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 5

Lactate trafficking in the tanycytic network is necessary to sustain energy homeostasis.

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Lactate trafficking in the tanycytic network is necessary to sustain ene...
(A–C) Lactate levels in the mediobasal hypothalamus (C) assessed using microdialysis (A) in Cx43TanycyteKO mice compared with Cx43loxP/loxP mice, before (basal) and after an i.p. injection of saline followed by glucose (2 mg/kg BW) (B). The bar graph in C represents the AUC during glucose treatment in Cx43loxP/loxP mice or Cx43TanycyteKO littermates, in which gene recombination was either induced by infusing the recombinant TAT-Cre protein into the 3V (n = 4, white dots) or injecting the AAV1/2 Dio2:Cre into the lateral ventricle (n = 5, black dots). (D) Comparison of mRNA expression levels of Mct1, Mct4, Ldha, Ldhb, Glut1, Glut2, and Cx30 in Tomato-positive cells between Cx43+/+ tdTomatoTanycyte and Cx43TanycyteKO tdTomatoTanycyte mice. (E) Change in food intake between day 0 and day 10 following TAT-Cre injection into Cx43TanycyteKO mice compared with Cx43loxP/loxP control mice. (F) BWs of Cx43TanycyteKO mice and Cx43loxP/loxP control mice on day 0 (d0) and on day 10 (d10) following TAT-Cre injection. (G and H) Change in fat mass (G) and lean mass (H) between day 0 and day 10 following TAT-Cre injection in Cx43TanycyteKO mice compared with Cx43loxP/loxP control mice. (I–L) Cumulative food intake (I), ambulatory activity (J), energy expenditure (K), and RER (L) before and 6 days after TAT-Cre injection into the 3V. (M) O2 consumption at rest 6 days after TAT-Cre injection into the 3V, during the dark and light phases. (N) mRNA expression levels of Mct2, Cartpt, Pomc, Agrp, and Npy in Tomato-negative cells from Cx43+/+ versus CX43TanycyteKO mice. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA followed by an uncorrected Fisher’s LSD test (C, left graph, and I–L), 2-tailed, unpaired Student’s t test (C, right graph, D–F, between genotypes, and G, M, and N), 2-tailed, paired Student’s t tests (F, between day 0 and day 10 within the same genotype), and Mann-Whitney U test (H).