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Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase

Nature Medicine volume 8, pages 1288–1295 (2002)Cite this article

Abstract

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.

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Figure 1: Adiponectin action in C2C12 myocytes.
Figure 2: Adiponectin increases AMPK activity and phosphorylation of ACC in soleus muscle in vivo.
Figure 3: Actions of DN-AMPK on myocytes and hepatocytes.
Figure 4: Adiponectin increases AMPK activity and phosphorylation of ACC in the liver in vivo.
Figure 5: DN-AMPK inhibits the effects of Ad on liver gluconeogenesis and in vivo glucose levels.

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Acknowledgements

We thank M.J. Birnbaum, O. Ezaki and N. Kubota for helpful suggestions; K. Motojima for the PEPCK and G6Pase cDNA probes; and K. Kirii, M. Shibata, A. Okano and T. Nagano for technical assistance. This work was supported by a grant from the Human Science Foundation (to T.K.), a Grant-in-Aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology (to T.K.), a Grant-in-Aid for Creative Scientific Research 10NP0201 from the Japan Society for the Promotion of Science (to T.K.), and by Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare (to T.K.) and NIH grants PO1 DK 56116 and RO1 DK 43051.

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Author notes

  1. T. Yamauchi and J. Kamon: T.Y. and J.K. contributed equally to this study.

Authors and Affiliations

  1. Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    T. Yamauchi, J. Kamon, Y. Ito, H. Waki, S. Uchida, S. Yamashita, S. Kita, K. Ueki, K. Eto, S. Kimura, R. Nagai & T. Kadowaki

  2. CREST of Japan Science and Technology Corporation, Saitana, Japan

    T. Yamauchi, H. Waki, M. Noda, K. Eto, Y. Akanuma & T. Kadowaki

  3. Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Medicine, Diabetes and Metabolism, Harvard Medical School, Boston, Massachusetts, USA

    Y. Minokoshi & B.B. Kahn

  4. Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan

    M. Noda & Y. Akanuma

  5. Institute of Biology-CNRS, Pasteur Institute of Lille, Lille, France

    P. Froguel

  6. U465 INSERM, Centre de Recherches Biomedicales des Cordeliers, Paris Cedex, France

    F. Foufelle & P. Ferre

  7. The Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK

    D. Carling

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  1. T. Yamauchi
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Correspondence to T. Kadowaki.

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Yamauchi, T., Kamon, J., Minokoshi, Y. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8, 1288–1295 (2002). https://doi.org/10.1038/nm788

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