MCT2 Expression and Lactate Influx in Anorexigenic and Orexigenic Neurons of the Arcuate Nucleus

Cortés‐Campos, Christian; Elizondo‐Vega, Roberto; Carril, Claudio A; Martínez, Fernando Martínez; Boric, Katica; Nualart, Francisco; García-Robles, María De Los Ángeles

doi:10.1371/journal.pone.0062532

Cited by 61 publications

(60 citation statements)

References 47 publications

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“…with glucosamine, an inhibitor of GK, have an increased dietary intake [57]. Tanycytes have been implicated in an indirect control of the anorexigenic neuronal activity by glucose [11], [58]. Here we confirmed our prior report in which GK was detected in tanycytes rather than hypothalamic neurons.…”

Section: Discussionsupporting

confidence: 90%

Dynamic Localization of Glucokinase and Its Regulatory Protein in Hypothalamic Tanycytes

et al. 2014

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Glucokinase (GK), the hexokinase involved in glucose sensing in pancreatic β cells, is also expressed in hypothalamic tanycytes, which cover the ventricular walls of the basal hypothalamus and are implicated in an indirect control of neuronal activity by glucose. Previously, we demonstrated that GK was preferentially localized in tanycyte nuclei in euglycemic rats, which has been reported in hepatocytes and is suggestive of the presence of the GK regulatory protein, GKRP. In the present study, GK intracellular localization in hypothalamic and hepatic tissues of the same rats under several glycemic conditions was compared using confocal microscopy and Western blot analysis. In the hypothalamus, increased GK nuclear localization was observed in hyperglycemic conditions; however, it was primarily localized in the cytoplasm in hepatic tissue under the same conditions. Both GK and GKRP were next cloned from primary cultures of tanycytes. Expression of GK by Escherichia coli revealed a functional cooperative protein with a S0.5 of 10 mM. GKRP, expressed in Saccharomyces cerevisiae, inhibited GK activity in vitro with a Ki 0.2 µM. We also demonstrated increased nuclear reactivity of both GK and GKRP in response to high glucose concentrations in tanycyte cultures. These data were confirmed using Western blot analysis of nuclear extracts. Results indicate that GK undergoes short-term regulation by nuclear compartmentalization. Thus, in tanycytes, GK can act as a molecular switch to arrest cellular responses to increased glucose.

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Section: Discussionsupporting

confidence: 90%

Dynamic Localization of Glucokinase and Its Regulatory Protein in Hypothalamic Tanycytes

et al. 2014

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“…MCT-1 and -2 can transport lactate into the cell (31–33). While MCT-2 expression is largely restricted to the testis, heart, and brain, MCT-1 is widely expressed including in hematopoietic cells (31, 34, 35).…”

Section: Resultsmentioning

confidence: 99%

Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Abebayehu

Spence

Qayum

et al. 2016

The Journal of Immunology

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Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. While IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells (BMMC) were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent. LA selectively altered IL-33 signaling, suppressing TAK1, JNK, ERK, and NFκB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to HIF-1α, which was enhanced in BMMC treated with LA. Since HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and -3p species were measured. In fact, LA selectively suppressed miR-155-5p in a HIF-1α-dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33-induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, since LA injected intraperitoneally into C57BL/6 mice suppressed IL-33-induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation.

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“…AP = action potential. 25 To elucidate whether lactate acts extracellularly as an endogenous ligand or intracellularly, we blocked F I G U R E 6 GIRK channel blocker abrogates the lactate-mediated reduction in spike frequency and hyperpolarization after induction of epileptiform activity and also abolishes the lactate-induced outward currents. Two-way ANOVA indicated nonsignificant interaction between neuronal subtype and lactate effect (neuronal subtype x lactate) and lactate failed to produce changes in the two neuronal subtypes equally.…”

Section: Pyruvate Does Not Mimic the Action Of Lactate And Mct2 Blomentioning

confidence: 99%

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

Jorwal

Sikdar

2019

Epilepsia

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Objective: Much evidence suggests that the subiculum plays a significant role in the regulation of epileptic activity. Lactate acts as a neuroprotective agent against many conditions that cause brain damage. During epileptic seizures, lactate formation reaches up to ~6 mmol/L in the brain. We investigated the effect of lactate on subicular pyramidal neurons after induction of epileptiform activity using 4-aminopyridine (4-AP-0Mg 2+ ) in an in vitro epilepsy model in rats. The signaling mechanism associated with the suppression of epileptiform discharges by lactate was also investigated. Methods: We used patch clamp electrophysiology recordings on rat subicular neurons of acute hippocampal slices. Immunohistochemistry was used for demonstrating the expression of hydroxycarboxylic acid receptor 1 (HCA1) in the subiculum. Results: Our study showed that application of 6 mmol/L lactate after induction of epileptiform activity reduced spike frequency (control 2.5 ± 1.23 Hz vs lactate 1.01 ± 0.91 Hz, P = .049) and hyperpolarized the subicular neurons (control −51.8 ± 1.9 mV vs lactate −57.2 ± 3.56 mV, P = .002) in whole cell patch-clamp experiments. After confirming the expression of HCA1 in subicular neurons, we demonstrated that lactate-mediated effect occurs via HCA1 by using its specific agonist. All values are mean ±SD. Electrophysiological recordings revealed the involvement of Gβγ and intracellular cAMP in the lactate-induced effect. Furthermore, current-clamp and voltage-clamp experiments showed that the G protein-coupled inwardly rectifying potassium (GIRK) channel blocker tertiapin-Q, negated the lactateinduced inhibitory effect, which confirmed that lactate application results in outward GIRK current. Significance: Our finding points toward the potential role of lactate as an anticonvulsant by showing lactate-induced suppression of epileptiform activity in subicular neurons. The study gives a different insight by suggesting importance of endogenous metabolite and associated signaling factors, which can aid in improving the present therapeutic approach for treating epilepsy.

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MCT2 Expression and Lactate Influx in Anorexigenic and Orexigenic Neurons of the Arcuate Nucleus

Cited by 61 publications

References 47 publications

Dynamic Localization of Glucokinase and Its Regulatory Protein in Hypothalamic Tanycytes

Dynamic Localization of Glucokinase and Its Regulatory Protein in Hypothalamic Tanycytes

Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

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