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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >N-acetylation of hypothalamic α-melanocyte- stimulating hormone and regulation by leptin
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N-acetylation of hypothalamic α-melanocyte- stimulating hormone and regulation by leptin

机译：下丘脑α-黑素细胞刺激激素的N-乙酰化和瘦素调节

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摘要

The central melanocortin system is critical in the regulation of appetite and body weight, and leptin exerts its anorexigenic actions partly by increasing hypothalamic proopiomelanocortin (POMC) expression. The POMC-derived peptide α-melanocyte-stimulating hormone (αMSH) is a melanocortin 4 receptor agonist, and its potency in reducing energy intake is strongly increased by N-acetylation. The reason for the higher biological activity of N-acetylated αMSH (Act-αMSH) compared with that of N-desacety-lated αMSH (Des-αMSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic αMSH levels are decreased in leptin-deficient ob/ob mice and increased in leptin-treated ob/ob and C57BL/6J mice. The increase in total αMSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in Act-αMSH. Consistent with this observation, leptin rapidly induced the enzymatic activity of a N-acetyltransferase in the hypothalamus of mice. In 293T cells expressing the melanocortin 4 receptor, Act-αMSH is far more potent than Des-αMSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of Act-αMSH. Moreover, Des-αMSH is rapidly degraded in the hypothalamus after intracerebroventricular injection in rats and was less potent in inhibiting energy intake. The results suggest that leptin activates a N-acetyltransferase in POMC neurons, leading to increased hypothalamic levels of Act-αMSH. Due to its increased stability, this posttranslational modification of αMSH may play a critical role in leptin action via the central melanocortin pathway.
机译：中央黑皮质素系统在调节食欲和体重方面至关重要，瘦素部分通过增加下丘脑的原黑皮质素（POMC）表达发挥其厌食作用。源自POMC的肽α-黑素细胞刺激激素（αMSH）是黑皮质素4受体激动剂，并且其通过N-乙酰化而在减少能量摄入方面的效力大大增强。与N-去乙酰基化的αMSH（Des-αMSH）相比，N-乙酰化的αMSH（Act-αMSH）具有更高的生物活性的原因尚不清楚，并且尚未研究瘦素对乙酰化的调节。我们在这里显示，总的下丘脑αMSH水平在瘦素缺陷型ob / ob小鼠中降低，在瘦素治疗的ob / ob和C57BL / 6J小鼠中升高。注射瘦素后3小时，总αMSH升高，这完全是由于Act-αMSH升高。与该观察结果一致，瘦素在小鼠的下丘脑中迅速诱导N-乙酰基转移酶的酶活性。在表达黑皮质素4受体的293T细胞中，Act-αMSH在刺激cAMP积累方面比Des-αMSH更有效，这是由Act-αMSH的稳定性显着提高引起的。此外，在大鼠脑室内注射后，Des-αMSH在下丘脑中迅速降解，并且在抑制能量摄入方面作用较弱。结果表明，瘦素激活POMC神经元中的N-乙酰基转移酶，导致下丘脑的Act-αMSH水平升高。由于其增加的稳定性，αMSH的这种翻译后修饰可能通过中央黑皮质素途径在瘦素作用中起关键作用。

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