Nature Medicine
11, 400 - 408 (2005)
Published online: 20 March 2005; | doi:10.1038/nm1214
Angiopoietin-related growth factor antagonizes obesity and insulin resistanceYuichi Oike1, Masaki Akao1, Kunio Yasunaga2, Toshimasa Yamauchi3, Tohru Morisada1, Yasuhiro Ito1, Takashi Urano1, Yoshishige Kimura1, Yoshiaki Kubota1, Hiromitsu Maekawa1, Takeshi Miyamoto1, Keishi Miyata1, Shun-ichiro Matsumoto2, Juro Sakai4, Naomi Nakagata5, Motohiro Takeya6, Haruhiko Koseki7, Yoshihiro Ogawa8, Takashi Kadowaki3
& Toshio Suda11
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. 2
Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, 305-8585, Japan. 3
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. 4
Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan. 5
Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan. 6
Department of Pathology, Kumamoto University, Kumamoto 860-0811, Japan. 7
RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama 230-0045, Japan. 8
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Correspondence should be addressed to Yuichi Oike oike@sc.itc.keio.ac.jpAngiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet−induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.
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