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 3

Inhibition of lactate transport in tanycytes alters energy balance.

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Inhibition of lactate transport in tanycytes alters energy balance. (A) ...
(A) Schematic model for FACS used to isolate putative GFP- and Tomato-positive tanycytes and POMC neurons, respectively. (B) Relative expression of Mct1, Mct2, and Mct4 in tanycytes and POMC neurons (gene expression levels were normalized to the levels in POMC neurons, arbitrarily set at 1). See also Supplemental Figure 2 for characterization of the sorted cells. (C and D) Mct1 (C) and Mct4 (D) mRNA expression levels in GFP-positive and -negative cells in Mct1/4TanScramble and Mct1/4TanycyteKD mice. (E) Schematic model representing the inhibition of Mct1 and Mct4 in tanycytes. (F) Whole-cell current-clamp recordings performed in ACSF containing 2.5 mM glucose showing the spontaneous firing rate of a POMC neuron from an Mct1/4TanycyteKD mouse and another from an Mct1/4TanScramble mouse. (G) Comparison of firing rates of POMC neurons between Mct1/4TanScramble tdTomatoPOMC and Mct1/4TanycyteKD tdTomatoPOMC mice. (H) BWs of Mct1/4TanScramble and Mct1/4TanycyteKD mice. (I) Food intake by Mct1/4TanScramble and Mct1/4TanycyteKD mice during the dark and light phases. (J) Linear regression between food intake and BW for Mct1/4TanScramble and Mct1/4TanycyteKD mice. (K) Linear regression between energy expenditure and BW for Mct1/4Scrambled and Mct1/4TanycyteKD mice. (L–N) Z-rearing (L), number of meals (M), and meal size (N) during the dark and light phases for Mct1/4TanScramble and Mct1/4TanycyteKD mice. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed unpaired t test (B and H), Mann-Whitney U test (G), ordinary 1-way ANOVA followed by an uncorrected Fisher’s LSD test (C and D), 2-way ANOVA followed by an uncorrected Fisher’s LSD test (I and L–N), and Pearson’s correlation (J and K).