Minokoshi Yasuhiko, Kim Young-Bum, Peroni Odile D, Fryer Lee G D, Müller Corinna, Carling David, Kahn Barbara B
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Nature. 2002 Jan 17;415(6869):339-43. doi: 10.1038/415339a.
Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulating food intake, energy expenditure and neuroendocrine function. Leptin stimulates the oxidation of fatty acids and the uptake of glucose, and prevents the accumulation of lipids in nonadipose tissues, which can lead to functional impairments known as "lipotoxicity". The signalling pathways that mediate the metabolic effects of leptin remain undefined. The 5'-AMP-activated protein kinase (AMPK) potently stimulates fatty-acid oxidation in muscle by inhibiting the activity of acetyl coenzyme A carboxylase (ACC). AMPK is a heterotrimeric enzyme that is conserved from yeast to humans and functions as a 'fuel gauge' to monitor the status of cellular energy. Here we show that leptin selectively stimulates phosphorylation and activation of the alpha2 catalytic subunit of AMPK (alpha2 AMPK) in skeletal muscle, thus establishing a previously unknown signalling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC, thereby stimulating the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. Our data identify AMPK as a principal mediator of the effects of leptin on fatty-acid metabolism in muscle.
瘦素是一种由脂肪细胞分泌的激素，在调节食物摄入、能量消耗和神经内分泌功能方面发挥着关键作用。瘦素刺激脂肪酸氧化和葡萄糖摄取，并防止脂质在非脂肪组织中积累，否则可能导致称为“脂毒性”的功能损害。介导瘦素代谢作用的信号通路仍不明确。5'-AMP激活蛋白激酶（AMPK）通过抑制乙酰辅酶A羧化酶（ACC）的活性，有力地刺激肌肉中的脂肪酸氧化。AMPK是一种异源三聚体酶，从酵母到人类都保守存在，作为一种“燃料表”来监测细胞能量状态。在这里，我们表明瘦素选择性地刺激骨骼肌中AMPK的α2催化亚基（α2 AMPK）的磷酸化和激活，从而建立了一条以前未知的瘦素信号通路。AMPK的早期激活是由瘦素直接作用于肌肉引起的，而后期激活则取决于瘦素通过下丘脑-交感神经系统轴发挥作用。与激活AMPK同时，瘦素抑制ACC的活性，从而刺激肌肉中的脂肪酸氧化。阻断AMPK激活会抑制瘦素刺激的ACC磷酸化。我们的数据确定AMPK是瘦素对肌肉中脂肪酸代谢影响的主要介质。
