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I had an Epiphany: Desire to Voluntarily Exercise May Be Epigenetically Determined in the Womb

24 January 2020: Should I go to the gym and exercise or sit on the couch and watch a movie? This is a question that we have all asked ourselves many times!

Robert Waterland and his research group at Baylor College of Medicine have provided the first evidence that voluntary expenditure of energy, at least in mice, is determined in part by epigenetic changes established in early development (MacKay et al., Nat Commun, 2019).

This study showed that hypothalamic AgRP neuron-specific knockout of Dnmt3a leads to cell type-specific disruption of DNA methylation and the developmental upregulation of 1681 genes and downregulation of 2063 genes in these neurons, resulting in a decrease in voluntary exercise. Specifically, AgRP neuron-specific hypomethylation of the Bmp7 promoter increased its expression, causing widespread effects on TGFB signaling in the arcuate nucleus. These findings demonstrate a crucial role for DNA methylation in the normal development of the hypothalamic energy balance circuitry, and indicate that epigenetic mechanisms established early in life regulate an individual’s desire for physical activity.

Thus, choosing to go to the gym may be more difficult for some people than others not only because of social and genetic influences, but also because of epigenetic programming to reduce energy expenditure. This intriguing postulate may now also be investigated in humans since Waterland and his colleagues have recently defined a genomic atlas of related regions of systemic interindividual variation (CoRSIVs) that epigenetically control the expression of human metastable epialleles (Gunasekara et al., Genome Biol, 2019) - a novel subset of genes that is regulated epigenetically like the agouti gene in the Avy mouse (Waterland & Jirtle, Mol Cell Biol, 2003). The era of human environmental epigenomics and epidemiology is upon us.