Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet
Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet
复制标题
DOI：
10.1016/j.cmet.2007.04.004
复制
发表时间：
2007-05-01
期刊：
影响因子：
29
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Tanaka, Tomohiro;Masuzaki, Hiroaki;Nakao, Kazuwa
关于中枢黑素皮质素系统在控制外周组织燃料代谢中的作用，我们所知甚少。骨骼肌amp活化蛋白激酶（AMPK）被瘦素激活，并作为脂肪酸p氧化的主要调节因子。为了阐明中枢黑素皮质素系统在肌肉AMPK调节中的未知作用，我们用黑素皮质素激动剂MT-II或拮抗剂SHU9119在脑室内治疗有意识、不受约束的小鼠。MT-II增强了AMPK及其靶乙酰辅酶a羧化酶（ACC）的磷酸化，而不依赖于热量摄入。相反，在集中表达内源性黑素皮质素拮抗剂的KKA(y)小鼠中，通过共同给药SHU9119或瘦素消除了AMPK/ACC磷酸化。重要的是，在瘦素过表达的转基因小鼠中，高脂肪饮食诱导的AMPK/ACC磷酸化的衰减并没有被中央瘦素逆转，而是被MT-II显著恢复。我们的数据为中枢黑素皮质素系统在瘦素-骨骼肌AMPK轴中的关键作用提供了证据，并突出了该系统作为瘦素抵抗的治疗靶点。
Little is known about the role of the central melanocortin system in the control of fuel metabolism in peripheral tissues. Skeletal muscle AMP-activated protein kinase (AMPK) is activated by leptin and serves as a master regulator of fatty acid P-oxidation. To elucidate an unidentified role of the central melanocortin system in muscle AMPK regulation, we treated conscious, unrestrained mice intracerebroventricularly with the melanocortin agonist MT-II or the antagonist SHU9119. MT-II augmented phosphorylation of AMPK and its target acetylCoA carboxylase (ACC) independent of caloric intake. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the coadministration of SHU9119 or in KKA(y) mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat-diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin but was markedly restored by MT-II. Our data provide evidence for the critical role of the central melanocortin system in the leptin-skeletal muscle AMPK axis and highlight the system as a therapeutic target in leptin resistance.