Dietary Fatty Acid Composition Modulates Obesity and Interacts with Obesity-Related Genes

Abstract

The prevalence of obesity is skyrocketing worldwide. The scientific evidence has associated obesity risk with many independent factors including the quality of dietary fat and genetics. Dietary fat exists as the main focus of dietary guidelines targeting obesity reduction. To prevent/minimize the adipogenic effect of dietary fatty acids (FA), intakes of long-chain saturated- and trans-FA should be reduced and substituted with unsaturated FA. The optimal proportions of dietary unsaturated FA are yet to be defined, along with a particular emphasis on the need to achieve a balanced ratio of n-3:n-6 polyunsaturated FA and to increase monounsaturated FA consumption at the expense of saturated FA. However, inter-individual variability in weight loss in response to a dietary intervention is evident, which highlights the importance of exploring gene-nutrient interactions that can further modulate the risk for obesity development. The quality of dietary fat was found to modulate obesity development by interacting with genes involved in fatty acid metabolism, adipogenesis, and the endocannabinoid system. This review summarizes the current knowledge on the effect of the quality of dietary fat on obesity phenotype and obesity-related genes. The evidence is not only supporting the modulatory effect of fat quality on obesity development but also presenting a number of interactions between obesity-related genes and the quality of dietary fat. The identified gene-FA interaction may have a clinical importance and holds a promise for the possibility of using genetically targeted dietary interventions to reduce obesity risk in the future.

Full text

Vol.:(0123456789)
Lipids (2017) 52:803–822
DOI 10.1007/s11745-017-4291-9
1 3
REVIEW ARTICLE
Dietary Fatty Acid Composition Modulates Obesity andInteracts
withObesity‑Related Genes
ShathaS.Hammad1,2· PeterJ.Jones1,2
Received: 11 May 2017 / Accepted: 18 August 2017 / Published online: 9 September 2017
© AOCS 2017
importance and holds a promise for the possibility of using
genetically targeted dietary interventions to reduce obesity
risk in the future.
Keywords Dietary fatty acids· Fat quality· Obesity·
Body composition· Obesity-related gene· Gene–diet
interaction
Abbreviations
11β-HSD1 11β-hydroxysteroid dehydrogenase type-1
BMI Body mass index
C/EBP-α 1 CCAAT-enhancer binding protein-α
FA Fatty acids
MCFA Medium-chain fatty acid
MCT Medium-chain triglyceride
MUFA Monounsaturated fatty acid
n-3 PUFA Omega-3 polyunsaturated fatty acid
n-6 PUFA Omega-6 polyunsaturated fatty acid
PPARα Proliferator activated receptor-alpha
PPARδ Proliferator activated receptor-delta
PPARγ Proliferator activated receptor-gamma
PUFA Polyunsaturated fatty acid
SCAT Subcutaneous adipose tissue
SFA Saturated fatty acid
SREBP1 Sterol regulatory element binding protein-1
FTO Fat mass and obesity-associated gene
VAT Visceral adipose tissue
WC Waist circumference
Introduction
Obesity is a medical condition in which excess body fat
accumulates to the extent that it may have negative impacts
on health [1]. Obesity is one of the largest health problems
Abstract The prevalence of obesity is skyrocketing
worldwide. The scientific evidence has associated obesity
risk with many independent factors including the quality
of dietary fat and genetics. Dietary fat exists as the main
focus of dietary guidelines targeting obesity reduction. To
prevent/minimize the adipogenic effect of dietary fatty acids
(FA), intakes of long-chain saturated- and trans-FA should
be reduced and substituted with unsaturated FA. The optimal
proportions of dietary unsaturated FA are yet to be defined,
along with a particular emphasis on the need to achieve a
balanced ratio of n-3:n-6 polyunsaturated FA and to increase
monounsaturated FA consumption at the expense of satu-
rated FA. However, inter-individual variability in weight
loss in response to a dietary intervention is evident, which
highlights the importance of exploring gene–nutrient inter-
actions that can further modulate the risk for obesity devel-
opment. The quality of dietary fat was found to modulate
obesity development by interacting with genes involved in
fatty acid metabolism, adipogenesis, and the endocannabi-
noid system. This review summarizes the current knowledge
on the effect of the quality of dietary fat on obesity phe-
notype and obesity-related genes. The evidence is not only
supporting the modulatory effect of fat quality on obesity
development but also presenting a number of interactions
between obesity-related genes and the quality of dietary
fat. The identified gene–FA interaction may have a clinical
* Peter J. Jones
Peter.Jones@umanitoba.ca
1 Department ofFood andHuman Nutritional Sciences,
University ofManitoba, Winnipeg, MBR3T2N2, Canada
2 Richardson Centre forFunctional Foods andNutraceuticals,
University ofManitoba, 196 Innovation Drive, Winnipeg,
MBR3T6C5, Canada

