Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.
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)-alpha 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-alpha 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.
Yamauchi
Toshimasa
T
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Nio
Yasunori
Y
Maki
Toshiyuki
T
Kobayashi
Masaki
M
Takazawa
Takeshi
T
Iwabu
Masato
M
Okada-Iwabu
Miki
M
Kawamoto
Sachiko
S
Kubota
Naoto
N
Kubota
Tetsuya
T
Ito
Yusuke
Y
Kamon
Junji
J
Tsuchida
Atsushi
A
Kumagai
Katsuyoshi
K
Kozono
Hideki
H
Hada
Yusuke
Y
Ogata
Hitomi
H
Tokuyama
Kumpei
K
Tsunoda
Masaki
M
Ide
Tomohiro
T
Murakami
Kouji
K
Awazawa
Motoharu
M
Takamoto
Iseki
I
Froguel
Philippe
P
Hara
Kazuo
K
Tobe
Kazuyuki
K
Nagai
Ryozo
R
Ueki
Kohjiro
K
Kadowaki
Takashi
T
D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D011485:Protein Binding / Q000235:genetics; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D054411:Receptors, Leptin
D052242:Adiponectin; D001786:Blood Glucose; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse