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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: [email protected];
[email protected]
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.
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-
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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https://doi.org/10.1017/S0007114507803400 Published online by Cambridge University Press
British Journal of Nutrition (2007), 98, 1095–1100 doi: 10.1017/S0007114507803400
q The Authors 2007
Nutrigenomic approaches for benefit-risk analysis of foods and food

components: defining markers of health
Ruan Elliott1*, Catalina Pico2, Yvonne Dommels3, Iwona Wybranska4, John Hesketh5 and Jaap Keijer3
1
Institute of Food Research, Norwich, UK
2
University of the Balearic Islands, Palma de Mallorca, Spain
3
RIKILT-Institute of Food Safety, Wageningen, The Netherlands
4
Collegium Medicum, Jagiellonian University, Krakow, Poland
5
Institute of Cell and Molecular Biosciences, University of Newcastle, UK
(Received 1 November 2006 – Revised 7 March 2007 – Accepted 29 May 2007)
British Journal of Nutrition
To be able to perform a comprehensive and rigorous benefit-risk analysis of individual food components, and of foods, a number of fundamental
questions need to be addressed first. These include whether it is feasible to detect all relevant biological effects of foods and individual food
components, how such effects can confidently be categorised into benefits and risks in relation to health and, for that matter, how health can
be quantified. This article examines the last of these issues, focusing upon concepts for the development of new biomarkers of health. Clearly,
there is scope for refinement of classical biomarkers so that they may be used to detect even earlier signs of disease, but this approach defines
health solely as the absence of detectable disease or disease risk. We suggest that the health of a biological system may better be reflected by
its ability to withstand and manage relevant physiological challenges so that homeostasis is maintained. We discuss the potential for expanding
the range of current challenge tests for use in conjunction with functional genomic technologies to develop new types of biomarkers of health.
Risk-benefit: Nutrition: Biomarkers: Nutritional genomics
We all routinely perform our own personal version of benefit- . How can health be quantified?
risk analysis in the process of making day-to-day decisions, . Is it possible to detect all biological effects of a food
including our dietary choices. Of course, in relation to the component, food or diet?
food we select, this process will normally be anything but sys- . Can these effects confidently be categorised into benefits
tematic with heavy bias arising from many factors, such as and risks?
personal likes and dislikes, mood, time pressures, upbringing,
Within this article we will discuss some limitations of cur-
seasons, education and awareness of nutritional and health
rent approaches and then: (i) present some ways of thinking
issues.
about how to define health; (ii) consider the opportunities
Even the best informed, most health-conscious and motiv-
for quantifying risks and benefits of dietary (and other
ated consumer cannot be getting the analysis exactly right
environmental) factors that genomic technologies present;
because not all the information relevant to them is available.
(iii) propose possible routes forward, including potentially
And while the concept of rigorous benefit-risk analysis
useful experimental systems and criteria for selecting food
should underlie the development of dietary recommendations,
components that will allow validation and further concept
expert panels developing such recommendations have to work
development.
within the constraints of the current limited and fragmented
scientific knowledge base. Unexpected biological effects and
interactions (be they beneficial or detrimental) and inter-indi-
Developing biomarkers of health
vidual differences in nutritional requirements pose a particular
problem in this respect. Development of a system or frame- To date, most biomarkers have been developed for the purpose
work for performing comprehensive and rigorous benefit-risk of detecting disease or deviation from the ‘norm’ that may
analysis for individual food components, whole foods or signal disease development. From a clinical standpoint, the
diets, and defining a common scale of measurement for com- most useful biomarkers provide a definitive link to a very
paring the risks and the benefits would be enormously advan- specific disease risk or condition. There is much effort going
tageous1. Amongst the challenges involved, several key into the identification of markers that provide the earliest poss-
questions need to be answered. These include: ible indication of disease. There is undoubtedly scope to refine
Abbreviations: GSEA, gene set enrichment analysis.

* Corresponding author: Dr Ruan Elliott, fax þ 44 (0)1603 507723, email [email protected]
1096 R. Elliott et al.
some current biomarkers so that they can be used to provide

indications of more subtle shifts away from a healthy con-
dition. This might be achieved by focusing upon the functional
significance of the variations within the range of data that
would generally be considered ‘normal’; the aim being to
identify successively earlier indicators of any deterioration.
In assessing how nutrition impinges on health, these mar-
kers are useful but they can only indicate ‘health’ as the
absence of disease. Ideally, we should have markers of
optimal health. There are both practical and theoretical con-
siderations that need to be addressed for the development of
such markers. Optimal biomarkers must be analytically
robust, sensitive, quantitative and practical (e.g. non-invasive).
They also should be mechanism-linked so that implications of
changes can be understood. In general, the most useful
markers would be relevant for the whole population while
also being capable of accounting for the effects of parameters
such as age, gender, ethnicity and genotype.
Even with such refinements, individual markers used in
isolation will not be able to measure health reliably. Instead,
integrated multi-component biomarkers are required. Ideally,

