Geller Sarah, Zanou Nadège, Lagarrigue Sylviane, Zehnder Tamara, Gouelle Cathy, Santoro Tania, Repond Cendrine, Bezzi Paola, Amati Francesca, Bouzier-Sore Anne-Karine, Sharif Ariane, Pellerin Luc
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Glia. 2025 Nov;73(11):2253-2272. doi: 10.1002/glia.70066. Epub 2025 Jul 24.
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.
在下丘脑中，检测葡萄糖等能量底物对于调节食物摄入和外周能量稳态至关重要。星形胶质细胞与神经元之间通过乳酸交换的代谢相互作用已被提出作为一种下丘脑葡萄糖传感机制，但分子基础仍不确定。体外培养的小鼠下丘脑星形胶质细胞在基础条件下比皮质星形胶质细胞表现出更强的糖酵解表型。这与丙酮酸激酶同工型M2（Pkm2）的蛋白表达水平较高及其更显著的核定位有关。同时，下丘脑星形胶质细胞还表达较高水平的单羧酸转运体Slc16a3（Mct4），其依赖于Pkm2的表达。下丘脑星形胶质细胞与皮质星形胶质细胞相比更强的Mct4表达是一种内在特征，因为从成年小鼠组织直接分离后也存在这种特征。下丘脑星形胶质细胞高乳酸释放能力被证明取决于Mct4的表达，而不是Mct1的表达。与皮质星形胶质细胞不同，培养的下丘脑星形胶质细胞对谷氨酸不产生糖酵解增强反应，而是以AMPK依赖的方式根据葡萄糖浓度调节其乳酸生成，这种效应在体外培养的小鼠和人类下丘脑星形胶质细胞中均有观察到。我们的研究表明，下丘脑星形胶质细胞和皮质星形胶质细胞分别对葡萄糖和谷氨酸具有不同的糖酵解反应。这些结果揭示了星形胶质细胞的代谢特化，以实现不同区域特定的功能：下丘脑的葡萄糖传感与皮质区域依赖活动的神经元能量供应。