804 Lipids (2017) 52:803–822
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and its prevalence is skyrocketing worldwide [2–4]. Many
dietary, environmental, metabolic, and genetic factors are
likely involved in obesity development. Dietary fat is the
most energy-dense macronutrient, therefore, its consump-
tion may influence energy balance and consequently, body
weight and fatness [5, 6]. Even though the quantity of
dietary fat has an integral role in obesity development, the
effect of the quality of dietary fat on body fat accumulation
has been recognized by many researchers [6–9]. Different
fatty acids (FA) may vary in their obesity-inducing effect by
directing the metabolism toward a pathway of either oxida-
tion or storage [5, 10], as well as by influencing satiety and
appetite sensations [11, 12]. The consumption of long-chain
saturated FA (SFA) and trans-FA has been linked to obesity
and specifically to abdominal fat accumulation [6, 13], while
unsaturated FA, polyunsaturated FA (PUFA) and monoun-
saturated FA (MUFA), have been found to suppress appetite
as well as increase energy expenditure and fat oxidation rate,
therefore, induce favorable effects on regional and total fat
mass, as compared to the former two types [7–10, 12, 14].
Although excess body fat can mostly be modulated by
controlling obesity-related environmental factors, genetic
predisposition also plays an integral role in obesity develop-
ment [15, 16]. The genetic contribution to obesity explains
up to 84% of body mass index (BMI) [4]. Many genes have
been implicated in obesity development by several genome-
wide association studies [17–19]. Indeed, currently, at least
190 gene loci have been found to be associated with general
obesity and fat distribution [20]. Furthermore, epigenetic
modifications which are defined as the heritable changes in
gene expression that do not involve changes to the underly-
ing DNA sequence, such as DNA methylation and histone
modification, have been implicated in obesity development
[21–23]. Epigenome-wide association study identified 278
methylation sites associated with BMI [24]. Although many
genes are involved in the adipogenesis process, two main
points remain to be elucidated; the influence of genetic vari-
ation on body weight changes and whether nutrients can
modify the adipogenic effect of genes. It is therefore diffi-
cult to identify the main contributor to obesity development
and fat distribution due to the complex interactions between
environmental and genetic factors. However, the study of
gene–diet interactions holds promise of the eventual devel-
opment of a personalized prevention and treatment interven-
tion. The study of gene–diet interactions can be divided into
three main disciplines; nutrigenetics, nutrigenomics, and
nutriepigenomics, which are, respectively, the science of the
effect of genetic variation on dietary response, the science of
the role of nutrients in gene expression via interaction with
genetic structure, and the science of the role of nutrients on
gene expression via epigenetic modifications [25]. The type
of dietary fat has been reported to influence the function/
expression level of lipid metabolism and deposition-related
genes, and therefore, modulate obesity risk [26, 27]. A diet
high in SFA mostly upregulates the lipogenic genes; SFA
and trans-FA consumption increase the activity of hepatic
lipogenesis and the induction of de novo MUFA synthesis,
therefore, elevating the risk of excessive fat deposition [28,
29]. In contrast, the consumption of unsaturated FA down-
regulates lipogenesis-related genes and upregulates FA oxi-
dation-related genes, therefore, induces reductions in blood
triglyceride and FA levels, fatty acid-cellular uptake, as well
as the extent of fat deposition [28]. Here, we intend to con-
tribute to the fast-growing evidence regarding the effect of
dietary fat quality on obesity. Given the role of dietary FA
in obesity development and as being one important focus
of nutritional intervention targeting obesity reduction, the
objective is to firstly overview the clinical trial-based evi-
dence on the effect of dietary FA on adiposity. Secondly, an
emerging evidence indicates a modulatory effect of dietary
fat quality on the influence of genetic factors on fat deposi-
tion and distribution. Therefore, we identified and summa-
rized the evidence concerning the interaction between the
quality of dietary fat and adipogenesis/lipogenesis-related
genes. To achieve the objective of this paper, we searched
the PubMed database using different combinations of several
keywords including terms “dietary fatty acids, level polyun-
saturated fatty acid, level monounsaturated fatty acid, level
saturated fatty acid, gene-expression, polymorphism, epige-
netics, obesity, depot-specific, visceral, and subcutaneous”.
Overview oftheEffect ofDietary Fat
onDevelopment ofObesity
Fat Quality andBody Composition
Hypocaloric diets or adjusting the amount of a specific
macronutrient does not necessarily induce regional-specific
fat mass reduction, however, regional fat mass shift might be
induced by specific dietary component(s) [30]. The quality
of dietary fat has been suggested to play a vital role in fat
deposition and distribution [10, 31], despite the controversy
regarding the optimal type of dietary fat for obesity risk
reduction. Until recently, the main dietary recommendation
regarding the fat quality is to reduce the amount of SFA
consumption and to increase unsaturated FA, which has been
translated into higher intakes of omega-6 PUFA (n-6 PUFA),
especially in a Western-type diet. In this section, we briefly
review the clinical trial-based evidence.
Different dietary fats induce specific effects on body
weight and fat mass [6, 7, 10]. For instance, long-chain SFA
consumption has been shown to enhance body adiposity and
to shift fat accumulation toward visceral depots [32, 33],
where it correlates with BMI, waist-to-hip ratio, and fat mass
[34–36]. SFA consumption was found to have a significant

805Lipids (2017) 52:803–822
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direct correlation with fat cell size and number [37]. A
16-week high-fat diet (50% of total fat) supplemented with
9g/day of stearate induced an increase in gynoid and total fat
masses compared to energy-matched high-fat diet [38]. On
the other hand, medium-chain triglyceride (MCT), SFA that
contains 8–12 carbon atoms, has been suggested to increase
energy expenditure, thermogenesis, fat oxidation, and sati-
ety and to reduce fat accumulation in adipocytes [39]. Due
to their smaller chain length, compared to long-chain FA,
MCT-derived FA (MCFA) are more soluble and the majority
can be absorbed rapidly with no need for esterification and
incorporation into chylomicrons, therefore, swiftly metabo-
lized for energy via β-oxidation in the liver [39, 40]. These
differences in the absorption and metabolism make MCFA
a fast energy source that may potentially result in a negative
energy balance and weight loss [39]. Although the results
are inconclusive regarding the effectiveness of MCT and
the required dose to control body weight is not established
yet, several long- and short-term studies showed an effect
of MCT on increasing energy expenditure which therefore,
might influence body weight and fat deposition [41–48].
Evidence also indicates that MCT result in a regional fat
shift in total, abdominal, and depot-specific adipose tissue
as compared to long-chain FA [45]. In contrast, an accu-
mulating evidence shows negative impacts of long-chain
SFA on fat deposition [8, 10, 49], nevertheless, some con-
troversy remains over whether PUFA or MUFA induces the
most favorable effect on fat mass [10, 50]. Also, the optimal
amount of PUFA or MUFA that can be used to replace SFA
has not yet been defined [10].
There is still some discrepancy regarding the effective-
ness of PUFA on weight loss and maintenance [49, 51].
In the early-in-life expansion of fat depots, hyperplasia
and hypertrophy were found to be promoted by high n-6
PUFA consumption. This adipogenic effect was proven
by in vitro, animal, and human studies [52]. However, as
compared to SFA, dietary PUFA has been connected to a
smaller, less pathogenic, adipocyte cell size in human [37].
Summers et al. reported a reduction in abdominal subcu-
taneous fat induced by the consumption of a high ratio of
PUFA:SFA for 5weeks, compared to a high SFA control
diet, but no changes were detected in visceral adipose tissue
(VAT), waist circumference (WC), or body weight [53]. It is
worth mentioning that in this study, the SFA diet contained
a significantly higher amount of MUFA compared to the
PUFA rich diet which might have influenced the effect of
the control diet on body weight and blunted the possible
effect of PUFA rich diets on body weight and regional fat
mass. Other studies showed negative associations between
total PUFA consumption and PUFA:SFA ratio with VAT
and total body fat percent [35, 54]. Some contradiction in
the literature regarding the effect of dietary PUFA might
have resulted from the differences in the proportions of n-3
and n-6 PUFA, between studies, especially given their sug-
gested adipogenic differences. Adding omega-3 PUFA (n-3
PUFA) to a very low-calorie diet enhanced weight loss in
obese women compared to very low-calorie diet [55], how-
ever, Munro and Garg have reported an absence of effect
of adding n-3 PUFA on weight loss or weight maintenance
to a very low-calorie diet [51]. Smaller doses might be of
greater benefit as reported by Crochemore et al. where they
found a significant reduction in body weight and WC fol-
lowing 30days supplementation of 1.5g/day of fish oil as
compared to a higher dose of 2.5g/day [56]. Additionally,
conjugated linoleic acid has also been suggested to impose
beneficial effects on body weight and body composition [57,
58]. The supplementation of conjugated linoleic acid (3g/
day) and n-3 long-chain PUFA (3g/day) for 12weeks pre-
vented abdominal fat deposition and increased fat-free mass
and adiponectin levels, compared to a control supplementa-
tion consisting of 4.8g palm oil and 1.2g soybean oil [58].
Bjermo et al. reported that replacing SFA with n-6 PUFA
promoted cardiovascular benefits but did not influence
body weight [59]. Diets consisting of 10% of total energy
of PUFA failed to provide any additional favorable effect
on whole body weight, abdominal fat mass, or VAT mass
as compared to a macronutrient-matched low-PUFA (5% of
total energy) diet over a 12-week period, however, both diets
induced significant reductions in body weight and fat mass
[60, 61]. It is worth mentioning that the low-PUFA diet in
this study had a higher MUFA content (15% of total energy
compared to 10% in the PUFA enriched diet), therefore, the
higher MUFA content might induce favorable effects on obe-
sity indices and blunted the effect of the high PUFA diet.
MUFA consumption has been attracting particular recent
scientific interest regarding its beneficial effects on disease
and obesity risks [49, 62–65]. Adherence to a diet rich in
MUFA was not associated with obesity over the long term
[66, 67]. Even though Garaulet et al. have found no associa-
tion between MUFA consumption and fat cell size, how-
ever, the MUFA content of adipocytes has been found to be
inversely related to fat cell number, which might indicate a
preferential effect of MUFA in reducing hyperplasia [37].
Supplementing a high-fat diet with oleic acid (9g/day) for
16weeks induced a reduction in android fat mass as com-
pared to a placebo high-fat diet (50% of total fat) [38]. No
additional beneficial effects on body weight, WC, or total
fat mass were detected following hypocaloric MUFA rich
diet (22.5% MUFA, 11.25% PUFA, and 11.25% SFA) as
compared to the hypocaloric diet with equal FA proportions
(10% MUFA, 10% PUFA, and 10% SFA) in obese non-dia-
betic and type-2 diabetic individuals. However, this lack of
effect might have be caused by diabetes-related changes in
metabolism and/or lack of statistical power, as the authors
indicated [68]. Nimptsch et al. found an inverse association
between MUFA intake and prospective weight gain, while

