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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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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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)
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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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DOI: https://doi.org/10.1038/nm1214
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