Diets rich in sugar, salt, and fat alter taste perception and food preference, contributing to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here, we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of Drosophila melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

Interactions between genes and environment sculpt the responses of cells to environmental stimuli. In neuronal cells this process can lead to long term changes in the behavioral repertoire of animals, which in turn impacts disease risk. Here we show that the Polycomb Repressive Complex 2.1 (PRC2.1) modulates the physiology of sweet gustatory neurons and the taste behavior of D. melanogaster fruit flies in response to the food environment. A high sugar diet caused a redistribution of PRC2.1 chromatin occupancy resulting in the repression of a transcriptional network required for the responsiveness of the gustatory neurons to sweet stimuli. These changes led to lower sweet sensation, which in turn promoted obesity. Nearly half of the transcriptional changes mediated by PRC2.1 on a sugar diet persisted when animals were moved back to a control diet, causing a permanent decrease in sweet taste that was dependent on the constitutive activity of PRC2.1. Thus, our results point to a novel mechanism involved in modulating neural plasticity, behavior, and disease in response to the food environment.