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compilation © 2007 The

International Association for the Study of Obesity? 20078••7781Review ArticleNutrigenomic approaches for obesity research R. M. Elliott & I. T. Johnson

obesity reviews

Nutrigenomic approaches for obesity research

R. M. Elliott and I. T. Johnson

Institute of Food Research, Colney, Norwich, UK Keywords: Genetics, genomics, nutrition, obesity.

Accepted 27 November 2006

Address for correspondence: Dr RM Elliott and

Professor IT Johnson, Institute of Food
Research, Norwich Research Park, Colney,
Norwich, NR4 7UA, UK.
E-mail: ruan.elliott@bbsrc.ac.uk;
ian.johnson@bbsrc.ac.uk

OnlineOpen: This article is available free online at www.blackwell-synergy.com obesity reviews (2007) 8 (Suppl. 1), 77–81

interactions). Although the term ‘nutrigenomics’, in its

Background
At the individual level, weight gain is essentially the result
of energy intake exceeding expenditure for significant peri-
ods of time, but this obvious truth provides no insight into
the strategies needed to deal with the ever-increasing prob-
lem of obesity in Western populations. It is equally obvious,
however, that certain individuals are more prone to devel-
oping obesity than others. This phenomenon invites the
nutrition research community to explore the physiological
basis for such differences and ultimately to design more
targeted and personalized approaches to the control of
body weight (1).
Novel research strategies are required to understand the
molecular mechanisms controlling energy balance. In par-
allel with such studies, there is still much to be learned
about the metabolic consequences that follow when an
appropriate energy balance is not maintained, and how this
relates to risks of diseases such as hypertension, heart dis-
ease, stroke, diabetes and certain cancers. The developing
fields of nutrigenetics and nutrigenomics, with their accom-
panying battery of high-throughput technologies, provide
an unprecedented opportunity to cope with the complexity
of this condition and to develop the knowledge base
required.
Terminology: nutrigenetics and nutrigenomics
The term ‘nutrigenetics’ is generally used to refer to the
impact of genetic variation on optimal dietary requirements
for an individual (i.e. in the simplest terms: gene → diet
broadest sense, encompasses nutrigenetics, more com-
monly the main focus of nutrigenomics is considered to be
on how diet regulates gene function (transcription and
translation) and metabolism (i.e. diet → gene interac-
tions) (2).
Nutrigenetics and obesity
Genetic differences play an important role in the develop-
ment of obesity, although it is clear that these are by no
means the only contributing factors. Environmental and
social factors are also very important. The relative contri-
butions of genetic and socioeconomic factors to the devel-
opment of obesity, and the ways in which these interact in
human societies, are largely unknown.
The genetic code (DNA sequence) carried by any two
unrelated people is approximately 99.9% identical. It is
the variation in the sequence of the remaining 0.1% that
determines the genetic component of inter-individual dif-
ferences in disease risk, and presumably also their differing
responses to the nutritional environment. Sites in the DNA
where the sequences of individuals differ commonly (e.g.
in at least 1% of the population) are called polymorphisms;
the most common form being a single letter change in the
code termed a ‘single nucleotide polymorphism’ (SNP). As
each cell contains two copies of every gene (except those
present on the sex chromosomes), one individual may carry
various combinations of a polymorphism. The term ‘geno-
type’ refers to the combination of sequences in the two
copies of a gene for a particular polymorphism.

