Gene-nutrient interactions and susceptibility to human obesity
Castillo et al. Genes & Nutrition
Gene-nutrient interactions and susceptibility to human obesity
Joseph J. Castillo 0
Robert A. Orlando 0
William S. Garver 0
0 Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico Health Sciences Center , Albuquerque, NM 87131-0001 , USA
A large number of genome-wide association studies, transferability studies, and candidate gene studies performed in diverse populations around the world have identified gene variants that are associated with common human obesity. The mounting evidence suggests that these obesity gene variants interact with multiple environmental factors and increase susceptibility to this complex metabolic disease. The objective of this review article is to provide concise and updated information on energy balance, heritability of body weight, origins of gene variants, and gene-nutrient interactions in relation to human obesity. It is proposed that knowledge of these related topics will provide valuable insight for future preventative lifestyle intervention using targeted nutritional and medicinal therapies.
Energy balance; Gene-nutrient; Heritability; Metabolism; Obesity
The most recent report from the Centers for Disease
Control and Prevention indicates that 16.9% of children
and adolescents (2 to 19 years of age) and 34.9% of
adults (20 years of age and older) have obesity as defined
by a body mass index (BMI) greater than the
ageadjusted 95th percentile and 30 kg/m2, respectively [
To determine the molecular basis for obesity that has
reached epidemic proportions in the USA and other
developed countries, a large number of genome-wide
association studies (GWAS) have been performed to identify
obesity gene variants that increase susceptibility to this
common metabolic disease [
]. These GWAS and
subsequent transferability studies, in addition to
candidate gene studies performed in diverse populations
around the world, have identified gene variants that are
associated with common human obesity [
date, approximately 140 obesity susceptibility genes have
been found to be associated with measures of adiposity
(BMI, body fat percentage, and/or waist circumference),
and the recent progress is being made to define the
pathophysiology of human of human obesity [
chromosomal ideogram showing the loci of these obesity
susceptibility genes is provided (Fig. 1). The obesity
epidemic is a recent manifestation that has occurred during
the past few decades; and not all individuals or
populations are adversely affected, thereby suggesting
differences based on genetic variability and interaction with
environmental factors [
]. The combined
environmental factors comprising the “obesogenic environment”
include dietary nutrients, age, gender, ethnicity, duration
of sleep, amount of physical activity, sedentary behavior,
stress, smoking, alcohol consumption, use of medication,
and depression. It is generally accepted that, of these
environmental factors, a primary cause for susceptibility to
obesity is through gene-nutrient interactions. The
importance of gene-nutrient interactions in promoting
obesity and other complex metabolic diseases is
evidenced by the rapidly emerging scientific disciplines of
nutritional genetics (nutrigenetics) and nutritional
genomics (nutrigenomics) that may provide more effective
personalized healthcare [
]. It should be noted that a
number of brief review articles that focus on gene and
environment interactions in relation to obesity have
recently been published [
The cause of weight gain has often been considered in
terms of positive energy balance; the components of
which include increased energy intake, decreased energy
output, and energy deposition [
]. When energy in the
form of calories from food and drink is greater than
energy output resulting from (i) resting metabolic rate, (ii)
absorption and metabolism of dietary nutrients, (iii) heat
production or thermogenesis, and (iv) physical activity, a
state of positive energy balance results to promote
deposition of triacylglycerol within adipose tissue. In
contrast, when energy in the form of calories from food and
drink is less than energy output, a state of negative
energy balance results to promote lipolysis of
triacylglycerol and mobilization of fatty acids from adipose tissue.
