A2 noradrenergic nerve cell metabolic transducer and nutrient transporter adaptation to hypoglycemia: Impact of estrogen

Abstract

CNS neurons exhibit sustained activation by recurring hypoglycemia in the presence of estrogen. We investigated the impact of estradiol on fuel uptake and detection of energy imbalance by hindbrain A2 metabolosensory neurons during acute vs. chronic hypoglycemia. A2 neurons were laser dissected from estradiol benzoate (EB)- and oil (O)-implanted ovariectomized rats after single or serial injection of neutral protamine Hagedorn (NPH) insulin for single-cell qPCR or high-sensitivity Western blotting. Acute NPH increased A2 GLUT3 mRNA but not protein in EB, but decreased both profiles in O rats. Single insulin dosing did not alter monocarboxylate transporter-2 (MCT2) mRNAs in EB or O, but increased MCT2 protein in EB. Preceding hypoglycemia augmented baseline transporter mRNA and protein in O, but decreased GLUT4 and increased MCT2 proteins in EB. Chronic NPH increased A2 MCT2 and GLUT3 proteins in EB, but elevated GLUT4 protein in O. A2 phospho-AMPK (pAMPK) protein was progressively diminished by acute and chronic hypoglycemia in EB, but elevated in O after serial NPH. Dopamine-β-hydroxylase (DβH) transcripts were decreased in EB during acute and chronic hypoglycemia, but unaltered by serial NPH dosing in O. These results suggest that estrogen enhances A2 lactate utilization during acute hypoglycemia, thereby lessening AMPK activation relative to euglycemic controls. Cellular adaptation to chronic hypoglycemia may involve estrogen-dependent augmentation of lactate and GLUT3-mediated glucose uptake and hormone-independent increases in GLUT4 expression, coincident with diminished pAMPK-mediated signaling of energy deficiency. The data also imply that increased lactate and glucose uptake during recurring hypoglycemia may be required for sustained DβH transcriptional reactivity to this metabolic stress.