The physiological and cellular adaptations to extreme fasting in northern elephant seals (Mirounga angustirostris) (NES) are remarkable and may help elucidate the contribution of endocrine systems to lipid metabolism as well as regulation of cellular energy homeostasis in mammals. Recent studies have highlighted the importance of thyroid hormones in the maintenance of a lipid-based metabolism during prolonged fasting in weaned NES pups. Utilizing a transcriptomics approach, this study examines changes in global gene expression profiles before and after 6-8 weeks of fasting in NES pups, including those driven by TH. We produced a de novo assembly containing 202 were differentially expressed transcripts between early and late fasting. Upregulated genes included metabolic regulators and other genes involved in lipid metabolism. Differentially expressed transcripts also included those associated with cell structure and maintenance of the extracellular matrix, such as collagen, proteoglycans, and perlecan/nidogen, highlighting the multifunctional nature of blubber tissue, which plays both metabolic and structural roles in marine mammals.