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Blackwell Publishing LtdOxford, UKOBRObesity Reviews1467-7881© 2007 Queen’s Printer and Controller of HMSO; published with permission; Journal

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

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry
© 2007 Queen’s Printer and Controller of HMSO; published with permission
Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 77–81 77
78 Nutrigenomic approaches for obesity research R. M. Elliott & I. T. Johnson obesity reviews

The most recent update of the human obesity gene map complex associations indicates that the reliable detection
emphasizes just how complex the genetic component of of true associations, and the avoidance of false positives,
obesity alone is. There are currently more than 600 genes, will continue to be a significant challenge (6,7). Appropri-
markers and chromosomal regions that have been associ- ate study design and improved statistical approaches will
ated or linked with human obesity, and more are added to be vital (8–10). Ultimately, this type of work will require
this list with each update (http://obesitygene.pbrc.edu/) (3). studies involving very large numbers of human subjects.
To date, syndromes of obesity because of single-gene muta- There is therefore an obvious need to promote new inter-
tions have been described for at least 10 different genes. national collaborations, bringing together the large and
These cases provide immensely valuable insights into the well-defined cohorts of human subjects that have already
roles of these genes, and to their contributions to key been established, to achieve the study power necessary
processes, most notably appetite, that influence the devel- (11).
opment of obesity. However, such syndromes are extremely
rare and therefore of limited relevance to the majority of
Nutrigenomics and obesity
obese individuals.
The effects of the common genetic polymorphisms asso- The potential impact of functional genomic approaches
ciated with ‘sporadic’ obesity at the population level are (transcriptomics, proteomics and metabolomics) in nutri-
much harder to study for two main reasons. First, the tion has been reviewed extensively (12–16). This potential
effects of each polymorphism are more subtle, generally is now starting to be realized, with the publication of an
modulating the risk of developing obesity by perhaps a few increasing flow of nutrigenomic studies each giving new
percent, rather than inevitably leading to severe and intrac- mechanistic insights.
table weight gain. Their effects are more difficult to detect
reliably in a diverse population with varied lifestyles. Sec-
Transcriptomics
ond, interactions between genotypes for obesity-linked
genes may be important. For example, particular combina- The transcriptome is the complete collection of RNA tran-
tions of genotypes may cancel each other out. Alternatively, scripts produced from the DNA in a genome. Transcrip-
some combinations of genotypes may interact to enhance tomics is performed using microarray technology, which
or reduce risk to a greater extent than the sum of the effect enables the transcript levels for many tens of thousands of
of each genotype considered in isolation. genes to be studied simultaneously. This technology is ide-
Given the number of genes implicated so far, and the fact ally suited to the study of the metabolic syndrome and the
that many more may yet be identified, characterizing all the associated inflammatory signals that underlie many of the
genes involved in obesity, let alone examining their possible comorbidities linked to the obese state. Microarrays have
interactions, appears a truly daunting task. However, some been used to define the changes in patterns of gene expres-
recent developments help to make this work more feasible. sion at the level of RNA in the adipose and other tissues
These include the development of technologies capable of of different strains of lean and obese mice, revealing char-
parallel genotyping analysis for hundreds of thousands of acteristic and tissue-specific alterations in the expression of
SNPs from a single small blood or tissue sample (4). It is genes involved in adipogenesis, inflammation and gluco-
estimated that there are about 10 million SNPs in human neogenesis (17,18).
populations. This scale currently still exceeds the capacity More limited work has been performed with samples
of the new platform technologies, but SNPs that are from human subjects. Some regional differences in gene
located close together in the DNA sequence on the same expression within different fat depots have been described
chromosome tend to be inherited together. A set of such and a number of studies have examined the effects of
associated SNPs is termed a ‘haplotype’ and it turns out weight loss/caloric restriction on patterns of gene expres-
that most chromosome regions have only a few common sion in adipose tissue from obese subjects (19). Preliminary
haplotypes. So, while a chromosome region may contain studies have also been performed on the patterns of gene
many SNPs, it is possible that analysing only a few ‘tag’ expression in regions of the human brain that are known
SNPs can provide most of the information on the pattern to show differential responses to nutritional stimuli in
of genetic variation in that region. Defining these haplotype obese vs. lean individuals (20). These types of studies pro-
blocks and the most reliable tag SNPs are the goals of the vide a much broader perspective on the effects of obesity
International HapMap Project (http://www.hapmap.org/) than was possible before the development of microarrays
(5). Realizing these goals will help to bring the complexity and a wealth of new information and research leads. How-
of genetic studies down towards a level that may be ever, a more comprehensive and focused programme will
manageable. be required to obtain a robust overview for the changes in
In spite of the rapid pace of technical developments, the gene expression related to obesity and their biological sig-
history of genetic association studies addressing subtle and nificance in relation to health.

