Redox-dependent and ligand-independent trans-activation of insulin receptor by globular adiponectin.
Adiponectin/ACRP30 is an adipose tissue-derived hormone with antiatherogenic, antidiabetic, and insulin-sensitizing properties. Although the metabolic effects of adiponectin on glucose and lipid metabolism are well known, the signaling pathways triggered by adiponectin receptors remain to be elucidated. We report evidence that in hepatic cells, adiponectin stimulation produces a transient burst of reactive oxygen species (ROS) through activation of the small GTPase Rac1 and 5-lypoxigenase. Furthermore, adiponectin-induced oxidants cause the oxidation/inhibition of protein-tyrosine phosphatase (PTP) 1B, one of the major phosphotyrosine phosphatases involved in the control of insulin receptor phosphorylation. Adiponectin causes increased association of PTP1B to insulin receptor and the oxidation/inhibition of the phosphatase, ultimately provoking the ligand-independent trans-phosphorylation of insulin receptor. We also report evidence that redox signaling plays a key role in both mitogen-activated protein kinase activation and hepatic glucose consumption induced by adiponectin.


CONCLUSIONS
These results point to ROS as critical regulators of the cross-talk between adiponectin and insulin pathways and provide a redox-based molecular mechanism for the insulin-sensitizing function of adiponectin.
Fiaschi
Tania
T
Department of Biochemical Sciences, University of Florence, Florence, Italy.
Buricchi
Francesca
F
Cozzi
Giacomo
G
Matthias
Stephanie
S
Parri
Matteo
M
Raugei
Giovanni
G
Ramponi
Giampietro
G
Chiarugi
Paola
P
D052242:Adiponectin / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver; D010084:Oxidation-Reduction; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
D052242:Adiponectin; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases; D020830:rac1 GTP-Binding Protein