with BMI. The clinical significance of these results for implementation as part of weight management interventions needs further investigation.Nutrients 08/2014; 6(8):3130-3152. · 3.15 Impact Factor
The FTO gene rs9939609 obesity-risk allele and loss of control over
Marian Tanofsky-Kraff, Joan C Han, Kavitha Anandalingam, Lauren B Shomaker, Kelli M Columbo, Laura E Wolkoff,
Merel Kozlosky, Camden Elliott, Lisa M Ranzenhofer, Caroline A Roza, Susan Z Yanovski, and Jack A Yanovski
Background: Children with rs9939609 FTO variant alleles (homo-
zygous = AA and heterozygous = AT) are predisposed to greater
adiposity than are those with 2 wild-type alleles (TT).
Objective: Because FTO is highly expressed in hypothalamic re-
gions that are important for appetite, FTO genotype may affect
energy balance by influencing eating behavior. Loss of control
(LOC) eating, a behavior commonly reported by overweight youth,
predicts excessive weight gain in children. However, the relation
between FTO genotype and LOC eating has not been previously
Design: Two-hundred eighty-nine youth aged 6–19 y were geno-
typed for rs9939609, underwent body-composition measurements,
and were interviewed to determine the presence or absence of LOC
eating. A subset (n = 190) participated in a lunch buffet test meal
designed to model an LOC eating episode. Subjects with AA and AT
genotypes were grouped together for comparison with wild-type TT
Results: Subjects with at least one A allele (67.7%) had signifi-
cantly greater body mass indexes, body mass index z scores (P ,
0.01), and fat mass (P , 0.05). Of the AA/AT subjects, 34.7%
reported LOC compared with 18.2% of the TT subjects (P =
0.002). Although total energy intake at the test meal did not differ
significantly by genotype (P = 0.61), AA/AT subjects consumed
a greater percentage of energy from fat than did the TT subjects
(P , 0.01).
Conclusions: Children and adolescents with 1 or 2 FTO rs9939609
obesity-risk alleles report more frequent LOC eating episodes and
select foods higher in fat at a buffet meal. Both LOC eating and
more frequent selection of energy-dense, palatable foods may be
mechanisms through which variant FTO alleles lead to excess body
weight. Am J Clin Nutr 2009;90:1483–8.
Association studies have shown that common single nucleo-
tide polymorphisms (SNPs) in the first intron of the FTO (fat
mass and obesity–associated) gene (16q12.2) are consistently
associated with higher body mass index (BMI; in kg/m2) and
adiposity in both children and adults (1–5). However, the
mechanisms by which these FTO locus risk alleles affect the
development of obesity are not well understood. Rodent studies
indicate that FTO mRNA is highly expressed in brain areas
important for regulation of energy- and reward-driven con-
sumption (6, 7). Hypothalamic expression of FTO and another
nearby coregulated gene, Ftm, has been found to be affected by
energy intake (7). Food deprivation increases FTO expression in
the mouse hypothalamus (6, 7), consistent with the hypothesis
that genes at the FTO locus play a role in governing eating
behavior. Preliminary data suggest a link between FTO and
eating behavior in humans. Children and adults with at least one
rs9939609 FTO obesity-risk allele (homozygous = AA and
heterozygous = AT) were found to report greater energy intake,
on average, than youth with 2 wild-type alleles (TT) (8, 9). Two
small studies, one of 4–5-y-old children and another of 4–10-y-
old children, have suggested that rs9939609 AA/AT children
may eat more at laboratory meals than do TT children (10, 11).
Taken together, these studies further bolster the possibility that
energy intake plays a significant role in the relation between
FTO and body weight. However, specific eating behavior phe-
notypes associated with this genetic polymorphism have not yet
been identified. One compelling possibility is that high-risk
variants in FTO exert their influence on obesity via their effect
on eating behaviors that promote excessive weight gain.
