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

Nature Medicine volume 13, pages 332–339 (2007)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.).

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Author notes

  1. Toshimasa Yamauchi, Yasunori Nio and Toshiyuki Maki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Toshimasa Yamauchi, Yasunori Nio, Toshiyuki Maki, Masaki Kobayashi, Takeshi Takazawa, Masato Iwabu, Miki Okada-Iwabu, Sachiko Kawamoto, Naoto Kubota, Tetsuya Kubota, Yusuke Ito, Junji Kamon, Atsushi Tsuchida, Katsuyoshi Kumagai, Hideki Kozono, Yusuke Hada, Motoharu Awazawa, Iseki Takamoto, Kazuo Hara, Kazuyuki Tobe, Ryozo Nagai, Kohjiro Ueki & Takashi Kadowaki

  2. Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, University of Tokyo, Tokyo, 113-8655, Japan

    Toshimasa Yamauchi, Yasunori Nio, Masato Iwabu, Miki Okada-Iwabu, Naoto Kubota & Iseki Takamoto

  3. Core Research for Evolutional Science and Technology, Japan Science and Technology, Tokyo, 332-0012, Japan

    Toshimasa Yamauchi, Naoto Kubota, Yusuke Hada, Motoharu Awazawa, Iseki Takamoto, Kazuo Hara, Kazuyuki Tobe & Takashi Kadowaki

  4. Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8577, Japan

    Hitomi Ogata & Kumpei Tokuyama

  5. Bioscience Division I, Metabolic Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., Shimotsuga, 329-0114, Japan

    Masaki Tsunoda, Tomohiro Ide & Kouji Murakami

  6. Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Philippe Froguel

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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)

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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). https://doi.org/10.1038/nm1557

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