Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons
Tori Lhomme, … , Ruben Nogueiras, Vincent Prevot
Tori Lhomme, … , Ruben Nogueiras, Vincent Prevot
Published July 29, 2021
Citation Information: J Clin Invest. 2021;131(18):e140521. https://doi.org/10.1172/JCI140521.
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Research Article Metabolism Neuroscience

Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons

Abstract

Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the arcuate nucleus of the hypothalamus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive connexin-43 gap junction–mediated metabolic networks by arcuate tanycytes. Selective suppression of either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.

Authors

Tori Lhomme, Jerome Clasadonte, Monica Imbernon, Daniela Fernandois, Florent Sauve, Emilie Caron, Natalia da Silva Lima, Violeta Heras, Ines Martinez-Corral, Helge Mueller-Fielitz, Sowmyalakshmi Rasika, Markus Schwaninger, Ruben Nogueiras, Vincent Prevot

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Figure 1

Endogenous production of lactate sustains POMC neuronal activity.

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Endogenous production of lactate sustains POMC neuronal activity. (A) In...
(A) Infrared differential interference contrast (IR-DIC) image (left) of the ARH at the level of the ME showing a patch-clamp electrode placed onto the cell body of a POMC neuron identified via fluorescence (right) in a tdTomatoPOMC mouse. Scale bars: 50 μm. (B) Schematic model representing the modulation of POMC neuronal activity by lactate. Whole-cell current-clamp recording of a POMC neuron performed in ACSF containing a physiological concentration of glucose, showing that bath application of 4-CIN, an inhibitor of MCTs, blunted its spontaneous neuronal activity. Bottom traces show expansions of the recording at the indicated time points 1, 2, and 3. (C) Firing rate of POMC neurons before and after the bath application of 4-CIN. (D and E) A switch in ACSF glucose concentrations from 2.5 to 0 mM decreased the spontaneous firing rate of POMC neurons. In the same neuron, lactate reversed the glucose deprivation effect. (F) Inhibition of LDH with oxamate inhibited spontaneous POMC neuronal activity in ACSF with 2.5 mM glucose. Lactate, the substrate of LDH, did not reverse the inhibitory effect of oxamate on the same neuron. (G) Lack of compensation by lactate of the inhibitory effect of oxamate on the firing rate of POMC neurons. (H and I) Bath application of the LDH inhibitor oxamate inhibited the activity of POMC neurons in ACSF with 2.5 mM glucose. In the same neuron, pyruvate, the metabolite of LDH, reversed the inhibitory effect of oxamate. (J and K) Intracellular application of oxamate in POMC neurons inhibited their activity in ACSF with 2.5 mM glucose. In the same neuron, the bath application of pyruvate reversed the inhibitory effect of oxamate. *P < 0.05, **P < 0.01, and ***P < 0.001, by Wilcoxon matched-pairs test (C) and repeated-measures 1-way ANOVA with Tukey’s post hoc test (E, G, I, K).