these would examine a far broader concept of health than Fig. 1. Schematic representation of a measured response to a challenge test
simply defining acceptable values for each parameter indivi- in systems of varying robustness. The vertical axis in each graph represents
dually. Since biological processes impinge upon each other, the magnitude of the perturbation in a hypothetical biological parameter
analysis of patterns of parameters will be far more informa- measured following the challenge. The horizontal axis represents time follow-
ing the challenge. In the ‘healthy’ system (A) the challenge provokes only a
tive. The ‘omic’ technologies that measure large numbers of moderate perturbation and homeostatic mechanisms rapidly return the sys-
parameters in parallel offer significant opportunities in this tem to the basal state. Less robust systems may exhibit increased pertur-
respect. However, even with these new approaches, it is a bations following the challenge (e.g. B), delayed return to basal values (e.g.
major challenge to capture the functional status of a biological D) or combinations of the two (e.g. H). Use of functional genomic approach
would enable expansion of this approach combining the response profiles of
system with measurements at a single static point. Dynamic
many parameters using appropriate multivariate analytical procedures. The
measures, taken under varying conditions, may provide a ultimate goal would be to identify a set of parameters, measured at a single
starting point. time point, which accurately predicts kinetics of the response.
To employ ‘omic’ technologies for defining biological par-
ameters that can be used as markers of health, one first needs
to identify healthy subjects to work with, but the most obvious associated adverse health implications (e.g. impaired glucose
way to characterise people as healthy is to use validated mar- tolerance). On the other hand, it may not be safe simply to
kers of health. Overcoming this apparent paradox requires an assume the reverse: that the smallest observed deviation
alternative way of identifying genuinely healthy individuals. from baseline following a standard stress test represents the
We propose that an answer may lie in analysing the robustness healthiest condition.
of homeostatic control mechanisms, since a key feature of An alternative approach would be to test the robustness of a
health is the ability to cope with, and respond adequately to, homeostatic system against a series of challenges of increasing
stress (Fig. 1). This approach is already used; for example, magnitude. This would provide an indication of the system’s
cardiac health is assessed by the response to an exercise maximum capacity and a high capacity might be a suitable
challenge and oral glucose tolerance tests are used to assess indicator of health. However, some caution in the interpret-
glycaemic control. The concept of using measures of the ation is still required since there are common trade-offs
robustness of the system to cope with a suitable range of mod- between enhancing the robustness of a system to deal with
erate challenges (a so-called ‘stress test’) represents a poten- specific perturbations and increasing its fragility to other
tially powerful approach for assessing health status, which perturbations2,3.
could be used instead of, or in conjunction with, biomarkers The great advantage of applying ‘omic’ approaches in this
designed to detect disease risk. Acute challenge tests can be situation is that they can be used to identify and categorise
used as sensitive indicators to amplify the response to longer entire biological responses to different challenges applied
term differences in dietary patterns and lifestyles. during the proposed stress tests and for determining the rate
Robustness can be defined as ‘the ability to maintain per- and completeness of the return to the original pre-challenge
formance in the face of perturbations or uncertainty’ and bio- status for multiple parameters. This information, used in con-
logical systems employ a range of strategies, such as junction with available biological knowledge, can be used to
redundancy, modularity and feedback control, to achieve develop increasingly detailed and accurate models that
this2. Homeostatic robustness can be evaluated by determining describe homeostatic regulatory processes. These kinds of
the scale and duration of perturbations elicited in response to a models not only have the potential to provide new insights
standard challenge. Inappropriately large and/or prolonged into how biological systems function4,5, they also may provide
deviations from baseline, following an applied stress, may a means of identifying the earliest possible indications of long-
be used as biomarkers of reduction in robustness with term disturbances and compensatory processes3. In this regard,
Defining markers of health 1097
current intensive work into the processes underlying chronic ments covering a wide range of biological processes. The data
diseases is likely to be extremely valuable6 – 10. This will can be used in pattern-based analysis for defining healthy
identify responses characteristic of early pathological changes biomarker profiles and responses18,19. From another perspec-
and thereby help to discriminate these from normal homeo- tive, the data generated allow identification of both predicted
static processes. and unexpected effects; an essential component of any
Given the complexity of the human system, it is possible rigorous benefit-risk analysis.
that optimal health cannot be categorised as a single state. In most cases, moderate nutritional modifications are likely
Each individual may have the potential to exist in one or to elicit comparatively subtle effects that, even so, may have
more stable healthy states and these may differ from person profound biological effects in the long term. Detecting such
to person and shift with life-stage and lifestyle and be different changes is made more difficult by the degree of variation
for men and women. There may be more appropriate ways to between human volunteers. However, several lines of evi-
measure health than simply by seeking to define a single aver- dence suggest that the degree of intra-individual variation in
aged normal standard. Individuality can readily be built into multiple parameters determined using ‘omic’ methods is sub-
the challenge model by selecting stressors most appropriate stantially smaller than the inter-individual variation20 – 24.
to an individual’s specific life requirements. In the same Thus, study designs that enable individuals to act as their
way, this approach also provides the scope to account for own control are most appropriate. Transcriptomics, proteo-
the effects of genotype11. mics and metabolomics have been applied in a comparatively
small number of human nutritional studies to date25 – 28.
Nevertheless, these studies demonstrate that ‘omic’ methods
Challenge/stress tests for quantification of health status
are sufficiently sensitive to detect both acute and chronic
A number of standardised biological stress tests already effects of nutrition.

