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

Ou, Zhimin; Ma, Yanchen; Sun, Yingying; Zheng, Gaofeng; Wang, Shiyun; Xing, Rui; Chen, Xiang; Ying, Han; Wang, Jiajia; Lü, Qing; Zhao, Tong‐Jin; Chen, Ying

doi:10.1016/j.celrep.2019.02.060

Cited by 49 publications

(48 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the adult healthy brain, OPCs normally proliferate at very low levels, but mediate rapid repair responses to injury with increased proliferation and differentiation to mature myelinating cells (Psachoulia et al, 2009). Interestingly, Gpr17 specifically decorates a subset of OPCs responsible for such rapid reaction to damage (Viganò et al, 2016 (Ou et al, 2019) suggests that the massive reduction of Gpr17 expressing OPCs during ageing could contribute to age-associated neuronal deterioration and learning deficits also via this additional mechanism.…”

Section: Disruptionofgpr17+opcsinageingmentioning

confidence: 99%

Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

et al. 2021

View full text Add to dashboard Cite

Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age‐related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G‐protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate‐mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age‐related neuropathological contexts.

show abstract

Section: Disruptionofgpr17+opcsinageingmentioning

confidence: 99%

Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Chemogenetic approaches like DREADD have only recently been employed to study glial function, in particular, astrocyte function in motor coordination and memory (Agulhon et al, 2013;Sciolino et al, 2016;Nam et al, 2019). Chemogenetic approaches have also been used to study oligodendrocyte control of neural activity (Ou et al, 2019). Finally, the Watkins' group utilized DREADD approaches to study microglia in the spinal cord of rats via AAV9 mediated expression (Grace et al, 2016;Grace et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and the development of neuropathic pain in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CX 3 CR1 creER/+ :R26 LSL-hM4Di/+ transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) exclusively in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain initiation and maintenance. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1β). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after peripheral nerve injury. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.

show abstract

“…Other groups have identified its roles in myelination and metabolic role in oligodendrocytes 50 , mitigating ageing-related defects and ischemic damage in the brain 19,51 and heart 52 . The inconsistent report on whole-body Gpr17 knockout 50,53 is probably due to the physiological compensation and developmental adaption that are often associated with germ-line knockouts, which limits the interpretation of negative data as a true absence of a function 54 . Therefore, our studies using conditional knockout mice provide insights on the metabolic function of this orphan GPCR.…”

Section: Discussionmentioning

confidence: 99%

Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding

et al. 2019

View full text Add to dashboard Cite

Background Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism. Methods In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD). Results Adult PGKO mice on NCD displayed comparable body composition and metabolic features measured by indirect calorimetry. By contrast, PGKO mice on HFD demonstrated a sexually dimorphic phenotype with female PGKO mice displaying better metabolic homeostasis. Notably, female PGKO mice gained significantly less body weight and adiposity (p < 0.01), which was associated with increased energy expenditure, locomotor activity, and respiratory quotient, while males did not have an overt change in energy homeostasis. Though PGKO mice of both sexes had comparable glucose and insulin tolerance, detailed analyses of liver gene expression and serum metabolites indicate that PGKO mice could have reduced gluconeogenesis and increased lipid utilization on HFD. To elucidate the central-based mechanism(s) underlying the better-preserved energy and glucose homeostasis in PGKO mice on HFD, we examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, PGKO mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Conclusions Gpr17 deficiency in POMC neurons protects metabolic homeostasis in a sex-dependent manner during dietary and aging challenges, suggesting that Gpr17 could be an effective anti-obesity target in specific populations with poor metabolic control.

show abstract

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

Cited by 49 publications

References 46 publications

Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding

Contact Info

Product

Resources

About