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Article
Nature Medicine 13, 332 - 339 (2007)
Published online: 1 February 2007 | doi:10.1038/nm1557
Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions
Toshimasa Yamauchi1,2,3,7, Yasunori Nio1,2,7, Toshiyuki Maki1,7, Masaki Kobayashi1, Takeshi Takazawa1, Masato Iwabu1,2, Miki Okada-Iwabu1,2, Sachiko Kawamoto1, Naoto Kubota1,2,3, Tetsuya Kubota1, Yusuke Ito1, Junji Kamon1, Atsushi Tsuchida1, Katsuyoshi Kumagai1, Hideki Kozono1, Yusuke Hada1,3, Hitomi Ogata4, Kumpei Tokuyama4, Masaki Tsunoda5, Tomohiro Ide5, Kouji Murakami5, Motoharu Awazawa1,3, Iseki Takamoto1,2,3, Philippe Froguel6, Kazuo Hara1,3, Kazuyuki Tobe1,3, Ryozo Nagai1, Kohjiro Ueki1 & Takashi Kadowaki1,3
Abstract
Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr-/- mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-
signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR- signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.
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Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actionsNature Medicine Article (01 Mar 2007)
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