Methylation of the young brain may be the key to obesity

According to the World Health Organization, the global prevalence of obesity has almost tripled
since 1975.
There is no clear or definitive explanation for this dramatic increase – obesity is thought to be a multifactorial disease
at the role of both genes and the environment.
A new study focuses on the early epigenetic processes of brain development, which the authors believe may be one of
the keys to better understanding — and possibly eventually preventing — the condition.

A team of researchers reported in the journal Science Advances that neurons and glial cells in the mouse arcuate nucleus (the region of the hypothalamus that regulate energy balance) underwent sex-specific methylation changes
.
In addition, these events occurred in genomic regions
associated with human body mass index (BMI).

Susan Ozan, a developmental endocrinologist at the University of Cambridge who was not involved in the study, said the study "provides an important platform" to address the
relationship between brain development and obesity.
She added that the work is "brick in the wall" because it's fundamental
to understand how things are working in the first place so that you can later test how changes in the environment affect the baseline.

Study co-author Robert Waterland, an epigeneticist at the USDA/Baylor College of Medicine Child Nutrition Research Center, told The Scientist that he has long been interested in
the field of developmental programming.
He describes the phenomenon as "during critical periods of development, nutrients and other environmental influences can actually disrupt developmental pathways, leading to permanent changes in gene expression and metabolism, as well as risk of
disease.
" "There is a huge amount of data from epidemiological and animal model studies" that "supports the importance of these programmed effects," he added
.
In rodents, for example, the early postnatal period is a notoriously critical period, and overnutrition during this period may increase the risk of
obesity later in life.

Watland said he and his colleagues were interested
in understanding the process of regulating development planning.
They focused on assessing epigenetic events that occur at this early stage, as epigenetic regulation is "one of the key candidate mechanisms to explain the long-term persistence of these effects," he noted
.
The researchers looked at the critical window period in mice, known to end around 21 days after the pit was born, and locked in two time points on either side of that date (day 12 and day 35 after birth).

The researchers measured methylation and gene expression of neurons and glial cells within the arcuate nucleus of the hypothalamus of the mouse brain, "which is a kind of integrated center.
.
.
A lot of nutritional and hormonal signals are picked up there," Waterland said
.

The team found that neurons and glial cells in the arcuform nucleus underwent extensive methylation
between days 12 and 35.
Watland said the changes are likely "part of postpartum hypothalamic maturation.
"
In addition, most of these changes were sex-specific, and on average, female brain cells matured earlier than men's — that is, on day 12, the female cells had acquired some of the epigenetic changes
that were shown on day 35.
When the team evaluated the details of this maturation process through computational analysis, they found that methylation in both sexes occurred primarily at binding sites of neurodevelopmental transcription factors, while demethylation occurred at
binding motifs of genes directly involved in the response to food deprivation.

Waterland said the discovery suggests that the epigenetic maturation of the arcuate nucleus turns off genes needed for neurodevelopment "because it's all done on day 35" and turns on genes
for hypothalamic function.

The methylation changes observed in the mouse hypocyclus observed in the new study resonated with previous genome-wide association studies (GWAS), including a meta-analysis, which found that genomic locations associated with BMI overlapped
with genes and pathways involved in brain development.
So Waterland's team looked at human versions of genomic regions that undergo epigenetic changes in mice, and they found that, indeed, these affected sites contained genetic variants
associated with the heritability of human BMI.

"It's possible that the variation associated with BMI actually affects the way this epigenetic development plays a role in the human brain.
.
.
Or maybe they're independent," said
study co-author Harry McKay, a postdoc in Waterland's lab.

According to some researchers interviewed by The Scientist, the next step will be to examine whether this methylation also occurs in
humans.
"Our work does provide a pretty good reason to do this, because this part of the brain is also present in humans," McKay said, adding, "There is less research on it (in mice), but there is good reason to believe that it works fairly similarly
.
" INIMEC, a medical research institute affiliated with CONICET and the National University of Argentina Córdoba, was not involved in the study
.
She noted that previous studies have shown a "strong relationship" between rodent and human brain development in terms of methylation, adding that the 12th day part of postnatal mice corresponds to the last trimester
of human pregnancy.

Based on the results of the new study, as well as data from other epidemiological and animal models, which point to a link between brain development and obesity, the authors believe that it should be considered a neurodevelopmental disorder, an idea that has been discussed for several years
.

Margaret McCarthy, a neuroscientist at the University of Maryland School of Medicine who was not involved in the new study, said it was "a pretty plausible assumption.
"
We know from epidemiological data and animal model experiments that a tendency to be obese in adulthood can be set "very early in life," she notes, "We may be inclined to underestimate how the brain regulates metabolism or.
.
.
General feeding behavior
.
”

Cisternus says further experiments are needed to prove more definitively that obesity may be a neurodevelopmental disorder — for example, by assessing how changes in diet during brain development in mice affect epigenetics — but, she says, "it's a good first step in testing hypotheses.
"