Acta Veterinaria Hungarica 55 (2), pp.

229239 (2007)
DOI: 10.1556/AVet.55.2007.2.9

VETERINARY ASPECTS AND PERSPECTIVES

OF NUTRIGENOMICS: A CRITICAL REVIEW
S. Gy. FEKETE1* and D. L. BROWN2
1
Institute of Animal Breeding, Nutrition and Laboratory Animal Science,
Faculty of Veterinary Science, Szent Istvn University, H-1400 Budapest, P.O. Box 2,
Hungary; 2Department of Animal Science, New York State College of Agricultural &
Life Sciences at Cornell University, Morrison Hall, Ithaca, NY 14853, USA

(Received 24 September 2006; accepted 11 January 2007)

Nutrigenomics examines nutrient-gene interactions on a genome-wide

scale. Increased dietary fat or higher non-esterified fatty acids (NEFA) from star-
vation-induced mobilisation may enhance hepatic oxidation and decrease esterifi-
cation of fatty acids by reducing the expression of the fatty acid synthase gene.
The key factors are the peroxisome proliferator-activated receptors (PPARs). Die-
tary carbohydrates both independently and through insulin effect influence the
transcription of the fatty acid synthase gene. Oleic acid or n-3 fatty acids down-
regulate the expression of leptin, fatty acid synthase and lipoprotein lipase in
retroperitoneal adipose tissue. Protein-rich diets entail a shortage of mRNA nec-
essary for expression of the fatty acid synthase gene in the adipocytes. Conjugated
linoleic acids (CLAs) are activators of PPAR and also induce apoptosis in adipo-
cytes. Altered rumen microflora produces CLAs that are efficient inhibitors of
milk fat synthesis in the mammary gland (biohydrogenation theory). Oral zinc
or cadmium application enhances transcription rate in the metallothionein gene.
Supplemental CLA in pig diets was found to decrease feed intake and body fat by
activating PPAR-responsive genes in the adipose tissue. To prevent obesity and
type II diabetes, the direct modulation of gene expression by nutrients is also pos-
sible. Nutrigenomics may help in the early diagnosis of genetically determined
metabolic disorders and in designing individualised diets for companion animals.

Key words: Nutrigenomics, peroxisome proliferator-activated receptor,

conjugated linoleic acid, milk fat depression, lean carcass, microbiotome, disease
predisposition, metabolic imprinting, individualised diet

*
Corresponding author: Sndor Gyrgy Fekete; E-mail: Fekete.Sandor@aotk.szie.hu,
dietvet@yahoo.com; Fax: 0036 (1) 478-4128

0236-6290/$ 20.00 2007 Akadmiai Kiad, Budapest

230 FEKETE and BROWN

Basic notions

Gene expression is regulated by the transcription, translation, processing,

stability (half-life) and protein synthesis of messenger RNA (mRNA), ribosomes
and transfer RNAs (tRNAs). Dietary nutrients may directly or indirectly modify
gene expression (Clarke and Abraham, 1992). The accumulation of the related
data has led to the birth of a new science: nutrigenomics or nutritional genomics
(Roche, 2006). Nutrigenomics will examine nutrient-gene interactions on a ge-
nome-wide scale. In the short term, nutrigenomics is the measuring of nutrition-
responsive genome activity, whilst nutrigenetics is the science of population
variation (Mariman, 2006). New tools that take advantage of the numerous avail-
able whole-genome sequences to study diet-gene interactions include microar-
rays (transcriptomics), proteomics, metabolomics (Falus, 2003) and epigenomics.
Beyond inherited genetic abnormalities, alterations in gene expression can
also contribute to disease processes. Recently it has been suggested that the envi-
ronment may alter such genes and thus have a direct influence on disease. Diet is
a potent mechanism for altering the environment of cells in most organs, particu-
larly in the gastrointestinal tract. The latter is inhabited by a great number of mi-
crobes; the modern terms gaining currency for such populations are micro-
biotome or microbiota rather than microflora. When one takes microbial
genes from all the species present into account, then the so-called microbiotic
genome comprises approximately 100 times more genes than the body of
monogastric animals. The role of the gut microbiotome in systemic responses to
dietary nutrients, drugs and toxins is just as important as tissue metabolism
(Nicholson et al., 2005). Manipulation of the diet may be a way of changing mi-
croflora to treat intestinal disorders indirectly in addition to direct effects of
changing the character of nutrient supply on gene function that controls interme-
diary metabolism.
Dietary fat has profound effects on gene expression. Specific fatty acid-
regulated transcription factors have been identified in bacteria, amphibians and
mammals. In mammals, these factors include peroxisome proliferator-activated
receptors (PPAR, -/ and -), oestrogen receptors (ERs) and sterol regulatory
element binding proteins (SREBPs). PPARs were identified first in mouse liver
tissue (Schoonjans et al., 1996). Actually, they are members of the steroid and
thyroid nuclear receptor superfamily, being ligand-activated transcription factors.
The Greek letters after the name abbreviation mean three isotypes encoded by
different genes. All these receptors, after having been activated, migrate to the
nucleus. They are regulated either by direct binding of (oxidised) fatty acids,
fatty acyl-coenzyme A or oxidised fatty acid (eicosanoid) regulation of cell sur-
face receptors and that of intracellular calcium levels as well as activation of sig-
nalling cascades (Jump, 1999). At the cellular level, the physiological response
to fatty acids will depend on the quantity, chemistry and duration of the fat in-