exist12 – 16. For the determination of health, and benefit-risk Furthermore, integrated analysis of ‘omic’ data, by taking
analysis of dietary components, it is important to develop a small but consistent changes over several components of a
panel of nutrition-relevant stress tests. These tests should pathway into account, increases the power and the sensitivity
encompass the major aspects of healthy biological function of assessment. For example, de Boer and co-workers were
and, critically for assessment of diet-related benefit-risk, only able to identify fatty acid catabolism as an effect of quer-
should involve challenges that are known to impinge upon cetin exposure when a pathway analysis programme was
cell functions that are clearly sensitive to dietary components. used29. Another example is provided by Mootha and col-
We propose the following as examples: leagues, who described a method, termed gene set enrichment
analysis (GSEA), designed to identify sets of functionally
. Infection challenge
related genes that differ in expression between experimental
. Inflammatory challenge
groups30. Using this approach, they were able to identify a
. Cognitive challenge
specific set of genes involved in oxidative phosphorylation
. Carbohydrate challenge
(the OXPHOS set), which were expressed at lower levels in
. Lipid challenge
muscle of type 2 diabetics than in control subjects. They
. Xenobiotic challenge
then confirmed a similar pattern of down regulation of the
. Oxidative challenge
OXPHOS genes in the muscle of individuals with impaired
. DNA damage challenge
glucose tolerance. This finding contrasts with gene by gene
. Tissue damage challenge
analysis of the same dataset, employing standard statistical
. Exercise challenge.
methods with appropriate multiple test correction, which
This list is by no means intended to be exhaustive: substan- failed to identify any significant differences. The difference
tial expert input would be required to develop and validate a in expression of members of the OXPHOS gene set between
comprehensive panel of tests. In some cases the challenges the diabetic and control groups was typically very modest
and/or most appropriate readouts to test the function of (approximately 20 %) but strikingly consistent across the set
these systems are immediately obvious. In others cases, (94 of 106 genes). Such small differences would be difficult
further technical developments are required. Some of these to detect reliably on a gene by gene basis even by using
functions may be tested comparatively readily in human sub- methods such as real-time PCR, which are widely held to be
jects (e.g. carbohydrate and lipid metabolism and response to more sensitive and precise than arrays. Thus, currently, it is
exercise) whereas others would be more difficult to apply in possibly only in the context of global gene expression analysis
human subjects for obvious ethical reasons. In such cases, that such small differences can be detected and interpreted
the functions may be tested in tissue culture and animal with confidence.
models, and alternative approaches would be needed to take In addition to offering improved sensitivity, methods such
these tests forward for use in human subjects. as GSEA provide at least two other important benefits. First,
they have proven to be far more effective than single-gene
analyses at revealing common biological effects between inde-
Potential for application of genomic tools
pendent studies31,32. Second, by presenting observed differ-
The ‘omic’ technologies (i.e. transcriptomics, proteomics and ences in the form of defined biological processes/pathways,
metabolomics) are having a substantial impact across the spec- they make interpretation of study results in relation to avail-
trum of life science research17. These technologies have able knowledge more straightforward than considering the
potential for the development and validation of novel bio- possible biological implications of individual genes in the
markers of health because they provide simultaneous measure- gene lists typically generated using the more traditional
methods. For example, Mootha and colleagues were able to restriction, which is well known to slow ageing and increase
take forward the observation described earlier by identifying maximum lifespan in Drosophila and C. elegans, rats and
a subset of the OXPHOS genes that are coordinately expressed mice44, also improves a host of classical biomarkers of CVD
in multiple tissues and then providing direct evidence that this risk and inflammation in human subjects6,45,46. However,
co-regulation is mediated by PPAR-g coactivator 1a30. this model may not be appropriate to use in all contexts and
Since this original description, GSEA and variations on this advocacy of energy restriction for people must still be
type of analysis have repeatedly proven their power by provid- considered to be ill advised, based on current knowledge47.
ing new insights into the mechanisms underlying a range of For example, energy restriction can lead to reduction in
pathological conditions, including prostatic intraepithelial bone mineral density, muscle size and strength and aerobic
neoplasia33, myositis and dermomyasitis34, uterine fibroids35, capacity48,49. Exercise overcomes these effects and, therefore,
exposure to high dose statins36, leukaemia and lung a combination of energy restriction with exercise may be more
cancer31. Application and improvement of pathway analyses widely applicable. What is now needed is to use well-charac-
and GSEA in combination with other statistical methods that terised model challenge tests to develop the appropriate
take interactions into account, such as Random forests37, experimental design and data analysis required to incorporate
will further strengthen sensitivity and accuracy. the ‘omic’ technologies and validate their use for benefit-risk
Beyond application of these methods individually, inte- analysis.
gration of all the ‘omic’ technologies represents the most
powerful way forward. In the longer term, such a systems
Foods and food components
biology approach is necessary to cope with the full complexity
of human individuals, their diets and the interactions between It is essential to start with food components that are well-
the two. However, integrating transcriptomic, proteomic and characterised in terms of their metabolism, the cellular pro-
metabolomic datasets is challenging, not least because of the cesses they influence and links to specific health outcomes.
differences in the timescales of responses of RNA, protein The availability of comprehensive dose–response data, both
and metabolites38. This is a particularly important issue in acute and chronic, from human subjects and different model
relation to the challenge test concept, where measuring and organisms would be extremely valuable. Ultimately, the com-
interpreting the dynamics of the response is critical. In plexity of food has to be taken into account. For example, a
human subjects, changes in blood concentrations of many more complex food-based test has been developed for analys-
metabolites can be detected within minutes of ingesting test ing response to a combined glucose and lipid challenge50.
meals and these may persist for a number of hours. Alterations Determining the effects of chronic low exposures on health
in gene transcription profile are unlikely to occur quite so poses a particular technical and logistical challenge, but one
quickly but still can be readily detected within 2 h25. Acute that it is vital to address in the context of nutrition. One
changes in protein expression following food ingestion in approach to overcome this would be to test model organisms
human subjects have not yet been investigated using a proteo- with comparatively short lifespans. Alternatively, with other
mic approach. The complex dynamics of RNA, protein and models experimental durations could be used that are just suf-
metabolite interactions is an issue that is only just beginning ficiently long for a new state of equilibrium to be reached.
to be dealt with in simple model systems39. Nevertheless, Conveniently, the timescale to reach such a new equilibrium
while the methods necessary to realise full integration are could be determined using genomic technologies. In addition,
still in development, examples of studies employing more diet at one stage of life can impact on health at a later stage. In
than one ‘omic’ technology demonstrate that the descriptive particular, early life nutrition is thought to exert profound
power of the individual methods can be further enhanced, effects on metabolic ‘set points’ 51 – 53. Functional genomic
even using straightforward integration strategies40 – 42. technologies may be able to identify early biomarkers of
While maximising data capture is the obvious way to start, change, for example, in gene methylation54 – 56.
this is expensive and labour intensive. In the long run, the aim Looking beyond the current genomic approach, there are a
should be to define subsets of key parameters and profiles that wide array of technologies and model systems in development
will enable the complexity of biomarkers of health to be that may aid the establishment of biomarkers of health that can
reduced without compromising their power. It is possible then be translated into easy applicable tests. These include
that the dynamics of a response could be inferred from a imaging and nano sampling, allowing access to tissues that
single sample provided the interrelationships between the thus far are not accessible in living individuals57 – 59. Applied
key parameters analysed have been defined clearly. The to human subjects, this will diminish uncertainties arising
‘omics’ technologies can provide us with this insight. Low from translation from one species to the other. Furthermore,
cost, high throughput analytical platforms can then be devel- the availability of these tools, especially when they can be
oped to provide accurate quantification of the specific markers applied to human subjects, will reduce animal testing.
identified43.
It makes sense to test the new concepts outlined earlier by
Conclusions
exploiting established nutritional models. For example, the
oral glucose tolerance test provides a reference on which to Development of complex markers, based on the integration of
build a systems biology approach. This could be expanded challenge tests and genomic technologies represents an excit-
by systematic analysis of other standardised dietary challenges ing, if technically challenging, approach for application as
(e.g. lipid loading, vitamin supplementation). Similarly, the biomarkers of health and in nutritional benefit-risk analysis.
best available models of a healthy phenotype could be used To make routine use practical, such biomarkers of health
to evaluate challenge tests. For example, long-term energy ideally should be based around measurements performed on
Defining markers of health 1099
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DOI 10.1007/s11010-008-9744-2
Nutrigenomic basis of beneficial effects of chromium(III)

