Epigenetic mechanisms linking early nutrition to long term
Karen A. Lillycrop, Reader in Epigeneticsa,*, Graham C. Burdge, Reader in
aCentre for Biological Sciences, Institute of Developmental Sciences, Faculty of Natural and Environmental Sciences,
University of Southampton, Southampton SO16 6YD, UK
bAcademic Unit of Human Health and Development, Faculty of Medicine University of Southampton, Southampton SO16 6YD, UK
Traditionally it has been widely accepted that our genes together
with adult lifestyle factors determine our risk of developing non-
communicable diseases such as type 2 diabetes mellitus, cardio-
vascular disease and obesity in later life. However, there is now
substantial evidence that the pre and early postnatal environment
plays a key role in determining our susceptible to such diseases in
later life. Moreover the mechanism by which the environment can
alter long term disease risk may involve epigenetic processes.
Epigenetic processes play a central role in regulating tissue specific
long-term changes in gene expression and metabolism which
persist throughout the lifecourse. This review will focus on how
nutritional cues in early life can alter the epigenome, producing
different phenotypes and altered disease susceptibilities.
? 2012 Elsevier Ltd. All rights reserved.
Abbreviations: Avy, Agouti viable yellow; CVD, cardiovascular disease; CpG, cytosine and guanine nucleotides linked by
phosphate; DMR, differentially methylated region; Dnmt, DNA methyl transferase; GR, glucocorticoid receptor; HDAC, histone
deacetylase; HNF4a, Hepatocyte nuclear factor 4a; HFD, high-fat diet; HMT, histone methyl transferase; HOTAir, HOX transcript
antisense RNA; 11bHSDII, 11b-hydroxysteroid dehydrogenase type II; IAP, intracisternal-A particle; IGF2, insulin like growth
factor 2; Il13 ra2, interleukin 13 receptor a3; IUGR, intrauterine growth restricted; k, lysine; MeCP, methyl CpG binding protein;
miRNA, microRNA; ncRNA, non-coding RNA; NCD, non-communicable disease; PAR, predictive adaptive response; PEPCK,
phosphoenolpyruvate carboxykinase; Pdx1, pancreatic and duodenal homeobox 1; POMC, Pro-opiomelanocortin; PR, protein
restricted; PPAR, peroxisomal proliferator-activated receptor; RXRa, retinoid X receptora; Xist, X-inactive specific transcript.
* Corresponding author. Tel.: þ44 (0)2380 795259; Fax: þ44 (0)2380 798079.
E-mail address: firstname.lastname@example.org (K.A. Lillycrop).
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Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 667–676
Non-communicable disease (NCD) such as diabetes mellitus, cardiovascular disease (CVD) and
obesity, account for 60% of all deaths globally. The incidence of NCDs has risen sharply over the past
two decades. This increase in NCDs is not restricted to industrialised nations but is becoming partic-
ularly prevalent in developing nations as those countries undergo socioeconomic improvement.1
Although it is widely established that genotype in combination with adult lifestyle factors are crit-
ical determinants of NCD risk, there is increasing recognition that fixed genomic variations only
account for a small proportion of the variation in NCD risk2and that the rise in incidence of NCDs has
occurred too rapidly to be explained solely by such factors. There is now substantial evidence that the
fetal and early postnatal environment strongly influences the risk of developing NCD and that
epigenetic processes play a critical role in the mechanism by which early life environment influences
future disease risk. This reviewwill focus on the evidence thatearlylife nutrition caninduce the altered
epigenetic regulation of genes leading to persistent changes in metabolism and physiology, and as
a consequence altered disease susceptibility.
Early life environment and future disease risk
The association between the quality of the early life environment and future risk of adult disease
was first described by Forsdahl in 1977, who found that infant mortality rates were positively asso-
ciated with an increased risk of CVD in middle age.3Subsequent studies in the UK by David Barker and
colleagues found an inverse relationship between birth weight and increased CVD mortality.4
Numerous retrospective epidemiological studies have since confirmed the association between low
birth weight and later risk of CVD and shown that low birth weight is also associated with an increased
risk of obesity, hyperytension and type 2 diabetes mellitus.5However, in all of these studies, birth
weight is thought to represent a very crude indicator of the intrauterine environment, which may have
been compromised through a variety of maternal, environmental or placental factors.6
The effect in particular of early life nutrition on subsequent disease susceptibility has however been
most clearlyshown in studies of the Dutch Hunger Winter, a faminewhich occurred in the Netherlands
during the winter of 1944. These studies have shown that individuals whose mothers were exposed to
famine periconceptually and in the first trimester of pregnancy did not have reduced birth weights
compared to unexposed individuals, but did as adults exhibit an increased risk of obesity and CVD,
whereas individuals whose mothers were exposed in the later stages of gestation had reduced birth
weights and showed increased incidence of insulin resistance and hypertension.7However it is not just
under-nutrition which has long term phenotypic effects, over-nutrition in early life is also associated
with an increased susceptibility to metabolic disease which may account for the U-shaped or J-shaped
relationships observed in a number of studies between birth weight and risk of obesity or insulin
resistance in later life.8,9
Animal models of nutritional programming
These findings from the human epidemiological studies have been replicated in a variety of animal
models which have generally used either rats or mice fed either an isocaloric low protein diet, global
dietary restriction or a high-fat diet during pregnancy and/or lactation. Interestingly, offspring born to
dams fed these different diets exhibit to varying extents characteristics of humans with cardio-
metabolic disease including obesity, insulin resistance, hypertension and raised serum cholesterol
levels. For instance feeding rats a protein restricted diet (PR) during pregnancy has been reported to
result in impaired glucose homeostasis,10vascular dysfunction,11impaired immunity,12increased
susceptibility to oxidative stress,13increased fat deposition and altered feeding behavior.14,15The
induction during early life of persistent changes to the physiology of the offspring by alterations in
maternal diet implies the induction of long term changes to gene expression which in turn results in
the altered activities of metabolic pathways and homeostatic control processes.16,17For example,
feeding a PR diet to pregnant rats increased glucocorticoid receptor (GR) expression and reduced
expression of 11b-hydroxysteroid dehydrogenase type II (11bHSD)-2, the enzyme that inactivates
K.A. Lillycrop, G.C. Burdge / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 667–676
58. Kersh EN, Fitzpatrick DR, Murali-Krishna K et al. Rapid demethylation of the IFN-gamma gene occurs in memory but not
naive CD8 T cells. The European Journal of Immunology 2006 Apr 1; 176(7): 4083–4093.
