The specific protein phosphatase inhibitor okadaic acid differentially modulates insulin action.
The pleiotropic nature of insulin action suggests diverse mechanisms of signal transduction for the hormone. The specific protein phosphatase inhibitor, okadaic acid, is utilized to differentiate metabolic pathways that may be regulated by phosphorylation or dephosphorylation of key enzymes. In H-35 hepatoma cells, okadaic acid inhibits insulin-stimulated glycogen synthesis with an IC50 of 400 nM. In contrast, activation of lipogenesis by insulin is inhibited with an IC50 of 50 nM okadaic acid. The toxin also inhibits stimulation of lipogenesis in these cells by the insulin-sensitive inositol glycan enzyme modulator. In isolated rat adipocytes, insulin-stimulated lipogenesis is also inhibited by okadaic acid with an IC50 of approximately 1,700 nM. The antilipolytic effect of insulin in these cells is more sensitive to okadaic acid, exhibiting an IC50 of 150 nM. Maximal activation of lipogenesis by insulin is dramatically reduced by okadaic acid with no effect on the concentration required for half-maximal activation, whereas the sensitivity of insulin-induced antilipolysis is attenuated by okadaic acid, with no apparent reduction in the maximal effect of the hormone. Taken together, these data suggest that specific phosphatases may be differentially involved in some of the metabolic pathways regulated by insulin.
Hess
S L
SL
Laboratory of Molecular Oncology, Rockefeller University, New York, New York 10021.
Suchin
C R
CR
Saltiel
A R
AR
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D004988:Ethers, Cyclic; D006003:Glycogen / Q000096:biosynthesis; D007328:Insulin / Q000502:physiology*; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D004988:Ethers, Cyclic; D007328:Insulin; D008055:Lipids; D019319:Okadaic Acid; D006003:Glycogen; D010749:Phosphoprotein Phosphatases