on obesity and diabetes
Francis C. Lau Æ Manashi Bagchi Æ Chandan K. Sen Æ
Debasis Bagchi
Received: 19 December 2007 / Accepted: 13 March 2008 / Published online: 18 July 2008
Ó Springer Science+Business Media, LLC. 2008
Abstract Insulin resistance has been shown to be the Keywords Chromium(III) Insulin resistance
major contributing factor to the metabolic syndrome, which Diabetes Obesity Weight management Nutrigenomics
comprises a cluster of risk factors for metabolic aberrations
such as obesity, dyslipidemia, hypertension, and hyper- Introduction
glycemia. Additionally, insulin resistance has been
associated with the occurrence of cardiovascular disease It is estimated that in developed countries up to 35% of the
and type 2 diabetes. Epidemiological studies indicate that population have one or more attributes of insulin resis-
obesity and diabetes have become alarmingly prevalent in tance, the major contributing factor of metabolic syndrome
recent years. Substantial evidence suggests that dietary (MS) [1]. Insulin-resistance-related disorders such as type
interventions and regular exercise greatly improve body 2 diabetes mellitus (T2D) and obesity have reached epi-
mass index and lipid profile as well as alleviate insulin demic proportions in the recent years [2]. These emerging
resistance. Therefore, dietary supplements such as insulin- epidemics are exacerbated by the expansion of the aged
sensitizing agents may be beneficial in the prevention and population because aging facilitates aberrant insulin regu-
treatment of obesity and type 2 diabetes. Numerous in vitro lations [3, 4]. It is predicted that the aged population will
and in vivo studies suggest that chromium supplements, increase to 32% (currently at 18%) by the year 2050 [5]. To
particularly niacin-bound chromium or chromium-nicotin- alleviate the socioeconomic burden inflicted by insulin-
ate, may be effective in attenuating insulin resistance and resistance-related disorders as well as increase the health-
lowering plasma cholesterol levels. Utilizing the powerful related quality of life among the ever-growing aging
technology of nutrigenomics to identify the genes regulated population, it is of great importance to explore means to
by chromium supplementation may shed some light on the forestall or prevent these diseases.
underlying mechanisms of chromium-gene interactions, Studies have shown that suboptimal intake of chro-
and thus provide strategies to mitigate and prevent insulin- mium(III) is a major contributing factor for chronic
resistance-related disorders. diseases such as T2D and cardiovascular diseases (CVD)
[6]. Chromium deficiency resulting from suboptimal diet
has been shown to augment the MS-associated risk factors
such as elevated levels of blood glucose, circulating insu-
F. C. Lau M. Bagchi D. Bagchi lin, cholesterol and triglycerides, and decreased lean body
InterHealth Research Center, Benicia, CA 94590, USA mass [7]. However, these conditions are readily correctable
by chromium supplementation [6, 8]. Indeed, chromium
C. K. Sen
Laboratory of Molecular Medicine, Department of Surgery, was first identified five decades ago as an essential trace
Ohio State University, Columbus, OH 43210, USA element required to maintain normal glucose tolerance and
thus termed ‘‘glucose tolerance factor’’ (GTF) based on its
D. Bagchi (&) biological function [9, 10]. Therefore, chromium supple-
Department of Pharmacy Sciences, Creighton University
Medical Center, 2500 California Plaza, Omaha, NE 68178, USA mentation may present a key factor for the intervention of
e-mail: [email protected]; [email protected] MS-related diseases.
123
2 Mol Cell Biochem (2008) 317:1–10
Chromium valence states and biological activity in vivo [22–24]. For instance, the inorganic form of Cr(III)
chloride (CrCl3) complex has been shown to be excreted
Chromium is a transition metal with valence states ranging more quickly than its organic counterparts such as niacin-
from -2 to +6 [11]. The biological activity of chromium is bound Cr(III) (NBC) and Cr(III) picolinate (CrPic) [23,
conferred by its valence state. The common stable valence 25]. Indeed, an in vivo study comparing the absorption and
forms include the inert metallic chromium Cr(0), trivalent retention of CrCl3, CrPic, and NBC has revealed that there
chromium Cr(III), and hexavalent chromium Cr(VI) were significant differences in the bioavailability of these
[12, 13]. Cr(VI) is commonly found in industrial chemicals three Cr complexes [25]. This study measured the
used in stainless steel manufacture, metal finishing and absorption and retention of radiolabeled 51Cr over a period
chrome plating, welding, pigment production, leather tan- of 12 h post-ingestion. The average percent 51Cr retained
ning, wood preservatives, and as corrosion inhibitors in the majority of the fluids and tissues over the 12-h time
[12, 14]. Studies have shown that Cr(VI) is a potent car- course was significantly higher in rats gavaged with NBC
cinogen and a respiratory irritant which causes lipid than those with CrCl3 and CrPic [25].
peroxidation, DNA damage, cell death [7, 14]. Cr(III), on The mode of Cr(III) absorption and transport has
the other hand, is an essential micronutrient that is required recently been reported [26]. It has been shown that Cr(III)
for normal carbohydrate, protein, and lipid metabolism, is absorbed by the gastrointestinal tract, bound by trans-
and enhanced glucose-insulin sensitivity [6]. Although the ferrin in the bloodstream, and then transferred to various
underlying mechanism by which Cr(III) exerts its benefi- tissues in the transferring-bound state. The major Cr(III)
cial effects remain unclear, numerous in vitro and in vivo target tissues have been identified as liver and kidneys [27].
studies have indicated that Cr(III) plays an important role Cr(III) is released and processed intracellularly after
in the maintenance of normal blood glucose level, the transport to tissues by transferrin. A portion of the trans-
reduction of plasma cholesterol and triglycerides, and the ferred Cr(III) is bound to low-molecular weight chromium-
inhibition of oxidative stress and inflammatory cytokine binding substances (LMWCr) or chromodulins [28, 29].
secretion [15]. LMWCr is a mammalian oligopeptide of approximately
1.5 kDa that binds four chromic ions [30–32]. The
LMWCr-bound chromium is expelled from cells into the
Dietary sources and daily intake bloodstream and then excreted in the urine [26, 27]. Insulin
has been shown to stimulate intracellular processing of
Dietary sources of Cr(III) include seafood, oysters, meat, Cr(III), thus confirming the connection between chromium
liver, cheese, whole grains, fruits, green beans, spinach, and insulin signaling [33–35].
and broccoli. Brewer’s yeast, identified as a source of GTF, The average dietary Cr(III) intake for adults is generally
is particularly enriched in organic Cr(III) ligand complexes lower than the minimum suggested daily Cr(III) intake of
[10]. It has been used in numerous studies to isolate and 50 lg [36, 37]. In fact, up to 90% of the US population
characterize the organic ligand component(s) of GTF [16]. failed to meet the minimum ESADDI [32]. This problem is
Subsequently, it has been proposed that the naturally exacerbated by the fact that Cr(III) is poorly absorbed.
occurring GTF is a complex of Cr(III), nicotinate, and While other essential trace metals such as copper, iron, and
glutathione based on its similar biological activity to GTF zinc are absorbed on the order of 10–40%, Cr(III) is
found in Brewer’s yeast and its ability to bind tightly to absorbed 0.5–2% depending on dietary intake [36]. Even a
insulin [17]. Therefore, Cr(III) nicotinate (NBC) and other well-balanced meal formulated by nutritionists does not
Cr(III) complexes have been synthesized and widely used provide the minimum suggested daily Cr(III) intake [6].
as dietary supplements [18]. Chromium deficiency is particularly prevalent in certain
The Estimated Safe and Adequate Daily Dietary Intake demographics such as athletes, pregnant women, and the
(ESADDI) for Cr(III) established by the National Research elderly [38]. This is due to enhanced chromium loss
Council (NRC) is 50–200 lg/day which corresponds to resulting from strenuous exercise, long periods of stress
0.71–2.9 lg/kg/day for a 70 kg adult [19, 20]. A comparable during pregnancy, and age-related inability to efficiently
Reference Daily Intake (RDI) for Cr was set at 120 lg/day absorb or convert inorganic chromium into the active form
by the Food and Drug Administration (FDA) [21]. [39, 40]. Further chromium losses are attributed to con-
suming refined foods, especially those enriched in simple
sugars, because these foods are not only low in chromium
Bioavailability, deficiency, and diseases but they also facilitate chromium loss through urine
excretion [33, 41].
Chromium bioavailability is highly dependent on the nat- The common indications of chromium deficiency in
ure of the Cr(III) ligand complexes ingested or formed humans include insulin resistance, hyperglycemia, and
123
Mol Cell Biochem (2008) 317:1–10 3
lipid abnormalities [24, 42, 43]. Severe chromium defi- significant changes in hepatic lipid peroxidation and DNA
ciency arose in patients receiving total parenteral nutrition fragmentation, hematology and clinical chemistry, and his-
(TPN) without chromium supplementation [44]. These topathological parameters examined [57].
patients developed diabetic-like symptoms such as glucose Clinical records have revealed no evidence of toxicity in
intolerance, weight loss, and neuropathy. However, these patients receiving Cr(III)-supplemented TPN for more than
symptoms were reversed by chromium supplementation 20 years [24]. Human clinical studies have generally
[45, 46]. Therefore, chromium is now included in TPN demonstrated evidence of efficacy for Cr(III) supplemen-
solutions [47]. tation in improving insulin sensitivity and/or blood lipid
Animal studies have shown that rats on a chromium profiles [58].
deficient diet developed aortic plaques and elevated blood
cholesterol. These abnormalities were abolished upon
chromium supplementation [48]. The beneficial effects of Chromium interventions in metabolic syndrome,
supplemental chromium have also been reported in other obesity, and diabetes
animals such as mice, monkeys, pigs, cattle, and horses
[42, 49]. Metabolic syndrome, also known as the ‘‘insulin resistance
syndrome’’ or ‘‘syndrome X,’’ is associated with cellular
deregulation of insulin action [59, 60]. Insulin resistance
Supplementation, safety, and efficacy occurs when the ability of insulin to stimulate glucose
metabolism is disrupted resulting in high levels of glucose
Cr(III) dietary supplements exist mainly in the form of and insulin in the blood. Insulin signaling transduction
CrCl3, CrPic, and the oxygen-coordinated niacin-bound pathways in adipose and muscle cells are intricate pro-
chromium or NBC [13, 48]. A substantial number of cesses involving binding of insulin to its receptor,
studies have devoted to evaluating the safety and efficacy activation of kinases, and caveolin-mediated translocation
of these Cr(III) supplements. of glucose transporter 4 (GLUT4) leading to the uptake of
There has been in vitro evidence demonstrating that glucose [61–63]. A major characteristic of insulin resis-
CrPic was genotoxic and caused mutation at the hypo- tance is the reduction in the insulin-regulated, GLUT4-
xanthine (guanine) phosphoribosyltransferase locus of the mediated glucose uptake in adipocytes and muscle cell
Chinese hamster ovary (CHO) cells [50, 51]. CrPic has also [64]. A recent study showed that NBC supplementation
been shown to induce clastogenesis or chromosomal increased the phosphorylation of AMP-activated protein
damage in CHO cells whereas at the same physiologic dose kinase (AMPK) and endothelial nitric oxide synthase
neither CrCl3 nor NBC incurred any clastogenic effect (eNOS) as well as facilitated the translocation of GLUT4 to
[52]. Since the clastogenic effect only occurred in CrPic the cell membrane through regulation of caveolins in
and picolinic acid but not in CrCl3, NBC, or nicotinic acid, streptozotocin-induced diabetic rats [65]. This study pre-
it was concluded that the observed clastogenicity was sented for the first time a novel mechanism by which NBC
induced by picolinic acid and not by chromium per se [53]. mediates glucose uptake, hence further supported the