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78 Nutrigenomic approaches for obesity research R. M. Elliott & I. T. Johnson
The most recent update of the human obesity gene map
emphasizes just how complex the genetic component of
obesity alone is. There are currently more than 600 genes,
markers and chromosomal regions that have been associ-
ated or linked with human obesity, and more are added to
this list with each update (http://obesitygene.pbrc.edu/) (3).
To date, syndromes of obesity because of single-gene muta-
tions have been described for at least 10 different genes.
These cases provide immensely valuable insights into the
roles of these genes, and to their contributions to key
processes, most notably appetite, that influence the devel-
opment of obesity. However, such syndromes are extremely
rare and therefore of limited relevance to the majority of
obese individuals.
The effects of the common genetic polymorphisms asso-
ciated with ‘sporadic’ obesity at the population level are
much harder to study for two main reasons. First, the
effects of each polymorphism are more subtle, generally
modulating the risk of developing obesity by perhaps a few
percent, rather than inevitably leading to severe and intrac-
table weight gain. Their effects are more difficult to detect
reliably in a diverse population with varied lifestyles. Sec-
ond, interactions between genotypes for obesity-linked
genes may be important. For example, particular combina-
tions of genotypes may cancel each other out. Alternatively,
some combinations of genotypes may interact to enhance
or reduce risk to a greater extent than the sum of the effect
of each genotype considered in isolation.
Given the number of genes implicated so far, and the fact
that many more may yet be identified, characterizing all the
genes involved in obesity, let alone examining their possible
interactions, appears a truly daunting task. However, some
recent developments help to make this work more feasible.
These include the development of technologies capable of
parallel genotyping analysis for hundreds of thousands of
SNPs from a single small blood or tissue sample (4). It is
estimated that there are about 10 million SNPs in human
populations. This scale currently still exceeds the capacity
of the new platform technologies, but SNPs that are
located close together in the DNA sequence on the same
chromosome tend to be inherited together. A set of such
associated SNPs is termed a ‘haplotype’ and it turns out
that most chromosome regions have only a few common
haplotypes. So, while a chromosome region may contain
many SNPs, it is possible that analysing only a few ‘tag’
SNPs can provide most of the information on the pattern
of genetic variation in that region. Defining these haplotype
blocks and the most reliable tag SNPs are the goals of the
International HapMap Project (http://www.hapmap.org/)
(5). Realizing these goals will help to bring the complexity
of genetic studies down towards a level that may be
manageable.
In spite of the rapid pace of technical developments, the
history of genetic association studies addressing subtle and
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obesity reviews
complex associations indicates that the reliable detection
of true associations, and the avoidance of false positives,
will continue to be a significant challenge (6,7). Appropri-
ate study design and improved statistical approaches will
be vital (8–10). Ultimately, this type of work will require
studies involving very large numbers of human subjects.
There is therefore an obvious need to promote new inter-
national collaborations, bringing together the large and
well-defined cohorts of human subjects that have already
been established, to achieve the study power necessary
(11).
Nutrigenomics and obesity
The potential impact of functional genomic approaches
(transcriptomics, proteomics and metabolomics) in nutri-
tion has been reviewed extensively (12–16). This potential
is now starting to be realized, with the publication of an
increasing flow of nutrigenomic studies each giving new
mechanistic insights.
Transcriptomics
The transcriptome is the complete collection of RNA tran-
scripts produced from the DNA in a genome. Transcrip-
tomics is performed using microarray technology, which
enables the transcript levels for many tens of thousands of
genes to be studied simultaneously. This technology is ide-
ally suited to the study of the metabolic syndrome and the
associated inflammatory signals that underlie many of the
comorbidities linked to the obese state. Microarrays have
been used to define the changes in patterns of gene expres-
sion at the level of RNA in the adipose and other tissues
of different strains of lean and obese mice, revealing char-
acteristic and tissue-specific alterations in the expression of
genes involved in adipogenesis, inflammation and gluco-
neogenesis (17,18).
More limited work has been performed with samples
from human subjects. Some regional differences in gene
expression within different fat depots have been described
and a number of studies have examined the effects of
