Pancreastatin, a chromogranin-A-derived peptide, inhibits insulin-stimulated glycogen synthesis by activating GSK-3 in rat adipocytes.
We have previously found that pancreastatin (PST) inhibits glucose uptake in rat adipocytes by preventing GLUT4 translocation to the plasma membrane. We have also described that this effect is mediated by the cross-talk with insulin signaling, inhibiting Tyr-phosphorylation and PI3-kinase (PI3K) activity, via protein kinase C (PKC) activation. In the present work, we have further investigated the effects of PST on glucose metabolism and the signaling pathways involved in its regulation. As expected, we found that PST inhibited insulin-stimulated PKB activity, since it depends on PI3-kinase activity. Next, we studied the activity of the target enzyme of PKB, glycogen synthase kinase-3 (GSK-3). PST not only prevented the insulin effect decreasing GSK-3 activity, but PST itself was able to activate GSK-3 activity in rat adipocytes. As previously described, phosphorylation level of GSK-3 was negatively correlated with the activity. Thus, insulin stimulated GSK-3 serine phosphorylation, whereas PST inhibited this effect, and even decreased basal phosphorylation. The PST stimulation of GSK-3 activity seems to be mediated by PKC since it can be prevented by a specific PKC inhibitor (bisindolylmaleimide). Finally, the PST effect on GSK-3 activity resulted in an inhibition on both basal and insulin stimulated glycogen synthesis in rat adipocytes. This effect of PST can also be prevented by using a PKC inhibitor. In conclusion, the chromogranin-A-derived peptide PST inhibits glycogen synthesis in rat adipocytes by activating GSK-3 activity through the activation of PKC.
González-Yanes
C
C
Department of Medical Biochemistry and Molecular Biology, Investigation Unit University Hospital Virgen Macarena, School of Medicine, University of Seville, Spain.
Sánchez-Margalet
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V
D064413:3-Phosphoinositide-Dependent Protein Kinases; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006003:Glycogen / Q000096:biosynthesis*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008297:Male; D010187:Pancreatic Hormones / Q000378:metabolism / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D053379:Chromogranin A; D002864:Chromogranins; D007328:Insulin; D010187:Pancreatic Hormones; C506153:chromogranin A, rat; C050836:pancreastatin; D006003:Glycogen; D038341:Glycogen Synthase Kinases; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3