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Published on: January 4, 2018
Hindbrain Lactoprivic Regulation of Hypothalamic Third Ventricular Alpha-2 Tanycyte Metabolic Sensor Gene Expression
Rajesh K Yadav1, Subash Sapkota1, Karen P Briski2,3
1School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA.
Abstract:
Alpha-2 (α2-) tanycytes line the ventral wall of the third ventricle where they ostensibly engage in metabolic screening. The oxidizable glycolytic end-product L-lactate is a gauge of hindbrain energy stability that is imparted to forebrain glucose-regulatory loci by norepinephrine signaling. Current research used a validated whole-animal model for insulin-induced hypoglycemia (IIH) to address the premise that hindbrain lactate status imposes sex-specific control of eu- and/or hypoglycemic patterns of α2-tanycyte chemosensor gene transcription in vivo. Vimentin-immunopositive α2-tanycytes were laser-catapult-microdissected from male and female brain sections after subcutaneous insulin injection and caudal fourth ventricular (CV4) L-lactate- or vehicle infusion for single-cell multiplex qPCR analysis of glucose and energy sensor gene expression. Hindbrain lactate infusion reversed IIH repression of α2-tanycyte glucose transporter-2 mRNA in females and amplified (males) or reversed (females) up-regulated glucokinase gene transcription. Lactate increased α2-tanycyte ATP-sensitive potassium channel Kir6.2 mRNA levels in hypoglycemic rats of each sex, reversing transcriptional inhibition in males or amplifying up-regulated expression in females. In both sexes, IIH-associated down-regulation of energy sensor 5'-AMP-activated protein kinase catalytic subunit isoforms alpha-1 and - 2 gene profiles was correspondingly unaffected or reversed by lactate. Hypoglycemia increased or decreased α2-tanycyte alpha1a and beta1 receptor mRNA content, respectively; lactate caused opposite, sex-specific adjustments in transcriptional reactivity of the former gene yet did not affect the latter profile in either sex. Results show that hypothalamic α2-tanycytes are direct target for norepinephrine stimulation and document sex-dimorphic hindbrain lactoprivic regulation of chemosensor gene transcriptional responses to in vivo hypoglycemia.
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