Effects of adrenalectomy on neuronal substrate fuel transporter and energy transducer gene expression in hypothalamic and hindbrain metabolic monitoring sites.
It has been reported that adrenalectomy (ADX) and the potent type II glucocorticoid receptor agonist, dexamethasone, exert opposing effects on glucose utilization in specific brain regions, including the hypothalamus. The present study investigated the hypothesis that ADX alters neuronal substrate fuel transporter mRNA levels in characterized hypothalamic and hindbrain metabolic monitoring structures, and adjustments in these gene profiles are correlated with modified transcription of genes encoding the glucose sensor, glucokinase (GCK), and the energy-dependent, inwardly-rectifying potassium channel, K(ATP). The lateral hypothalamic area (LHA), ventromedial hypothalamic nucleus (VMN), and dorsal vagal complex (DVC) were microdissected from ADX and sham-operated male rats 2 h after neutral protamine Hagedorn insulin or vehicle injection, and evaluated by quantitative real-time RT-PCR for neuronal glucose (GLUT3, GLUT4), monocarboxylate (MCT2) transporter, GCK, and sulfonylurea receptor-1 (SUR1) mRNA content. ADX modified basal fuel transporter and energy transducer gene expression in a site-specific manner since this manipulation decreased MCT2 and GLUT3 transcription in the DVC only; increased or decreased GCK mRNA in the LHA and VMN, respectively; and decreased SUR1 gene profiles in the DVC and LHA. Adrenal removal did not alter baseline GLUT4 mRNA in any structure examined. ADX also prevented the following transcriptional responses to insulin-induced hypoglycemia: downregulated DVC MCT2, downregulated DVC and upregulated LHA and VMN GLUT3, upregulated LHA GLUT4, upregulated LHA GCK, and upregulated VMN SUR1. These results show that the adrenals regulate basal GLUT3 gene profiles in the DVC alone; during hypoglycemia, these glands suppress (DVC) or increase GLUT3 (LHA and VMH) mRNA, and selectively elevate GLUT4 transcripts in the LHA. The data demonstrate divergent adrenal control of DVC neuronal monocarboxylate transporter gene expression under basal (stimulatory) versus hypoglycemic (inhibitory) conditions. The current work also reveals contrasting adrenal regulation of baseline GCK mRNA in the LHA (inhibitory) and VMN (stimulatory), as well as adrenal-dependent hypoglycemic enhancement of LHA GCK and VMN SUR1 gene profiles. Additional research is required to characterize the impact of adrenal-sensitive substrate transporter and metabolic transducer function on fuel uptake and metabolic regulatory signaling in these brain sites.
Cherian
Ajeesh Koshy
AK
Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, La 71201, USA.
Briski
Karen P
KP
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000311:Adrenal Glands / Q000502:physiology*; D000315:Adrenalectomy; D000818:Animals; D005786:Gene Expression Regulation; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000502:physiology*; D007336:Insulin, Isophane; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D012249:Rhombencephalon / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D014158:Transcription, Genetic
D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D051274:Glucose Transporter Type 3; D051275:Glucose Transporter Type 4; D027501:Monocarboxylic Acid Transporters; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; C091633:Slc16a7 protein, rat; C495690:Slc2a3 protein, rat; C495694:Slc2a4 protein, rat; D064233:Sulfonylurea Receptors; D007336:Insulin, Isophane; D005941:Glucokinase