weight loss/caloric restriction on patterns of gene expres-
sion in adipose tissue from obese subjects (19). Preliminary
studies have also been performed on the patterns of gene
expression in regions of the human brain that are known
to show differential responses to nutritional stimuli in
obese vs. lean individuals (20). These types of studies pro-
vide a much broader perspective on the effects of obesity
than was possible before the development of microarrays
and a wealth of new information and research leads. How-
ever, a more comprehensive and focused programme will
be required to obtain a robust overview for the changes in
gene expression related to obesity and their biological sig-
nificance in relation to health.
© 2007 Queen’s Printer and Controller of HMSO; published with permission
obesity reviews Nutrigenomic approaches for obesity research
Proteomics
The proteome is the full complement of proteins produced
from the transcriptome, including all subsequent modifica-
tions that the proteins may undergo. To date, proteomics
has been used less extensively in nutrigenomic studies than
transcriptomics but it has just as much potential (21). The
use of protein expression patterns as ‘biomarkers of vul-
nerability’ to obesity-related diseases such as colorectal
cancer is one approach (22). Studies relating directly to the
physiology and biochemistry of obesity have examined pat-
terns of protein expression in adipocytes during differenti-
ation (23,24), the effects of a high-fat diet on protein
expression in different target tissues in mice (25) and have
compared skeletal muscle of lean and obese women (26).
In addition to its use in the analysis of gene expression
in tissues, proteomics provides a possible route for the
identification and validation of new protein biomarkers
that can be detected in plasma. The international HuPO
Plasma Proteome Project is providing new resources (pro-
tein databases and optimized experimental standards) that
will be essential for this kind of work (27).
Metabolomics
Metabolomics is the study of the sum total of endogenous
and exogenous metabolites in a cell, an organ, or in body
fluids, and is the newest of the ‘omic’ technologies. It is
ideally suited, both from a technical and scientific stand-
point, to the global analysis of metabolite patterns in body
fluids (plasma/serum/urine, etc.), which are comparatively
easy to access in human volunteers.
The mass spectrometry and nuclear magnetic resonance
techniques that are used to analyse the composition of these
fluids are capable of very high sample throughput at com-
paratively low cost (after the initial set-up of the machin-
ery). It is therefore possible to generate large datasets very
fast. These approaches have already been demonstrated to
be sensitive enough to detect the often subtle effects of
dietary modification, and should lend themselves readily to
the detection of metabolic differences, both between indi-
viduals with differing susceptibilities to chronic weight
gain, and within individuals who are undergoing significant
changes in body weight and adiposity (28,29).
There is also increasing interest in the use of metabolo-
mic profiles as markers of dietary habits and as a descriptor
of nutritional phenotype (30). Before this concept can be
developed further, the influence of potential confounding
factors (e.g. age, gender, ethnicity, physical activity and gut
microflora) has to be defined.
Another challenge is that present metabolomic technol-
ogies generate metabolite profiles for which the majority of
signals are not immediately identified. While these profiles
may be used with multivariate statistical tools for diagnos-
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Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 77–81
R. M. Elliott & I. T. Johnson 79
tic/classification analyses, the absence of the full range of
identified metabolites limits the biological interpretation of
the data.
The challenges and potential of nutrigenomics
and nutrigenetics
The potential of nutrigenomic and nutrigenetic approaches
is starting to be realized. A great deal of progress has
already been made and, by applying new analytical tools
to the data already generated, it has proven possible not
only to obtain lists of gene products and metabolites that
change in response under defined conditions but also to
gain insights into the overall biological processes involved.
Another emerging challenge that may well carry impli-
cations for the development of obesity research is that of
‘epigenomics’. This can be defined as the study of heritable
epigenetic signals, encoded in patterns of DNA methylation
and histone acetylation within the chromatin, that modu-
late the expression of genes (31). Epigenetic marks have
recently been shown to change in response to environmen-
tal factors over an individual’s lifetime (32), so even iden-
tical twins may ultimately develop differing susceptibilities
to adverse environmental factors. As the massive task of
mapping the human epigenome progresses, it will become
possible to explore the role of epigenetic effects, both as