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 VETERINARY ASPECTS AND PERSPECTIVES OF NUTRIGENOMICS: A CRITICAL REVIEW 231

gested. These mechanisms are also involved in the control of both carbohydrate
and lipid metabolism, cell differentiation and growth and cytokine, adhesion
molecule and eicosanoid production.
The differentiation of adipocytes is a transcriptional regulatory cascade,
involving the member of the CCAAT-enhancer binding protein (C/EBP) family,
SREBPs and the adipocyte determination and differentiation dependent factor 1,
which enhance the expression of PPAR. The latter induces exit from the cell
cycle and stimulates the production of adipocyte specific genes. The synchro-
nised functioning of this cascade is supported by the hormonal events of the or-
ganism (Brun et al., 1996). Normal adipocytes protect lean tissue from the lipo-
toxic effects of excess or oxidised lipids. The high-fat diet-induced adipocyte
hypertrophy and insulin resistance is mediated by PPAR (Kubota et al., 1999).
In fact, the development of insulin resistance during obesity (the type II diabetes)
can also be considered as a protective mechanism reducing glucose-derived lipo-
genesis in cells (Ungar, 2003).

Changes in body composition increased dietary fat

Increased dietary fat or higher NEFA from fat mobilisation caused by

starvation may enhance hepatic oxidation and decrease esterification of fatty ac-
ids by reducing fatty acid synthase expression, thereby preventing triglyceride
accumulation in the liver (Leone et al., 1999). Short-term (2-day) feed restriction
did not change either the number or the size of fat cells in white adipose tissues
owing to a declined mRNA expression of PPAR2, glucocorticoid receptors
(GR) and of their modulator, the 11-hydroxy-steroid dehydrogenase type 1
(11-HSD1). Long-term (14-day) feed restriction, however, resulted in an in-
creased number of smaller adipocytes, demonstrating the recovered expression of
PPAR2, GR and 11-HSD1 mRNA (Arai et al., 2004). This type of adaptation
may partly explain the fast regaining of extra kilos after weight reduction pro-
grammes.
Fasting activates glucose production and lipolysis; conversely, re-feeding
after fasting by a fat-free, high-carbohydrate diet activates fat synthesis by strik-
ingly enhancing fatty acid synthase transcription rate (Fukuda et al., 1999). Re-
feeding with lipids will decrease the activity of transcriptional enzymes (phos-
pho-fructokinase, pyruvate dehydrogenase and acetyl-CoA carboxylase) in the
liver, minimising fat deposition. The key factors in these pathways are the
PPARs. PPAR is mainly produced in the liver, following the diurnal rhythm of
blood corticosterone concentration. Its main role is to enhance hepatic lipid oxi-
dation. The multifunctional PPAR can be found in the majority of tissues; in
turn, the PPAR isotype is expressed in the fat tissue and regulates adipocyte dif-
ferentiation and lipid storage/mobilisation (Desvergne et al., 1998). Elements re-

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232 FEKETE and BROWN

sponsive to the peroxisome proliferators have been found in the promoter regions
of several genes encoding proteins that are involved in lipid metabolism. Activa-
tion of PPAR by free fatty acids, eicosanoids or xenobiotics help to bind PPAR
to specific areas of target genes, leading to activation or repression of gene ex-
pression. Interestingly enough, dietary fat does not suppress body lipid mobilisa-
tion in fresh lactating dairy cows (Komaragiri et al., 1998).
It is clearly demonstrated that dietary carbohydrates, both independently
and through insulin effect, deeply influence the transcription of the fatty acid
synthase gene in a number of species. In rodents, immobilisation stress, starva-
tion, diabetes and chemical compounds (e.g. clofibrate) may also stimulate the
expression of PPAR and peroxisomal -oxidation of fatty acids (Singh, 1997).
Ingestion of high-fat diets downregulates insulin-responsive glucose transporter
(GLUT4) protein expression in adipose tissue, thereby increasing leptin gene ex-
pression (Houseknecht et al., 1998). In horses, the expression of muscle GLUT-4
depends not only on the dietary carbohydrate source (sugar or starch), but also on
physical activity.