806 Lipids (2017) 52:803–822
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saturated and PUFA intakes were linearly associated with
prospective weight gain [49]. Additionally, a MUFA-rich
diet containing 23% of total energy was found to prevent
further fat accumulation in abdominal region in abdominally
obese subjects [30]. A randomized, cross-over, ad libitum
feeding study found that a MUFA-rich diet (~23% MUFA
11% SFA of total energy) induced small but significant
reductions in body weight and fat mass, as compared to a
high SFA diet (~24% SFA and ~13% MUFA of total energy)
[8]. The reductions in fat mass and body weight following
the MUFA enriched diet were observed despite the lack of
significant differences in the intake of energy or fat dur-
ing the two diets [8]. Although Gillingham et al. reported
lack of statistical differences in body weight and total and
regional fat mass following diets rich in either SFA, high-
oleic canola oil, or flaxseed-high-oleic canola oil blend, this
study found a trend toward significance (p=0.055) in the
ratio of android:gynoid fat mass [5]. The observed lower
ratio of android:gynoid fat mass (mean±SEM 1.11±0.04)
following the MUFA diet as compared to a diet rich in either
SFA (1.12±0.04) or PUFA (1.13±0.04) might indicate
a favorable effect of MUFA on body fat redistribution.
Another trial was conducted to examine the effects of con-
sumption of different dietary oils varying in their unsatu-
rated fat contents on body composition and fat distribution
in a randomized controlled crossover weight-maintenance
full-feeding design [69]. This study has revealed favorable
effects of MUFA-rich diets, including regular canola oil or
high oleic canola oil, in terms of reducing body weight and
android fat mass as compared to a diet rich in flax/safflower
oil blend (PUFA-rich diet) [7]. Additionally, there is general
agreement regarding the effectiveness of the Mediterranean
diet, rich in α-linolenic acid and oleic acid, for weight and fat
mass reduction/maintenance [64, 67, 70–74]. In summary,
there is general agreement that substituting long-chain SFA
with unsaturated FA induces beneficial effects on weight
loss. While the evidence regarding the effect of PUFA con-
sumption on obesity is showing a less clear conclusion,
MUFA holds promise for effective dietary substitution for
SFA.
Fat Quality andEnergy Expenditure
Levels of energy expenditure and fat oxidation are important
regulators of fat deposition. A decrease in the level of fat
oxidation, especially in skeletal muscle; the main site for fat
oxidation, can dramatically increase obesity risk [75, 76].
The fat oxidation rate is greatly influenced by insulin sen-
sitivity which in turn might be affected by dietary fat qual-
ity. An animal trial showed that consumption of n-6 PUFA
appeared to prevent insulin resistance compared to a diet
rich in SFA [77]. In n-3 PUFA-fed rats, compared to lard
(SFA)-fed rats PUFA increased lipid oxidation, enhanced
the activation of AMP-activated protein kinase (AMPK; a
key enzyme in cellular energy homeostasis), and improved
insulin signaling in skeletal muscle [78]. Furthermore, oleic
acid may contribute to the prevention of palmitate-induced
insulin resistance by ameliorating palmitate-induced mito-
chondrial dysfunction in rat [79]. As compared to SFA con-
sumption, consumption of MUFA [80, 81] and supplemen-
tation of long-chain n-3 PUFA [82, 83] were reported to
improve insulin sensitivity in humans. The beneficial effects
of unsaturated FA on insulin sensitivity and energy metabo-
lism might be translated into a reduction in obesity risk.
Most of the existing evidence supports higher rates of
whole body FA oxidation and diet-induced thermogenesis
following unsaturated FA consumption compared to SFA
consumption, however, data regarding the oxidative differ-
ences between PUFA and MUFA are less clear [10]. The
lower oxidation rates of saturated compared to unsaturated
FA reduce the energy expenditure level and increase their
propensity to be stored in adipocytes [10, 84–86]. The data
regarding PUFA effects on energy expenditure are less con-
clusive, especially because most studies that evaluated the
effect of PUFA on energy expenditure have not specified the
source of this fat, i.e. n-3 versus n-6, which would decrease
the applicability of their results. An increasing body of evi-
dence indicates increasing increments in fat oxidation rate,
diet-induced thermogenesis, and energy expenditure with
higher dietary MUFA levels [10, 14, 86–88]. In a recent
randomized parallel-arm clinical trial, increased fat oxida-
tion and reduced body fatness were observed in men who
received 56g/day of conventional or high-oleic peanuts for
4weeks during an energy-restricted diet, as compared to a
hypocaloric-control diet [9]. Even though Gillingham et al.
have found that replacing SFA with high-oleic canola oil or
flaxseed-high-oleic canola oil blend did not induce favorable
effects on energy expenditure or fat oxidation, they reported
a trend (p=0.055) for increasing the ratio of android/gynoid
fat mass following a high-oleic canola diet compared to a
diet rich in flaxseed-high-oleic canola [5]. Piers et al. have
reported a small but significant reduction in body weight fol-
lowing a 4-week MUFA-rich diet compared to an SFA-rich
diet, however, no significant differences in energy expendi-
ture or substrate oxidation rate were found between the two
diets [8]. Furthermore, Kien and Bunn reported increases in
FA oxidation in women and an elevation of energy expendi-
ture in men following 28days of high oleic acid-rich diet,
as compared to a diet rich in palmitic acid [14]. Substituting
dietary palmitic acid with oleic acid was associated with
increased physical activity and resting energy expenditure
[88].
Moreover, in normal weight subjects, the majority of
studies reported no short-term difference in fat oxidation fol-
lowing a high-fat meal enriched with MUFA, PUFA, or SFA
[10, 87, 89], while high PUFA and MUFA meals elevated