In fact, several clinical cases have linked CrPic to neph- beneficial effects of NBC as observed in numerous animal
rotoxicity resulting in renal failure [54, 55]. and human studies.
On the other hand, numerous studies on the safety of NBC It is estimated that MS-associated factors are present in
have generally shown that there is no toxic effect associated 25–35% of the population in Western countries [1]. MS is
with NBC [56, 57]. A comprehensive pharmacotoxicology characterized by increased plasma triglyceride level
rodent study has been conducted to evaluate the safety of accompanied by a reduced high-density lipoprotein (HDL)
NBC [56]. Acute oral and dermal toxicity as well as primary leading to perturbed insulin signal transduction [66].
dermal and eye irritation studies have not produced any signs Impairment in insulin signaling increases cardiovascular
of toxicity or irritation induced by NBC. Ames bacterial risk factors and contributes to diseases such as athero-
reverse mutation and mouse lymphoma mutagenicity assays sclerosis and type 2 diabetes (T2D) [4, 67]. It has been
have shown that NBC was non-mutagenic. A 90-day sub- shown that obesity correlates positively with the preva-
chronic toxicity study has not shown any toxicological lence of MS [68]. While MS was present in 4.6% of normal
effects of NBC [56]. A recent long-term safety study has weight and 22.4% of overweight men, it was present in an
revealed that rats orally administered with a human equiv- astounding 59.6% of obese men [68].
alent dose of 1,000 lg/day elemental Cr(III) in the form of Obesity is a multifactoral chronic condition that is
NBC for a duration of 52 weeks showed no signs of characterized by an excess of body adiposity resulting from
NBC-induced toxicological effects [57]. Specifically, the tipping the balance between caloric intake and energy
results from this study have indicated that there were no expenditure in favor of the former [69, 70]. Clinically
123
obesity is defined as a body mass index (BMI) greater than without affecting muscle mass [79]. Blood chemistry
30 kg/m2, whereas overweight is defined as a BMI greater analysis indicated no perturbations or adverse effects from
than 25 kg/m2 [71]. According to these definitions, the daily intake of 600 lg of NBC for 2 months [79].
number of overweight or obese adult Americans has A growing body of evidence has demonstrated that
recently surpassed the number of normal weight adult chromium may play an important role in preventing ath-
Americans for the first time in history [72, 73]. Obesity is erosclerosis and CVD by reducing plaque buildup in the
also a major risk factor for T2D [74, 75]. Diabetes is the arteries, lowering total cholesterol (TC), low-density
most prevalent endocrine disorder affecting more than lipoprotein (LDL), and triglyceride levels [80–84]. Fur-
170 million people globally, and this number is expected to thermore, a number of human studies have provided
double in the year of 2030 [63]. T2D is the most common evidence to suggest that chromium supplementation may
form of diabetes accounting for more than 90% of the be beneficial for patients with T2D and gestational diabetes
diabetic patients [63]. It is not surprising, then, to find that [85–88].
the prevalence of obesity paralleled that of T2D in recent Numerous studies have reported efficacy of NBC sup-
years to reach epidemic proportions [2]. This alarming plementation on glucose and insulin regulation [8, 48].
phenomenon imposes a tremendous burden on the health A randomized, double-blind, placebo-controlled study has
care resources. Unless preventive measures are taken to been carried out to investigate the effect of NBC supple-
forestall this global epidemic, it will get worse in the years mentation on insulin sensitivity [89]. Twenty-six
to come. The current strategies used to treat obesity and subclinical chromium deficient, otherwise healthy young
T2D include pharmacotherapy, dietary interventions, and adults were randomly assigned to the placebo group
lifestyle modifications [76, 77]. (n = 11) or the Cr-supplemented group (n = 15) receiving
Since its identification as the central component of the GTF 220 lg/day elemental Cr(III) in the form of NBC.
50 years ago, trivalent chromium has been widely used in Although there was no significant difference in the percent
dietary interventions to improve insulin sensitivity and to curb change of fasting immunoreactive insulin (IRI) level
weight gains [8]. Numerous studies have provided evidence of between the placebo group and the Cr-supplemented group
efficacy that Cr(III) supplementation is beneficial in main- at the conclusion of the trial, the subjects within the Cr-
taining healthy carbohydrate and lipid metabolism, regulating supplemented group (n = 6) with high initial fasting IRI
appetite and reducing sugar cravings, and reducing fat mass levels (56 pmol/l) exhibited a statistically significant
and increasing lean body mass [48]. decrease in IRI level (38 pmol/l) after 90 days of supple-
To evaluate the effect of Cr(III) supplementation com- mentation. The results suggested that NBC supplementation
bined with exercise on weight management, Grant et al. may benefit these subjects by improving insulin sensitivity
conducted a clinical study involving 43 young, healthy over time [89].
sedentary, obese women for a period of 9 weeks [78]. The Another double-blind clinical trial has been carried out
subjects were divided into four groups: CrPic supple- to evaluate the efficacy of NBC on blood glucose and tri-
mented without exercise (CP), exercise training with glyceride parameters [90]. Twenty volunteers received
CrPic-supplemented (E/CP), exercise training with placebo either a daily dose of 300 lg elemental Cr(III) in the form
(E/P), and exercise training with NBC-supplemented of NBC or a placebo for 3 months. The mean fasting
(E/CN) [78]. Chromium supplements were taken orally glucose levels in the NBC-supplemented group were low-
twice a day as 200 lg tablets for a total of 400 lg/day for ered significantly, while glucose levels remained
those receiving chromium supplements. The placebo unchanged in the placebo group. NBC supplementation
tablets contained inert ingredients. The results revealed that also attenuated the mean blood triglycerides and glycos-
not only was CrPic ineffective in reducing weight, it ylated hemoglobin (Hb1Ac), a biomarker for long-term
actually increased the body weight in the CP group [78]. glucose control [90].
No significant changes in body weight were observed in the Although evidence supports the use of Cr(III) especially
E/P or E/CP groups. On the contrary, E/CN group showed a in the form of NBC in promoting insulin sensitivity,
significant weight loss and a significant lowered insulin healthy blood glucose, and weight loss, there exists
response to an oral glucose load indicating for the first time controversy as to which form of Cr(III) is beneficial. In a
that combining with exercise, NBC was effective in pro- 6-month randomized, double-blind, placebo-controlled
moting weight loss and reducing certain CVD and T2D risk clinical trial, Cr(III) in the form of CrPic was given to
factors [78]. overweight patients with T2D who received more than 50
A subsequent clinical study has shown that oral intake of units of insulin daily and was found to be ineffective in
600 lg/day NBC over a two-month period by African- improving lipid profile, BMI, blood pressure, and insulin
American women who were undergoing a modest dietary requirements [91]. Subsequently, the same research group
and exercise regimen resulted in a significant fat loss conducted a similar study using Cr(III) in the form of
123
chromium yeast showed no evidence that treatment with TC, TC-to-HDLC ratio, LDL cholesterol, and triglyceride
chromium yeast was effective in improving glycemic levels while increased HDLC in the plasma of these obese
control in T2D patients [92]. The effect of high dose CrPic diabetic mice (Fig. 1). OGTT demonstrated a significant
supplementation on middle-aged healthy subjects of nor- improvement on the clearance of blood glucose between
mal body weight and BMI with T2D was evaluated and the one- and two-hour of glucose challenge in the NBC group
results showed improved glucose and insulin metabolism as compared to that in the PBO group. These findings are
[86]. The result of this study may have been confounded by consistent with the beneficial effects of NBC on glucose
the fact that the subjects were taking various medications and lipid metabolism observed previously in other human
including sulfonylurea drugs, phenformin, and insulin. and animal studies [97].
Several patients were taking more than one medication To delineate the underlying physiological benefits of
[86]. Even though no significant toxic effects have been NBC in the current study, the effect of NBC supplemen-
observed in the inorganic CrCl3, it is poorly absorbed by tation on the transcriptome of subcutaneous fat of these
the body and may not be an efficacious Cr(III) dietary obese diabetic mice was screened by high-throughput
supplement [15, 93]. However, available evidence suggests whole mouse genome expression microarrays. Unbiased
that supplemental Cr(III) in the form of NBC is more genome-wide interrogation of the transcriptome revealed,
bioavailable, efficacious, and safe. Therefore, the chro- for the first time, that NBC supplementation consistently
mium controversy seems to have arisen from the dispute of altered the expression of a small subset (approximately
which form of chromium is more effective [76]. 0.61%) of the 41,101 probe sets in the adipose tissues of
the obese diabetic rats. NBC supplementation exerted a
positive effect on the transcriptome of fat tissues with more
Chromium(III) and gene regulation: nutrigenomics up-regulated genes. Specifically, while there were 161
approach genes up-regulated, only 91 genes were suppressed by
NBC supplementation. The results indicated a specific
The underlying mechanism for the observed beneficial effect of chromium-gene regulation rather than a random,
effects of chromium remains to be elucidated. With the genome-wide perturbation caused by the supplement [97].
completion of the Human Genome Project, a new wave of Selected candidate genes with a significant fold change
powerful multidisciplinary technologies has emerged for C1.2 from microarray screening (Fig. 2) were further
the study of diet-gene interactions in the field of nutra- verified by real-time RT-PCR analysis. The genes that were
ceutical research [72, 94]. Nutrigenomics is a genome-wide up-regulated in the fat tissue by NBC supplementation
high-throughput screening (HTS) technology applied to were mostly the muscle-specific genes such as those
investigate how diets affect gene expression patterns
(transcriptome) [95, 96].
A recent study has utilized the nutrigenomics approach
to investigate the effect of oral niacin-bound chromium
(NBC) supplementation on the transcriptome of subcuta-
neous adipose tissues from obese mice homozygous for
type 2 diabetes spontaneous mutation (Leprdb) [97]. Male
Leprdb mice were randomly divided into the NBC-supple-
mented (n = 7, NBC) or placebo (n = 7, PBO) group.
Supplementation regimen began when the mice were
10 week of age and lasted for a period of 10 weeks. Lipid
profiles were analyzed at week 6 post-supplementation and
the results were compared to baseline data collected at
week 0 presupplementation. Parameters assessed included
blood glucose level, TC, HDL cholesterol (HDLC), tri-
glycerides, LDL, and the TC-to-HDLC ratio. Oral glucose
tolerance test (OGTT) was carried out at week 8 post-
supplementation. Mice were euthanized at week 10 post-
supplementation. Subcutaneous fat was extracted from the Fig. 1 Improvement of plasma lipid profiles by NBC supplementa-
mice for isolation of total RNA, which was used for the tion in type 2 diabetic rats. Lipid profiles in placebo-fed and NBC-fed
type 2 diabetic rats were analyzed at week 6 post-supplementation
high-density comprehensive mouse genome (45,101 probe
and results were expressed in percentage of placebo [97]. Data
sets) expression microarrays [97]. Blood lipid profile indicate mean ± SD with n = 7 per group. *P \ 0.005, indicates
indicated that NBC supplementation significantly lowered statistical significance as compared to the placebo group
123
adipose tissue of the NBC-supplemented obese diabetic

