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Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1


Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca2+ influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca2+ concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1α expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.

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Figure 1: Decreased mitochondria, oxidative type I myofibres and exercise capacity in skeletal muscle of muscle-R1KO mice.
Figure 2: Mechanisms of abnormal glucose and insulin homeostasis in muscle-R1KO mice.
Figure 3: Adiponectin/AdipoR1 increase PGC-1α expression and activity, and mitochondrial biogenesis in C2C12 myocytes.
Figure 4: Adiponectin-induced Ca 2+ influx by AdipoR1 in C2C12 myocytes and Xenopus oocytes.
Figure 5: Adiponectin-induced Ca 2+ influx is required for CaMKK and AMPK activation and PGC-1α expression.
Figure 6: The effect of exercise on muscle-R1KO mice.


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We thank B. M. Spiegelman for critical discussions and reading of the manuscript; T. Yokomizo for discussion and support; A. Tsuchida, K. Hara, Y. Hada, Y. Nio, T. Maki, T. Takazawa, Y. Iwata, M. Kobayashi, S. Kawamoto, K. Kobayashi, K. Hirota, Y. Shiomi, T. Mitsumatsu, L. Hirose, Y. Sea, M. Nakamura and K. Take for technical help and support; and S. Suzuki, K. Miyata, C. Ueda, A. Itoh and A. Okano for technical assistance. This work was supported by Grant-in-aid for Scientific Research (S) (20229008) (to T.K.), (B) (20390254) (to T.Y.), Targeted Proteins Research Program (to T.K.), the Global COE Research Program (to T.K.) and Translational Systems Biology and Medicine Initiative (to T.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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M.I., M.O.-I., T.Y., K.S., T.N., M.F., M.Y., S.N., R.N., M.T., H.O., N.K., I.T., Y.K.H. and N.Y. performed experiments. T.K. and T.Y. conceived and supervised the study. K.T., T.S. and K.H. supervised the study. T.Y., T.K., M.I. and M.O-I. wrote the paper. All authors interpreted data.

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Correspondence to Toshimasa Yamauchi or Takashi Kadowaki.

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The authors declare no competing financial interests.

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Iwabu, M., Yamauchi, T., Okada-Iwabu, M. et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319 (2010).

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