Binge-eating episodes, defined as discrete time periods during
which the consumption of a large amount offood is accompanied
1From the Unit on Growth and Obesity, Program on Developmental En-
docrinology and Genetics, Eunice Kennedy Shriver National Institute of
Child Health and Human Development, National Institutes of Health, De-
partment of Health and Human Services, Bethesda, MD (MT-K, JCH, KA,
LBS, KMC, LEW, CE, LMR, CAR, and JAY); Uniformed Services Univer-
sity of the Health Sciences, Bethesda, MD (MT-K, LBS, KMC, LEW, CE,
and LMR); the Nutrition Department, Clinical Center, National Institutes of
Health, Bethesda, MD (MK); and the Division of Digestive Diseases and
Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Department of Health and Human Services
2MT-K and JCH contributed equally to this work.
3The opinions and assertions expressed herein are those of the authors
and are not to be construed as reflecting the views of the Uniformed Services
University of the Health Sciences or the US Department of Defense.
4Supported by the Intramural Research Program, National Institute of
Child Health, National Institutes of Health (grant Z01-HD-00641 to JAY),
and supplemental funding from NCMHD (to JAY) and the Uniformed Serv-
ices University of the Health Sciences (grant R072IC to MTK).
5Address correspondence to JA Yanovski, Unit on Growth and Obesity,
PDEGEN, NICHD, National Institutes of Health, 10 Center Drive, Hatfield
Clinical Research Center, Room 1-3330, MSC 1103, Bethesda, MD 20892-
1103. E-mail: firstname.lastname@example.org.
Received July 24, 2009. Accepted for publication September 22, 2009.
First published online October 14, 2009; doi: 10.3945/ajcn.2009.28439.
Am J Clin Nutr 2009;90:1483–8. Printed in USA. ? 2009 American Society for Nutrition
by a sense of loss of control (LOC) over eating (12), are common
of LOC while eating, regardless of whether the reported amount
of food consumed is unambiguously large—is common in youth
(13). The term LOC eating therefore encompasses both binge
episodes as well as eating episodes during which the amount of
food consumed may not be unambiguously large. Most of the
literature on pediatric LOC eating describes children who report
at least one episode in the month before assessment (13). LOC
eating in children is associated with overweight and high body
fat mass (13). Both reported binge (14–16) and LOC (17) eating
in youth predict excessive body weight gain in longitudinal
studies of children and adolescents. One study has suggested that
young, overweight children who self-report binge-eating epi-
sodes consume more energy than do those without such be-
haviors at laboratory test meals (18). A second laboratory meal
study, performed in a sample of nonoverweight and overweight
children and adolescents, found that those who reported LOC
eating consumed more energy from carbohydrate and less en-
ergy from protein than did those without LOC eating (19).
To our knowledge,no study has examined therelation between
the FTO rs9939609 obesity risk allele and LOC eating. We
therefore genotyped children
rs9939609 and conducted interviews to determine the presence
or absence of LOC eating episodes. We hypothesized that LOC
eating would be reported more frequently among children with
rs9939609 AA and AT alleles than among those with TT. In
addition, a subset of these children participated in a standardized
buffet meal in the laboratory. On the basis of extant literature
(8–11), we hypothesized that those with at least one obesity risk
allele would consume more energy than would those without
FTO variant alleles.
