Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) 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 Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha 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.
Iwabu
Masato
M
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Yamauchi
Toshimasa
T
Okada-Iwabu
Miki
M
Sato
Koji
K
Nakagawa
Tatsuro
T
Funata
Masaaki
M
Yamaguchi
Mamiko
M
Namiki
Shigeyuki
S
Nakayama
Ryo
R
Tabata
Mitsuhisa
M
Ogata
Hitomi
H
Kubota
Naoto
N
Takamoto
Iseki
I
Hayashi
Yukiko K
YK
Yamauchi
Naoko
N
Waki
Hironori
H
Fukayama
Masashi
M
Nishino
Ichizo
I
Tokuyama
Kumpei
K
Ueki
Kohjiro
K
Oike
Yuichi
Y
Ishii
Satoshi
S
Hirose
Kenzo
K
Shimizu
Takao
T
Touhara
Kazushige
K
Kadowaki
Takashi
T
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D054419:Receptors, Adiponectin / Q000172:deficiency / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014982:Xenopus laevis
D052242:Adiponectin; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D054419:Receptors, Adiponectin; D015534:Trans-Activators; D014157:Transcription Factors; C475419:adiponectin receptor 1, mouse; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose; D002118:Calcium