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Review Article
Macronutrients and the FTO gene expression in hypothalamus; a
systematic review of experimental studies
Saeid Doaei
a
, Naser Kalantari
b
, Nastaran Keshavarz Mohammadi
c
,
Ghasem Azizi Tabesh
d
, Maryam Gholamalizadeh
e,
*
a
Student’s Research Committee, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid
Beheshti University of Medical Sciences, Tehran, Iran
b
Department of Community Nutrition, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
c
Department of Public Health, Faculty of Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
d
Department of Human Genetics, Faculty of Human Genetics, Tehran University of Medical Sciences, Tehran, Iran
e
Student’s Research Committee, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
ARTICLE INFO
Article history:
Received 28 May 2016
Accepted 17 January 2017
Available online 24 January 2017
Keywords:
Obesity
Gene expression
FTO
Macronutrients
ABSTRACT
The various studies have examined the relationship between FTO gene expression and macronutrients
levels. In order to obtain better viewpoint from this interactions, all of existing studies were reviewed
systematically. All published papers have been obtained and reviewed using standard and sensitive
keywords from databases such as CINAHL, Embase, PubMed, PsycInfo, and the Cochrane, from 1990 to
2016. The results indicated that all of 6 studies that met the inclusion criteria (from a total of 428
published article) found FTO gene expression changes at short-term follow-ups. Four of six studies found
an increased FTO gene expression after calorie restriction, while two of them indicated decreased FTO
gene expression. The effect of protein, carbohydrate and fat were separately assessed and suggested by all
of six studies. In Conclusion, The level of FTO gene expression in hypothalamus is related to
macronutrients levels. Future research should evaluate the long-term impact of dietary interventions.
© 2017 Published by Elsevier B.V. on behalf of Cardiological Society of India. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents
1. Introduction . . .................................................................................................... 278
2. Methodology . .................................................................................................... 278
2.1. Data sources ................................................................................................ 278
2.2. Data extraction . . . ........................................................................................... 278
2.3. Outcome variables ........................................................................................... 278
2.4. Intervention components ...................................................................................... 279
2.5. Assessment of methodological rigor ............................................................................. 279
3. Results . . ........................................................................................................ 279
3.1. Components of effective interventions . . ......................................................................... 279
3.2. Effect of calorie restriction . . . .................................................................................. 279
3.3. Effect of increased dietary fat .................................................................................. 279
3.4. Effect of amino acids . . ....................................................................................... 279
3.5. Effect of carbohydrates . ....................................................................................... 279
4. Discussion ........................................................................................................ 280
Disclosure ........................................................................................................ 280
References . . . .................................................................................................... 280
* Corresponding author.
E-mail address: mgholamalizadeh84@yahoo.com (M. Gholamalizadeh).
http://dx.doi.org/10.1016/j.ihj.2017.01.014
0019-4832/© 2017 Published by Elsevier B.V. on behalf of CardiologicalSociety of India. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
Indian Heart Journal 69 (2017) 277–281
Contents lists available at ScienceDirect
Indian Heart Journal
journal homepage: www.elsevier.com/locate/ihj
1. Introduction
Obesity is a major public health challenge worldwide in 21
century.
1
Obesity has important role in a large number of diseases,
including coronary heart disease, type 2 diabetes, cancer,
hypertension, dyslipidemia and stroke.
2–5
The prevalence rates
of overweight and Obesity are worriedly increasing in the
worldwide. More than 12% of the adult population are obese.
6
Obese adolescents were reached from 5% to 21% from 1980 to
2012.
7
The role of various factors in the formation and progression of
obesity has been shown. Genetics, life style and environmental
factors are the most important factors that have been associated
with obesity.
8
Numerous studies have reported that unhealthy
lifestyle including low physical activity and poor nutrition are the
main cause of obesity
9–13
and, therefore, suggested lifestyle
changes as strategies to prevent and combat obesity.
14–19
On the
other hand it has also been noticed that even with lifestyle
changes, the success rate in reducing obesity is not always
satisfactory.
20
Here the role of genetics in obesity is highlighted as
an explanation to this dilemma. The results of recent studies in the
field of nutritional genomics create uncertainties in understanding
the role and importance of lifestyle in occurring obesity and/or
decrease imagined role of the lifestyle in obesity.
Severalstudies have exploredthe interactions betweengenomics
and diet and its relationship with hyperlipidemia and
hypertension.
21–25
Recentstudies in the field of nutritional genomics
have demonstrated that geneticbackground plays an important role
not only in probability of occurring obesity but also in people's
response to the lifestyle intervention.
26–34
Several genes have been
studied in relationto obesity, whichone of the most important genes
is FTO (Fat mass and obesity-associated protein).
FTO gene expression is associated with regulation of foodintake
and energy balance.
35–41
Also recent studies have tried to explore
the interaction of dietary components with FTO gene expression in
hypothalamus. As there is no systematic review on these studies,
this study aims to fill this gap and contribute to better
understanding of the interaction of dietary components and FTO
gene expression.
