Molecular Mechanism of Moderate Insulin Resistance in Adiponectin-Knockout Mice

Wataru YANO; Naoto KUBOTA; Shinsuke ITOH; Tetsuya KUBOTA; Motoharu AWAZAWA; Masao MOROI; Kaoru SUGI; Iseki TAKAMOTO; Hitomi OGATA; Kumpei TOKUYAMA; Tetsuo NODA; Yasuo TERAUCHI; Kohjiro UEKI; Takashi KADOWAKI

doi:10.1507/endocrj.K08E-093

ORIGINALS

Molecular Mechanism of Moderate Insulin Resistance in Adiponectin-Knockout Mice

Wataru YANO, Naoto KUBOTA, Shinsuke ITOH, Tetsuya KUBOTA, Motoharu AWAZAWA, Masao MOROI, Kaoru SUGI, Iseki TAKAMOTO, Hitomi OGATA, Kumpei TOKUYAMA, Tetsuo NODA, Yasuo TERAUCHI, Kohjiro UEKI, Takashi KADOWAKI

Author information

Wataru YANO
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Naoto KUBOTA
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Translational Systems Biology and Medicine Initiative, University of Tokyo
Division of Applied Nutrition, National Institute of Health and Nutrition
Shinsuke ITOH
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Tetsuya KUBOTA
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Division of Applied Nutrition, National Institute of Health and Nutrition
Division of Cardiovascular Medicine, Toho University, Ohashi Hospital
Motoharu AWAZAWA
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Masao MOROI
Division of Cardiovascular Medicine, Toho University, Ohashi Hospital
Kaoru SUGI
Division of Cardiovascular Medicine, Toho University, Ohashi Hospital
Iseki TAKAMOTO
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Translational Systems Biology and Medicine Initiative, University of Tokyo
Division of Applied Nutrition, National Institute of Health and Nutrition
Hitomi OGATA
Graduate School of Comprehensive Human Sciences, University of Tsukuba
Kumpei TOKUYAMA
Graduate School of Comprehensive Human Sciences, University of Tsukuba
Tetsuo NODA
Department of Cell Biology, Japanese Foundation for Cancer Research-Cancer Institute
Yasuo TERAUCHI
Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine
Kohjiro UEKI
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Takashi KADOWAKI
Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo
Translational Systems Biology and Medicine Initiative, University of Tokyo
Division of Applied Nutrition, National Institute of Health and Nutrition

Keywords: Adiponectin, Insulin resistance, Adiponectin-knockout mice, Euglycemic-hyperinsulinemic clamp

JOURNAL FREE ACCESS

2008 Volume 55 Issue 3 Pages 515-522

DOI https://doi.org/10.1507/endocrj.K08E-093

View "Advance Publication" version (April 30, 2008).

Details

Abstract

Adiponectin has been proposed to act as an antidiabetic adipokine, suppressing gluconeogenesis and stimulating fatty acid oxidation in the liver and skeletal muscle. Although adiponectin-knockout (adipo(-/-)) mice are known to exhibit insulin resistance, the degrees of insulin resistance and glucose intolerance are unexpectedly only moderate. In this study, the adipo(-/-) mice showed hepatic, but not muscle, insulin resistance. insulin-stimulated phosphorylation of IRS-1 and IRS-2 was impaired, the IRS-2 protein level was decreased, and insulin-stimulated phosphorylation of Akt was decreased in the liver of the adipo(-/-) mice. However, the triglyceride content in the liver was not increased in these mice, despite the decrease in the PPARalpha expression involved in lipid combustion, since the expressions of lipogenic genes such as SREBP-1 and SCD-1 were decreased in association with the increased leptin sensitivity. Consistent with this, the down-regulation SREBP-1 and SCD-1 observed in the adipo(-/-) mice was no longer observed, and the hepatic triglyceride content was significantly increased in the adiponectin leptin double-knockout (adipo(-/-)ob/ob) mice. On the other hand, the triglyceride content in the skeletal muscle was significantly decreased in the adipo(-/-) mice, probably due to up-regulated AMPK activity associated with the increased leptin sensitivity. In fact, these phenotypes in the skeletal muscle of these mice were no longer observed in the adipo(-/-)ob/ob mice. In conclusion, adipo(-/-) mice showed impaired insulin signaling in the liver to cause hepatic insulin resistance, however, no increase in the triglyceride content was observed in either the liver or the skeletal muscle, presumably on account of the increased leptin sensitivity.

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