ABOVE: Photomicrograph of a cross-section of a mouse hypothalamus. The small bright triangular patch of cells at the bottom is the arcuate nucleus. Image courtesy of Drs. Harry Mackay and Robert Waterland

According to the World Health Organization, the prevalence of obesity has nearly tripled worldwide since 1975. There is no clear or definitive explanation for this dramatic increase—obesity is recognized as a multifactorial disorder in which both genes and environment play roles. A new study focuses on early epigenetic processes in brain development, with the authors arguing that they could be one of the keys to better understand—and perhaps eventually prevent—the condition.

A team of researchers reported on September 28 in Science Advances that mice undergo sex-specific methylation changes in neurons and glia in the arcuate nucleus, a hypothalamic region that regulates energy balance. Furthermore, these events occur in genomic regions similar to those associated with body mass index (BMI) in humans. 

The study “provides an important platform” to address questions on the relationship between brain development and obesity, says University of Cambridge developmental endocrinologist Susan Ozanne, who was not involved in the research. The work is an “initial brick in the wall,” she adds, as it is fundamental to first understand how things would occur normally in order to later test how changes in the environment affect that baseline. 

Study coauthor Robert Waterland, an epigeneticist at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, tells The Scientist that he has long been fascinated by the field of developmental programming. He describes the phenomenon as “essentially the idea that during critical periods of development, nutrition and other environmental influences can actually perturb developmental pathways, and thereby cause permanent changes in gene expression and metabolism and risk of disease.” There are “tons of data” from epidemiology and animal model studies, “supporting the importance of these programming effects,” he adds. In rodents, for instance, the early postnatal period is known to be critical, and overnutrition during this period may result in an increased risk of obesity later in life.

Waterland says he and his colleagues were interested in understanding the processes that mediate developmental programming. They focused on assessing the epigenetic events occurring during this early stage, as epigenetic regulation is “one of the key candidate mechanisms to explain the long-term persistence of these effects,” he notes. The researchers looked at the critical window in mice, known to end around 21 days after a pup is born, zeroing in on two timepoints flanking that date (postnatal days 12 and 35). The researchers measured methylation and gene expression in neurons and glia within the mouse brain’s hypothalamic arcuate nucleus, “a kind of a master integrative center . . . where a lot of nutrient and hormonal signals are received,” says Waterland. 

The team found that neurons and glia of the arcuate nucleus undergo extensive methylation between day 12 and day 35. These changes are likely “part of the maturation of the hypothalamus during this postnatal period,” says Waterland. Moreover, most of these changes are sex-specific and, on average, methylation of these brain cells matures earlier in females than in males—that is, at day 12, cells in females have already acquired some of the epigenetic changes they display at day 35. When the team performed computational analyses to assess the details of this maturation, they found that methylation in both sexes was mainly occurring on binding sites for neurodevelopmental transcription factors, and demethylation on binding motifs of genes associated with the immediate response to food deprivation. 

This finding suggests that epigenetic maturation in the arcuate nucleus turns off genes needed for neurodevelopment, “because that’s all done” by day 35, and turns on genes for hypothalamus function, Waterland says.

The methylation changes occurring in the mouse hypothalamus observed in this new study resonate with previous genome-wide association studies (GWAS)—including a meta-analysis—that have found that genomic positions associated with BMI overlap with genes and pathways involved in brain development. Waterland’s team thus looked at the human versions of the genomic regions that experienced the epigenetic changes in mice, and they found that, indeed, these affected sites contain genetic variants associated with heritability of human BMI. 

“It could be the case that variants that are linked to BMI actually affect the way this epigenetic development plays out in the human brain . . . or it could be the case that they’re separate,” says study coauthor Harry MacKay, a postdoc in Waterland’s lab. 

According to some of the researchers that spoke to The Scientist, the next step will be to check whether this methylation also occurs in humans. “Our work does give a fairly good reason for doing so, because this part of the brain does exist in humans as well,” says MacKay, adding that it’s “less well studied [than in mice], but there’s every reason to believe that it works in a fairly similar way.” Carla Cisternas, a neuroendocrinologist at INIMEC, a medical research institute affiliated with CONICET and the National University of Córdoba, Argentina, who was not involved in the study, concurs. Previous research suggests that there is a “strong relationship” between rodent and human brain development in terms of methylation, she notes, adding that day 12 for postnatal mice partially corresponds to the last trimester of pregnancy in humans.

Based on the results of the new study as well as other epidemiological and animal model data pointing to a link between brain development and obesity, the authors argue that it should be considered a neurodevelopmental disorder, an idea that has been discussed for some years now. 

This is “quite a reasonable hypothesis,” says Margaret McCarthy, a neuroscientist at the University of Maryland School of Medicine who did not participate in the new study. We know from epidemiological data and animal model experiments that the propensity to develop obesity in adulthood can be programmed “very early in life,” she notes, “and we probably tend to underestimate how important the brain is to regulating things like metabolism or . . . general feeding behaviors.” 

Cisternas says that further experiments are needed to show more conclusively that obesity may be a neurodevelopmental disease—for example, by assessing how changes in diet affect epigenetics during brain development in mice—but, she says, “this is a nice first step” in testing the hypothesis.