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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake
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Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

机译：瘦素激活下丘脑乙酰辅酶A羧化酶以抑制食物摄入

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摘要

Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptin-mediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.
机译：下丘脑脂肪酸代谢最近与食物摄入和能量稳态的控制有关。我们报告说脑室内（ICV）注射瘦素，同时抑制AMP激活激酶（AMPK），激活乙酰辅酶A羧化酶（ACC），脂肪酸生物合成中的关键调节酶，在弓状核（Arc）和室旁核中（PVN）在下丘脑。组成性活性AMPK的Arc过表达阻止了响应ICV瘦素的Arc ACC激活，从而支持了AMPK位于瘦素的Arc细胞内信号传导途径中ACC上游的假设。用5-十四烷氧基-2-糠酸（一种特定的ACC抑制剂）抑制下丘脑ACC，可以阻止瘦素介导的食物摄入，体重和食源性神经肽NPY的mRNA水平下降。这些结果表明，下丘脑的ACC激活对瘦素的厌食作用做出了重要贡献。此外，我们发现ICV瘦素上调了弧中的丙二酰辅酶A（脂肪酸生物合成的中间产物）的水平，而上调了PVN中的棕榈酰辅酶A（脂肪酸生物合成的主要产物）的水平。两种水平的升高都被5-十四烷基氧基-2-糠酸以及瘦素介导的吞咽障碍所阻止。这些数据表明丙二酰-辅酶A是电弧中瘦素信号传导途径中ACC的下游介体，暗示棕榈酰-辅酶A而不是丙二酰-辅酶A可能是中继PVN中ACC信号的效应子。总之，这些发现凸显了瘦素的厌食信号级联反应中下丘脑ACC激活的特定部位影响。

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