8 FALL | 2014 ALN World | alnmag.com
feature | Nutritional Genomics
Robert Waterland, Associate Professor of Molecular
and Human Genetics at Baylor College of Medicine and
Associate Professor, Department
of Pediatrics; USDA/ARS Children’s
Nutrition Research Center in the
United States, set out to study the
relationships among diet, behaviour
and weight in early life. He specu-
lated that dietary deficiency of
methyl donors such as folate during
post-weaning development would
cause hypomethylation of DNA, and
therefore dysregulation in a growth
He took as a working assumption
that nutrition during development
may induce persistent changes in
the epigenetic regulation of genom-
ically imprinted genes. He found that indeed this was the
case. And for the first time, demonstrated this in vivo8.
One of the most surprising—and we think potentially
significant—findings was the epigenetic impact of three
diets: a natural diet, a synthetic diet with comparable levels
of methyl donors and synthetic diet without methyl donors.
Professor Waterland assumed that of the three, only the
methyl donor-deficient diet would produce the dysregulated
state. But, only the natural diet resulted in normal epigenetic
outcomes. Even the methyl donor-rich synthetic diet did not
produce the properly methylated state.
Why did an ostensibly nutritionally-replete synthetic diet
early in life cause persistent changes in gene expression?
What are the implications of this for processed “modern”
foods? Synthetic dietary supplements? No answers yet,
though clearly, mimicking mother nature can be tricky.
From here Professor Waterland turned his eye directly
on obesity. He knew that, in mice, obese agouti viable
yellow mothers produced offspring that tended to obesity.
He set out to identify the developmental timing and
physiological basis of the obesity-promoting effect.
In this study9, he and his co-workers found that female
offspring of obese mothers became obese in adulthood,
but male offspring did not—in the females fetal growth
restriction was followed by adult-onset obesity.
The central analysis focused on the female wild-type
offspring, which interestingly did not have an abnormally
increased appetite that fueled their obesity. The source of
their obesity instead appeared to be their blunted activity.
The implications are as curious as they are fascinating.
In the lab, female mice are more physically active than
males. They choose to run on the wheel more often than
the males, and in general are more spontaneously active.
This finding suggests that fetal growth restriction affects
some developmental pathway that changes the female’s
natural drive for physical activity.
In a further groundbreaking observation in the same
study, Waterland’s group showed that the obesity-promoting
effect definitively occurs during fetal development and
not during early life. Shortly after birth, litters of lean and
of obese mothers were cross-fostered.An obese female’s
lactation is impaired, which results in persistent stunting
of the offspring, yet even when reared by a lean, fully-
lactating mother, the offspring of obese females still
became obese in adulthood. It appears the pattern of fetal
growth restriction followed by sufficient nutrition causes
a developmental mismatch, and in adult females, obesity
It has been found that there is a similar pattern in
humans. Humans who are growth restricted in utero
show a greater risk of metabolic syndrome/type 2
diabetes as adults. It is postulated that the suboptimal
uterine conditions create limited nutrition, so the fetus
redistributes blood flow to help in the development of
vital organs. This is called the brain-sparing effect9.
But what is altered in these patterns? Professor
Waterland is hunting for the answers. His hunch is the
hypothalamus10 and he is now on the path to discover
the source of dysregulation through the neuronal
development of this brain structure, which links the
nervous and endocrine systems. The hypothalamus
coordinates hormonal and behavioural phenomena,
including food intake, energy expenditure and circadian
YOU ARE WHAT YOU (AND YOUR BACTERIA) EAT
When you eat, food gets broken down in the stomach and
then passes to the body’s sorting centre, the gut, whereby
enzymes from the pancreas and the gut break it down
further. The gut’s prodigious bacterial population, called
the microbiota, processes what remains by fermentation
and sends the results out to nourish your body.
What’s important here is that optimum function—
nutrients and absorption by
the body—all depend on
processing by the entire gut,
which is quite long and varies
in its bacterial populations
from one segment to the
next. Furthermore, what is
broken down, and where, may
provoke epigenetic responses
in your genome and that of
your gut bacteria.
Here’s why this matters to
health. The human intestinal
system evolved when people
ate food in a natural state, like leaves,
fruits, whole grains and roots. These are fibrous, and the
gut digests them in several stages. So each section of the
gut progresses digestion and each section of the gut has