Winters are challenging environmental periods, consisting of decreased temperature and nutrient limitations. The Eurasian common shrew, Sorex araneus, despite pairing the extrinsic demands of winters with one of the highest measured mammalian metabolisms, has a vast temperate distribution. Winter survival of these small, non-hibernating mammals depends on a seasonal size plasticity, known as Dehnel’s phenomenon, where shrews drastically reduce in size during autumn and winter, decreasing the energy allocated to the maintenance of larger tissues, with rapid regrowth in spring. This phenotype is an incredibly rare energy saving process, requiring mechanisms to both degenerate and regenerate the brain, a functionally important tissue that does not typically grow beyond development. Due to the unique nature of this phenotype and potential parallels to human neurodegeneration, my dissertation research focused on discovering the molecular mechanisms and evolutionary history underlying Dehnel’s phenomenon. Similar to both hibernation and human neurodegeneration, the molecular mechanisms and evolutionary history of extraordinary seasonal size change may be integrally linked to metabolic regulation. To test this hypothesis, I used a stable of genomic analyses, including seasonal transcriptomics, comparative genomics, and comparative transcriptomics. In my first chapter, I characterized the gene expression of brain shrinkage and regrowth in relation to liver expression and metabolite concentrations. Results indicated a seasonal metabolic switch between lipid and glucose metabolism mediated via crosstalk between the brain and liver. Validating this proposed coordinated plasticity in metabolism and brain size, in my second chapter I proceeded to analyze selection on expression of the shrew hypothalamus. I identified an evolutionary upregulation of genes involved in blood brain barrier development, which I proposed improves metabolic sensing as brain size change occurs. Finally, I tested candidate regulatory genes for positive selection using our newly generated chromosome-level genome assembly. I found signatures of selection in genes associated with transitions between lipid and glucose metabolism, as well as in genes related to immunity, longevity, and neural development. Overall, my dissertation suggests that the abnormally high metabolism of the Eurasian common shrew contributed to the evolutionary trajectory toward Dehnel’s phenomenon and other related life-history traits.