Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in estab-lishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and tran-scriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and occurs in genomic regions enriched for heritability of body mass index in humans. Our results offer a potential explanation for both the limited ontogenic windows for and sex differences in sensitivity to developmental programming of obesity and provide a rich resource for epigenetic analyses of developmental programming of energy balance.

Automated summary

Recent studies have confirmed that obesity is primarily a neurodevelopmental disease influenced by nutrition during critical ontogenic windows. This study examines the role of epigenetic mechanisms in establishing and maintaining the brain's energy balance circuitry, specifically in the hypothalamic arcuate nucleus. The results indicate that postnatal epigenetic maturation is cell type and sex specific, occurring in genomic regions associated with body mass index heritability. These findings provide valuable insights into the limited ontogenic windows for developmental programming of obesity and the sex differences in sensitivity, and offer a resource for epigenetic analysis of energy balance programming.