807Lipids (2017) 52:803–822
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the thermic effect of a meal compared to SFA [90–93]. The
contradiction on the effect of different dietary fats on rates
of fat oxidation and energy expenditure might be due to the
variations in study design or methodology between differ-
ent trials. However, Krishnan and Cooper, have comprehen-
sively reviewed the available evidence from the long-term
intervention and postprandial meal challenge regarding the
effect of different dietary FA in a high-fat diet/meal on sub-
strate utilization, diet-induced thermogenesis, and fat oxida-
tion. These authors report that unsaturated FA, especially
MUFA, greatly increase diet-induced thermogenesis and
fat oxidation as compared to SFA (MUFA≥PUFA˃SFA)
[10]. The question remains whether or not the increased fat
oxidation rate seen with MUFA consumption is sufficient to
induce fat mass loss.
Fat Quality andEnergy Consumption
The quality of dietary fat has been suggested to modulate
energy consumption, the second arm of the energy balance
equation, therefore, modulate obesity risk. Energy intake
might be reduced when the ghrelin levels are reduced and
peptide-YY, cholecystokinin, and glucagon-like peptide-1
levels are increased [11, 94]. A high-fat meal that is enriched
with either PUFA or MUFA was found to suppress post-
prandial ghrelin levels in obese women to a significantly
greater extent compared to a high-fat high-SFA meal, while
a PUFA rich meal was able to significantly elevate peptide-
YY compared to SFA and MUFA-rich meals in women with
obesity [11]. However, these changes in satiety signals were
not translated into shifts in the subjective appetite ratings
(VAS) or changes in subsequent energy intake [11]. Also,
Strik et al. did not support a specific role of SFA, MUFA,
and PUFA on the subjective rating of hunger and fullness
sensations as well as the subsequent food consumption over
6-h period [95]. Another study has reported an increase in
cholecystokinin levels, a significant increase in fullness, and
a reduction in hunger following PUFA and MUFA liquid
meals in healthy subjects as compared to SFA meal [94].
Current evidence supports the effect of the degree of FA
saturation on satiety subjective and physiological appetite
responses [11, 90, 94], however, it has yet to be elucidated
whether MUFA or PUFA is most influential in controlling
energy consumption [94, 96]. Anandamide, a FA neuro-
transmitter derived from the eicosatetraenoic acid and an
essential n-6 polyunsaturated fatty acid, acts as an endog-
enous ligand for the cannabinoid receptor that stimulates
appetite sensation which might increase energy consumption
[12, 97]. Adequate consumption of long-chain n-3 PUFA
and obtaining an n-6:n-3 PUFA ratio as close as possible
to unity can blunt any possible adverse effects of arachi-
donic acid metabolites and hyperactivity of the cannabinoid
system [98, 99]. Furthermore, the high oleic acid content
of the diet was suggested to control appetite sensation and
therefore, reduce energy intake by elevating post-prandial
oleoylethanolamide level, which itself regulates food intake
by influencing metabolic and reward systems [12, 97, 100].
This finding is novel in humans and might hold promise for
using oils rich in oleic acid to control energy intake [12].
Taking the above-mentioned evidence, different dietary FA
differently impact body composition, energy expenditure,
and energy consumption, therefore, influence obesity risk
in unalike ways. In summary, the optimal diet for weight
reduction/maintenance has to be balanced in n-6:n-3 ratio,
as close as possible to unity, and enriched in MUFA at the
expense of long-chain SFA.
Nutrition is one of the most important factors that modu-
lates the influence of genes on obesity risk. The aim of stud-
ying gene–nutrient interactions is to ultimately use genetic
profile to personalize dietary recommendation. Given the
effect of dietary fat quality on obesity, the next section sum-
marizes the evidence concerning the effect of fat quality on
lipogenesis/adipogenesis-related genes.
The Effect ofDietary Fat onAdipogenesis‑Related
Genes
As noted earlier, gene–nutrient interactions may eventu-
ally help to prevent/control obesity in high-risk individu-
als by designing personalized nutritional strategies. Dietary
FA have been found to modulate the expression levels of
several genes and transcriptional factors that are involved
in cellular responsiveness to metabolic signals and/or the
regulation of lipid and energy metabolism [28, 30]. The
effects of dietary FA on obesity might depend on their chain
length and desaturation degree. The two transcription fac-
tors, sterol regulatory element binding protein-1 (SREBP1)
and peroxisome proliferator activated receptor (PPAR), have
emerged as key mediators of gene regulation by dietary FA,
therefore, the literature has mainly focused on the interac-
tion of FA with these two transcriptional factors. Three main
mechanisms underlie the gene–FA interaction; dietary influ-
ences on membrane FA composition, transcriptional regula-
tion, and post-transcriptional processes [101]. Epigenetics
(non-DNA sequence-related heritable changes) and genetics
(DNA sequence-related heritable changes) may interact to
modify the expression of genes, thereby, the risk for obesity
and associated disease.
Obesity‑Related Transcriptional Factors
Of the obesity-related genes that have been identified, two
main transcriptional factors, PPAR and SREBP1 exist as
key mediators of the effect of hormones and nutrients on the
expression of fat accumulation-related genes [102]. Figure1

808 Lipids (2017) 52:803–822
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displays the effects of these two transcriptional factors on
adipogenesis and lipogenesis processes in adipose tissue
and liver.
PPAR are transcriptional factors expressed mainly in
skeletal muscle, liver, and brown adipose tissue which
regulate the expression levels of several genes. PPAR are
involved in the regulation of cellular differentiation, devel-
opment, and the metabolism of lipid, protein, and carbo-
hydrate [28, 103]. Three types of PPAR have been identi-
fied; beta (PPARδ), alpha (PPARα), and gamma (PPARγ)
[103, 104]. Little is known about the role of PPARδ in lipid
metabolism, however, the activation of adipocyte PPARδ
might be involved in obesity risk reduction by enhancing
the expression of FA oxidation- and utilization-related genes
[105]. The activation of PPARα enhances FA oxidation path-
ways, increases energy expenditure, reduces de novo syn-
thesis of FA in the liver and adipose tissue, and promotes
thermogenesis in brown adipose tissue, therefore, reducing
the level of fat deposition [28, 106–108]. PPARα activity is
downregulated by insulin signals and enhanced by high free
FA levels. PPARγ, expressed mainly in white and brown
adipose tissue, is involved in adipocyte differentiation, and
regulates the metabolic and endocrine functions of adipose
tissue [28, 109]. In contrast to PPARα, PPARγ activation
promotes the expression levels of lipogenesis- and adipo-
genesis-related genes yet ameliorate whole body insulin
resistance and hypertriglyceridemia [28, 109–112]. PPARγ
is part of the adipocyte differentiation program and its activ-
ity is induced by higher levels of insulin, SREBP1, and FA
[113]. PPARγ has been identified as a regulator of the levels
of leptin, resistin, and adiponectin, modulating adipokines
levels reflects an important role of PPARγ as a determinant
of dietary intake, energy homeostasis, and obesity risk [104,
112]. The effect of PPARγ on adiposity levels has been veri-
fied by the strong positive relationships between the expres-
sion levels of PPARγ and several lipogenic enzymes as well
as VAT adiponectin levels [31]. Therefore, PPAR influence
obesity risk differently; the activation of PPARδ and PPARα
reduces obesity risk by increasing energy expenditure and
Fig. 1 The effect of peroxisome proliferator-activated receptor alpha (PPARα), gamma (PPARγ), and delta (PPARδ) and sterol regulatory ele-
ment-binding proteins-1c (SREBP1c) on adipogenesis and lipogenesis processes in adipose tissue and liver