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry
© 2007 Queen’s Printer and Controller of HMSO; published with permission
Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 77–81
obesity reviews Nutrigenomic approaches for obesity research R. M. Elliott & I. T. Johnson 79

tic/classification analyses, the absence of the full range of


Proteomics
identified metabolites limits the biological interpretation of
The proteome is the full complement of proteins produced the data.
from the transcriptome, including all subsequent modifica-
tions that the proteins may undergo. To date, proteomics
The challenges and potential of nutrigenomics
has been used less extensively in nutrigenomic studies than
and nutrigenetics
transcriptomics but it has just as much potential (21). The
use of protein expression patterns as ‘biomarkers of vul- The potential of nutrigenomic and nutrigenetic approaches
nerability’ to obesity-related diseases such as colorectal is starting to be realized. A great deal of progress has
cancer is one approach (22). Studies relating directly to the already been made and, by applying new analytical tools
physiology and biochemistry of obesity have examined pat- to the data already generated, it has proven possible not
terns of protein expression in adipocytes during differenti- only to obtain lists of gene products and metabolites that
ation (23,24), the effects of a high-fat diet on protein change in response under defined conditions but also to
expression in different target tissues in mice (25) and have gain insights into the overall biological processes involved.
compared skeletal muscle of lean and obese women (26). Another emerging challenge that may well carry impli-
In addition to its use in the analysis of gene expression cations for the development of obesity research is that of
in tissues, proteomics provides a possible route for the ‘epigenomics’. This can be defined as the study of heritable
identification and validation of new protein biomarkers epigenetic signals, encoded in patterns of DNA methylation
that can be detected in plasma. The international HuPO and histone acetylation within the chromatin, that modu-
Plasma Proteome Project is providing new resources (pro- late the expression of genes (31). Epigenetic marks have
tein databases and optimized experimental standards) that recently been shown to change in response to environmen-
will be essential for this kind of work (27). 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
Metabolomics
mapping the human epigenome progresses, it will become
Metabolomics is the study of the sum total of endogenous possible to explore the role of epigenetic effects, both as
and exogenous metabolites in a cell, an organ, or in body causes and possible consequences of obesity.
fluids, and is the newest of the ‘omic’ technologies. It is Continuing development of improved statistical and
ideally suited, both from a technical and scientific stand- bioinformatic tools means that the conclusions of the
point, to the global analysis of metabolite patterns in body data analyses are becoming more robust and sensitive.
fluids (plasma/serum/urine, etc.), which are comparatively New text-mining tools are starting to make it easier to
easy to access in human volunteers. interrogate the full body of scientific literature and thus to
The mass spectrometry and nuclear magnetic resonance place new findings within the context of current scientific
techniques that are used to analyse the composition of these knowledge. The next challenge is to develop tools to inte-
fluids are capable of very high sample throughput at com- grate the different types of data and start to realize the
paratively low cost (after the initial set-up of the machin- vision of nutritional systems biology. In all these areas,
ery). It is therefore possible to generate large datasets very the European Nutrigenomics Organization (NuGO, http://
fast. These approaches have already been demonstrated to www.nugo.org) is working to identify bottlenecks and
be sensitive enough to detect the often subtle effects of emerging technical requirements and seeking solutions to
dietary modification, and should lend themselves readily to them.
the detection of metabolic differences, both between indi- Not least among the many challenges are the needs for
viduals with differing susceptibilities to chronic weight quality control, standardization, data capture and storage
gain, and within individuals who are undergoing significant of nutrigenomic and nutrigenetic data. The ‘omic’ tools
changes in body weight and adiposity (28,29). produce vast quantities of data rapidly. If we are to make
There is also increasing interest in the use of metabolo- use of this information, rather than drown in the flood, it
mic profiles as markers of dietary habits and as a descriptor is essential that the data collected are of high quality and
of nutritional phenotype (30). Before this concept can be are captured in a manner that enables them to be stored
developed further, the influence of potential confounding and exchanged readily. Standardization of data capture for
factors (e.g. age, gender, ethnicity, physical activity and gut microarray studies has already been addressed (33) and
microflora) has to be defined. equivalent procedures are in development for proteomic
Another challenge is that present metabolomic technol- and metabolomic studies (34,35). Refinements to these
ogies generate metabolite profiles for which the majority of data capture systems are likely to include appropriate
signals are not immediately identified. While these profiles data-quality metrics and specialty-specific metadata. For
may be used with multivariate statistical tools for diagnos- example, NuGO is working with international organiza-

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry
© 2007 Queen’s Printer and Controller of HMSO; published with permission
Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 77–81
80 Nutrigenomic approaches for obesity research R. M. Elliott & I. T. Johnson obesity reviews

tions from other specialties on the development of the development of targeted strategies to reduce obesity inci-
Reporting Structure for Biological Investigations Tiered dence and severity and the burden of chronic disease at the
Checklist (RSBI-TC, http://www.mged.org/Workgroups/ population level.
rsbi/rsbi.html), both through contributions to the design However, it is important to note what the main barriers
of core modules and through the development of the are in this area of research, as these could prevent such a
nutrition-specific component. full exploitation of the potential of nutrigenetics and
Finally, beyond the ‘omic’ technologies, there is clearly nutrigenomics. The human system is immensely complex
an emerging need for the development of non-invasive tech- and individual variation very diverse. Coping with this may
niques that will allow biological processes to be visualized be difficult, as will designing and executing studies of suf-
in remote tissues in vivo. These will be essential for future ficient power to define the effects of, and interaction
studies with human volunteers to confirm that the dietary between, genetic, epigenetic and dietary factors, which may
effects characterized in model systems also occur in target be subtle in the short term but profound over many years
tissues in humans in the manner predicted. or a lifetime.

Conclusion Conflict of Interest Statement


Thus, to date, nutrigenomic/nutrigenetic research in obesity No conflict of interest was declared.
has provided insights in three major areas. First, the iden-
tity of many genes in which polymorphisms can affect the
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This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry
© 2007 Queen’s Printer and Controller of HMSO; published with permission
Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 77–81
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This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry
© 2007 Queen’s Printer and Controller of HMSO; published with permission
Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 77–81