Journal
ENDOCRINOLOGY
Volume 148, Issue 3, Pages 1359-1366Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2006-0750
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Funding
- NATIONAL CANCER INSTITUTE [R01CA154314] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK054393] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA154314] Funding Source: Medline
- NIDDK NIH HHS [R01 DK054393-04, DK 54393, R01 DK054393] Funding Source: Medline
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Elevated TNF alpha levels are associated with insulin resistance, but the molecular mechanisms linking cytokine signaling to impaired insulin function remain elusive. We previously demonstrated a role for Akt in insulin regulation of protein kinase C beta II alternative splicing through phosphorylation of serine/ arginine- rich protein 40, a required mechanism for insulinstimulated glucose uptake. We hypothesized that TNF alpha attenuated insulin signaling by dephosphorylating Akt and its targets via ceramide-activated protein phosphatase. Western blot analysis of L6 cell lysates demonstrated impaired insulin-stimulated phosphorylation of Akt, serine/ arginine- rich protein 40, and glycogen synthase kinase 3 beta in response to TNF alpha and the short chain C6 ceramide analog. TNF alpha increased serine/ threonine phosphatase activity of protein phosphatase 1 ( PP1) in response to C6, but not insulin, suggesting a ceramide-specific effect. Myriocin, an inhibitor of de novo ceramide synthesis, blocked stimulation of the PP1 activity. Ceramide species measurement by liquid chromatography-mass spectrometry showed consistent increases in C24:1 and C16 ceramides. Effects of TNF alpha and C6 on insulin-stimulated phosphorylation of glycogen synthase kinase 3 beta were prevented by myriocin and tautomycin, a PP1 inhibitor, further implicating a de novo ceramide-PP1 pathway. Alternative splicing assays demonstrated that TNF alpha abolished insulin-mediated inclusion of the protein kinase C beta II exon. Collectively, our work demonstrates a role for PP1-like ceramide-activated protein phosphatase in mediating TNF alpha effects blocking insulin phosphorylation cascades involved in glycogen metabolism and alternative splicing.
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