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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kahn, B.B. & Flier, J.S. Obesity and insulin resistance. J. Clin. Invest. 106, 473–481 (2000).
Shulman, G.I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).
Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).
Fruebis, J. et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc. Natl. Acad. Sci. USA 98, 2005–2010 (2001).
Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med. 7, 941–946 (2001).
Berg, A.H., Combs, T.P., Du, X., Brownlee, M. & Scherer, P.E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature Med. 7, 947–953 (2001).
Combs, T.P., Bergm, A.H., Obici, S., Scherer, P.E. & Rossetti, L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J. Clin. Invest. 108, 1875–1881 (2001).
Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A.H. & Wakil, S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613–2616 (2001).
Hardie, D.G., Carling, D. & Carlson, M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Ann. Rev. Biochem. 67, 821–855 (1998).
Winder, W.W. & Hardie, D.G. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol. 277, E1–E10 (1999).
Mu, J., Brozinick, J.T. Jr., Valladares, O., Bucan, M. & Birnbaum, M.J. A role for AMP-activated protein kinase in contraction—and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell. 7, 1085–1094 (2000).
Lochhead, P.A., Salt, I.P., Walker, K.S., Hardie, D.G. & Sutherland, C. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49, 896–903 (2000).
Stein, S.C., Woods, A., Jones, N.A., Davison, M.D. & Carling, D. The regulation of AMP-activated protein kinase by phosphorylation. Biochem. J. 345, 437–443 (2000).
Woods, A. et al. Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol. Cell. Biol. 20, 6704–6711 (2000).
Minokoshi, Y. et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).
Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).
Fryer, L.G., Parbu-Patel, A. & Carling, D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J. Biol. Chem. 277, 25226–25232 (2002).
Tsao, T.S, Murrey, H.E., Hug, C., Lee, D.H. & Lodish, H.F. Oligomerization state-dependent activation of NF-κB signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J. Biol. Chem. 277, 29359–29362 (2002).
Woods, A., Salt, I., Scott, J., Hardie, D.G. & Carling, D. The α1 and α2 isoforms of the AMP-activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro. FEBS Lett. 397, 347–351 (1996).
Hayashi, T. et al. Metabolic stress and altered glucose transport. Activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 49, 527–531 (2000).
Kaburagi, Y. et al. Site-directed mutagenesis of the juxtamembrane domain of the human insulin receptor. J. Biol. Chem. 268, 16610–166222 (1993).
Onishi, M. et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol. Cell. Biol. 18, 3871–3879 (1996).
Tontonoz, P., Hu, E. & Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR γ2, a lipid-activated protein transcription factor. Cell 79, 1147–1156 (1994).
Ueki, K. et al. Restored insulin-sensitivity in IRS-1-deficient mice treated by adenovirus-mediated gene therapy. J. Clin. Invest. 105, 1437–1445 (2000).
Tsubamoto, Y. et al. Hexamminecobalt(III) chloride inhibits glucose-induced insulin secretion at the exocytotic process. J. Biol. Chem. 276, 2979–2985 (2001).
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.
The authors declare no competing financial interests.
About this article
Cite this article
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
A preliminary evaluation of the circulating leptin/adiponectin ratio in dogs with pituitary-dependent hyperadrenocorticism and concurrent diabetes mellitus
Domestic Animal Endocrinology (2021)
An adiponectin receptor agonist antibody stimulates glucose uptake and fatty-acid oxidation by activating AMP-activated protein kinase
AdipoRon: A Novel Insulin Sensitizer in Various Complications and the Underlying Mechanisms: A Review
Current Molecular Pharmacology (2020)
Cellular Signalling (2020)
Frontiers in Endocrinology (2020)