Department of Pediatrics, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada T6G 2S2.
Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9691-6. doi: 10.1073/pnas.1103267108. Epub 2011 May 18.
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.
脑特异性肉毒碱棕榈酰转移酶-1（CPT-1c）参与了中枢神经系统对食物摄入的控制。在本文中，我们探讨了下丘脑 CPT-1c 在瘦素的厌食作用中的作用。我们首先表明，在大鼠下丘脑弓状核中过表达腺病毒载体 CPT-1c 会增加食物摄入，并同时上调食欲肽神经肽 Y（NPY）和 Bsx（NPY 的转录因子）。然后，我们证明这种过表达拮抗了中枢瘦素或复合 Cerulenin（脂肪酸合酶抑制剂）诱导的厌食作用。CPT-1c 的过表达也阻止了瘦素诱导的 NPY 和 Bsx 下调。此外，大脑 CPT-1c 缺失的小鼠中，中枢瘦素或 Cerulenin 的厌食作用受损。这两种厌食作用都需要提高下丘脑弓状核（Arc）丙二酰辅酶 A 的水平，丙二酰辅酶 A 是一种脂肪酸代谢中间产物，作为下丘脑控制食物摄入的介质而出现。因此，这些数据表明 CPT-1c 参与了瘦素的下丘脑厌食信号通路中丙二酰辅酶 A 的作用。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。瘦素处理降低了 Arc 神经酰胺水平，这种降低对于瘦素诱导的厌食作用以及 NPY 和 Bsx 的下调非常重要。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，神经酰胺从头合成在丙二酰辅酶 A 和 CPT-1c 介导其对摄食和 NPY 和 Bsx 表达的作用中起下游作用。总之，我们提供了关于丙二酰辅酶 A、CPT-1c 和神经酰胺代谢在瘦素的下丘脑信号通路中的重要作用的见解。
