open access: Nature Reviews: Key Advances in Medicine

(HNF-4α), a crucial regulator of gene expression
in pancreatic islet β cells, have impaired
glucose tolerance. In 2011, Sandovici et al.
reported how maternal diet in rats affects the
epigenetic regulation of the Hnf4a locus in
pancreatic islets of offspring. 2 The researchers
found that a low-protein maternal diet
led to underexpression of Hnf4a in the islets
of the offspring. Mechanistically, the underexpression
could be attributed in part to
his tone modifications at the gene enhancer
region of Hnf4a, which led to changes in
chromatin looping that ultimately weakened
the interaction between the enhancer region
and a specific promoter region. The normative
age-dependent epigenetic silencing
of the Hnf4a locus was exacerbated in rats
exposed in utero to a low-protein diet. These
data add to the growing experimental literature
showing epigenetic consequences from
the manipulation of early life undernutrition
in metabolically relevant tissues.
Previous studies in rats have shown that
neonatal administration of the adipokine
leptin can reverse developmental programming
leading to metabolic compromise as
well as some of the associated epi genetic
changes. 3 Such studies are provocative
in that they suggest that develop mental
program ming in humans might be reversible.
Pinney et al. examined how administration
of exenatide, an analogue of the
incretin glucagon-like peptide 1, acts to
prevent the development of glucose intolerance
in adulthood in rats subjected to intrauterine
growth restriction. 4 Rats subjected
to this abnormal intrauterine environ ment
develop glucose intolerance and are characterized
by progressive epi genetic silencing
of pancreatic islet transcription factor
Pdx1. The 2011 paper found that injection
of exenatide during postnatal day 1–6 in
rats after intrauterine growth restriction
increased Pdx1 transcription by normalizing
post-translational and epigenetic changes
© Paul Hakimata | Dreamstime.com
Key advances
related to this gene, including Pdx1 activator
phosphorylation, histone acetylation and
trimethylation, and DNA methylation at the
CpG island in the Pdx1 promoter. Exenatide
is already in use in the treatment of adults
with type 2 diabetes mellitus (T2DM), and
this study provides an experimental proof
of concept for its usage early in life prior to
disease onset.
Prophylactic treatment of at-risk individuals
early in life is generally more efficacious
and provides greater health and cost
benefits than treatment after a disease
de velops. This is particularly the case for
diseases such as diabetes mellitus, where
the cost of treat ing associated morbidities
and complica tions compounds over many
years. How ever, beyond the obvious research
program that would be needed to validate
such interventions, a challenge remains:
how do we identify infants whose particular
developmental programming has placed
them at increased metabolic risk? Birth
weight is not a satisfactory proxy, given that
metabolically adverse developmental programming
can occur independent of birth
weight. 5 A recent paper by Godfrey et al.
—to which I contributed—has suggested that
the epigenetic state at birth can both predict
childhood adiposity and be a measure of prenatal
nutritional exposures. 6 Umbilical cord
tissue-derived DNA was sourced from two
independent large-scale prospective cohorts,
and the methylation status at specific CpGs
in the promoter region of RXRα, which
encodes a transcription factor involved in
fat metabolism and insulin sensitivity, was
measured after a preliminary genome-wide
scan. A positive correlation between degree
of RXRα methyla tion at one specific site in
the promoter and childhood body adiposity
at age 6 years or 9 years was found in
both within-cohort and between-cohort
replicates. Additionally, a negative association
was observed between mater nal carbohydrate
intake during the first tri mes ter of
pregnancy and the degree of methylation at
ENDOCRINOLOGY
■ Changes in promoter–enhancer interactions underlie the epigenetic regulation of a
transcription factor in rat pancreatic islets induced by poor maternal diet 2
■ The trajectory towards onset of type 2 diabetes mellitus (T2DM) in the growth-compromised
newborn rat can be reversed by an incretin analogue that normalizes epigenetic
modifications associated with pancreatic β-cell dysfunction 4
■ Strong relationships exist between epigenotype at birth and later adiposity, and between
maternal nutrition and offspring epigenotype in humans 6
■ The epigenetic states of genes associated with T2DM and obesity might be a
presymptomatic marker of the lifetime risk of T2DM in humans 7
■ The phenotypic effects of early life overnutrition can be transgenerationally transmitted
through the paternal line in mice 9
this site. In contrast to the small effect sizes
typically seen with genetic polymorp hisms
associated with metabolic disease risk, this
single site epigenotype could account for
at least 25% of the variance in child hood
adipo sity. This association was obser ved
across a healthy population, indicating
that develop mental programming of metabolic
risk and associated epigenetic variation
occurs across the normative range of
developmental experiences.
Genes for which polymorphisms have
strong associations with disease risk might
be anticipated to have epimutations (aberrant
epigenetic marks). One such gene is
FTO, which has been identified by genomewide
association studies as being involved
in obesity risk. In a prospective study of
nonsymptomatic indivi duals of a mean age
of 30 years by Toperoff et al., 7 those who
showed hypomethylation at an intronic
CpG site of FTO in blood samples had
an increased risk of develop ing impaired
glucose metabolism by a mean age of
43 years. This pattern was also seen in a
sepa rate case–control analysis, although the
level of hypomethylation in cases relative to
controls was small, as was the effect size. 7
These findings were made in a tissue not
specifically related to metabolic function,
and the differential methylation levels may
have been established in early development
before major cell differentiation had
occurred, although this inference is contingent
on the long-term stability of the FTO
epigenotype after its establishment. The
methylation levels could not be explained
by the presence or absence of the risk allele,
indicating that their association with disease
risk was independent of DNA sequence.
Global prevalence of maternal obesity
and ges tational diabetes mellitus is rising,
and both are risk factors for the development
of meta bolic disorder in offspring; 8
there fore, the potential for an escalating
prevalence of intergenerationally induced
T2DM is a par ticular concern. Epigenetic
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