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Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.

Author(s): Norikazu Maeda, Iichiro Shimomura, Ken Kishida, Hitoshi Nishizawa, Morihiro Matsuda, Hiroyuki Nagaretani, Naoki Furuyama, Hidehiko Kondo, Masahiko Takahashi, Yukio Arita, Ryutaro Komuro, Noriyuki Ouchi, Shinji Kihara, Yoshihiro Tochino, Keiichi Okutomi, Masato Horie, Satoshi Takeda, Toshifumi Aoyama, Tohru Funahashi, Yuji Matsuzawa

Publication date: 2002-06-30

Journal: Nature medicine

Keywords: Adiponectin, Adipose Tissue, metabolism, Animals, Carrier Proteins, Cells, Cultured, Diet, Fatty Acid-Binding Proteins, Fatty Acids, Nonesterified, blood, Fish Proteins, Insulin Receptor Substrate Proteins, Insulin Resistance, physiology, Intercellular Signaling Peptides and Proteins, Lipid Metabolism, Mice, Mice, Knockout, Myocardium, cytology, Phosphatidylinositol 3-Kinases, Phosphoproteins, Proteins, genetics, RNA, Messenger, Transcription, Genetic, Tumor Necrosis Factor-alpha

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Abstract

Here 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-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha 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-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha 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-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.