It should be noted that although the physical laws of
thermodynamics provide exact values for these energy
transformations, the relative sign and magnitude of these
values does not provide information concerning the
physiological basis responsible for changes in energy
]. Moreover, although incapable of being
measured using current technology, mathematical
models have predicted that even small energy surpluses
or deficits (~1%) over time results in weight gain or
weight loss, respectively [
Heritability of body weight and interaction with environmental factors
A study performed by Sir Francis Galton over 100 years
ago provided the first evidence suggesting that measures
of growth (height and body weight) may be heritable
]. Since that time, the Hereditary Abilities Study,
which represented the first comprehensive study
performed in the USA to investigate heritability of physical
traits, indicated that the greater part for variance of
heritability was genetic [
]. This finding was consistent
with several other studies, indicating a high heritability
of body weight among twins that may or may not have
been influenced by interaction with the environment
]. A more recent study has reported that both
BMI and waist circumference are of high heritability
(77%), with only modest environmental effects for
children living in an obesogenic environment [
respect to the variance of heritability for BMI, a systematic
review of twin studies (140,525 twins) and family studies
(42,968 family members) indicated a wide range (47 to
90%) of heritability resulting from population differences
]. The population differences affecting variance of
heritability for BMI has stimulated an interest in
understanding how obesity susceptibility genes interact with
environmental factors to increase weight gain, in what
has formally become known as “gene-environment
interactions,” defined as a response or adaptation to an
environmental agent, a behavior, or a change in behavior,
conditional to the genotype of the individual [
example, a study using 12 monozygotic twins who
consumed a 1000 kcal/day surplus of calories for a period of
100 days while maintaining a sedentary lifestyle
demonstrated a gene-nutrient interaction in relation to weight
]. The results from this study showed a
significant within twin-pair resemblance in adaptation to the
excess calories (≥3 times more variance in response
between twin-pairs than within twin-pairs) indicating that
genetic susceptibility must have influenced the weight
gain. Moreover, a study designed to assess genetic and
environmental influences using 114 monozygotic twins,
81 dizygotic twins, and 98 virtual twins (same age but
unrelated siblings) indicated that genetic susceptibility
contributed ~65% to heritability for BMI [
heritability of childhood obesity was also closely examined
and confirmed in a study using 8234 children that
demonstrated a fourfold increase in risk for childhood
obesity if one parent was obese and a tenfold increase
risk for childhood obesity if both parents were obese
]. Therefore, it is now accepted that heritability can
contribute an estimated 40–70% to the variation of BMI
within populations [
]. It should also be noted that
genetic architecture for different forms of obesity,
whether rare Mendelian (syndromic and non-syndromic)
or non-Mendelian (common) obesity, are believed to
display variable phenotypes due to interactions with
other genes [
The “common disease, common variant” hypothesis
states that genetic risk for common diseases is due to
variants of high frequency [
]. It was once thought
that common variants of high frequency would explain
common disease heritability, defined as the proportion
of phenotypic variance in a population due to additive
genetic factors. However, after identifying hundreds of
different variants associated with common diseases, the
combination of variants were found to account for only
a small proportion of the estimated heritability . In
other words, although the estimated heritability for BMI
within populations was 40–70% (heritability inferred
indirectly from population data and provided in the
denominator), only a few percent of the actual
heritability was accounted for through the combined
phenotypic effect size or penetrance of known
variants (heritability determined directly from effect sizes
and provided in the numerator) [
]. Thus, there
was increasing concern that identification of “missing
heritability,” or what has more appropriately been
termed “hidden heritability,” would be necessary to
understand how variants contribute to common
diseases for successful translation of this information
into clinical practice [
]. It is speculated that the
identified GWAS variants may be in partial
linkagedisequilibrium with low-frequency variants with larger
phenotypic effect sizes, thereby accounting for the
missing heritability [
]. Although some
lowfrequency variants of intermediate effect size were
found to exist in partial linkage-disequilibrium with
GWAS variants, other studies suggest that these rare
variants are unlikely to account for the missing
]. Moreover, it was proposed that the
amount of missing heritability was overestimated and
therefor represented as “phantom heritability” and
that unidentified gene interactions (gene-gene and
gene-nutrient) may account for any remaining
heritability . Finally, in hopes of resolving the case of
missing heritability for common diseases, studies now
indicate that imputed variants are capable of
accounting for a large proportion (~30%) of the estimated
heritability for body weight, with the remaining
proportion likely accounted for by unidentified gene
Thrifty and drifty genotype hypotheses
Consistent with obesity susceptibility gene variants
interacting with an obesogenic environment to increase
obesity, James V. Neel proposed the thrifty genotype
hypothesis based on positive selection (adaptation) of
“thrifty genes” resulting from seasonal food shortages
and episodic famines during human evolution [
A number of years later, John R. Speakman proposed the
drifty genotype hypothesis based on neutral selection
(genetic drift) of “drifty genes” resulting from predation
release characterized by liberation from predation
pressures due to the advent of fire and development of more
advanced weapons technology, thereby, in effect,
increasing the upper limit of body weight set points [
]. In support of both these hypotheses, commentaries
published by experts in the field suggest that positive
and neutral selection of gene variants has occurred
during human evolution to optimize efficient storage of
food energy for later use when food becomes limiting
]. This commentary is also evidenced by a recent
study performed with 9416 individuals in 14 European
countries indicating that although environmental
differences masked genetic differentiation for BMI, it was
determined that 8% of the captured additive genetic
variance for BMI was reflected in population genetic
]. However, some studies have questioned
the thrifty genotype hypothesis due to the high
prevalence of obesity within certain populations, such as those
populations in the South Pacific, because past seasonal
food shortages and episodic famines are believed not to
have occurred, and that a recent comprehensive study
performed using signatures of positive selection at
obesity susceptibility gene variants did not find evidence for
the “thrifty gene” hypothesis [
]. However, other
studies have provided evidence of “thrifty gene variants”
present within the CREBFR gene among Samoans and
the PPARGC1A gene among Tongans in the South
Pacific, thereby explaining high rates of obesity among
these two populations [
]. Therefore, it is anticipated
that the intellectual debate concerning origin of obesity
susceptibility genes will continue.
