Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding
Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding
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DOI：
10.1073/pnas.1103267108
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发表时间：
2011-06-07
影响因子：
11.1
通讯作者：
Lopaschuk, Gary D.
中科院分区：
文献类型：
--
作者：
Gao, Su;Zhu, Guangjing;Lopaschuk, Gary D.
脑特异性肉碱棕榈酰基转移酶-1 （CPT-1c）与中枢神经系统对食物摄入的控制有关。在本文中，我们探讨下丘脑CPT-1c在瘦素的厌氧性作用中的作用。我们首先发现，腺病毒在大鼠下丘脑弓状核中过度表达CPT-1c会增加食物摄入量，并同时上调摄氧神经肽Y （NPY）和Bsx （NPY的转录因子）。然后，我们证明这种过表达可以拮抗中央瘦素或复合蓝绿蛋白（脂肪酸合成酶抑制剂）诱导的厌食作用。CPT-1c的过表达也阻断瘦素诱导的NPY和Bsx的下调。此外，在大脑CPT-1c缺失的小鼠中，中枢瘦素或蓝蛋白的厌食作用受损。这两种厌食效应都需要下丘脑弓状核丙二酰辅酶a水平升高，丙二酰辅酶a是一种脂肪酸代谢中间体，在下丘脑控制食物摄入中起中介作用。因此，这些数据表明CPT-1c与瘦素下丘脑厌食信号通路中的丙二酰辅酶a作用有关。此外，神经酰胺代谢似乎在瘦素对摄食的中枢控制中发挥作用。瘦素治疗降低了Arc神经酰胺水平，这种降低在瘦素诱导的厌食作用和NPY和Bsx的下调中很重要。有趣的是，我们的数据表明，瘦素通过丙二酰辅酶a和CPT-1c影响神经酰胺代谢，神经酰胺新生生物合成在丙二酰辅酶a和CPT-1c下游作用，介导它们对NPY和Bsx摄食和表达的影响。总之，我们提供了对丙二酰辅酶a、CPT-1c和神经酰胺代谢在瘦素下丘脑信号通路中的重要作用的见解。
Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT-1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways.