Andrews MT, Russeth KP, Drewes LR, Henry P-G. Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor. Am J Physiol Regul Integr Comp Physiol 296: R383-R393, 2009. First published December 3, 2008 doi:10.1152/ajpregu.90795.2008.-Hibernating mammals use reduced metabolism, hypothermia, and stored fat to survive up to 5 or 6 mo 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 13 C-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 a 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 13 C 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.hibernation; -hydroxybutyrate; glucose; 13 C magnetic resonance spectroscopy; blood-brain barrier NATURAL HIBERNATORS FACE UNIQUE challenges in surviving physiological extremes that would normally lead to death in most species of mammals. Profound reductions in heart rate and oxygen consumption, in conjunction with near-freezing body temperatures, require a multitude of cellular and molecular adaptations for a hibernator to avoid injury (reviewed in Ref. 1). One of the more striking adaptations is the ability to survive 5-6 mo without feeding by switching over to a lipidbased metabolism. In the absence of food, survival relies on the liberation and mobilization of fatty acids stored in the hibernator's white adipose tissue. However, some organs, most notably the brain, cannot use fat as its sole source of fuel. In this paper, we examine the hypothesis that fat-derived ketone bodies provide the critical fuel for the brain and heart during a hibernator's prolonged period of starvation.Brain function in mammals requires a relatively high rate of energy metabolism, and under normal circumstances, the predominant fuel is D-glucose. However, there are several circumstances such as starvation, diabetes, suckling neonate...