Intake of different oils

Ingestion of high amounts of oleic acid or n-3 fatty acids downregulates

the expression of leptin, fatty acid synthase, lipoprotein lipase and phosphoe-
nolpyruvate carboxykinase (PEPCK) in retroperitoneal adipose tissue of pigs.
There is no effect in subcutaneous adipose tissue. Hsu and Huang (2006) have
proved that reduced fat mass in rats fed a high oleic acid-rich safflower oil diet is
associated with changes in the expression of hepatic PPAR and adipose
SREBP-1c regulated genes, called also as adipocyte determination and differen-
tiation factor (Rosen et al., 2000). The third class of transcription factors directly
influencing adipogenesis is the class of the cytosine-cytosine-adenine-adenine-
thymine enhancers (C/EBPs).

Effect of protein-rich diets

Protein-rich diets cause a shortage of mRNA necessary for expression of

the fatty acid synthase gene in the adipocytes, resulting in the moderation of total
body fat. Such an effect cannot be observed in the liver tissue (Clarke, 1993).
Hepatic fat synthesis, in turn, can be inhibited by providing unsaturated fatty ac-
ids in the diet.

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 VETERINARY ASPECTS AND PERSPECTIVES OF NUTRIGENOMICS: A CRITICAL REVIEW 233

Special role of essential fatty acids

Dietary essential fatty acids are the precursors of eicosanoids. Among the
eicosanoids derived from arachidonic acid, prostaglandin E2 is known to possess
immunosuppressive actions. Thus, it has been a prevailing hypothesis that the
immunomodulatory roles of dietary fatty acids are mediated, at least partly,
through the alteration of prostaglandin biosynthesis. Summarising, it becomes
clear now that multiple steps in various receptor-mediated signalling pathways
can be modulated by dietary fatty acids. In turn, PPAR expression is nutrition-
ally regulated by high-fat diet, fasting and linoleic acid.

Newly discovered physiological features of conjugated linoleic acids (CLAs)

CLAs are potent activators of PPARs and, in turn, this function is thought
to be related to the anticarcinogenic effect of certain CLAs. Moreover, CLAs in-
duce apoptosis in adipocytes. The anti-inflammatory effect of some CLAs can be
explained by the inhibition of proinflammatory cytokine mRNA expression, in-
cluding interleukin-6 (IL-6), tumour necrosis factor (TNF) and, on the con-
trary, by the induction of gene expression of PPAR both in vivo (in weaned pig-
lets challenged with lipopolysaccharide) and in blood mononuclear cell culture
(Changhua et al., 2005).
Milk is one of the richest natural sources of CLAs. The ruminant milk fat
derives from two sources: approximately half of it comes from the uptake of
blood fatty acids, whilst the remaining part is formed by the de novo fatty acid
synthesis in the mammary gland. Composition and function of the rumen micro-
flora have great influence on the pattern of fatty acids available to the mammary
gland. Under normal conditions, the linoleic acid (cis-9, cis-12 C18:2) first be-
comes conjugated linoleic acid, CLA (cis-9, trans-11 CLA or rumenic acid),
which in turn transforms into vaccenic acid (trans-11 C18:1) and finally into
stearic acid (C18:0). There is also a reverse pathway from vaccenic acid under
the influence of 9-desaturase enzyme activity in the liver, adipose tissue and
mammary gland to form rumenic acid (Griinari et al., 2000). The same metabolic
pathway has been demonstrated both in lactating women and in dairy cows
(Mosley et al., 2006a, b). Of the latter, cis-9, trans-11 CLA gives more than two-
thirds of the CLAs in milk-fat and it is also present in beef meat.
Under certain circumstances (for example, with ingestion of diets low in
effective fibre), the rumen environment and bacterial population differ from the
average. Altered microflora will produce CLAs other than rumenic acid; the con-
centration of trans-10, cis-12 CLA may increase. The latter is an efficient inhibi-
tor of milk fat synthesis in the mammary gland and is part of the biohydrogena-
tion theory of milk fat depression (Bauman et al., 2006). The trans-10, cis-12