SUBJECTS AND METHODS
Children and adolescents aged 6–19 y who were participat-
ing in nonintervention metabolic protocols (clinicaltrials.gov:
to assess associations between genotype, body composition, and
the presence or absence of LOC eating. Those participating in
one protocol (NCT00320177) had also been tested with a labo-
ratory buffet meal paradigm intended to assess energy intake at
a “binge” meal. By design, youth were enriched for overweight
(BMI ?95th percentile for age and sex) (20). Participants were
recruited through posted flyers, mailings to local family physi-
cians and pediatricians, and mailings to parents in Montgomery
County and Prince George’s County, MD, school districts re-
questing children willing to participate in studies investigating
hormones and growth in youth. Individuals were excluded if
they had a significant medical condition, were taking medication
known to affect body weight, had a psychiatric disorder that
might impede protocol compliance, or had abnormal hepatic,
renal, or thyroid function. Pregnant girls were not eligible for the
study, nor were children who had lost .5 lb (2.3 kg) in the past
3 mo or who were undergoing weight-loss treatment. The in-
stitutional review board of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development approved the
clinical protocols. After a complete description of the study was
given to children and their parents, written informed assent and
consent for their participation and genetic analyses were ob-
tained. Data collection took place between July 1996 and Feb-
All children were screened for eligibility after fasting over-
night. Each participant’s weight and height were measured by
using calibrated electronic instruments as described previously
(21). BMI was calculated as weight (in kg) divided by the square
of height (in m). BMI SD scores (BMI z scores) were calculated
according to the Centers for Disease Control and Prevention
2000 growth charts (22). Body composition was measured as
previously described (21, 23) by using air-displacement pleth-
ysmography (Life Measurement Inc, Concord, CA) to determine
fat-free mass and fat mass. All participants underwent a medical
history and a physical examination performed by an endocri-
nologist or a trained nurse practitioner.
Each child supplied a whole blood sample from which ge-
nomic DNAwas isolated by using the QIAamp DNA Blood Maxi
Kit (QIAGEN Inc, Valencia, CA) or by a commercial company
(Lofstrand Laboratories Ltd, Gaithersburg, MD). Genotyping of
the FTO SNP rs9939609 was performed by using a TaqMan
SNP Genotyping Assay (Applied Biosystems Inc, Foster City,
CA). All assays were performed in duplicate, and an automatic
allele calling quality value of 0.95 was used to determine ge-
notype assignment. Subjects with indeterminate results with the
TaqMan assay were genotyped by direct sequencing of the
polymerase chain reaction amplicon containing the rs9939609
CTATGGTTCTACAGTTCCAGTCATTT-3# and reverse primer
Loss of control eating
The Eating Disorder Examination version 12OD/C.2 (EDE)
(24) or the EDE adapted for children (25) was administered to
each participant to determine the presence or absence of LOC
eating as described previously (26, 27). The EDE has good in-
terrater reliability for all episode types (Spearman correlation
coefficients: ?0.70) (28). Tests of the EDE adapted for children
have also shown good interrater reliability (Spearman rank
correlations from 0.91 to 1.00) and discriminant validity in
eating disordered samples and matched control subjects aged 8–
14 y (29). In the nonoverweight and overweight 6–13-y-olds
studied in our laboratory, the child version of the EDE showed
excellent interrater reliability with a Cohen’s j for presence of
the different eating episode categories of 1.00 (P , 0.001) (26).
Buffet test meal
During a screening visit, participants were acclimated to the
laboratory food intake setting by consuming a high-calorie shake
(787 kcal, 52% carbohydrate, 11% protein, and 37% fat). Those
unable to consume at least one-half of the shake under these
conditionswere considered unable toacclimate andwere deemed
ineligible. To ensure that participants found the foods offered at
TANOFSKY-KRAFF ET AL
the buffet test meal to be acceptable, participants completed
a food-preference questionnaire on which they rated how much
they liked 57 foods that children commonly consume (30) (in-
cluding the 28 foods offered on our buffet) using 10-point Likert
scales (31). If children disliked .50% of the foods offered on the
buffet, they were excluded from the study.
For the test meal, the experimental design was based on the
adult literature that has examined binge-eating behaviors in
a laboratory setting, where most studies used a prolonged dep-
the morning after an overnight fast and were provided with
astandard 280-kcal(74%carbohydrate, 7%protein, and 19%fat)
breakfast. Participants remained at the National Institutes of
Health Clinical Center for the next 6 h, during which they were
observed to ensure that they consumed no calorie-containing
items. Children were allowed to participate only in sedentary
activities. In the afternoon, children reported on their level of
hunger by completing a visual analog scale ranging from “not at
all” to “extremely” hungry. Each participant was then presented
with a multiple-item, 9835-kcal test meal buffet designed to
contain an array of palatable foods, as previously described (18).
