Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions


Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr−/− mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-α signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-α signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Adenovirus-mediated expression of Adipor1 or Adipor2 in the liver of Lepr−/− mice improves insulin resistance and ameliorates diabetes.
Figure 2: Adenovirus-mediated expression of AdipoR1 in the liver of Lepr−/− mice results in activation of AMP kinase pathways.
Figure 3: Adenovirus-mediated expression of Adipor2 in the liver of Lepr−/− mice results in activation of PPAR-α pathways.
Figure 4: Targeted disruption of Adipor1 results in increased glucose production, whereas that of Adipor2 results in decreased glucose uptake.
Figure 5: Targeted disruption of both Adipor1 and Adipor2 results in abrogation of adiponectin binding and adiponectin actions, leading to marked glucose intolerance and insulin resistance.
Figure 6: Targeted disruption of both Adipor1 and Adipor2 results in dysregulation of AMPK and PPAR-α pathways, leading to increased EGP and decreased GIR.


  1. 1

    Hug, C. & Lodish, H.F. The role of the adipocyte hormone adiponectin in cardiovascular disease. Curr. Opin. Pharmacol. 5, 129–134 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Scherer, P.E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55, 1537–1545 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Matsuzawa, Y. The metabolic syndrome and adipocytokines. FEBS Lett. 580, 2917–2921 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

    CAS  Article  Google Scholar 

  5. 5

    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 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Berg, A.H., Combs, T.P., Du, X., Brownlee, M. & Scherer, P.E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7, 947–953 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Tomas, E. et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc. Natl. Acad. Sci. USA 99, 16309–16313 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Kersten, S., Desvergne, B. & Wahli, W. Roles of PPARs in health and disease. Nature 405, 421–424 (2000).

    CAS  Article  Google Scholar 

  11. 11

    Yamauchi, T. et al. Globular adiponectin protected ob/ob mice from diabetes and apoE deficient mice from atherosclerosis. J. Biol. Chem. 278, 2461–2468 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003).

    CAS  Article  Google Scholar 

  13. 13

    Tsuchida, A. et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J. Biol. Chem. 279, 30817–30822 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Wellen, K.E. & Hotamisligil, G.S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Kubota, N. et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J. Biol. Chem. 277, 25863–25866 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8, 731–737 (2002).

    CAS  Article  Google Scholar 

  18. 18

    Kubota, N. et al. Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J. Biol. Chem. 281, 8748–8755 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Nawrocki, A.R. et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J. Biol. Chem. 281, 2654–2660 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Miyake, K. et al. Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. J. Clin. Invest. 110, 1483–1491 (2002).

    CAS  Article  Google Scholar 

  21. 21

    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 

  22. 22

    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 

  23. 23

    Matschinsky, F.M. et al. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55, 1–12 (2006).

    CAS  Article  Google Scholar 

  24. 24

    Long, Y.C. & Zierath, J.R. AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest. 116, 1776–1783 (2006).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    CAS  Article  Google Scholar 

  27. 27

    Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Kamei, N. et al. Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 281, 26602–26614 (2006).

    CAS  Article  Google Scholar 

  31. 31

    Staels, B. et al. Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393, 790–793 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Delerive, P. et al. Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J. Biol. Chem. 274, 32048–32054 (1999).

    CAS  Article  Google Scholar 

  33. 33

    Tsuchida, A. et al. Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARα, PPARγ and their combination. Diabetes 54, 3358–3370 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Maddux, B.A. et al. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of α-lipoic acid. Diabetes 50, 404–410 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Rudich, A. et al. Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3–L1 adipocytes. Diabetes 47, 1562–1569 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Toyama, T. et al. PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem. Biophys. Res. Commun. 324, 697–704 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Inoue, I. et al. The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 50, 3–11 (2001).

    CAS  Article  Google Scholar 

  38. 38

    Cohen, P. et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297, 240–243 (2002).

    CAS  Article  Google Scholar 

  39. 39

    Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Hug, C. et al. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc. Natl. Acad. Sci. USA 101, 10308–10313 (2004).

    CAS  Article  Google Scholar 

Download references


We thank K. Kangawa, M. Yanagisawa, K. Nakao, M. Kasuga, T. Shimizu, T. Yokomizo, W. Ogawa, H. Watada, Y. Terauchi, I. Manabe, M. Yamaguchi, K. Kobayashi and Y. Iwata for advice and discussions. We are grateful to K. Okano, A. Itoh and K. Miyata for technical assistance. This work was supported by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan (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.) and Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health, Labour and Welfare (to T. K. and T.Y.).

Author information



Corresponding author

Correspondence to Takashi Kadowaki.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Adenovirus-mediated expression of AdipoR1 or AdipoR2 in the liver of db/db mice. (PDF 303 kb)

Supplementary Fig. 2

2 Generation of AdipoR1 knockout, AdipoR2 knockout and AdipoR1˙R2 double knockout mice. (PDF 330 kb)

Supplementary Fig. 3

Plasma adiponectin and expression levels of AdipoR1 and AdipoR2 in the liver, skeletal muscle, and white adipose tissue from AdipoR1 knockout, AdipoR2 knockout and AdipoR1˙R2 double knockout mice. (PDF 219 kb)

Supplementary Fig. 4

Adiponectin action, glucose metabolism and insulin signal transduction in AdipoR1 knockout, AdipoR2 knockout and AdipoR1˙R2 double knockout mice. (PDF 284 kb)

Supplementary Fig. 5

Phosphorylation of AMPK stimulated with adiponectin and Akt stimulated with insulin and expression levels of molecules involved in lipid metabolism, inflammation and oxidative stress in skeletal muscle and white adipose tissue of AdipoR1 knockout, AdipoR2 knockout and AdipoR1˙R2 double knockout mice. (PDF 565 kb)

Supplementary Methods (PDF 208 kb)

Supplementary Note (PDF 209 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yamauchi, T., Nio, Y., Maki, T. et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13, 332–339 (2007).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing