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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Kahn, B.B. & Flier, J.S. Obesity and insulin resistance. J. Clin. Invest. 106, 473–481 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Shulman, G.I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).

    CAS  Article  Google Scholar 

  4. 4

    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).

    CAS  Article  Google Scholar 

  5. 5

    Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med. 7, 941–946 (2001).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    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).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  PubMed  Google Scholar 

  11. 11

    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).

    Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Minokoshi, Y. et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    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).

    CAS  Article  Google Scholar 

  20. 20

    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).

    CAS  Article  Google Scholar 

  21. 21

    Kaburagi, Y. et al. Site-directed mutagenesis of the juxtamembrane domain of the human insulin receptor. J. Biol. Chem. 268, 16610–166222 (1993).

    CAS  PubMed  Google Scholar 

  22. 22

    Onishi, M. et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol. Cell. Biol. 18, 3871–3879 (1996).

    Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

  25. 25

    Tsubamoto, Y. et al. Hexamminecobalt(III) chloride inhibits glucose-induced insulin secretion at the exocytotic process. J. Biol. Chem. 276, 2979–2985 (2001).

    CAS  Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to T. Kadowaki.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

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

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing