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 4

Lactate trafficking through the tanycytic network is necessary to sustain POMC neuronal activity.

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Lactate trafficking through the tanycytic network is necessary to sustai...
(A) Schematic model representing the involvement of the tanycytic network in shuttling lactate to POMC neurons. Cx, connexins. (B–E) Representative whole-cell current-clamp recording of a POMC neuron (B and D) in ACSF containing a physiological concentration of glucose (2.5 mM), showing that the bath application of CBX decreased the spontaneous firing rate of the neuron (B and C) and that bath application of lactate reversed this effect (D and E). (F) Cx43TanycyteKO model. Tanycyte-specific deletion of Cx43 was carried out by infusing the TAT-Cre fusion protein into the 3V of Cx43loxP/loxP mice. (G) mRNA expression levels of Cx43 in Tomato-positive and -negative cells in Cx43+/+ and Cx43TanycyteKO mice. (H and I) Images (H) showing the maximal and minimal diffusion through ARH tanycytes of the fluorescent glucose analog 2-NBDG (green) injected into a single tanycyte in a control Cx43loxP/loxP mouse and a Cx43TanycteKO mouse, respectively, via a patch pipette for 20 minutes (H), and quantification of the diffusion (I); the 2 animals highlighted in green in the quantitative data in I correspond to the extremes shown in H. Scale bars: 50 μm. (J) Schematic model representing the involvement of a tanycytic network mediated by Cx43 gap junctions in lactate shuttling to POMC neurons. This model was tested by recording the electrical activity of POMC neurons in Cx43TanycyteKO mice. (K and L) Representative whole-cell current-clamp recording performed in ACSF containing 2.5 mM glucose showing the spontaneous firing rate of a POMC neuron from a Cx43loxP/loxP tdTomatoPOMC (top trace) and a Cx43TanycyteKO tdTomatoPOMC (top trace) mouse, as quantified in L. (M and N) Representative whole-cell current-clamp recording of a POMC neuron from a Cx43TanycyteKO tdTomatoPOMC mouse performed in ACSF containing 2.5 mM glucose, showing that the bath application of 5 mM lactate increased its firing rate, as quantified in N. *P < 0.05 and **P < 0.01, by Wilcoxon matched-pairs test (C, E, and N), 2-tailed, unpaired Student’s t test (G and I), and Mann-Whitney U test (L).