C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism
C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism
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DOI：
10.1074/jbc.m310991200
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发表时间：
2004-01-30
影响因子：
4.8
通讯作者：
Ronnett, GV
中科院分区：
文献类型：
--
作者：
Landree, LE;Hanlon, AL;Ronnett, GV
C75是一种脂肪酸合成酶（FAS）的合成抑制剂，据推测可改变下丘脑中调节进食行为的神经元的代谢，从而导致C75治疗后出现的摄食量减少和体重显著减轻。在本研究中，我们的特点是适合原代培养的皮质神经元的研究，旨在调查的后果C75治疗和神经元中的脂肪酸代谢的改变。我们证明，在初级皮质神经元，C75抑制FAS活性和刺激肉毒碱棕榈酰转移酶-1（CPT-1），与其在外周组织中的作用一致。C75改变神经元ATP水平和AMP活化蛋白激酶（AMPK）活性。神经元ATP水平受C75处理的双相方式影响，最初降低，随后长时间升高至对照水平以上。浅蓝菌素，一种FAS抑制剂，引起ATP水平的类似双相变化，尽管水平不超过对照。C75和浅蓝菌素调节AMPK磷酸化和活性。TOFA是乙酰辅酶A羧化酶的抑制剂，可增加ATP水平，但不影响AMPK活性。几个下游途径受到C75处理的影响，包括葡萄糖代谢和乙酰辅酶A羧化酶（ACC）磷酸化。这些数据表明，C75调节能量中间体的水平，从而影响能量传感器AMPK。下丘脑神经元中的类似作用可以形成C75对摄食行为的影响的基础。
C75, a synthetic inhibitor of fatty acid synthase (FAS), is hypothesized to alter the metabolism of neurons in the hypothalamus that regulate feeding behavior to contribute to the decreased food intake and profound weight loss seen with C75 treatment. In the present study, we characterize the suitability of primary cultures of cortical neurons for studies designed to investigate the consequences of C75 treatment and the alteration of fatty acid metabolism in neurons. We demonstrate that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues. C75 alters neuronal ATP levels and AMP-activated protein kinase (AMPK) activity. Neuronal ATP levels are affected in a biphasic manner with C75 treatment, decreasing initially, followed by a prolonged increase above control levels. Cerulenin, a FAS inhibitor, causes a similar biphasic change in ATP levels, although levels do not exceed control. C75 and cerulenin modulate AMPK phosphorylation and activity. TOFA, an inhibitor of acetyl-CoA carboxylase, increases ATP levels, but does not affect AMPK activity. Several downstream pathways are affected by C75 treatment, including glucose metabolism and acetyl-CoA carboxylase (ACC) phosphorylation. These data demonstrate that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK. Similar effects in hypothalamic neurons could form the basis for the effects of C75 on feeding behavior.