809Lipids (2017) 52:803–822
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fat oxidation, in contrast, PPARγ induces lipogenesis and
adipogenesis and augments obesity risk.
SREBP are membrane-bound transcriptional factors that
are involved in the uptake and biosynthesis of FA and tri-
glyceride (SREBP1) as well as cholesterol (SREBP2) [114].
Insulin is an important regulator of SREBP transcriptional
and protein levels, also insulin-induced activation of sev-
eral lipogenesis genes requires upregulation of the expres-
sion levels of SREBP1 [28, 115]. Therefore, the induction
of SREBP1 and PPARγ activities increases the lipogenesis
and adipogenesis of triglyceride in adipose tissue by aug-
menting the expression of several adipogenic and lipogenic
enzymes [28, 31].
The Role ofSaturated Fatty Acid ontheExpression
ofObesity‑Related Genes
The effects of SFA on the expression of adipogenesis and
lipogenesis-related genes were found to be modulated by
the FA chain length. Short-chain FA consumption reduced
the PPAR-induced activation of some hepatic lipogenic
genes which might reduce the obesity risk [28]. Adipose
tissue-MCFA have shown an ability to downregulate the
expression levels of PPARγ and its downstream metabolic
target genes as well as to improve insulin sensitivity and
reduce lipoprotein lipase activity in adipocyte [40]. On the
other hand, long-chain SFA consumption has been reported
to upregulate the activity of SREBP1c and PPARγ which
activates the lipogenic genes including stearoyl-CoA desatu-
rase, fatty acid synthase, and acetyl-CoA carboxylase [26,
29]. Furthermore, the expression levels of PPARγ- and
PPARγ-induced activation of adipogenic and lipogenic
genes have been enhanced by a diet rich in trans-FA [28].
SFA is suggested to modulate gene expression by changing
the cellular membrane composition which will change the
intra-cellular substrate-to-product ratio of a target gene and
therefore, will enhance/prevent its expression levels. For
instance, SFA can mediate its effect on SREBP1 by chang-
ing the cellular membrane composition to possess more
SFA which would decrease cholesterol and SFA levels in
the endoplasmic reticulum, and therefore, increases SREBP1
maturation [28]. An animal trial presented a suggested
mechanism by which the quality of dietary fat might modu-
late abdominal obesity; compared to SFA, the expression
levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-
HSD1) and CCAAT-enhancer binding protein-α (C/EBP-α)
in retroperitoneal fat depot were higher following trans-FA
and lower following PUFA consumption [116]. 11β-HSD-1
converts inactive corticosteroids into potent glucocorticoids,
expressed in various tissues including liver and adipose tis-
sue. Its expression is regulated by C/EBP-α, and the higher
activity of this enzyme is associated with an increased VAT
mass [109, 116]. The amplification of glucocorticoids action
by SFA and trans-FA as compared to PUFA may increase
fat deposition and insulin resistance and may, partly, explain
the adipogenic and pathogenic effect of SFA and trans-FA
[116].
The Role ofUnsaturated Fatty Acid ontheExpression
ofObesity‑Related Genes
Unsaturated FA suppress expression levels of FA biosyn-
thesis-related genes and upregulate FA oxidation-related
gene expression levels. PUFA consumption, in general,
has been found to induce activation of PPARα and several
genes related to lipid oxidation and thermogenesis, result-
ing in an increased FA oxidation rate and a reduced risk
of adipogenesis [28, 117, 118]. PUFA consumption has
been found to suppress expression levels of many lipogenic
genes and chiefly reduce the expression level of SREBP1
by either inhibiting mRNA gene expression or obstructing
the proteolytic processing of SREBP1 precursor [26, 113,
117, 119]. PUFA consumption induces an opposite effect
of SFA consumption on SREBP1 expression by the same
mechanism reported earlier [28]. These 2 types of dietary
PUFA induce different effects on fat metabolism and depo-
sition; n-6 PUFA is suggested to promote fat deposition,
while n-3 might induce the reverse effect. N-3 PUFA con-
sumption was found to be associated with a reduction in
PPARγ expression level and has been reported to suppress
de novo lipogenesis [106, 120]. In contrast, n-6 PUFA have
been reported to induce early activation of PPARγ and are
recognized for having higher PPARγ-affinity as compared
to other FA [121]. SREBP1c expression level was reported
to be related directly to adipose tissue content of n-6 PUFA,
while n-3 (α-linoleic acid) PUFA was found to blunt the
lipogenic effects of n-6 PUFA by reducing expression levels
of SREBP1c and fatty acid synthase in adipose tissue in
rats [31]. Dietary n-3 PUFA was found to inhibit expres-
sion and nuclear transcription of SREBP1 therefore, reduc-
ing lipogenesis [106]. Such possible adipogenic effects of
n-6 PUFA are suggested to be manifested when the ratio
of n-6:n-3 PUFA is larger than unity, which is clearly dem-
onstrated in a typical Western diet [31, 122]. A high dose
of n-3 PUFA is required to blunt the adipogenic effect of
n-6 PUFA [31, 123], the optimal n-6:n-3 PUFA ratio can
be best achieved by supplementing n-3 PUFA and reduc-
ing dietary n-6 PUFA consumption in a diet. The favorable
effects of n-3 PUFA are suggested to be induced by changing
the n-6:n-3 PUFA ratio of cellular membrane and plasma
phospholipid contents which might alter the enzymatic
activity and metabolic pathways, as well as by reducing the
cellularity of adipose tissue and inhibiting hyperplasia and
hypertrophy of adipocytes [123, 124]. Additionally, the ben-
eficial effects of a balanced n-6:n-3 PUFA ratio might also
be explained by an anti-inflammatory effect of n-3 PUFA