To model a binge-eating episode, participants received pre-
recorded instructions to “Let yourself go, and eat as much as you
want,” and were given unrestricted time to consume their meal
any references to food and from which the commercials had been
removed. Subjects ate alone in a room free of food-containing
stimuli. All food items presented were weighed to the nearest 0.1
g before and after the test session. Nutrient intakes were cal-
culated by using data from the US Department of Agriculture
(USDA) National Nutrient Database for Standard Reference
(release 16; USDA, Agricultural Research Service) and manu-
facturer information, when available. After completion of the test
meal, the families left the National Institutes of Health, and no
further data were collected regarding children’s intake during the
rest of the day.
Data analytic plan
All analyses were performed with SPSS 16.0 (33). Loga-
rithmic transformations were made for total energy intake, and
arcsine transformations were conducted for the percentage of
macronutrient content (fat, protein, and carbohydrate) intake.
Departure of genotype distribution from Hardy-Weinberg equi-
librium was assessed by using chi-square analysis; t tests and chi-
square analyses were used to analyze participant demographics
based on genotype. Analyses of covariance (ANCOVA), ac-
counting for age, sex, and race, were used to examine the as-
sociation of FTO rs9939609 (AA/AT and TT) with BMI. The
same covariates in addition to height were considered in the
model examining body fat mass. Pearson’s chi-square tests and
binary logistic regression accounting for BMI z score were used
to examine associations between genotype and LOC eating
presence. ANCOVAs were used to examine total energy intake
(kcal) and percentages of energy intake from protein, carbohy-
drate, and fat based on genotype as well as the interaction of
genotype by LOC status. The interaction term was not signifi-
cant in any model; therefore, the data are not shown. Each model
included sex, age, race (coded non-Hispanic white and all other
racial-ethnic minorities), socioeconomic status (34) (coded into
2 categories based on the median split), fat-free mass, percent-
age fat mass as covariates, and the number of buffet foods re-
ported as acceptable. Reported means and SEs were adjusted for
all variables included in each model. Differences were consid-
ered significant when P values were ,0.05. All tests were 2-
Two-hundred eighty-nine children and adolescents were
genotyped. Fifty-three (18.3%) were homozygous for the obesity
risk allele (AA) for the FTO SNP rs9939609, 137 (47.4%) were
heterozygous (AT), and 99 (34.3%) were wild type (TT). The
overall frequency of the A allele was 0.43. Genotype frequencies
did not differ significantly (v2= 0.22, P = 0.90) from Hardy-
Weinberg equilibrium expectations (AA = 17.7%, AT = 48.7%,
and TT = 33.6%).
Participant demographics by genotype are shown in Table 1.
As has been done in prior studies, homozygous (AA) and het-
erozygous (AT) risk allele youth were grouped together (8, 9).
The presence of at least one copy of the A allele was associated
Demographic characteristics of the participants by genotype
TT (n = 99)AT or AA (n = 190)P value
Female sex (%)
Median socioeconomic status score
BMI z score
Fat mass (kg)
Fat-free mass (kg)
Hunger before meal2
Total energy intake (kcal)3
13.60 6 0.261
13.34 6 0.20
22.85 6 0.8
0.71 6 0.1
16.86 6 1.7
46.83 6 1.2
73.6 6 2.4
1448.8 6 104.5
25.87 6 0.6
1.2 6 0.1
21.40 6 1.2
45.70 6 0.8
72.5 6 1.7
1428.3 6 103.0
1Mean 6 SE (all such values).
2Hunger was rated on a visual analog scale ranging from 0 (“not at all”) to 100 (“extremely").
3Total energy intake was adjusted for covariates as described in Subjects and Methods.
FTO VARIANTS AND LOC EATING
with significantly higher BMI and BMI z scores (P , 0.01) and
adiposity (P , 0.05; Table 1).
