Overweight Mice Show Coordinated Homeostatic and Hedonic Transcriptional Response across Brain

Obesogenic diets lead to overeating and obesity by inducing the expression of genes involved in hedonic and homeostatic responses in specific brain regions. However, how the effects on gene expression are coordinated in the brain so far remains largely unknown. In our study, we provided mice with access to energy-dense diet, which induced overeating and overweight, and we explored the transcriptome changes across the main regions involved in feeding and energy balance: hypothalamus, frontal cortex, and striatum. Interestingly, we detected two regulatory processes: a switch-like regulation with differentially expressed (DE) genes changing over 1.5-fold and "fine-tuned" subtler changes of genes whose levels correlated with body weight and behavioral changes. We found that genes in both categories were positioned within specific topologically associated domains (TADs), which were often differently regulated across different brain regions. These TADs were enriched in genes relevant for the physiological and behavioral observed changes. Our results suggest that chromatin structure coordinates diet-dependent transcriptional regulation.