title: In situ coexpression of glucose and monocarboxylate transporter mRNAs in metabolic-sensitive caudal dorsal vagal complex catecholaminergic neurons: transcriptional reactivity to insulin-induced hypoglycemia and caudal hindbrain glucose or lactate repletion during insulin-induced hypoglycemia.
abstract: The neurochemical phenotype(s) of metabolic sensing neurons in the dorsal vagal complex (DVC) remains unclear. These studies utilized single-cell quantitative real-time RT-PCR, in conjunction with laser-catapult microdissection, to address the hypothesis that DVC A2 neurons express genes that encode the characterized metabolic transducers, e.g. glucokinase (GCK) and the energy-dependent potassium channel, K(ATP). Studies show that either glucose or lactate alters synaptic firing of DVC chemosensory neurons, and that delivery of the latter fuel into the caudal hindbrain amplifies insulin-induced hypoglycemia (IIH) and elevates neuronal glucose and monocarboxylate transporter, GCK, and sulfonylurea-1 mRNA in the DVC. We thus examined the additional premise that IIH modifies A2 substrate transporter and metabolic transducer gene profiles, and that such transcriptional responses may be reversed by exogenous lactate and/or glucose. Individual tyrosine hydroxylase (TH)-immunoreactive (-ir) A2 neurons were microdissected from the caudal DVC 2 h after injection of insulin or saline, and continuous caudal fourth ventricular (CV4) infusion of lactate, glucose, or artificial cerebrospinal fluid. The data show that IIH decreased MCT2, but elevated GLUT3, GLUT4, GCK, and SUR-1 transcripts in A2 neurons. Blood glucose levels in insulin-injected rats were further reduced by CV4 infusion of either lactate or glucose. Lactate plus insulin reversed hypoglycemic reductions in MCT2 mRNA and further augmented GLUT3 transcripts in A2 neurons, whereas glucose infusion in insulin-injected rats further increased GLUT3 and GCK gene profiles. The present results demonstrate that caudal DVC A2 neurons express molecular markers for metabolic sensing, and genes that encode glucose and monocarboxylate transporters. Evidence that IIH reduces A2 MCT2, but elevates GLUT3 and GLUT4 gene profiles suggests that glucose may be a primary energy source to these cells during hypoglycemia, while decreased lactate uptake, alone or relative to glucose uptake, may be a critical manifestation of systemic glucose deficiency at the cellular level. Findings that singular fuel repletion does not normalize hypoglycemic patterns of glucose transporter, GCK, or SUR-1 mRNA expression in A2 neurons imply that sufficient supply of both energy substrates is required for metabolic balance, and that cellular adaptation to the prevalence of either fuel may increase cellular dependence on glucose-specific metabolites or other products.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209, USA. briski@ulm.edu
authors.forename: K P
authors.initials: KP
authors.lastname: Briski
authors.forename: A K
authors.initials: AK
authors.lastname: Cherian
authors.forename: N K
authors.initials: NK
authors.lastname: Genabai
authors.forename: K V
authors.initials: KV
authors.lastname: Vavaiya
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011955:Receptors, Drug / Q000235:genetics; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D064233:Sulfonylurea Receptors; D027981:Symporters / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D018528:ATP-Binding Cassette Transporters; D002395:Catecholamines; D005947:Glucose; D051246:Glucose Transport Proteins, Facilitative; D007004:Hypoglycemic Agents; D007328:Insulin; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C577509:Abcc8 protein, rat