It is widely accepted that adaptation to the extreme cold has evolved at the expense of high thermal sensitivity. However, recent studies have demonstrated significant capacities for warm acclimation in Antarctic fishes. Here, we report on hepatic metabolic reorganization and its putative molecular background in the Antarctic eelpout (Pachycara brachycephalum) during warm acclimation to 5°C over 6 wk. Elevated capacities of cytochrome c oxidase suggest the use of warm acclimation pathways different from those in temperate fish. The capacity of this enzyme rose by 90%, while citrate synthase (CS) activity fell by 20% from the very beginning. The capacity of lipid oxidation by hydroxyacyl-CoA dehydrogenase remained constant, whereas phosphoenolpyruvate carboxykinase as a marker for gluconeogenesis displayed 40% higher activities. These capacities in relation to CS indicate a metabolic shift from lipid to carbohydrate metabolism. The finding was supported by large rearrangements of the related transcriptome, both functional genes and potential transcription factors. A multivariate analysis (canonical correspondence analyses) of various transcripts subdivided the incubated animals in three groups, one control group and two responding on short and long timescales, respectively. A strong dichotomy in the expression of peroxisome proliferator-activated receptors-1α and -β receptors was most striking and has not previously been reported. Altogether, we identified a molecular network, which responds sensitively to warming beyond the realized ecological niche. The shift from lipid to carbohydrate stores and usage may support warm hardiness, as the latter sustain anaerobic metabolism and may prepare for hypoxemic conditions that would develop upon warming beyond the present acclimation temperature.