Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.
Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.
Yamauchi
Toshimasa
T
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Kamon
Junji
J
Ito
Yusuke
Y
Tsuchida
Atsushi
A
Yokomizo
Takehiko
T
Kita
Shunbun
S
Sugiyama
Takuya
T
Miyagishi
Makoto
M
Hara
Kazuo
K
Tsunoda
Masaki
M
Murakami
Koji
K
Ohteki
Toshiaki
T
Uchida
Shoko
S
Takekawa
Sato
S
Waki
Hironori
H
Tsuno
Nelson H
NH
Shibata
Yoichi
Y
Terauchi
Yasuo
Y
Froguel
Philippe
P
Tobe
Kazuyuki
K
Koyasu
Shigeo
S
Taira
Kazunari
K
Kitamura
Toshio
T
Shimizu
Takao
T
Nagai
Ryozo
R
Kadowaki
Takashi
T
D052242:Adiponectin; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D003920:Diabetes Mellitus / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011506:Proteins; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D005947:Glucose