Caudal hindbrain 'sensing' of glucoprivation activates central neural mechanisms that enhance systemic glucose availability, but the critical molecular variable(s) that is(are) linked to detection of local metabolic insufficiency remain(s) unclear. Current data support the metabolic coupling of neurons and glia in the brain via intercellular trafficking of the glycolytic product, lactate, as a substrate for neuronal oxidative respiration. The present studies investigated the hypothesis that lactate insufficiency may be monitored by local metabolically-'sensitive' neurons as an indicator of CNS energy imbalance. Using complementary in vivo models for experimental manipulation of lactate availability within the caudal hindbrain, we evaluated the effects of 1) caudal fourth ventricular (CV4) administration of the monocarboxylate transporter inhibitor, -cyano-4-hydroxycinnamate (4CIN) and 2) CV4 delivery of graded concentrations of exogenous L-lactate during insulin-induced hypoglycemia (IIH) on blood glucose levels and immediate-early gene expression within the hindbrain. The present data show that 4CIN treatment of euglycemic animals resulted in dose-dependent increases in blood glucose, whereas the degree and duration of hypoglycemia elicited by insulin administration were exacerbated by exogenous lactate delivery to the caudal fourth ventricle. Immunocytochemical processing of the hindbrain for the inducible cFos gene product, Fos, revealed that 4CIN enhanced Fos immunoreactivity in the dorsal vagal complex (DVC), e.g. the nucleus of the solitary tract and dorsal vagal motor nucleus, and adjacent area postrema, sites where cells characterized by unique sensitivity to diminished glucose and/or glycolytic intermediate/endproduct levels reside, and medial vestibular nucleus (MV), and that CV4 L-lactate infusion increased Fos labeling within the DVC and MV after insulin-induced hypoglycemia. Taken together, these results support the view that lactate is a critical monitored metabolic variable in caudal hindbrain detection of energy imbalance resulting from glucoprivation, and that diminished uptake and/or oxidative catabolism of this fuel activates neural mechanisms that increase systemic glucose availability.