The obesogenic environment consists of a complex
interplay of contributing factors that influence behavior
effecting dietary choice, physical activity, and/or
metabolism responsible for maintaining energy balance [
number of studies suggest that both sedentary behavior
(viewing television, playing video games, doing cognitive
work, and listening to music) and reduced overall
physical activity in addition to shorter sleep duration
promote the overconsumption of dietary nutrients,
particularly fats and refined carbohydrates [
increased consumption of a high-fat diet, particularly a
high-fat diet enriched with saturated fatty acids, has
been found to be strongly associated with increased
adiposity in children [
]. Moreover, another recent
study performed using 810 participants indicated a
highly significant association of saturated fatty acid
consumption (but not plant protein, carbohydrates, or other
types of fat) at 6 months with body weight at 18 months
of age . Consistent with these results, obesity
susceptibility genes have been reported to preferentially
interact with saturated fatty acids, but not monounsaturated
fatty acids or polyunsaturated fatty acids, to promote
weight gain [
]. For these reasons, it is widely
accepted that high-fat diets, characterized by enhanced
palatability and high energy density, may have a primary
role for the obesity epidemic. However, it should also be
noted that increased consumption of carbohydrates,
particularly refined carbohydrates and sugar-sweetened
beverages, during the past 30 years also parallels the
increased prevalence of obesity [
Susceptibility genes for human obesity
Over the course of the decade (1996–2005) preceding
GWAS, an extensive amount of work was performed to
identify susceptibility genes for human obesity. The
culmination of these studies resulted in the identification of
140 candidate susceptibility genes [
]. However, to date
only a limited number (~25%) of these obesity
susceptibility genes have been validated using independent
studies. These genes now represent a comprehensive list of
obesity susceptibility candidates that are associated with
measures of adiposity (BMI, body fat percentage, and
waist circumference) [
]. It should be noted that
in most cases, the biological function of the encoded
proteins and gene products derived from these obesity
susceptibility genes remains undefined and therefore
further studies must be performed using cells grown in
culture, animal models, and diverse ethnic populations
before development of targeted nutritional or medicinal
Gene-nutrient interactions that promote obesity
The best characterized obesity susceptibility gene known
to interact with a dietary nutrient that predisposes to
weight gain was identified using a candidate gene
approach followed by a number of population-based
studies. The apolipoprotein A2 (APOA2) gene is a member
of the apolipoprotein multigene family for which the
encoded APOA2 protein is associated with high-density
lipoprotein (HDL), which modulates activity of
lipoprotein lipase to influence liver lipogenesis and adipose
]. An initial study indicated that individuals
who are homozygous affected for the loss-of-function
APOA2 variant (rs5082) had increased measures of
adiposity (body weight, BMI, and waist circumference)
characterized with increased consumption of food
composed of fat and protein compared to individuals who
are homozygous normal or heterozygous for this gene
variant . A second study identified an association
between homozygous affected individuals for the same
gene variant and consumption (≥22 g/day) of saturated
fat (but not unsaturated fat) compared to individuals
homozygous normal or heterozygous for this gene
]. A third study indicated an interaction between
this gene variant and consumption (≥ 22 g/day) of
saturated fat (but not unsaturated fat) resulting in a 6.8%
greater BMI compared to individuals homozygous
normal or heterozygous from his gene variant in the same
]. And finally, the physiological basis for
the APOE gene variant and saturated fat was shown to
result from behavioral changes that prevented weight
loss (do not skip meals) and less likelihood to exhibit
protective behavior (do not plan meals) based on the
modulation of plasma ghrelin [
]. A more recent
study has also reported that physical activity can
diminish the genetic effect of a different fat mass and
obesityassociated (FTO) gene variant (rs1421085) for adiposity
by 36–75% in a longitudinal multi-ethnic group
consisting of 17,423 individuals [
]. Finally, the GWAS that
identified the FTO gene also identified the
NiemannPick C1 (NPC1) gene to be associated with morbid-adult
