Hibernating mammals use reduced metabolism, hypothermia and stored fat to survive up to 5-6 months without feeding. We found serum levels of the fat-derived ketone, D--hydroxybutyrate (BHB), are highest during deep torpor and exist in a reciprocal relationship with glucose throughout the hibernation season in the thirteen-lined ground squirrel (Spermophilus tridecemlineatus). Ketone transporter monocarboxylic acid transporter 1 (MCT1) is upregulated at the blood-brain barrier as animals enter hibernation. Uptake and metabolism of ¹³C-labeled BHB and glucose were measured by high resolution NMR in both brain and heart at several different body temperatures ranging from 7 to 38°C. We show that BHB and glucose enter the heart and brain under conditions of depressed body temperature and heart rate, but that their utilization as fuel is highly selective. During arousal from torpor glucose enters the brain over a wide range of body temperatures, but metabolism is minimal as only low levels of labeled metabolites are detected. This is in contrast to BHB, which not only enters the brain but is also metabolized via the tricarboxylic acid (TCA) cycle. A similar situation is seen in the heart as both glucose and BHB are transported into the organ, but only ¹³C from BHB enters the TCA cycle. This finding suggests that fuel selection is controlled at the level of individual metabolic pathways and that seasonally induced adaptive mechanisms give rise to the strategic utilization of BHB during hibernation.