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Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; Department of Integrated Molecular Science on Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
Correspondence: Address all correspondence and requests for reprints to: Dr. Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp
Metabolic syndrome is thought to result from obesity and obesity-linked insulin resistance. Obesity in adulthood is characterized by adipocyte hypertrophy. Adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active "adipokines."
Heterozygous peroxisome proliferator-activated receptor-
knockout mice were protected from high-fat diet induced obesity, adipocyte hypertrophy, and insulin resistance. Systematic gene profiling analysis of these mice revealed that adiponectin/Acrp30 was overexpressed. Functional analyses including generation of adiponectin transgenic or knockout mice have revealed that adiponectin serves as an insulin-sensitizing adipokine. In fact, obesity-linked down-regulation of adiponectin was a mechanism whereby obesity could cause insulin resistance and diabetes.
Recently, we have cloned adiponectin receptors in the skeletal muscle (AdipoR1) and liver (AdipoR2), which appear to comprise a novel cell-surface receptor family. We showed that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMP-activated protein kinase, peroxisome proliferator-activated receptor-
ligand activities, and glucose uptake and fatty-acid oxidation by adiponectin. Obesity decreased expression levels of AdipoR1/R2, thereby reducing adiponectin sensitivity, which finally leads to insulin resistance, the so-called "vicious cycle." Most recently, we showed that osmotin, which is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes. This may facilitate efficient development of adiponectin receptor agonists.
Adiponectin receptor agonists and adiponectin sensitizers should serve as versatile treatment strategies for obesity-linked diseases such as diabetes and metabolic syndrome.
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P. E. Szmitko, H. Teoh, D. J. Stewart, |