810 Lipids (2017) 52:803–822
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which would ameliorate inflammatory status and enhance
insulin sensitivity, and therefore, modulate adipogenesis
and lipogenesis [31, 99]. Downregulation of the expression
level of adiponectin gene was found to be induced by dietary
enrichment with soybean high in n-6 PUFA, coconut high
in MCFA, and lard high in LC-SFA, as compared to fish oil
[125], which might partly emphasize the superiority of n-3
PUFA in improving insulin sensitivity. Improving insulin
sensitivity can modulate energy and lipid metabolism.
Little has been reported on the effect of MUFA on expres-
sion levels of adipogenic/lipogenic genes. Dietary MUFA
upregulate the expression level of mitochondrial uncoupling
protein-2 as well as PPARγ and its target genes which might
alter energy balance, insulin resistivity, and adiposity level
[118, 126]. However, MUFA consumption failed to suppress
lipogenesis or to modulate PPARα activity as compared to a
high n-3 PUFA diet in rats [106]. On the other hand, MUFA
consumption in an isocaloric diet was found to prevent the
reduction in postprandial adiponectin gene expression levels
in peripheral tissue, improve insulin resistance, and induce
preferential body fat distribution i.e., lower central deposi-
tion, compared to high carbohydrate diet in insulin resistance
subjects [30]. Given the above-mentioned evidence from
the clinical trials regarding the beneficial effects of dietary
MUFA on obesity, further research on the effect of MUFA
consumption on the expression levels of adipogenesis/lipo-
genesis-related genes is warranted to understand the underly-
ing mechanism behind the favorable effects of MUFA.
Fat Quality andEpigenetic Modifications
ofObesity‑Related Genes
Evidence regarding the role of dietary FA on epigenetic
regulations of the expression levels of obesity-related genes
is scarce [127]. However, a few studies have demonstrated
the epigenetic effects of FA consumption, especially PUFA,
on obesity control and prevention mostly in animal models
and cultured cells [22, 127–129]. The methylation of several
obesity-related genes was found to be influenced by the pro-
portions of PUFA:SFA, MUFA:SFA, and unsaturated fatty
acid:SFA, indicating a role of epigenetics in the physiologi-
cal responses to the quality of dietary fat [130]. Palmitate
treatment in human islets demonstrated changes in DNA
methylation and gene expression of 67 BMI-related genes
[131]. Additionally, in cultured cells, arachidonic acid, pal-
mitic acid, and oleic acid altered the DNA methylation of
several genes that regulate pathological processes including
obesity; arachidonic acid and palmitic acid induced similar
DNA methylation profile compared to oleic acid-induced
profile [132]. In a 7-week parallel controlled clinical trial
in 31 healthy normal-weight adults [133], overfeeding of
SFA changed the methylation in the promoter regions of 125
genes and significantly altered the expression of 28 genes
including acyl-CoA oxidase-1 in subcutaneous adipose tis-
sue. In the same trial, PUFA altered the methylation in the
promoter regions of 1797 genes including fat mass and obe-
sity- associated gene (FTO) but did not significantly affect
gene expression levels. The epigenetic targets, DNA methyl-
ation and histone modifications, were found to be involved in
n-3 PUFA-induced modification of leptin expression in the
adipose tissue of diet-induced obese mice [134]. Nutritional
epigenomics is an emerging field of research and since die-
tary fat quality is a main contributor to obesity development,
rigorous clinical trials are needed to directly assess the effect
of FA on epigenetic modifications of obesity-related genes.
The Interaction Between Fat Quality andSingle
Nucleotide Polymorphisms ofObesity‑Related Genes
Finally, dietary FA have been found to modulate the associa-
tion between body composition and many genetic variants of
obesity-related genes [111, 135–141], Table1 summarizes
available evidence on dietary fatty acid-adipogenic gene
interactions. The data show promising evidence of interac-
tions between dietary FA and several polymorphisms located
in genes that can co-ordinate the adipogenesis process either
via a metabolically-evident pathway such as PPARγ or via a
suggested mechanism such as Circadian Locomotor Output
Cycles Kaput. However, many factors might modulate the
interactions between dietary FA and genes, including ethnic-
ity and many environmental factors, therefore, large-scale
ethnic-specific longitudinal studies that account for many
environmental, behavioral, and cultural variables are still
required in order to eliminate as much as possible the con-
founders that might affect gene–nutrient interactions. The
long-term aim for studying the gene–nutrient interaction is
to instruct genotype-specific personalized dietary recom-
mendations for the prevention and treatment of obesity. To
achieve this goal, more randomized well-controlled clinical
trials are needed to validate gene–nutrient interactions.
Abdominal Fat Depots Vary inTheir Adipogenic
Effect
Quantifying of total and regional fat mass as well as dif-
ferentiating between the types of fat depots provide a clear
picture regarding the pathogenesis of obesity and therefore,
better insight to disease risk [142]. Subcutaneous adipose
tissue (SCAT) is the adipocyte that lies just beneath the skin,
while adipocyte that accumulates around the vital organ in
the abdominal cavity is known as VAT. Studies have shown
strong and independent associations between VAT depot,
rather than SCAT, with metabolic abnormalities and chronic
disease risks [143–147]. Anatomical, cellular, molecular,
physiological and clinical differences exist between VAT and

811Lipids (2017) 52:803–822
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Table 1 The effect of dietary fatty acid–gene interaction on body composition
Reference Participant/Diet Gene/SNP Response
[140] 1465 overweight or obese men and women in Spanish/
behavioural treatment program
PPARγa/rs1801282 Subjects carrying minor allele G were significantly less
obese than the homozygous major subjects CC when the
MUFA intake was high
[112] 2141 USA women/survey PPARγa/rs1801282 MUFA consumption was inversely associated with BMI in
the minor allele carriers
PUFA:SFA ratio was directly associated with lower BMI
among the homozygous major allele carrier
[158] 720 French–Canadian descent men and women/survey PPARγa/rs1801282 An increase in WC was associated with an increased level
of saturated fat intake in homozygous major allele carrier
but not among carriers of minor allele
[101] 308 European normal and obese, men and women/pro-
spective survey
PPARγa/rs1801282 Carriers of the minor allele G who consumed high amounts
of arachidonic acid had a significantly higher risk of obe-
sity than the carriers of major allele.
[159] 60 Brazilian obese women/a randomized trial PPARγa/rs1801282 The habitual MUFA intake inversely correlated with fat
oxidation and BMI in the obese G carriers
A lower PUFA intake in the long-term trial was associated
with an increase in the respiratory quotient only in G
carriers
[111] 592 Caucasian nondiabetic men and women/survey PPARγa/rs1801282 An inverse association was detected between PUFA:SFA
ratio and BMI among G carriers
[160] 3356 mixed population men and women/survey PPARγa/rs1801282 Carriers of G allele who consumed high PUFA:SFA ratio
had the greatest reduction in visceral fat
[101] 308 European normal and obese, men and women/pro-
spective survey
PPARγa/rs3856806 Carriers of the T allele who consumed low amounts of
linoleic acid had a significantly higher risk of obesity than
the carriers of the major allele
[161] 60Spanish obesewomen/controlled trial PPARγa/rs1801282
ADRB2b/rs1042714
Carriers of a combination of major rs1801282 CC and
minor rs1042714 GG who consumed a high MUFA diet
had an increase in carbohydrate oxidation and a smaller
weight loss
A combination of heterozygous of both SNP had a
greaterenergy expenditure and basal and postprandial fat
oxidation aftera short-term high SFA diet
[162] 260 Spanish obese Men and women/a randomized trial ADRB3c/rs4994 No significant differences on weight, BMI, WC, orfatmass
in either genotype group with both diets
[135] 2163 European ancestry and Puerto Rican obese men and
women/survey
FTOd/rs9939609 and rs1121980 Carriers of rs9939609 AA allele or rs1121980 TT allele had
a higher BMI than the other genotypes only when they had
a high SFA intake
[163] 776 Spanish women and men/a randomized trial FTOd/rs9939609 No interaction between the nutritional intervention and the
polymorphism was found
[164] 233 Spanish obese subjects men and women/a randomized
trial
FTOd/rs9939609 Lower levels of BMI, weight and fat mass were detected
after a PUFA diet in A allele carriers than TT genotype
subjects

