1. Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
2. CREST of Japan Science and Technology Corporation, 332-0012, Japan
3. Biological Research Laboratories, Nissan Chemical Industries, Saitama 349-0294, Japan
4. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, CREST and PRESTO of JST, Japan
5. Division of Hematopoietic Factors, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
6. Department of Chemistry and Biotechnology, School of Engineering, University of Tokyo, Tokyo 113-8656, and Gene Function Research Center, National Institute of AIST, Tsukuba 305-8562, Japan
7. Central Research Laboratories, Kyorin Pharmaceutical, Tochigi 329-0114, Japan
8. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
9. Department of Transfusion Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
10. Institute of Biology-CNRS, Pasteur Institute of Lille, UPRES A8090, 59000 Lille, France
11. These authors contributed equally to this work

Correspondence to: Takashi Kadowaki^1,2 Correspondence and requests for materials should be addressed to T.K. (Email: kadowaki-3im@h.u-tokyo.ac.jp). The GenBank accession numbers for human and mouse AdipoR1 are NM_015999 and BCO14875, and for human and mouse AdipoR2 are NM_024551 and XM_132831, respectively.

Abstract

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30)^{1, 2, 3, 4} is a hormone secreted by adipocytes that acts as an antidiabetic^{5, 6, 7, 8, 9, 10, 11, 12} and anti-atherogenic^{8, 12, 13} adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes². Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice^{5, 6, 7}. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes^{8, 9}. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase^{10, 11} and PPAR-^{5, 6, 12}. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning^{14, 15, 16}. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors^{17, 18, 19}. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA²⁰ supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase^{10, 11} and PPAR- ligand activities¹², as well as fatty-acid oxidation and glucose uptake by adiponectin.