Transcriptional Activation of Nucleus tractus solitarii/Area postrema Catecholaminergic Neurons by Pharmacological Inhibition of Caudal Hindbrain Monocarboxylate Transporter Function

Abstract

Evidence that intracerebral lactate administration alters electrophysiological sensitivity of metabolic-signaling neurons and hypoglycemic counterregulation suggests that this substrate fuel is a monitored indicator of in central nervous system energy balance. Catecholaminergic (CA) neurons in the caudal hindbrain nucleus tractus solitarii (NTS)/area postrema (AP) complex participate in the origin and/or relay of stimuli that signal deficient glucose provision to the brain. The present studies evaluated the responsiveness of this neurochemical phenotype to lactate insufficiency by investigating the effects of pharmacological inhibition of local monocarboxylate transporter activity on the transcriptional status of these cells. Adult female rats were sacrificed by transcardial perfusion 2 h after infusion of graded doses of the monocarboxylate transporter inhibitor, α-cyano-4-hydroxycinnamic acid (4-CIN), or vehicle into the caudal fourth ventricle, and tissue sections through the NTS/AP were processed by dual-label immunofluorescence histochemistry for demonstration of cytoplasmic tyrosine hydroxylase (TH) and the inducible nuclear AP-1 regulatory factor, Fos. While vehicle administration resulted in negligible Fos immunostaining within the NTS, 4-CIN-treated animals exhibited dose-dependent increases in mean numbers of Fos-ir- and TH-/Fos-ir-positive neurons in this structure. These data show that pharmacological suppression of lactate trafficking in the caudal hindbrain elicits the genomic activation of NTS/AP CA neurons. In light of evidence implicating this neurochemical phenotype in signaling of cellular energy imbalance, the current results support the view that diminished uptake and/or catabolism of lactate may underlie CA neuronal activation of neural pathways governing compensatory behavioral and physiological responses to metabolic substrate deficiency.

Lactate is a critical “sensed” variable in caudal hindbrain monitoring of CNS metabolic stasis

“…The near-complete absence of Fos-ir in neighboring neural structures lacking metabolismsensitive neurons, at any dose of 4CIN, supports the premise that this nuclear label identifies, in part, sensing neurons that participate in the initiation or relay of signaling of lactate insufficiency or, alternatively, suppression of energy-surfeit signaling, and argues against the possibility of nonspecific drug actions on local neurons. This view is supported by our recent report that DVC and AP tyrosine hydroxylase-ir-positive neurons, a phenotype characterized by electrophysiological reactivity to energy fuel availability, exhibit dose-proportionate colabeling for Fos in response to CV4 4CIN (21). Although we presume that GI neurons in the DVC and AP are susceptible to transcriptional activation by pharmacological lactoprivation, the possibility that GS cells also may be genomically reactive to this manipulation cannot be disregarded.…”

Monocarboxylate transporters: new players in body weight regulation

“…Such results have been observed in both hypothalamus and dorsal vagal complex, two regions implicated in glucose and energy homeostasis regulation (46)(47)(48). Furthermore, inhibition of MCTs in these specific brain metabolic-sensitive regions is associated with a defect of energy deficiency counter-regulatory responses (49,50). Finally, a study has demonstrated that blockade of MCTs in the dorsal vagal complex resulted in dose-dependent increases in glycaemia, demonstrating the importance of monocarboxylate transport at least in glucose homeostasis (51).…”

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

“…DVC A2 noradrenergic neurons are a plausible source of this regulatory stimulus, as these cells express the neuronal monocarboxylate transporter variant MCT2 (6), respond electrically to exogenous lactate (24), and undergo transcriptional activation during lactate shortage (51). During hypoglycemia, A2 cells exhibit decreased MCT2, but increased GLUT3 protein expression, suggesting that decreased lactate uptake alone or relative to glucose uptake is a critical manifestation of systemic glucose deficiency to these cell (6).…”