2. Methodology
2.1. Data sources
This systematic review was conducted and reported in
accordance with the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses guidelines that have been used for
other gene expression-related systematic reviews.
42
The search
covered all available research from January 1990 to January 2016 in
CINAHL, Embase, PubMed, PsycINFO, and the Cochrane Library. The
bibliographies of included articles were hand-searched, and
promising titles were reviewed in order to locate articles not
catalogued in the major databases. In cases that reviewer was
unable to determine whether an article pertained to the study by
title, the abstract was reviewed. The search terms used were (Body
Mass Index OR Body Weight OR Obesity OR Overweight OR obese
OR FTO gene OR FTO gene expression OR hypothalamus OR diet OR
dietary component OR calorie OR calorie restriction OR protein OR
carbohydrate OR fat OR macronutrient.
This systematic review compares randomized controlled trials
studies that utilized dietary interventions including dietary
macronutrients modifications as interventions to change the level
of FTO gene expression. This review involves assessing dietary
interventions delivered through changes in macronutrients levels
to influence on FTO gene expression. Inclusion criteria consisted of:
randomized trials or trials without randomization or a control
group; a primary outcome including FTO gene expression; trials
that tested dietary interventions (through diet modification) and
subjects included rats and mice. Papers were excluded if the
articles were published in a language other than English.
2.2. Data extraction
The studies focused primarily on changes in calorie,
36–39
fat,
37,40
amino acid (Leucine),
36,41
and carbohydrate (Sucrose)
intake or administration.
37,39
2.3. Outcome variables
The initial search generated a total of 428 papers from all the
search databases. To obtain rigorous scientific evidence, only
randomized controlled trials studies were selected for this
systematic review in terms of key outcomes and interventions
used. One reviewer screened the study title and abstract as the first
screening stage and narrowed the articles to 334 papers. Two
reviewers then reviewed the abstract and narrowed the search
from 334 articles to 85 articles by eliminating duplicate papers
based on the same research. Articles that were nonintervention
studies, such as review papers, and cross-sectional studies were
also excluded. The primary outcome was change of FTO gene
expression with the use of macronutrients. Studies that did not
target FTO gene expression and were not macronutrients-based
Table 1
Methodological rigor of included studies.
Reference Randomization Blinding Inclusion/exclusion
criteria clearly
described
Adequate sample
sizecalculationsshown
Adequate
control
group*
Standard
measures
described
Comparison of baseline
parameters of completers
versusnoncompleters
80%
retention
rate**
MR
score
Gutierrez-
Aguilar
et al.
41
001 1 111 16
Olszewski
et al.
37
001 1 111 16
Boender
et al.
38
001 1 111 16
Johansson
et al.
42
101 1 111 17
Fredriksson
et al.
39
101 1 111 17
Poritsano
et al.
40
101 1 111 17
Notes: *Control group was reflective of study group in number, age and sex; **80% of participants completed the intervention.
Abbreviations: MR: methodological rigor.
278 S. Doaei et al. / Indian Heart Journal 69 (2017) 277–281
were excluded. Based on the inclusion criteria, two reviewers
examined the full papers and identified 6 studies that met the
inclusion criteria (see Table 1).
2.4. Intervention components
Detailed examination of the following components of effective
interventions was conducted: macronutrient intake or adminis-
tration, method used for intake/administration changes, subjects,
and duration of the intervention. The effectiveness of the
intervention was determined by reviewing the results of the
study and reporting the study findings.
2.5. Assessment of methodological rigor
Methodological rigor assessment was adapted to include
articles from those in use by the Cochrane Effective Practice and
Organization of Care Review Group and recent systematic
reviews.
42
The eight criteria were scored objectively using
published data and reflect potential bias (see Table 1). Studies
were rated independently by two reviewers. Each item was rated
as “yes”(1), “no”(0), or “not applicable”. A total methodological
quality score (ranging from 0 to 8) was calculated by summing up
all “yes”items. Studies were rated as having good methodological
quality if they met at least 75% of the criteria (six of eight items).
3. Results
3.1. Components of effective interventions
Two protein-based interventions, two fat-based interventions
and two carbohydrate-based interventions were included in this
systematic review. All of 6 studies indicated the effectiveness of
macronutrients on FTO gene expression.
3.2. Effect of calorie restriction
Four of six studies found that macronutrients intake decreased
FTO gene expression (36, 37, 38 and 40) and two study reported
that 48-h food deprivation had reduced FTO gene expression (39
and 41).
3.3. Effect of increased dietary fat
Two of the six studies that examined the impact of increased
dietary fat found reduced FTO gene expression after interven-
tion.
38,41
For instance, a study by Gutierrez-Aguilar et al.
40
on
tailored high fat diet interventions for Wistar male rats found a
significant decrease in FTO gene expression at 6 weeks post
intervention. Although, Boender et al. reported a non-significant
reduction of FTO expression after 8-day high-fat diet.
37
3.4. Effect of amino acids
Two studies assessed the impact of amino acid (ie, Leucine) on
gene expression outcome.