FTO genotype in relation to reported LOC eating and
On the basis of their responses to the EDE interview, 84
children reported at least one episode of LOC eating in the month
before assessment. Of the TT group, only 18 (18.2%) children
reported LOC eating, compared with 66 (34.7%) children with
the FTO gene variant (v2= 8.65, Fisher’s exact P = 0.002).
Furthermore, even after the contribution of BMI z score was
accounted for, having at least one A allele was associated with
a nearly 2 times greater odds of describing LOC eating episodes
[B = 0.68, Wald statistic = 4.7, (Exp)B = 1.98, P = 0.029].
A subset of youth (n = 190) participated in the laboratory
buffet meal test. These children did not differ from the entire
sample with regard to any variable except age; children who
participated were somewhat younger than those who did not
participate (13.2 6 0.2 compared with 13.9 6 0.3; P = 0.03).
Once covariates such as fat-free mass (as described in Subjects
and Methods) were taken into account, children with (n = 128)
and without (n = 62) the FTO variant did not differ with regard
to the amount of energy consumed at the buffet binge meal
(Table 1). This finding persisted when total energy intake ex-
pressed as percentage of the participants’ daily energy require-
ments was examined (P = 0.40) (35). However, youth with at
least one A allele consumed a significantly greater percentage of
energy from fat than did the TT subjects (P = 0.008; Figure 1).
No difference was found for the percentage of energy consumed
from either protein or carbohydrate (Figure 1). No significant
group differences were noted in palatability ratings for foods
found in the buffet meal. After completion of the meal, per-
ceived fullness did not differ significantly between youth with
and without the A allele (P = 0.72).
In a sample of nontreatment children and adolescents, we
replicated prior findings that youth carrying at least one
rs9939609 FTO risk allele are heavier and have more adiposity
than children with no A alleles (1, 2). In addition, youth with
variant alleles were more likely to report episodes of LOC eating
than were children identified as wild type, even after the control
of BMI adjusted for age and sex. We also found that the pres-
ence of the FTO variant was associated with the consumption of
a greater percentage of energy from fat at a test meal buffet
designed to capture the experience of a binge or LOC eating
episode. No differences were identified between children with
and without the A allele with regard to total energy intake,
percentage of energy consumed from protein or carbohydrate, or
fullness after the meal.
The finding that children with at least one A allele are more
likely to report LOC eating is novel and may provide important
information regarding the mechanism of weight gain for some
children. This relation was significant even after the contribution
of BMI z score was accounted for; indeed, youth with the FTOA
allele were almost twice as likely as were those with the wild-
type allele to report LOC eating. To date, no study of the FTO
gene has identified a distinct, potentially modifiable behavioral
eating phenotype that is associated with the allele, although
contradictory data exist for the effect of the interaction between
FTO genotype and exercise on body weight (36–38).
The effect of FTO genetic variation on human energy ex-
penditure is somewhat unclear. Fischer et al (39) found that
inactivation of FTO in mice resulted in leanness due to increased
energy expenditure. In human samples, the data are mixed. No
human studies have found changes in resting energy expenditure
associated with FTO genotype (11, 40); however, 2 studies, one
making use of the doubly labeled water method in children (11)
and the second based on self-report data in adults (41), found
evidence of greater activity energy expenditure among those
with 1 or 2 A alleles. In contrast, a prospective study of youth
based on self-reported data found no association with energy
Our findings associating the presence of the A allele with LOC
eating may have important implications. Preliminary data sug-
gest that reducing binge and LOC eating may be effective for
both weight loss (43) and obesity prevention (44). Therefore,
modifying a reported eating behavior phenotype associated with
the FTO variant may offer promise for youth with this genetic
predisposition for excess body weight gain. An important next
research step should examine whether response to interventions
for binge and LOC eating is affected by rs9939609 genotype.
