Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l'Alimentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-30, E-08028, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain.
Mol Neurobiol. 2018 Sep;55(9):7216-7228. doi: 10.1007/s12035-018-0921-3. Epub 2018 Feb 2.
Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and α-ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system.
脂代谢，特别是肉碱棕榈酰转移酶（CPT）1A 介导的脂肪酸氧化（FAO），已被描述为下丘脑中 ghrelin 作用的重要因素。然而，CPT1A 和 FAO 是否介导 ghrelin 对皮质的作用尚不清楚。在这里，我们表明 ghrelin 对小鼠下丘脑和皮质中的 CPT1 活性和γ-氨基丁酸（GABA）代谢产生不同的影响。在下丘脑，ghrelin 增强 CPT1A 活性，而 GABA 转氨酶（GABAT）活性，即 GABA 分流代谢的关键酶，保持不变。然而，在皮质中，ghrelin 处理后 CPT1A 活性和 GABAT 活性降低。此外，在原代皮质神经元中，ghrelin 通过减少 CPT1A 来减少 GABA 的释放。通过使用 CPT1A 基因敲除小鼠，我们观察到 CPT1A 的基因缺失再现了 ghrelin 对皮质神经元中 GABA 释放的影响，导致线粒体耗氧量、柠檬酸和α-酮戊二酸的细胞含量以及 GABA 分流酶活性降低。综上所述，这些观察结果表明，ghrelin 诱导的 CPT1A 活性变化调节线粒体功能，导致 GABA 代谢的变化。这一证据表明，ghrelin 对 GABA 释放的作用在大脑内具有区域特异性，为 ghrelin 在中枢神经系统中的差异作用提供了基础。
