Nature Medicine
8, 1288 - 1295 (2002)
Published online: 7 October 2002; | doi:10.1038/nm788
Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinaseT. Yamauchi1, 2, 8, J. Kamon1, 8, Y. Minokoshi3, Y. Ito1, H. Waki1, 2, S. Uchida1, S. Yamashita1, M. Noda2, 4, S. Kita1, K. Ueki1, K. Eto1, 2, Y. Akanuma2, 4, P. Froguel5, F. Foufelle6, P. Ferre6, D. Carling7, S. Kimura1, R. Nagai1, B.B. Kahn3
& T. Kadowaki1, 21
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2
CREST of Japan Science and Technology Corporation, Saitana, Japan
3
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
4
Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
5
Institute of Biology-CNRS, Pasteur Institute of Lille, Lille, France
6
U465 INSERM, Centre de Recherches Biomedicales des Cordeliers, Paris Cedex, France
7
The Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK
8
T.Y. and J.K. contributed equally to this study.
Correspondence should be addressed to T. Kadowaki kadowaki-3im@h.u-tokyo.ac.jpAdiponectin (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.
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