obesity in European populations [
]. When this study
was published, it was unknown whether the NPC1 gene
risk variants (644A > G encoding His215Arg and
2572A > G encoding Ile858Val) increased or decreased
NPC1 protein function. To address this question and
further investigate the NPC1 gene in relation to obesity,
the BALB/cJ Npc1 mouse model was used possessing a
retroposon insertion that prematurely terminated
protein translation, thereby producing a non-functional
truncated NPC1 protein [
]. The results
indicated that compared to the Npc1 homozygous normal
(Npc1+/+) mice, the Npc1 heterozygous (Npc1+/-) mice
with decreased gene dosage were susceptible to weight
gain when fed a high-fat diet, but not when fed a low-fat
]. This study was extended using
BALB/cJC57BL/6J hybrid Npc1+/- mice that were also susceptible
to weight gain and impaired glucose tolerance when fed
a high-fat diet compared to hybrid Npc1+/+ mice fed the
same diet [
]. Moreover, a subsequent study found
that the C57BL/6J Npc1+/- mice are susceptible to
weight gain when fed a high-fat diet compared to
C57BL/6J Npc1+/+ mice fed the same diet [
independent study has since been reported that rare
human NPC1 gene loss-of-function mutations among male
heterozygotes (but not female heterozygotes) have a
significantly higher BMI compared to matched
controls and that Npc1+/- mice fed a HFD have
significantly increased fat storage compared to Npc1+/+
mice fed the same diet [
]. The physiological basis
for the Npc1 gene-nutrient interaction has recently
been characterized by increased liver glycolysis and
lipogenesis with an accumulation of hepatic
triacylglycerol and cholesterol, in combination with
decreased white adipose tissue activation of
hormonesensitive lipase and decreased triacylglycerol lipolysis
]. In support of these results, cellular energy
metabolism studies indicated that Npc1+/- fibroblasts had
significantly increased glycolysis and lipogenesis in
addition to significantly decreased substrate (glucose
and endogenous fatty acid) oxidative metabolism
resulting in an accumulation of triacylglycerol and
cholesterol (Fig. 2). Finally, instead of examining just
one obesity susceptibility gene and interaction with a
dietary nutrient, a relatively large number of validated
obesity susceptibility genes (32) were examined using
a genetic risk score that was found to interact with a
dietary nutrient. The first study used a combined
cohort of 6934 women from the Nurses’ Health Study
(NHS) and 4423 men from the Health Professionals
Follow-Up Study (HPFS) which indicated an increase
in relative risk of 1.19 for less than one serving per
month of a sugar-sweetened beverage, 1.67 for one to
four servings per month, 1.58 for two to six servings
per month, and 5.06 for one or more servings per
]. A subsequent study using a genetic risk
score and combined cohort indicated an increase in
relative risk of 1.61 for less than one serving of fried
food per week, 2.12 for one to three servings per
week, and 2.72 for four or more servings per week
]. In yet a third study, a genetic risk score of 32
obesity susceptibility genes was used to determine
interaction with self-reported intake of various foods
(healthy and unhealthy) using 18 combined cohorts of
European ancestry (68,317 individuals) [
Interestingly, although there was no significant gene-diet
Fig. 2 A general diagram showing the physiological basis responsible for the NPC1 gene-nutrient interaction that promotes weight gain and
susceptibility to obesity. Mouse model tissues (liver and adipose) and fibroblasts grown in culture indicate (i) increased glycolysis (oxidation of
glucose and conversion to pyruvate in the cytoplasm), (ii) decreased oxidative metabolism (conversion of pyruvate to acetyl-CoA and condensation
with oxaloacetate to produce citrate in the mitochondria), (iii) increased lipogenesis pathway (transport of citrate from the mitochondria
and conversion to acetyl-CoA and malonyl-CoA for lipid (cholesterol and fatty acid) synthesis in the cytoplasm), and (iv) decreased lipolysis pathway
(transport of fatty acid from the cytoplasm and conversion of fatty acid to acetyl-CoA in the mitochondria)
interaction detected using the genetic risk score for
obesity traits (BMI), the results did reveal that two
genes (LRRN6C and MTIF3) for obesity traits were
actually stronger for individuals consuming healthy
Nutritional and pharmacological intervention
The current literature clearly indicates that public health
interventions are unable to achieve success in long-term
weight loss. A basic science approach must be
incorporated to more directly address behavioral and