mice. GPI1 gene product is a multifunctional protein also
known as autocrine motility factor (AMF), neuroleukin,
and differentiation and maturation mediator [102, 103].
GPI1 protein catalyzes the interconversion of glucose-6-
phosphate to fructose-6-phosphate. It is involved in both
glycolysis and glucogenesis [104]. Glycolytic genes such
as ENO3 and GPI have been found to be down-regulated in
the visceral adipose tissues of morbidly obese individuals
[105]. Thus, the current study suggests that NBC supple-
mentation facilitates the homeostasis of glycolysis through
up-regulation of ENO3 and GPI1 in the obese diabetic
mice.
It has been shown that glucose transport and metabolism
to glucose-6-phosphate are essential for insulin regulation
Fig. 2 Selected candidate genes from microarray analysis. Differen- of calcium homeostasis in vascular smooth-muscle cells
tial gene expression in the adipose tissue of placebo- or NBC-treated (VSMC) through a glucose-6-phosphate-dependent carbo-
obese diabetic mice was analyzed with Affymatrix mouse genome
hydrate-responsive element in the calcium-ATPase gene
microarray (430 v2.0). Selected candidate genes with a fold change
C1.2 were chosen for further verification by real-time RT-PCR [106]. Bioactive Cr(III) has been linked to the enhancement
analysis. The expression of genes depicted in the graph exhibited a of VSMC calcium transport by stimulating plasmalemmal
significant change induced by NBC supplementation when compared calcium-ATPase mRNA and protein expression [107]. The
to that by placebo supplementation as confirmed by real-time
current study showed that calsequestrin expression was
RT-PCR (P B 0.05). Data represent average fold change ± SD
(n = 4) of genes which were up-regulated (j) or down-regulated induced by NBC supplement. Since calsequestrin is the
(h) by NBC-supplementation. Refer to Table 1 for abbreviation of most abundant calcium-binding protein responsible for
genes [97] calcium storage in the sarcoplasmic reticulum and that
elevated intracellular free calcium level has been observed
involved in glycolysis, muscle contraction, muscle metab- in adipocytes, it is plausible to speculate that NBC sup-
olism, and muscle development (Table 1). These findings plementation decreases the free intracellular calcium level
are of great importance because studies have shown that by increasing the levels of calsequestrins [108]. The
adipocytes and skeletal myoblasts are derived from a expression of tropomyosin-1 (TPM1) was up-regulated by
common mesodermal stem cell lineage and that preadipo- NBC supplementation. TPM1 encodes for the a-subunit of
cytes may differentiate into myogenic lineage [98, 99]. the tropomyosin family of proteins. Calcium influx from
Adipose tissue contains pluripotent cells; in addition, sarcoplasmic reticulum facilitates tropomyosin-coordinated
mesenchymal cells isolated from adipose tissue can dif- muscle contraction [109–111]. It has been demonstrated
ferentiate along other cell lineages including osteogenic, that differentiation of preadipocytes into adipocytes is
chondrogenic, and myogenic lineages [100]. Therefore, accompanied by a gradual decrease in the expression of
adipose tissues are capable of differentiating into myocytes extracellular matrix and cytoskeletal proteins such as
if they are instructed to do so by myogenic signals. fibronectin and tropomyosin [112]. Expression of these up-
Enolase 3 (ENO3) was the most NBC-sensitive gene up- regulated NBC-specific myogenic genes in adipocytes over
regulated in the fat tissues of the obese diabetic mice. time has been shown to diminish the fat content of these fat
Enolase is a dimeric glycolytic enzyme that catalyzed the cells [113].
interconversion of 2-phosphoglycerate and phosphoenol- The NBC-suppressed genes included cell-death-induced
pyruvate. ENO3 encodes for the b-enolase subunit which DNA fragmentation factor (CIDEA), thermogenic uncou-
accounts for more than 90% of the enolase activity in adult pled protein 1 (UCP1), and tocopherol transfer protein
human muscle [101]. A clinical study has indicated that a (TTP) (Table 1). It has been revealed that CIDEA is
patient with mutation in the ENO3 gene, which resulted in expressed at high levels in brown adipose tissue (BAT),
reduced level of b-enolase enzyme in the muscle, exhibited which is the major site of adaptive thermogenesis [114].
exercise intolerance and myalgia. Ultrastructural analysis Mice deficient in CIDEA are lean and resistant to diet-
has revealed focal sarcoplasmic accumulation of glycogen induced obesity and diabetes [115]. These CIDEA-knock-
beta particles in the patient that may lead to metabolic out mice exhibit higher metabolic rate and lipolysis in BAT
myopathy caused by defects in distal glycolysis [101]. The suggesting a functional role for CIDEA in modulating
glucose phosphate isomerase 1 (GPI1) gene, which is also energy balance and adiposity [115]. UPC1 is another
involved in glycolysis, was found to be up-regulated in the NBC-suppressed gene that is otherwise highly expressed in
123
Table 1 Altered gene expression in response to NBC supplementation