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234 FEKETE and BROWN

C18:2 has been shown to decrease mRNA expression for acetyl-CoA carboxy-
lase, fatty acid synthase, 9 desaturase, lipoprotein lipase, fatty acid binding pro-
tein, glycerol phosphate acyltransferase and acylglycerol phosphate acyltrans-
ferase (Baumgard et al., 2002). The biohydrogenation hypothesis has been con-
firmed both in cows and sheep and in lactating mice (Lin et al., 2004), by apply-
ing the above-mentioned CLA isomer. Kim et al. (2001) isolated from rumen
content a bacterium (Megasphaera elsdenii) capable of synthesising trans-10,
cis-12 CLA, while Mosley et al. (2002) demonstrated the biohydrogenating abil-
ity of mixed rumen microbes in vitro. This means that a natural bacterial product
in low amounts is capable of influencing mammary gene expression and thereby
controlling milk fat production. The dose-response relation is curvilinear (Lock
et al., 2007).

Metals and gene function

Bivalent metals strongly influence gene expression. For instance, both

parenteral and oral zinc or cadmium application enhance the transcription rate of
the metallothionein (MT) gene in intestinal tissue (Ouellette et al., 1982). Cad-
mium acts also in prolonging the half-life of MT mRNA in hepatocytes. This ef-
fect on the half-life prolongation of MT mRNA is metal and tissue specific: the
influence of cadmium is stronger than that of zinc, and the intensity of effect in
spermatocytes and spermatids is higher than in hepatocytes and fibroblasts (De et
al., 1991). Zinc acts as part of the zinc-fingers, fixing activator proteins to the
active segments of the DNA. Appropriate zinc supply is essential to the balanced
regulation for gene expression of pro-inflammatory enzymes like cyclo-
oxygenase-2 (COX-2). Recently, Fong et al. (2005) have demonstrated that im-
provement of zinc status results in a significant reduction of COX mRNA abun-
dance. The dietary supplementation with zinc oxide increases insulin-like growth
hormone I (IGF-I) and IGF-I receptor gene expression in the small intestine of
weanling piglets (Li et al., 2006). Iron influences transferrin and ferritin concen-
trations by exerting an effect on mRNA stability and the translation rate
(Bremner and Beattie, 1990).

Vitamins may influence gene expression

Vitamin A exerts its regulatory function in the form of retinol and retinoic
acid. The most important target tissues are in the adrenal glands, testes, cerebel-
lum, kidneys, prostate, cerebral cortex, skin and the viscera. After retinoic acid
binds to its receptor, it will stimulate the transcription and translation of vitamin
A-responsive genes, including some involved in cell differentiation (growth
hormone, glycerolphosphate dehydrogenase and leptin production among oth-

Acta Veterinaria Hungarica 55, 2007

 VETERINARY ASPECTS AND PERSPECTIVES OF NUTRIGENOMICS: A CRITICAL REVIEW 235

ers). Deficient vitamin A status was found to negatively influence hepatic

PEPCK gene expression in mice. By the oral application of retinoic acid that ex-
pression could be restored (Scribner et al., 2005).
Like those of retinoic acid, the actions of active vitamin D are mediated by
nuclear hormone receptors. The vitamin D receptor directly binds to DNA at vi-
tamin D responsive elements as a homodimer or heterodimer to activate gene
transcription. Ligand binding to the vitamin D receptor forms a complex of coac-
tivators that modulates gene expression in different cell types (Bohnsack and
Hirschi, 2004). A role for biotin in gene expression has been recognised by the
significant depression of ornithine transcarboxylase gene expression in biotin de-
ficiency. The consequent loss of enzyme activity is the basis for hyperam-
monaemia (Yuichi et al., 1996).
In the experiment of Selvaraj and Klasing (2006), broiler chickens were
fed lutein and eicosapentaenoic acid (EPA) enriched feed mixtures. Lutein and
EPA interacted to modify inducible nitric oxide synthase and mRNA levels
through the PPAR and retinoid acid X receptor pathway. For another example
of modulation of products important to antioxidation, Tsai et al. (2005) demon-
strated that garlic organosulphur substances upregulate the expression of the -
class of glutathione S-transferase in rat primary hepatocytes.

