Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn B B, Kadowaki T
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Nat Med. 2002 Nov;8(11):1288-95. doi: 10.1038/nm788. Epub 2002 Oct 7.
Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
脂联素（Ad）是一种由脂肪细胞分泌的激素，可调节能量平衡以及葡萄糖和脂质代谢。然而，介导脂联素代谢作用的信号通路仍未完全明确。在此我们表明，在骨骼肌中，球状和全长脂联素均可刺激5'-AMP激活的蛋白激酶（AMPK）的磷酸化和激活，而在肝脏中只有全长脂联素能起到这种作用。与激活AMPK同时，脂联素刺激肌细胞中乙酰辅酶A羧化酶（ACC）的磷酸化、脂肪酸氧化、葡萄糖摄取和乳酸生成，刺激肝脏中ACC的磷酸化并减少参与糖异生的分子，还能降低体内葡萄糖水平。用显性负性突变体阻断AMPK激活可抑制上述每种效应，表明脂联素对葡萄糖利用和脂肪酸氧化的刺激是通过激活AMPK实现的。我们的数据可能提供了一种新的模式，即一种源自脂肪细胞的抗糖尿病激素脂联素激活AMPK，从而在体外和体内直接调节葡萄糖代谢和胰岛素敏感性。