Gene expression Gene name Gene abbreviation Function
NBC-stimulated Enolase 3 ENO3 Glycolysis and gluconeogenesis

Calsequestrin 1 CASQ1 Calcium storage, muscle contraction
Tropomyosin 1 TPM1 Calcium-regulated muscle contraction
Glucose phosphate isomerase 1 GPI1 Glycolysis and gluconeogenesis
NBC-suppressed Cell death-inducing DNA fragmentation factor CIDEA Lipid metabolism
Uncoupling protein 1 UCP1 Brown fat thermogenesis
Tocopherol transfer protein TTP a-tocopherol trafficking
Quantitative real-time RT-PCR was used to verify the NBC-induced alteration of gene expression in the adipose tissues of obese diabetic mice.
Candidate genes were selected from microarray analysis with fold change C1.2. The expression of the genes was significantly (P \ 0.05) altered
by NBC treatment as compared to placebo supplementation [97]
BAT [116]. Indeed, ultrastructural analysis indicates that that the molecular mechanism behind the beneficial effects
brown adipocytes contain numerous large mitochondria of chromium has begun to come to light [120]. Using the
packed with UCP1 [116]. UPC1 has been found to mediate powerful tool of nutrigenomics, it is possible to identify
the thermogenic activity of BAT and impaired BAT candidate genes that are regulated by chromium supple-
activity has been proposed to play an important role in the mentation. The physiologic nutrigenomic study by Rink
development of obesity [114]. TTP is involved in the et al. clearly offers a working basis for the elucidation of
transport of a-tocopherol (vitamin E) from hepatocytes to chromium-gene regulation in mammalian biological sys-
peripheral tissues including adipose tissues which serve as tems and provides strategies to identify novel targets for
the major a-tocopherol storage [117]. Vitamin E readily weight intervention by Cr(III) supplementation [97].
interconverts and equilibrates between lipoproteins and
TTP is likely to be responsible for the incorporation of a-
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Artikel 1
Nutrigenomic approaches for obesity research
Nutrigenomic and nutrigenetic approaches have shown potential in understanding gene

