Angiopoietin-related growth factor antagonizes obesity and insulin resistance.
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.
Oike
Yuichi
Y
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. oike@sc.itc.keio.ac.jp
Akao
Masaki
M
Yasunaga
Kunio
K
Yamauchi
Toshimasa
T
Morisada
Tohru
T
Ito
Yasuhiro
Y
Urano
Takashi
T
Kimura
Yoshishige
Y
Kubota
Yoshiaki
Y
Maekawa
Hiromitsu
H
Miyamoto
Takeshi
T
Miyata
Keishi
K
Matsumoto
Shun-ichiro
S
Sakai
Juro
J
Nakagata
Naomi
N
Takeya
Motohiro
M
Koseki
Haruhiko
H
Ogawa
Yoshihiro
Y
Kadowaki
Takashi
T
Suda
Toshio
T
D000091308:Angiopoietin-Like Protein 6; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D001685:Biological Factors / Q000235:genetics / Q000502:physiology*; D004041:Dietary Fats; D004734:Energy Metabolism; D007333:Insulin Resistance; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009765:Obesity / Q000517:prevention & control*
D000091308:Angiopoietin-Like Protein 6; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C477602:Angptl6 protein, mouse; D001685:Biological Factors; D004041:Dietary Fats