Effects of Caudal Fourth Ventricular Lactate Infusion on Hypoglycemia-Associated MCT2, GLUT3, GLUT4, GCK, and Sulfonylurea Receptor-1 Gene Expression in the Ovariectomized Female Rat LHA and VMH: Impact of Estradiol

Abstract

Cellular metabolic stasis is monitored in the lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH), the classically defined hypothalamic "anoretic" and "satiety" centers, respectively. Neuronal glucose (GLUT3, GLUT4) and monocarboxylate (MCT2) transporter genes are expressed in both sites, suggesting that glucose and lactate, a product of astrocytic glycolysis, may fuel aerobic respiration in local neurons. Evidence that glucose utilization in the hypothalamus, but not other brain regions, is reported to vary according to cyclic estradiol secretion suggests that this hormone may regulate uptake and/or catabolism of this fuel. We investigated the hypothesis that estradiol exerts site-specific regulatory effects on basal and insulin-induced hypoglycemia (IIH)-associated MCT2 and neuronal glucose transporter mRNA profiles, and expression of genes that encode the substrate sensor, glucokinase (GCK), and the sulfonylurea receptor-1 (SUR) subunit of the energy-dependent potassium channel, K(ATP), in the female rat LHA and VMH. As caudal fourth ventricular (CV4) lactate infusion intensifies hypoglycemia in this gender, we also examined whether demonstrable LHA and VMH gene responses to IIH are correspondingly amplified. MCT2, GLUT3, GLUT4, GCK, and SUR1 mRNA levels in the LHA and VMH did not differ between saline-injected ovariectomized (OVX) rats implanted with estradiol benzoate (EB) or oil (O). LHA: IIH had no impact on gene profiles, excluding SUR1, in EB-treated animals, but decreased these transcripts, with the exception of GCK, in OVX + O rats. CV4 lactate infusion in hypoglycemic OVX + EB animals suppressed each mRNA profile, but reversed IIH-associated reductions in MCT2, GLUT3, and GLUT4 gene expression in OVX + O. VMH: IIH increased MCT2 and GLUT4 transcripts in OVX + EB, but not OVX + O rats and decreased GCK mRNA in both groups. Lactate plus insulin treatment elevated VMH MCT2, GLUT3, SUR1, and GCK gene expression in EB- and O-implanted OVX rats, but augmentation of the former three profiles was greater in the presence of EB. The data show that LHA and VMH neurons exhibited dissimilar, estradiol-dependent adjustments in neuronal lactate and glucose transporter, GCK, and SUR1 gene expression during IIH, and that in the presence of estradiol, caudal hindbrain lactate infusion during IIH elicited divergent changes in MCT2, GLUT3, GCK, and SUR1 gene expression in the LHA and VMH, where these transcripts were, respectively, diminished or augmented. These results support the need to investigate the potential impact of site-specific adjustments in fuel uptake and KATP regulation of membrane voltage on general and specialized, e.g., chemosensory, neuronal functions.

Monocarboxylate transporters: new players in body weight regulation

“…Finally, lactate infusion in this brain area reversed the insulin-induced hypoglycaemia-mediated reduction of MCT2 expression and increase of GLUT3 expression (45). 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).…”

Sexual Dimorphism in Offspring Glucose-Sensitive Hypothalamic Gene Expression and Physiological Responses to Maternal High-Fat Diet Feeding

“…A previous study reported glucose-sensitive modulation of Mct2 , Glut3, and Sur1 expression in lateral and ventromedial hypothalamic areas of male rats ( 41 ). The same gene expression changes were also investigated in ovariectomized and estradiol-replaced female rats and showed that estradiol treatment blunted hypoglycemia-associated gene expression changes in ovariectomized rats ( 42 ). These data thus further support the hypothesis that sex steroids have a significant effect on mechanisms conveying neuronal glucose-sensitivity.…”

Influence of VMH fuel sensing on hypoglycemic responses

“…Many of the glucose sensing components found in pancreatic β-cells, including the type 1 sulfonylurea receptor (SUR1) subunit of ATP-sensitive potassium (K ATP ) channels, glucose transporters (GLUT) 2, 3 and 4, glucokinase and monocarboxylate transporters (MCTs) have been identified in the hindbrain 14 . However, it is still unclear whether hindbrain catecholaminergic neurons are directly or indirectly activated by glucose deprivation.…”