812 Lipids (2017) 52:803–822
1 3
Table 1 (continued)
Reference Participant/Diet Gene/SNP Response
[101] 308 European normal-weight and obese, men and women/
prospective survey
LEPe/rs7799039 Carriers of A allele who consumed a higher amount of
linoleic acid were found to be at a lower risk for obesity
[165] 200 Mexican normal-weight and obese men and women/
survey
LEPRf/rs8179183 and rs1137101 Carriers of rs1137101 G allele with a high SFA intake had
~3 times higher risk of obesity
[166] 1083 Caucasian origin men and women/survey ADIPOQg/rs17300539 A allele carriers who consumed a higher amount of MUFA
had a lower BMI and a reduced obesity risk
[101] 308 European normal and obese, men and women/pro-
spective survey
HSLh/rs34845087 Carriers of the G allele who consumed high amounts of ara-
chidonic acid showed a tendency to a lower risk of obesity
than the carriers of the major allele.
[138] 1171 African American and European American men and
women/survey
LPLi/rs320 A higher intake of PUFA was associated with lower BMI
and WC in major TT allele carriers
[167] 391 Spanish obese men and women/a randomized trial GLP1Rj/rs6923761 Lack of association of rs6923761 with weight loss after
either high MUFA or PUFA hypocaloric diets was
reported
[168] 1100 European descent men and women/prospective
survey
CLOCKk/rs1801260 Minor allele GG carriers who consumed a high SFA intake
had larger WC than non-carriers
[102] 11091 European men and women/survey CEBPBL/rs4253449 Higher intake of MUFA, PUFA, and SFA were associated
with a higher risk of weight gain among minor allele
carriers
[169] 258 Spanish obese men and women/a randomized trial CNR1m/rs1049353 No significant differences on weight, BMI, WC, orfatmass
in either genotype group with both diets
[170] 1147 Puerto Ricans men and women/survey BDNFn/rs6265 Compared to A allele carriers, a low PUFA intake in men
with the GG was associated with a higher BMI, and
higher waist and hip circumferences
Compared to A allele carriers, a lower BMI was associated
with a high PUFA intake in women with GG
Compared to A allele carriers, a lower BMI and hip
circumference were associated with a high SFA intake in
women with the GG
[171] 2212 white women and men/analysis of two independent
study
REV-ERB-ALPHA circadiano/rs2314339 Consuming a higher amount of MUFA in the Mediterranean
population was associated with a higher BMI in major GG
allele carriers
[172] 1754 French men and women/survey STAT3p/rs8069645, rs744166, rs2306580, rs2293152,
rs10530050
A high SFA consumption in individuals carrying ≥2 risk
alleles was associated with an increased risk of abdominal
obesity compared with those carrying ≤1 risk alleles
[173] 268 Normal-weight and obese, black and white women in
South African
IL6q/rs1800795, rs2069845, rs1554606 In white women only, a higher n-3 PUFA intake and a
reduced n-6:n-3 PUFA ratio were associated with a lower
BMI in carriers of rs1800795 C allele, rs1554606 T allele
and rs2069845 AG genotype

813Lipids (2017) 52:803–822
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Table 1 (continued)
Reference Participant/Diet Gene/SNP Response
[174] 737 Spanish men and women/a randomized trial IL6q/rs1800795 CC carriers had the lowest body weight gain following the
Mediterranean diet supplemented with virgin olive oil (but
not with nuts)
[175] 378 normal-weight and obese, black and white women in
South African
TNFαR/rs361525 An increased SFA intake in A carriers was associated with
a higher adiposity increase as compared to GG
An increased MUFA intake in A carriers was associated
with a higher weight as compared to GG
[176] 223 Black South African obese and normal weight
women/survey
TNFαR/rs1800629 No gene–nutrient interaction was found in any dietary fatty
acid with this SNP on obesity
[101] 308 European normal and obese, men and women/pro-
spective survey
TNFαR/rs1800629 Interactions of high intakes of linoleic acid and arachidonic
acid and A allele carriers showed a higher obesity risk
[177] 261 Spanish obese men and women/survey TNFαR/rs1800629 No significant differences on weight, BMI, WC, or fat mass
in either genotype group with both diets
[178] 936 European origin men and women/survey TACES/rs10495563 The deleterious association of the A allele with obesity was
observed in subjects with a low n-6 PUFA intake
[165] 200 Mexican normal-weight and obese men and women/
survey
APOA5t/rs662799 and rs3135506 Carriers of rs3135506 GG genotype with a high SFA con-
sumption had an increased risk of obesity.
[179] 2280 non-Hispanic whites men and women/survey APOA5t/rs662799 and rs3135506 Rs662799 C minor allele carriers with the high MUFA
intake had a lower obesity risk compared with TT carriers
[180] 3462 Whites and Hispanic men and women/follow-up
survey
APOA2u/rs5082 CC genotype with a high SFA intake was associated with a
higher obesity prevalence
[181] 2071 Puerto Ricans origin and Northern European ances-
try men and women/survey
APOA2u/rs5082 CC carriers who consumed a greater amount of SFA from
a high-fat dairy foods had a greater BMI than those who
consume less dairy fat
[182] 737 Iranian diabetic patients men and women/survey APOA2u/rs5082 Carriers of CC allele with a high SFA intake had higher
BMI
[165] 200 Mexican normal-weight and obese men and women/
survey
APOA2u/rs3813627 and rs5082 No interaction was found between SFA intake and APOA2
SNP
[183] 1225 Spanish overweight and obese men and women/
survey
APOA2u/rs5082 A high SFA intake was associated with a greater WC in
minor allele homozygotes CC compared with non-minor
allele carriers
[184] 4602 Asian and Mediterranean obese men and women/
survey
APOA2u/rs5082 In both populations, the CC genotype was associated with a
greater degree of obesity in those consuming a high SFA
diet
[185] 700 Iranian diabetic men and women/cross-sectional APOBv/Ins/Del SNP within the first exon A high n-3 PUFA consumption decreased the obesity risk in
carriers of the Del allele of APOB gene
[186] 920 Puerto Rican origin men and women/survey LRP1w/rs1799986, rs715948, and rs1800191 A high intake of SFA was associated with a higher BMI,
and higher waist and hip circumferences in carriers of
rs1799986 T allele compared to CC. High palmitic and
stearic acids induced the strongest effect on BMI