physiological reasons for the continuing obesity epidemic
]. The goal for successful nutritional and
pharmacological intervention of obesity depends on
delineating the physiological basis for how obesity
susceptibility genes promote positive energy balance and
weight gain responsible for obesity. For instance, the
FTO and melanocortin 4 receptor (MC4R) gene variants
tend to increase preference for calorie-dense foods
enriched with fat and decrease satiety. Although
nutritional therapies have not yet been identified that
stimulate regions of the brain (arcuate nucleus of the
hypothalamus) to promote satiety for individuals
harboring these gene variants, a recent study has reported that
a new pharmacological agonist (setmelanotide) has been
successful in producing sustained reduction in hunger
and body weight (51.0 kg after 42 weeks in one patient
and 20.5 kg after 12 weeks in a second patient) for
patients with proopiomelanocortin deficiency as a result of
]. Moreover, other pharmacological
therapies that are being used to treat obesity include orlistat
(Xenical), lorcaserin hydrochloride (Belviq), phentermine
and topiramate (Qsymia), bupropion and naltrexone
(Contrave), and liraglutide (Saxenda). With respect to
the NPC1 gene that interacts with a high-fat diet to
cause dysregulation of differential energy metabolism
pathways, different therapies will be required to limit
hepatic lipogenesis and adipose lipolysis. Of course, for
any of the obesity susceptibility genes and encoded
proteins that are now being investigated, the overall goal of
achieving complete efficacy for nutritional and
pharmacological interventions will be modeled after the success
of recombinant leptin for those individuals with
congenital leptin deficiency [
]. Finally, in closing this
section, it should be noted that all macronutrients
(carbohydrates, protein, and fat) have unique properties
that will impact regulation of energy metabolism genes
and/or encoded protein to affect whole-body energy
The current epidemic of obesity represents a complex
metabolic disease characterized in part by the interaction
of obesity susceptibility gene variants with dietary
nutrients. The continued investigation of gene-nutrient
interactions responsible for this health problem will be
important for several reasons. First, diseases such as
obesity and associated complications result from
undefined and complex interactions between susceptibility
gene variants and various environmental factors [
The obesity susceptibility genes described in this review
article interact with nutrients to either increase
consumption of saturated fat or refined carbohydrates and
to alter regulation of central metabolism pathways to
increase weight [
]. Second, the identification of
gene-nutrient interactions should be at the forefront in
attempts to understand the etiology and pathophysiology
of nutrition-related diseases, particularly obesity .
Third, the interaction of obesity susceptibility genes with
nutrients will allow for more effective individual, family,
and community preventative lifestyle intervention and
eventually development of targeted nutritional or
medicinal therapies [
]. Therefore, the overarching
goal for investigating gene-nutrient interactions is to
provide a plausible physiological approach to
personalized nutritional or medicinal therapy that will more
effectively address the current epidemic of common
APOA2: Apolipoprotein A2; BMI: Body mass index; FDA: Food and Drug
Administration; FTO: Fat mass and obesity associated; GWAS: Genome-wide
association study; HDL: High-density lipoprotein; HPFS: Health Professionals
Follow-Up Study; MC4R: Melanocortin 4 receptor; NHS: Nurse’s Health Study;
NPC1: Niemann-Pick C1
This work was supported in part by the National Center for Research
Resources and the National Center for Advancing Translational Sciences of
the National Institutes of Health (NIH) through grant number UL1 TR000041,
a grant from Dedicated Health Research Funds of the University of New
Mexico School of Medicine, and private funding through the University of
New Mexico Foundation for the investigation of genetic and metabolic
Availability of data and materials
Authors will make any data relevant to this review article available upon
JJC contributed to the manuscript writing and editing and figure generation.
RO and WSG contributed to the manuscript writing and editing. All authors
read and approved the final manuscript.
Ethics approval and consent to participate
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The authors declare that they have no competing interests.
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