An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart.
Adiponectin promotes cardioprotection by various mechanisms, and this study used primary cardiomyocytes and the isolated working perfused heart to investigate cardiometabolic effects. We show in adult cardiomyocytes that adiponectin increased CD36 translocation and fatty acid uptake as well as insulin-stimulated glucose transport and Akt phosphorylation. Coimmunoprecipitation showed that adiponectin enhanced association of AdipoR1 with APPL1, subsequent binding of APPL1 with AMPKα2, which led to phosphorylation and inhibition of ACC and increased fatty acid oxidation. Using siRNA to effectively knockdown APPL1 in neonatal cardiomyocytes, we demonstrated an essential role for APPL1 in mediating increased fatty acid uptake and oxidation by adiponectin. Importantly, enhanced fatty acid oxidation in conjunction with AMPK and ACC phosphorylation was also observed in the isolated working heart. Despite increasing fatty acid oxidation and myocardial oxygen consumption, adiponectin increased hydraulic work and maintained cardiac efficiency. In summary, the present study documents several beneficial metabolic effects mediated by adiponectin in the heart and provides novel insight into the mechanisms behind these effects, in particular the importance of APPL1.
Fang
Xiangping
X
Dept. of Biology, York Univ., Toronto, Ontario, Canada.
Palanivel
Rengasamy
R
Cresser
Justin
J
Schram
Kristin
K
Ganguly
Riya
R
Thong
Farah S L
FS
Tuinei
Joseph
J
Xu
Aimin
A
Abel
E Dale
ED
Sweeney
Gary
G
D048868:Adaptor Proteins, Signal Transducing; D000263:Adenylate Kinase / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D018955:CD36 Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C515694:Appl1 protein, rat; D018955:CD36 Antigens; D002352:Carrier Proteins; D005227:Fatty Acids; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; C504339:adiponectin receptor 1, rat; C506573:adiponectin receptor 2, rat; D000263:Adenylate Kinase