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)-α 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-α 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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We thank K. Kangawa, M. Yanagisawa, K. Nakao, M. Kasuga, T. Shimizu, T. Yokomizo, W. Ogawa, H. Watada, Y. Terauchi, I. Manabe, M. Yamaguchi, K. Kobayashi and Y. Iwata for advice and discussions. We are grateful to K. Okano, A. Itoh and K. Miyata for technical assistance. This work was supported by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan (to T.K.), a grant-in-aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology (to T. K.) and Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health, Labour and Welfare (to T. K. and T.Y.).
The authors declare no competing financial interests.
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Yamauchi, T., Nio, Y., Maki, T. et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13, 332–339 (2007). https://doi.org/10.1038/nm1557
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