Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways.
The binding of the adaptor protein APPL1 to adiponectin receptors is necessary for adiponectin-induced AMP-activated protein kinase (AMPK) activation in muscle, yet the underlying molecular mechanism remains unknown. Here we show that in muscle cells adiponectin and metformin induce AMPK activation by promoting APPL1-dependent LKB1 cytosolic translocation. APPL1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances LKB1 cytosolic localization by anchoring this kinase in the cytosol. Adiponectin also activates another AMPK upstream kinase Ca2+/calmodulin-dependent protein kinase kinase by activating phospholipase C and subsequently inducing Ca2+ release from the endoplasmic reticulum, which plays a minor role in AMPK activation. Our results show that in muscle cells adiponectin is able to activate AMPK via two distinct mechanisms as follows: a major pathway (the APPL1/LKB1-dependent pathway) that promotes the cytosolic localization of LKB1 and a minor pathway (the phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathway) that stimulates Ca2+ release from intracellular stores.
Zhou
Lijun
L
Departments of Biochemistry, San Antonio, Texas 78229-3900.
Deepa
Sathyaseelan S
SS
Cellular and Structural Biology, San Antonio, Texas 78229-3900.
Etzler
Julie C
JC
Cellular and Structural Biology, San Antonio, Texas 78229-3900.
Ryu
Jiyoon
J
Cellular and Structural Biology, San Antonio, Texas 78229-3900.
Mao
Xuming
X
Pharmacology, San Antonio, Texas 78229-3900.
Fang
Qichen
Q
Shanghai Diabetes Institute, Jiaotong University Affiliated Sixth Hospital, Shanghai 200233, China.
Liu
Dianna D
DD
Cellular and Structural Biology, San Antonio, Texas 78229-3900.
Torres
Jesus M
JM
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Granada, Avenida de Madrid s/n, 18012 Granada, Spain.
Jia
Weiping
W
Shanghai Diabetes Institute, Jiaotong University Affiliated Sixth Hospital, Shanghai 200233, China.
Lechleiter
James D
JD
Cellular and Structural Biology, San Antonio, Texas 78229-3900.
Liu
Feng
F
Departments of Biochemistry, San Antonio, Texas 78229-3900; Pharmacology, San Antonio, Texas 78229-3900; The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Dong
Lily Q
LQ
Cellular and Structural Biology, San Antonio, Texas 78229-3900; Pharmacology, San Antonio, Texas 78229-3900; The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D009132:Muscles / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C510733:Appl1 protein, mouse; D002352:Carrier Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium