A GPR17-cAMP-Lactate Signaling Axis in Oligodendrocytes Regulates Whole-Body Metabolism

Summary: The CNS plays a pivotal role in energy homeostasis, but whether oligodendrocytes are involved has been largely unexplored. Here, we show that signaling through GPR17, a G-protein-coupled receptor predominantly expressed in the oligodendrocyte lineage, regulates food intake by modulating hypothalamic neuronal activities. GPR17-null mice and mice with an oligodendrocyte-specific knockout of GPR17 have lean phenotypes on a high-fat diet, suggesting that GPR17 regulates body weight by way of oligodendrocytes. Downregulation of GPR17 results in activation of cAMP-protein kinase A (PKA) signaling in oligodendrocytes and upregulated expression of pyruvate dehydrogenase kinase 1 (PDK1), which promotes lactate production. Elevation of lactate activates AKT and STAT3 signaling in the hypothalamic neurons, leading to increased expression of Pomc and suppression of Agrp. Our findings uncover a critical role of oligodendrocytes in metabolic homeostasis, where GPR17 modulates the production of lactate, which, in turn, acts as a metabolic signal to regulate neuronal activity. : Ou et. al. show that Gpr17 in oligodendrocytes contributes to whole-body metabolic regulation. Gpr17-deficient mice exhibit decreased body weight on long-term high-fat feeding by reducing food intake. Loss of Gpr17 increases oligodendrocytic lactate production, which results in the lean phenotype of the KO animals. Keywords: oligodendroyctes, GPR17, lactate, metabolic homeostasi