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

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

  • Cell Rep. 2019 Mar 12;26(11):2984-2997.e4. doi: 10.1016/j.celrep.2019.02.060.
Zhimin Ou 1,  Yanchen Ma 1,  Yuxia Sun 1,  Gege Zheng 1,  Shiyun Wang 1,  Rui Xing 2,  Xiang Chen 1,  Ying Han 3,  Jiajia Wang 4,  Q Richard Lu 5,  Tong-Jin Zhao 6,  Ying Chen 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian, China.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian, China; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
  • 3 The First Affiliated Hospital of Xiamen University, Xiamen, 361101 Fujian, China.
  • 4 Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
  • 5 Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Electronic address: richard.lu@cchmc.org.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian, China. Electronic address: zhaotj@xmu.edu.cn.
  • 7 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian, China. Electronic address: yingchen@xmu.edu.cn.
PMID: 30865888 DOI: 10.1016/j.celrep.2019.02.060
Abstract

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.

Keywords

GPR17; lactate; metabolic homeostasis; oligodendroyctes.

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