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Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply.

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  • معلومة اضافية
    • المصدر:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101468876 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-6606 (Electronic) Linking ISSN: 17566606 NLM ISO Abbreviation: Mol Brain Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: London : BioMed Central
    • الموضوع:
    • نبذة مختصرة :
      The medium-chain fatty acids octanoic acid (C8) and decanoic acid (C10) are gaining attention as beneficial brain fuels in several neurological disorders. The protective effects of C8 and C10 have been proposed to be driven by hepatic production of ketone bodies. However, plasma ketone levels correlates poorly with the cerebral effects of C8 and C10, suggesting that additional mechanism are in place. Here we investigated cellular C8 and C10 metabolism in the brain and explored how the protective effects of C8 and C10 may be linked to cellular metabolism. Using dynamic isotope labeling, with [U- 13 C]C8 and [U- 13 C]C10 as metabolic substrates, we show that both C8 and C10 are oxidatively metabolized in mouse brain slices. The 13 C enrichment from metabolism of [U- 13 C]C8 and [U- 13 C]C10 was particularly prominent in glutamine, suggesting that C8 and C10 metabolism primarily occurs in astrocytes. This finding was corroborated in cultured astrocytes in which C8 increased the respiration linked to ATP production, whereas C10 elevated the mitochondrial proton leak. When C8 and C10 were provided together as metabolic substrates in brain slices, metabolism of C10 was predominant over that of C8. Furthermore, metabolism of both [U- 13 C]C8 and [U- 13 C]C10 was unaffected by etomoxir indicating that it is independent of carnitine palmitoyltransferase I (CPT-1). Finally, we show that inhibition of glutamine synthesis selectively reduced 13 C accumulation in GABA from [U- 13 C]C8 and [U- 13 C]C10 metabolism in brain slices, demonstrating that the glutamine generated from astrocyte C8 and C10 metabolism is utilized for neuronal GABA synthesis. Collectively, the results show that cerebral C8 and C10 metabolism is linked to the metabolic coupling of neurons and astrocytes, which may serve as a protective metabolic mechanism of C8 and C10 supplementation in neurological disorders.
      (© 2021. The Author(s).)
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    • Contributed Indexing:
      Keywords: Capric acid (C10); Caprylic acid (C8); MCFA; MCT; Mitochondria; Neurotransmitter recycling; β-hydroxybutyrate
    • الرقم المعرف:
      0 (Caprylates)
      0 (Decanoic Acids)
      0 (Epoxy Compounds)
      0RH81L854J (Glutamine)
      4G9EDB6V73 (decanoic acid)
      56-12-2 (gamma-Aminobutyric Acid)
      EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
      IY9XDZ35W2 (Glucose)
      MSB3DD2XP6 (etomoxir)
    • الموضوع:
      Date Created: 20210904 Date Completed: 20220204 Latest Revision: 20220204
    • الموضوع:
      20250114
    • الرقم المعرف:
      PMC8414667
    • الرقم المعرف:
      10.1186/s13041-021-00842-2
    • الرقم المعرف:
      34479615