Possible practical-clinical applications

Lean meat production: Supplemental CLA in swine diets, by activating

PPAR-responsive genes in adipose tissue, stimulates fat oxidation in the perox-
isomes, reducing both voluntary feed intake and whole body fat content (Dugan
et al., 1997). Nevertheless, data concerning the antiadipogenic action of CLA
isomers are conflicting: McNeel and Mersmann (2003) found both CLAs and
oleic acid ineffective in increasing PPAR or lipoprotein lipase mRNA expres-
sion, and these compounds showed no influence on fat cell proliferation and dif-
ferentiation. According to Granlund et al. (2005), the effect of trans-10, cis-12
CLA on lipid accumulation during adipocyte differentiation depends upon the
timing and length of treatment, but only to a smaller extent on dosage. A better
knowledge of the metabolism of long-chain fatty acids would help in designing
daily rations for transient high-yielding dairy cows. Instead of supplemental fat
for the fresh cow, the provision of absorbable amino acids and glucogenic pre-
cursors, such as absorbed glucose, propionate and isobutyrate, should be empha-
sised (Drackley, 1999). By application of the inhibitor trans-10, cis-12 CLA,
milk fat production could be reduced during the critical periods of dairy cows in
a controlled manner. In addition, flushing effects (sow, ewe) can partly be ex-
plained by the effect of excess portions (i.e. high-carbohydrates with the concen-
trate intake) that activate fat synthesis by strikingly enhancing the fatty acid syn-
thase transcription rate.

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236 FEKETE and BROWN

Cis-9, trans-11 CLA or rumenic acid, present in milk fat and beef meat,
has been found to have anticarcinogenic effect in rats, where it was found to be
capable of reducing the incidence of mammary cancer (Aimutis, 2004). Overex-
pression of cyclo-oxygenase-2 (COX-2) is thought to be one of the causative fac-
tors of breast tumour genesis. By repressing the activation of COX-2 transcrip-
tion, mixtures of CLA isomers were able to counterbalance carcinogenic in-
flammation in cell culture (Degner et al., 2006). In the case of colon cancer cells
exclusively the trans-10, cis-12 CLA was capable of inhibiting cell cycle pro-
gression via induction of a cyclin-dependent kinase inhibitor, the p21 (Cho et al.,
2006).
Some of these compounds (the type of effective molecule depends on the
disease, but mostly the cis-9, trans-11 CLA) have also proved to have antia-
therogenic, antiobesity and antidiabetic characteristics both against type I and
type II diabetes. To prevent obesity and type II diabetes, the direct modulation of
gene expression by nutrients is also a potential mechanism (Patti and Kahn,
2004). The influence of diet on the phenotypic manifestation in some cases is
drastically determinant. The prenatal (maternal) nutrient supply may influence
not only the development of adipose tissue, but also the colour of the offspring
mouse pups (Waterland and Garza, 1999; Waterland and Jirtle, 2004). The inci-
dence of this so-called metabolic imprinting significantly depends upon the
type of placenta, too.
Promoting research: Nutrigenomics holds great promise for discoveries in
veterinary and human medicine, including profiles and characteristics of dietary
and body protein metabolism, development of food allergy, absorption and me-
tabolism of nutrients, their functions in uterine development, growth, reproduc-
tion and health, finding biomarkers of nutritional status and diseases (Kussmann
et al., 2006) and even assisting in target-designed drug development (Swanson et
al., 2003).
In human fields of study, there are already preliminary results from apply-
ing synthetic compounds to influence peroxisome proliferator-activated receptors
and/or liver X receptors (LXR) in order to cure dyslipidaemia, diabetes, obesity
and atherosclerosis (Barish, 2006). Nevertheless, it should be borne in mind that
these treatments involve delicately balanced sophisticated pathways, therefore
the expected result may be accompanied by undesirable side effects. For exam-
ple, even though fat accumulation can be prevented using trans-10, cis-12 CLA,
via the modulation of PPAR receptor, glucose homeostasis can also be altered.
Moreover, in the veterinary field, nutrigenomical databanks make possible
the selection for metabolic disease resistance. Hopefully, in the near future,
nutrigenomics may provide us with clearly determined, cell-physiologically ap-
propriate nutrient allowances for production animals. Data will enable us to
screen susceptible breeds or individuals and to give guidance for optimised or
individualised diets to prevent the onset of polygenic, nutrition-related disor-

Acta Veterinaria Hungarica 55, 2007

 VETERINARY ASPECTS AND PERSPECTIVES OF NUTRIGENOMICS: A CRITICAL REVIEW 237

ders in genetically predisposed individuals for companion and pet animals

(Roche, 2006) and reliable, effective functional feeds for both categories (Pi-
anetti et al., 2002; Swanson et al., 2003; Herzog et al., 2004).

Acknowledgements

This review of the literature could not have been prepared without the financial
support of the HAESF/CIEES and the kind, open and friendly help of all the co-workers
of the Department of Animal Science, Cornell University, Ithaca, NY.

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