36,41
Olszewski et al. found that
anorexigenic Leucine had reduced FTO gene expression in
organotypic cultures of the hypothalamus at 48 h post interven-
tion.
36
While Johansson et al. found that Leucine intake had
increased FTO gene expression at 48 h post intervention.
41
3.5. Effect of carbohydrates
Two studies assessed the impact of carbohydrate administra-
tion on gene expression outcome. Poritsano et al.
39
found that
increased glucose administration had increased FTO gene expres-
sion at 48 h post intervention. While Boender et al.
37
reported that
increased sucrose intake had insignificantly reduced FTO gene
expression at 8 days post intervention. Also, Olszewski et al. found
Table 2
Summary of Study description.
Reference Study design Sample
characteristic
Intervention/control/
components
Intervention
duration
Results
Dietary fat
Gutierrez-
Aguilar
et al.
40
Experimental 30 rats
(15 animals per
group)
Group 1) High fat diet
Group 2) normal diet
6 weeks FTO gene expression was reduced in the high fat group
Boender
et al.
37
Experimental 24 rats
(12 rats per
group)
Group 1) High fat and
high sucrose diet
Group 2) restricted
feeding
Group 3) Normal diet
8 days FTO gene expression was increased in restricted feeding group
Amino acids
Olszewski
et al.
36
Experimental 14 mice
(7 animals per
group)
Group 3) 48-h
supplemented with
leucine
Group 4) Control
48-h FTO gene expression was reduced in Leucine added group
Johansson
et al.
41
Experimental 16 mice
(8 mice per
group)
Group 1) leucine-spiked
water
Group 2) Water alone
48-h FTO gene expression was increased in the intervention group
Calorie restriction
Olszewski
et al.36
Experimental 16 mice
(8 animals per
group)
Group 1) High calorie
diet
Group 2) 16-h fasting
16-h FTO gene expression was increased in 48-h fasting group
Fredriksson
et al.
38
Experimental 24 rats
(eight animals
per group)
Group 1) Low calorie diet
Group 2) Food-deprived
Group 2) Normal diet
48-h Expression of the FTO gene is up-regulated during starvation
Glucose
Poritsano
et al.
39
Experimental 6–10 mice per
group
Group 1) Low calorie diet
And Glucose
administration
Group 2) Normal diet
Group 3) Low calorie diet
48-h FTO gene expression was reduced after low calorie diet and increased after
Glucose administration in the intervention group
S. Doaei et al. / Indian Heart Journal 69 (2017) 277–281 279
no changes in hypothalamic FTO expression after a 48-h palatable
sucrose feeding (Table 2).
36
4. Discussion
The present systematic review investigates the potential impact
of dietary components (such as protein, carbohydrate and fat) on
FTO gene expression. Based on this review of 6 intervention
studies, there is some evidence that suggest the possibility that
macronutrients affect hypothalamic FTO expression. Also most of
studies (4 of 6 studies) indicated that higher macronutrients levels
can decrease FTO gene expression (36, 37, 38 and 40) and two
studies reported decrease FTO gene (39 and 41).
There is no clear evidence about the reason of existing
contradiction between short-term and long-term effects of
macronutrients on FTO gene expression. But it may depends on
the wide range of FTO gene roles in hypothalamus.
43–50
The recent
studies reported that FTO has a role in macronutrients
metabolism.
43–45
For instance, a study by Gulati et al.
45
found
an important role of FTO in matching cellular amino acids levels
with mammalian target of rapamycin complex 1 (mTORC1)
signaling. On the other hand, many studies found that FTO gene
polymorphisms had a critical role in FTO gene expression level and
its effects on obesity.
46,47
Although other studies reported that FTO
gene polymorphisms weren’t linked with FTO gene expres-
sion.
48,49
The literature currently available is also insufficient to
examine the impact of wide range of polymorphisms on FTO gene
expression.
This review suggests that both the level of calorie and the level
of each macronutrients have a potential to change FTO gene
expression level. Because of the variation in duration of interven-
tion (48-h to 6 weeks), it is not clear what length of intervention is
most effective. Only one study included long-term follow-up data
(more than 48-h intervention),
40
and there is no enough evidence
on the optimal FTO gene expression with regard to healthy weight
management.
The present review emphasize on the possibility that changes in
macronutrients levels affect hypothalamic FTO expression and
thereby affect regulation of appetite and body weight. We need
further investigation of the relationship between macronutrients
and hypothalamic FTO expression in future research.
These type of studies may contribute to determining ways in
which nutrition specialists and researchers can make more
informed decisions about which types of macronutrients and diet
are most suitable in achieving sustainable weight reduction via
impact the level of FTO gene expression. Although it was not found
any clear evidence of an exacteffect of dietary interventions on FTO
gene expression, the use of dietary modifications have the
potential to assist researchers in dealing with the obesity epidemic.
Future research should include mediating factors associated with
the impact of dietary intervention on FTO gene expression, and
should also include more long-term follow-up. In addition,
assessment of FTO gene expression related health outcomes, such
as obesity and Diabetes should be included in future research.
Disclosure
The authors report no conflicts of interest in this work.
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