products and metabolites that change in response to defined conditions, providing insights into
biological processes. The study of epigenomics, focusing on heritable epigenetic signals that
modulate gene expression, is an emerging challenge with implications for obesity research. he
development of improved statistical and bioinformatic tools is leading to more robust and sensitive
data analyses, aiding in the exploration of the role of epigenetic effects in obesity. Quality control,
standardization, and data capture and storage of nutrigenomic and nutrigenetic data are crucial due
to the vast quantities of data produced by 'omic' tools. The European Nutrigenomics Organization
(NuGO) is actively working to identify bottlenecks, emerging technical requirements, and seeking
solutions in the field.
At the individual level, weight gain is essentially the result of energy intake exceeding
expenditure for significant periods of time, but this obvious truth provides no insight into the
strategies needed to deal with the ever-increasing problem of obesity in Western populations. It is
equally obvious, however, that certain individuals are more prone to developing 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. The potential impact of functional genomic approaches
(transcriptomics, proteomics and metabolomics) in nutrition 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.
Artikel 2
Nutrigenomic Approaches For Benefit-Risk Analysis Of Foods And Food Components:

Defining Markers Of Health
Even the best informed, most health-conscious and motivated consumer cannot be getting
the analysis exactly right because not all the information relevant to them is available. And while
the concept of rigorous benefit-risk analysis should underlie the development of dietary
recommendations, expert panels developing such recommendations have to work within the
constraints of the current limited and fragmented scientific knowledge base. Unexpected biological
effects and interactions (be they beneficial or detrimental) and inter-individual differences in
nutritional requirements pose a particular problem in this respect. Development of a system or
framework for performing comprehensive and rigorous benefit-risk analysis for individual food
components, whole foods or diets, and defining a common scale of measurement for comparing
the risks and the benefits would be enormously advantageous.
The artikel discusses the potential for categorizing optimal health as multiple stable states,
varying between individuals and influenced by life-stage, lifestyle, and gender. It proposes the
development of a panel of nutrition-relevant stress tests to assess health and the impact of dietary
components, including challenges such as infection, inflammation, cognitive, carbohydrate, lipid,
xenobiotic, oxidative, DNA damage, tissue damage, and exercise challenges. The application of
genomic tools, specifically transcriptomics, proteomics, and metabolomics, is highlighted for the
development and validation of novel biomarkers of health, as well as for detecting acute and
chronic effects of nutrition. The artikel emphasizes the importance of 'omic' methods in detecting
subtle but potentially profound biological effects of moderate nutritional modifications, and the
need for study designs that enable individuals to act as their own control. Integrated analysis of
'omic' data is discussed as a means to increase the power and sensitivity of assessment, enabling
the identification of consistent changes over several components of a pathway and sets of
functionally related genes that differ in expression between experimental groups.
Artikel 3
Nutrigenomic basis of beneficial effects of chromium(III) on obesity and diabetes
Insulin resistance has been shown to be the major contributing factor to the metabolic
syndrome, which comprises a cluster of risk factors for metabolic aberrations such as obesity,
dyslipidemia, hypertension, and hyperglycemia. Additionally, insulin resistance has been
associated with the occurrence of cardiovascular disease and type 2 diabetes. Epidemiological
studies indicate that obesity and diabetes have become alarmingly prevalent in recent years.
Substantial evidence suggests that dietary interventions and regular exercise greatly improve body
mass index and lipid profile as well as alleviate insulin resistance. Therefore, dietary supplements
such as insulinsensitizing agents may be beneficial in the prevention and treatment of obesity and
type 2 diabetes. Numerous in vitro and in vivo studies suggest that chromium supplements,
particularly niacin-bound chromium or chromium-nicotinate, may be effective in attenuating
insulin resistance and lowering plasma cholesterol levels. Utilizing the powerful technology of
nutrigenomics to identify the genes regulated by chromium supplementation may shed some light
on the underlying mechanisms of chromium-gene interactions, and thus provide strategies to
mitigate and prevent insulinresistance-related disorders.
The artikel discusses the effects of NBC supplementation on gene expression in the
adipose tissues of obese diabetic mice, as verified by quantitative real-time RT-PCR. - It highlights
the altered gene expression in response to NBC supplementation, including both stimulated and
suppressed genes related to various functions such as glycolysis, muscle contraction, lipid
metabolism, and thermogenesis. - The paper also covers the benefits of chromium(III) complexes
in animal and human health, as well as the potential risks associated with chromium picolinate,
including mutagenic and toxic effects. - Several studies on chromium deficiency during total
parenteral nutrition and its association with glucose intolerance and diabetes are referenced. - The
artikel also mentions the mutagenic and chromosome-damaging effects of chromium(III)
picolinate in cell studies, as well as reported cases of chronic renal failure and toxicity associated
with over-the-counter chromium picolinate ingestion.

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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

Nutrigenomic approaches for obesity research

R. M. Elliott and I. T. Johnson

Accepted 27 November 2006

Address for correspondence: Dr RM Elliott and

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

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

Conclusion Conflict of Interest Statement

Nutrigenomic approaches for benefit-risk analysis of foods and food

Risk-benefit: Nutrition: Biomarkers: Nutritional genomics

Abbreviations: GSEA, gene set enrichment analysis.

some current biomarkers so that they can be used to provide

integrated multi-component biomarkers are required. Ideally,

A number of standardised biological stress tests already effects of nutrition.

Nutrigenomic basis of beneficial effects of chromium(III)

adipose tissue of the NBC-supplemented obese diabetic

Table 1 Altered gene expression in response to NBC supplementation

NBC-stimulated Enolase 3 ENO3 Glycolysis and gluconeogenesis

Nutrigenomic approaches for obesity research

Nutrigenomic and nutrigenetic approaches have shown potential in understanding gene

Nutrigenomic Approaches For Benefit-Risk Analysis Of Foods And Food Components:

Nutrigenomic basis of beneficial effects of chromium(III) on obesity and diabetes

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