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-13C]C8 and [U-13C]C10 as metabolic substrates, we show that both C8 and C10 are oxidatively metabolized in mouse brain slices. The 13C enrichment from metabolism of [U-13C]C8 and [U-13C]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-13C]C8 and [U-13C]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 13C accumulation in GABA from [U-13C]C8 and [U-13C]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.

中文翻译：

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中链脂肪酸辛酸和癸酸的星形胶质细胞代谢通过升高的谷氨酰胺供应促进神经元中 GABA 的合成

中链脂肪酸辛酸 (C8) 和癸酸 (C10) 作为几种神经系统疾病的有益大脑燃料正受到关注。已经提出 C8 和 C10 的保护作用是由酮体的肝脏产生驱动的。然而，血浆酮水平与 C8 和 C10 的脑效应相关性较差，表明存在其他机制。在这里，我们研究了大脑中的细胞 C8 和 C10 代谢，并探讨了 C8 和 C10 的保护作用如何与细胞代谢相关联。使用动态同位素标记，以 [U-13C]C8 和 [U-13C]C10 作为代谢底物，我们发现 C8 和 C10 在小鼠脑切片中均被氧化代谢。[U-13C]C8 和 [U-13C]C10 代谢产生的 13C 富集在谷氨酰胺中尤为突出，表明 C8 和 C10 代谢主要发生在星形胶质细胞中。这一发现在培养的星形胶质细胞中得到了证实，其中 C8 增加了与 ATP 产生相关的呼吸，而 C10 增加了线粒体质子泄漏。当 C8 和 C10 作为脑切片中的代谢底物一起提供时，C10 的代谢优于 C8。此外，[U-13C]C8 和 [U-13C]C10 的代谢均不受依托莫西的影响，表明它不依赖于肉碱棕榈酰转移酶 I (CPT-1)。最后，我们表明抑制谷氨酰胺合成选择性地减少了脑切片中 [U-13C]C8 和 [U-13C]C10 代谢在 GABA 中的 13C 积累，证明星形胶质细胞 C8 和 C10 代谢产生的谷氨酰胺可用于神经元 GABA合成。集体，