59. Bhattacharya SK, Ramchandani S, Cervoni N et al. A mammalian protein with specific demethylase activity for mCpG DNA.
Nature 1999 Feb 18; 397(6720): 579–583.
60. Zhu B, Zheng Y, Angliker H et al. 5-Methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T
mismatch glycosylase) and in a related avian sequence. Nucleic Acids Research 2000 Nov 1; 28(21): 4157–4165.
61. Barreto G, Schafer A, Marhold J et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethy-
lation. Nature 2007 Feb 8; 445(7128): 671–675.
62. Jost JP. Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyl-
deoxycytidine. Proceedings of the National Academy of Sciences of the United States of America 1993 May 15; 90(10): 4684–
*63. Park JH, Stoffers DA, Nicholls RD et al. Development of type 2 diabetes following intrauterine growth retardation in rats is
associated with progressive epigenetic silencing of Pdx1. The Journal of Clinical Investigation 2008 Jun; 118(6): 2316–2324.
*64. Ozanne SE, Sandovici I & Constancia M. Maternal diet, aging and diabetes meet at a chromatin loop. Aging (Albany NY) 2011
May; 3(5): 548–554.
65. Sandovici I, Smith NH, Nitert MD et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer
interaction at the Hnf4a gene in rat pancreatic islets. The Proceedings of the National Academy of Sciences of the United
States of America 2011 Mar 29; 108(13): 5449–5454.
*66. Heijmans BT, Tobi EW, Stein AD et al. Persistent epigenetic differences associated with prenatal exposure to famine in
humans. The Proceedings of the National Academy of Sciences of the United States of America 2008 Nov 4; 105(44): 17046–
67. Tobi EW, Lumey LH, Talens RP et al. DNA methylation differences after exposure to prenatal famine are common and
timing- and sex-specific. Human Molecular Genetics 2009 Nov 1; 18(21): 4046–4053.
68. Steegers-Theunissen RP, Obermann-Borst SA, Kremer D et al. Periconceptional maternal folic acid use of 400 microg per
day is related to increased methylation of the IGF2 gene in the very young child. PLoS ONE 2009; 4(11): e7845.
*69. Godfrey KM, Sheppard A, Gluckman PD et al. Epigenetic gene promoter methylation at birth is associated with child’s later
adiposity. Diabetes 2011 May; 60(5): 1528–1534.
70. Jackson AA, Dunn RL, Marchand MC et al. Increased systolic blood pressure in rats induced by a maternal low-protein diet
is reversed by dietary supplementation with glycine. Clinical Science (London) 2002 Dec; 103(6): 633–639.
71. Brawley L, Torrens C, Anthony FW et al. Glycine rectifies vascular dysfunction induced by dietary protein imbalance during
pregnancy. The Journal of Physiology 2004 Jan 15; 554(Pt 2): 497–504.
72. Burdge GC, Lillycrop KA, Jackson AA et al. The nature of the growth pattern and of the metabolic response to fasting in the
rat are dependent upon the dietary protein and folic acid intakes of their pregnant dams and post-weaning fat
consumption. British Journal of Nutrition 2008 Mar; 99(3): 540–549.
73. Lillycrop KA, Phillips ES, Jackson AA et al. Dietary protein restriction of pregnant rats induces and folic acid supple-
mentation prevents epigenetic modification of hepatic gene expression in the offspring. Journal of Nutrition 2005 Jun;
74. Burdge GC, Lillycrop KA, Phillips ES et al. Folic acid supplementation during the juvenile-pubertal period in rats modifies
the phenotype and epigenotype induced by prenatal nutrition. Journal of Nutrition 2009 Jun 1; 139(6): 1054–1060.
K.A. Lillycrop, G.C. Burdge / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 667–676