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 2

Lactate supply by tanycytes sustains the activity of POMC neurons.

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Lactate supply by tanycytes sustains the activity of POMC neurons. (A an...
(A and B) Representative images showing vimentin (green, A and B), MCT1 (red, A), and MCT4 (red, B) immunoreactivities in primary cultures of tanycytes. DAPI counterstaining is shown in blue (B). Scale bars: 10 μm. (C) Lactate secretion in cultured tanycytes exposed to different conditions (no treatment [Ctrl], 2-DG, CBX, or 4-CIN). (D) Intracellular lactate in cultured tanycytes exposed to different conditions. (E) IR-DIC (left panel) and fluorescence (right panel) images of the ARH at the level of the ME showing a recording from a paired tanycyte and POMC neuron (dyad), filled with lucifer yellow (LY, green) and Alexa Fluor 594 (red), respectively. Scale bars: 50 μm. (F) Responses of a POMC neuron and an ARH tanycyte to a current modulation from –50 pA to 0 pA with a step of 10 pA and a duration of 1 second, and to a voltage modulation from –100 mV to 100 mV with a step of 10 mV and a duration of 300 ms, respectively. (G–J) Schematic model (G) and a representative recording (H) of an ARH tanycyte-POMC neuron dyad (J) in whole-cell patch-clamp mode showing that dialyzing a tanycyte with 5 mM lactate prevented the inhibitory effect of exogenous glucose deprivation (0 mM glucose [0 Glc]) on neuronal firing (H and I). In the same neuron, the inhibition of MCTs by the bath application of 4-CIN cancelled this effect (H and I). Bottom traces show expansions of the recording at the time points 1, 2, 3, and 4 indicated in the trace above. (K–N) Schematic model (K) and representative recording (L) of an ARH tanycyte-POMC neuron dyad (N) in whole-cell patch-clamp mode showing that dialyzing the tanycyte with 10 mM oxamate inhibited POMC neuronal firing (L and M). Bottom traces show expansions of the recording at the time points 1, 2, and 3 indicated in the trace above. In the same neuron, this inhibition was compensated for by the bath application of 5 mM lactate (L and M). *P < 0.05, **P < 0.01, and ***P < 0.001, by ordinary 1-way ANOVA followed by Tukey’s post hoc test (C and D) and repeated-measures 1-way ANOVA followed by Tukey’s post hoc test (I and M) (see Supplemental Table 1 for statistical details).