Contraryto expectations, childrenwiththepresence ofanFTO
variant did not consume more energy at a meal designed to
model an episode of binge or LOC eating. Although consistent
with one study that made use of food records (42), this finding is
in contrast with that of 2 relatively small studies that reported
that youth with the variant consumed more energy at laboratory
test meals (10, 11). However, the paradigm carried out in these
studies differed from the present analysis in that our participants
were given a standard breakfast and all were very hungry before
the test meal. Studies examining the relation between food
deprivation and disinhibited eating have yielded mixed results,
with some data supporting a relation (45, 46) and other research
finding no correlation (47, 48). As suggested by the data of
Wardle et al (10), children with the FTO variant may be more
susceptible to overeating in the absence of hunger rather than to
overeating when hungry. Indeed, experiencing LOC eating
would seem, at least in the latter parts of an eating episode, to
FIGURE 1. Macronutrient content of the test meal by genotype.
Participants with the AA or AT genotype consumed a significantly greater
percentage of energy from fat than did the participants with the TT genotype.
n = 190. **P , 0.008. Adjusted back-transformed arcsine percentage data
TANOFSKY-KRAFF ET AL
potentially predispose toward eating in the absence of hunger.
Interestingly, youth with A alleles consumed more energy from
fat at the laboratory test meal. This finding is particularly no-
table because children with and without the A allele did not
differ significantly in their reported palatability for the buffet
foods. If the observed style of eating promotes consumption of
more energy-dense foods outside of the laboratory setting, our
findings may help explain why youth with the FTO A allele are
heavier than TT children. Supporting these observations, greater
energy density consumption has been associated with the FTO
variant in children making use of a test meal paradigm (11) as
well as food records (8). However, a third study based on 3-d food
diaries found that dietary energy density was not modified by
FTO variants (49).
The strengths of this study include the use of a semistructured
clinical interview for the assessment of LOC eating and air-
displacement plethysmography to determine body composition.
In addition, the study involved a well-controlled laboratory meal,
and the inclusion of boys and girls who were not seeking weight-
loss treatment and who were of a broad age and weight range. A
primary limitation was that LOC eating was positively correlated
with increased body weight. Although the relation between LOC
eating and the A allele was significant even after the contribution
of BMI z score was accounted for, it is difficult to disentangle
whether such associations are causes or consequences of the
relation. Other limitations include that all participants were
provided the same standardized breakfast before the test meal,
regardless of body weight. It is possible that heavier youth re-
quired substantially more energy than what was provided for
breakfast to have equal satiety, thereby potentially masking
some differences between groups with regard to genotype.
However, we accounted for body composition in all analyses.
Furthermore, because all participants in our study were very
hungry when they were served the test meal, our paradigm may
not have captured the dysregulated eating potentially attribut-
able to the A allele. Although laboratory feeding studies have
been shown to illuminate behavioral differences in intake ef-
fectively (32), such paradigms may not fully capture eating
patterns observable in a naturalistic setting. Indeed, the use of
a large buffet and the instruction provided to the children may
have stimulated even restrained youth to overeat. Finally, having
children watch television while eating may have been a limita-
tion. Television viewing has been shown to increase food intake
even in those who are unrestrained, healthy eaters (50).
In conclusion, report of LOC eating is a behavioral phenotype
more frequently reported by children and adolescents with 1 or 2
FTO rs9939609 obesity risk alleles. Furthermore, children with
the A allele appear to have a preference for fat when offered
a variety of palatable foods at a buffet meal. Both LOC eating
and more frequent selection of energy-dense palatable foods
may be mechanisms through which variant FTO alleles lead to
excess body weight.
The authors’ responsibilities were as follows—MT-K, JCH, SZY, and JAY:
primarily responsible for developing the study design and conceived the hy-
pothesis for this article; MT-K, JCH, and JAY: supervised the data collection;
MT-K, JCH, LBS, and JAY: conducted the data analysis; and MK, KA, KMC,
LEW, CE, LMR, and CAR: contributed to data collection and provided crit-
ical input on data analyses and on versions of the manuscript. All authors
participated in the interpretation of the results and approved the final version
of the manuscript. JCH, JAY, and MK, are commissioned officers in the US
Public Health Service, Department of Health and Human Services. None of
the authors reported any conflicts of interest.
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