Glia; auth.: S.Geller (group Fajas)

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Hypothalamic Astrocytes Exhibit Glycolytic Features Making Them Prone for Glucose Sensing

Sarah Geller 1 2, Nadège Zanou 3 4, Sylviane Lagarrigue 4, Tamara Zehnder 5, Cathy Gouelle 4 5, Tania Santoro 1 6, Cendrine Repond 4, Paola Bezzi 5 7, Francesca Amati 4 8, Anne-Karine Bouzier-Sore 9, Ariane Sharif 10, Luc Pellerin 1 11

. 2025 Nov;73(11):2253-2272.

 doi: 10.1002/glia.70066. Epub 2025 Jul 24.

Abstract

In the hypothalamus, detection of energy substrates such as glucose is essential to regulate food intake and peripheral energy homeostasis. Metabolic interactions between astrocytes and neurons via lactate exchange have been proposed as a hypothalamic glucose-sensing mechanism, but the molecular basis remains uncertain. Mouse hypothalamic astrocytes in vitro were found to exhibit a stronger glycolytic phenotype in basal conditions than cortical astrocytes. It was associated with higher protein expression levels of the Pyruvate Kinase Isoform M2 (Pkm2) and its more prominent nuclear localization. In parallel, hypothalamic astrocytes also expressed higher levels of the monocarboxylate transporter Slc16a3 (Mct4), which were dependent on Pkm2 expression. The stronger Mct4 expression in hypothalamic versus cortical astrocytes is an intrinsic characteristic, as it was also present after their direct isolation from adult mouse tissue. The high lactate release capacity of hypothalamic astrocytes was demonstrated to depend on the expression of Mct4, but not Mct1. Unlike cortical astrocytes, hypothalamic astrocytes in culture do not respond to glutamate with enhanced glycolysis, but instead, they modulate their lactate production according to glucose concentrations in an AMPK-dependent manner, an effect observed in both mouse and human hypothalamic astrocytes in vitro. Our study shows that hypothalamic and cortical astrocytes are geared to have distinct glycolytic responses to glucose and glutamate, respectively. These results reveal a metabolic specialization of astrocytes in order to fulfill distinct area-specific functions: glucose-sensing in the hypothalamus versus activity-dependent neuronal energetic supply in cortical regions.