causes and possible consequences of obesity.
Continuing development of improved statistical and
bioinformatic tools means that the conclusions of the
data analyses are becoming more robust and sensitive.
New text-mining tools are starting to make it easier to
interrogate the full body of scientific literature and thus to
place new findings within the context of current scientific
knowledge. The next challenge is to develop tools to inte-
grate the different types of data and start to realize the
vision of nutritional systems biology. In all these areas,
the European Nutrigenomics Organization (NuGO, http://
www.nugo.org) is working to identify bottlenecks and
emerging technical requirements and seeking solutions to
them.
Not least among the many challenges are the needs for
quality control, standardization, data capture and storage
of nutrigenomic and nutrigenetic data. The ‘omic’ tools
produce vast quantities of data rapidly. If we are to make
use of this information, rather than drown in the flood, it
is essential that the data collected are of high quality and
are captured in a manner that enables them to be stored
and exchanged readily. Standardization of data capture for
microarray studies has already been addressed (33) and
equivalent procedures are in development for proteomic
and metabolomic studies (34,35). Refinements to these
data capture systems are likely to include appropriate
data-quality metrics and specialty-specific metadata. For
example, NuGO is working with international organiza-
80 Nutrigenomic approaches for obesity research R. M. Elliott & I. T. Johnson
tions from other specialties on the development of the
Reporting Structure for Biological Investigations Tiered
Checklist (RSBI-TC, http://www.mged.org/Workgroups/
rsbi/rsbi.html), both through contributions to the design
of core modules and through the development of the
nutrition-specific component.
Finally, beyond the ‘omic’ technologies, there is clearly
an emerging need for the development of non-invasive tech-
niques that will allow biological processes to be visualized
in remote tissues in vivo. These will be essential for future
studies with human volunteers to confirm that the dietary
effects characterized in model systems also occur in target
tissues in humans in the manner predicted.
Conclusion
Thus, to date, nutrigenomic/nutrigenetic research in obesity
has provided insights in three major areas. First, the iden-
tity of many genes in which polymorphisms can affect the
propensity to develop obesity and related conditions such
as diabetes and cardiovascular disease and, second, char-
acteristic changes in patterns of gene expression in adipose
and other tissues associated with obesity. In turn, these
have provided indications as to the processes involved and
their biological consequences.
Cutting-edge work in this area at the moment involves
further validation, optimization and standardization of the
‘omic’ technology platforms and how they are used for
nutritional studies as well as the development of improved
statistical and bioinformatic methods to enable the full
biological meaning of the vast datasets produced to be
extracted. New biomarkers of health, and the more rigor-
ous characterization of lean and obese phenotypes at the
molecular level are being developed. The different ‘omic’
and bioinformatic approaches to realize the vision of nutri-
tional systems biology are in the process of integration, and
non-invasive techniques to facilitate future studies in
humans are in development.
What could the full exploitation of nutrigenomic/
nutrigenetic approaches provide during the next
25 years?
In 5–10 years, a detailed overview of the molecular mech-
anisms that control energy balance will be available. In 5–
15 years, a mechanistic definition of the metabolic conse-
quences of failure to maintain appropriate energy balance
and how this relates to the development of associated dis-
eases is likely. A longer time frame (up to 20 years) will see
detailed analyses of the basis of individual variation in
obese individuals, both in the propensity to develop obesity
and the propensity to develop associated diseases. In par-
allel with this, and perhaps 25 years away, is the creation
of a comprehensive knowledge base to be used for the
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obesity reviews
development of targeted strategies to reduce obesity inci-
dence and severity and the burden of chronic disease at the
population level.
However, it is important to note what the main barriers
are in this area of research, as these could prevent such a
full exploitation of the potential of nutrigenetics and
nutrigenomics. The human system is immensely complex
and individual variation very diverse. Coping with this may
be difficult, as will designing and executing studies of suf-
ficient power to define the effects of, and interaction
between, genetic, epigenetic and dietary factors, which may
be subtle in the short term but profound over many years
or a lifetime.
Conflict of Interest Statement
No conflict of interest was declared.
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