814 Lipids (2017) 52:803–822
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Table 1 (continued)
Reference Participant/Diet Gene/SNP Response
[187] Meta-analyses using data from 14 studies of US and Euro-
pean whites and 4 of African Americans
LRP1w/7 SNP in White and 12 SNP in African Americans A high intake of SFA was associated with an increased
BMI, and higher waist and hip circumferences among
whites, but not African Americans, TT allele carriers of
rs2306692
ADIPOQ Adiponectin, ADRB2 adrenergic receptor beta2, ADRB3 adrenergic beta-3-receptor, APOA2 apolipoprotein-A2, APOA5 apolipoprotein-A5, APOB apolipoprotein-B, BDNF brain-
derived neurotrophic factor, BMI body mass index, CEBPB CCAAT/enhancer binding protein-b, CLOCK circadian locomotor output cycles kaput, CNR1 cannabinoid receptor-1, GLP1R gluca-
gon-like peptide-1 receptor, HSL hormone sensitive lipase, IL6 interleukin-6, LEP leptin, LEPR leptin receptor, LPL lipoprotein lipase, LRP1 low density lipoprotein related receptor protein-1,
MUFA monounsaturated fatty acid, PPARγ peroxisome proliferator-activated receptors gamma, PUFA polyunsaturated fatty acid, SFA saturated fatty acid, SNP single nucleotide polymorphism,
STAT3 signal transducer and activator of transcription-3, TACE tumor necrosis factor alpha converting enzyme, TNFα tumor necrosis factor alpha, WC waist circumference
Role in obesity: aPPARγ role in obesity is fully described in the text; bADRB2 is involved in energy expenditure and lipolysis; cADRB3 is located mainly in adipose tissue and is involved in
the regulation of lipolysis and thermogenesis; dFTO is considered as the most significant candidate gene that implicated in the development of obesity, however, the function of this gene is
unknown yet; eLEP is involved in energy balance by inhibiting hunger; fLEPR mutation of the LEPR gene results in leptin insensitivity, hyperphagia, morbid obesity; gADIPOQ is involved
in insulin sensitivity and energy metabolism; hHSL plays a crucial role in the hydrolysis of triacylglycerol; iLPL hydrolases triglyceride which are carried on lipoprotein; jGLP1R is involved
in satiety control; kCLOCK is involved in metabolic alterations; LCEBPB activation induces the division of cells; mCNR1 is an endogenous ligand of endocannabinoid system and is located
in several brain areas and adipose tissue; nBDNF suppresses food intake and is involved in the conversion of white fat into brown fat in adipose tissue; oREV-ERB-ALPHA circadian functions
as a coordinator of metabolic responses that adhere to circadian patterns; pSTAT3 is a transcription factor and it is involved in body weight control, glucose homeostasis, leptin sensitivity, and
appetite control; qIL6 higher circulating concentrations of this cytokine have been associated with obesity and visceral adipose tissue deposition; RTNFα polymorphism was associated with
increased risk for obesity; STACE releases the soluble form of tumor necrosis factor from their membrane-bound precursors, TNFα is overexpressed and highly released from the adipose tissue
of obese humans; tAPOA5 is regarded as an important modulator in the metabolism of triglycerides; uAPOA2 is involved in lipid metabolism and in the regulation of food intake; vApoB is the
key protein involved in the synthesis and secretion of chylomicrons and very-low-density lipoprotein; wLRP1 mediates lipoprotein remnant uptake, is highly expressed in adipocyte, and has
been suggested to play a role in adipogenesis, cell signaling, and energy and glucose metabolism

815Lipids (2017) 52:803–822
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SCAT [143, 148]. These variations between SCAT and VAT
might influence their responsiveness to nutritional interven-
tion. For instance, a systematic review showed a dissimilar
responsiveness of VAT and SCAT to weight loss energy-
restricted diet [149].
Depot-specific variations were also detected in mRNA
expression levels and in the activity of several fat metabo-
lism-related genes and transcriptional factors. Compared to
VAT, higher activation levels of PPARγ and several down-
stream genes have been detected in SCAT [110, 150], in
contrast, the expression of PPARα in VAT has been reported
to be higher than SCAT [151]. These two properties might
reflect biological defense mechanism against visceral obesity
by directing fat deposition from VAT to SCAT. On the other
hand, PPARγ expression was found to be elevated in VAT
of obese subjects as compared to non-obese subjects, which
indicating obesity-induced metabolic changes that might be
involved in directing fat deposition toward the pathological
fat depot [152]. Guiu-Jurado et al. have reported a significant
inverse association between BMI and two lipogenic genes
(fatty acid synthase and Acetyl-CoA Carboxylase-1) as well
as with PPARα in SCAT, while expression levels of these
genes remained similar in VAT regardless of the degree of
obesity [153]. Furthermore, the level of hormone-sensitive
lipase in SCAT was found to be twofold lower than cor-
responding levels in VAT, explaining the elevated level of
lipolysis in VAT of obese women [154]. The expression level
of apolipoprotein-E, which plays an important role in lipid
metabolism and modulate adipocyte substrate metabolism
and storage, was found to be lower in VAT as compared to
SCAT [155]. Also, a depot-specific difference in perilipin
levels was suggested to contribute to differences in basal
lipolysis and adipocyte size; levels of perilipin were found
to be higher in VAT as compared to SCAT in women [154].
Additionally, nesfatin-1, an anorexigenic peptide, has been
found to be secreted in a depot-specific manner, preferen-
tially by SCAT [156]. No data are available regarding the
effect of adipocyte-produced nesfatin-1 on energy homeosta-
sis yet, however, this might reflect a favorable role of SCAT
over VAT. Therefore, the detected depot-specific variation
in expression levels of adipokines as well as adipogenic/
lipogenic genes might contribute to the variation in the adi-
pogenic and pathogenic capacity of VAT.
Despite the well-established variations in the health
risk posed by VAT versus SCAT, little is known about the
effects of different dietary treatments on each depot. How-
ever, compared to SFA and MUFA dietary mixture, dietary
docosahexaenoic acid has significantly reduced mRNA fatty
acid synthase, hormone sensitive lipase, lipoprotein lipase,
and leptin in VAT in rats, however, the expression levels
of these enzymes in SCAT were not affected by n-3 PUFA
[157]. A direct association was found between n-6 PUFA
concentrations and SREBP1c expression levels in both fat
depots, however, the responsiveness degree was higher in
VAT than SCAT [31].
Additionally, the FA composition of adipocytes is sug-
gested to reflect FA composition over a long period [150].
SCAT and VAT have shown variations in their FA contents
which may indicate variations in the pathological capacities
of different FA. The degree of obesity, central obesity, and
visceral fat were negatively associated with MUFA and n-3
PUFA content in visceral region [32]. Also, MUFA were
found to contribute to the highest proportion of SCAT region
as compared to its proportion in VAT [32, 150]. On the other
hand, a positive association was found between n-6 PUFA
content in adipose tissue and central obesity, and no differ-
ence in PUFA content has been found between SCAT and
VAT [32]. Sabin et al. reported that palmitic acid induced
significantly higher lipid accumulation in VAT as compared
to oleate, in contrast, the latter was associated with fat depo-
sition in SCAT [33]. Dietary PUFA perfectly mirrored their
content in adipose tissue, particularly SCAT [1, 150, 157],
however, MUFA and SFA contents in adipocyte might not
mirror their abundance in the diet because of the endogenous
synthesis of these FA [1, 150]. In this regard, the SFA con-
tent in adipocyte imposes some controversy; Garaulet et al.
reported a depot-specific variation in SFA contents of obese
adult subjects, where SFA was significantly higher in the
perivisceral region [32]. In contrast, Caron-Jobin et al. pre-
sented a negative correlation between BMI in obese women
and the adipocyte stearic acid content, which is the most
abundant SFA in Western diet and can be also synthesized
endogenously [150]. This latter finding can be explained
by an increased level of de novo synthesis of unsaturated
FA from dietary SFA, especially given the finding that the
increased desaturation level in SCAT is associated with
overall obesity and with higher levels of stearoyl-CoA
desaturase mRNA expression and protein abundance [150].
Therefore, the quality of dietary fat can even modulate the
distribution of body fat and further affect obesity level and
consequences.
Evidence suggests that the quality of fat determines
the risk of fat deposition and fat distribution. This effect
is directed, partly, by modulating the expression levels of
adipogenic and lipogenic genes, via genetic and epigenetic
modifications, as well as by the interaction with many
genetic variants. However, more clinical trials are needed
to validate the interactions between FA and adipogenesis-
related genes. The current clinical trial-based evidence sup-
port the beneficial effects of the increased consumption of
dietary unsaturated fatty acids, especially MUFA, at the
expense of SFA on weight loss/maintenance. The identified
interactions between obesity-related genes and the quality of
dietary fat may eventually lead to the use of genetic profile
for tailoring nutritional intervention provided to individuals
or population sub-group.

816 Lipids (2017) 52:803–822
1 3
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
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