Nature Medicine
8, 731 - 737 (2002)
Published online: 17 June 2002; | doi:10.1038/nm724
Diet-induced insulin resistance in mice lacking adiponectin/ACRP30Norikazu Maeda1, Iichiro Shimomura1, 4, Ken Kishida1, 5, Hitoshi Nishizawa1, 5, Morihiro Matsuda1, Hiroyuki Nagaretani1, Naoki Furuyama1, Hidehiko Kondo1, Masahiko Takahashi1, Yukio Arita1, Ryutaro Komuro1, Noriyuki Ouchi1, Shinji Kihara1, Yoshihiro Tochino1, Keiichi Okutomi2, Masato Horie2, Satoshi Takeda2, Toshifumi Aoyama3, Tohru Funahashi1
& Yuji Matsuzawa11
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
2
Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan
3
Department of Aging Biochemistry, School of Medicine, Shinshu University, Nagano, Japan
4
Current address: Department of Organismal Biosystems, Graduate School of Frontier Bioscience, Department of Medicine and Pathophysiology, Graduate School of Medicine, Osaka University, Osaka, Japan
5
K.K. and H.N. contributed equally to this study.
Correspondence should be addressed to Iichiro Shimomura ichi@imed2.med.osaka-u.ac.jp or ichi@fbs.osaka-u.ac.jpHere we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor- (TNF-) mRNA in adipose tissue and high plasma TNF- concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF- mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF- decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF- levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.
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