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Angiopoietin-related growth factor antagonizes obesity and insulin resistance

Nature Medicine volume 11, pages 400–408 (2005)Cite this article

Abstract

Angiopoietin-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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Figure 1: Obesity in Angptl6−/− mice on a normal diet.
Figure 2: Metabolic effects of AGF deficiency on a normal diet.
Figure 3: Angptl6 transgenic mice are lean as a result of a loss of WAT mass.
Figure 4: Metabolic and vascular alteration in Angptl6 transgenic mice.
Figure 5: Resistance to high-fat diet-induced obesity and related metabolic disorders seen in Angptl6 transgenic mice.
Figure 6: AGF decreased body weight and increased insulin sensitivity in high-fat fed-induced obese mice.

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Acknowledgements

We thank K. Fukushima for her assistance with the experiments. This work was supported by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science and Culture of Japan, by the Yamanouchi Foundation for Research on Metabolic Disorders and by the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

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Authors and Affiliations

  1. Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuichi Oike, Masaki Akao, Tohru Morisada, Yasuhiro Ito, Takashi Urano, Yoshishige Kimura, Yoshiaki Kubota, Hiromitsu Maekawa, Takeshi Miyamoto, Keishi Miyata & Toshio Suda

  2. Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, 305-8585, Japan

    Kunio Yasunaga & Shun-ichiro Matsumoto

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

    Toshimasa Yamauchi & Takashi Kadowaki

  4. Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, 153-8904, Japan

    Juro Sakai

  5. Center for Animal Resources and Development, Kumamoto University, Kumamoto, 860-0811, Japan

    Naomi Nakagata

  6. Department of Pathology, Kumamoto University, Kumamoto, 860-0811, Japan

    Motohiro Takeya

  7. RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, 230-0045, Japan

    Haruhiko Koseki

  8. Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan

    Yoshihiro Ogawa

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Correspondence to Yuichi Oike.

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Competing interests

The research concerned was performed under the Collaborative Research Agreement with Yamanouchi Pharmaceutical Co., Ltd.

Supplementary information

Supplementary Fig. 1

Gene targeting of the AGF locus. (PDF 58 kb)

Supplementary Fig. 2

Generation of AGF-transgenic mice. (PDF 73 kb)

Supplementary Fig. 3

AGF-stimulated intracellular signaling in C2C12 myocytes. (PDF 70 kb)

Supplementary Fig. 4

Impaired blood flow perfusion in AGF−/− females. (PDF 33 kb)

Supplementary Fig. 5

Increased insulin sensitivity in K14-AGF-transgenic mice7,8 despite a loss of WAT mass. (PDF 32 kb)

Supplementary Table 1 (PDF 15 kb)

Supplementary Methods (PDF 40 kb)

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Oike, Y., Akao, M., Yasunaga, K. et al. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat Med 11, 400–408 (2005). https://doi.org/10.1038/nm1214

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