Genomic convergence in hibernating mammals elucidates the genetics of metabolic regulation in the hypothalamus

Extreme metabolic adaptations can elucidate genetic programs that govern mammalian metabolism. Here, we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states and then used comparative genomics of hibernating versus nonhibernating lineages to identify cis elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.