Search

Aim: Defects in hepatic glycogen synthesis contribute to post‐prandial hyperglycaemia in type 2 diabetic patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352‐372) improves glucose tolerance in insulin‐resistant mice. Here, we seek to determine whether CST induces hepatic glycogen synthesis. Methods: We determined liver glycogen, glucose‐6‐phosphate (G6P), uridine diphosphate glucose (UDPG) and glycogen synthase (GYS2) activities; plasma insulin, glucagon, noradrenaline and adrenaline levels in wild‐type (WT) as well as in CST knockout (CST‐KO) mice; glycogen synthesis and glycogenolysis in primary hepatocytes. We also analysed phosphorylation signals of insulin receptor (IR), insulin receptor substrate‐1 (IRS‐1), phosphatidylinositol‐dependent kinase‐1 (PDK‐1), GYS2, glycogen synthase kinase‐3β (GSK‐3β), AKT (a kinase in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mammalian/mechanistic target of rapamycin (mTOR) by immunoblotting. Results: CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma noradrenaline and adrenaline levels. CST also directly stimulated glycogenesis and inhibited noradrenaline and adrenaline‐induced glycogenolysis in hepatocytes. In addition, CST elevated the levels of UDPG and increased GYS2 activity. CST‐KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST improved insulin signals downstream of IR and IRS‐1 by enhancing phospho‐AKT signals through the stimulation of PDK‐1 and mTORC2 (mTOR Complex 2, rapamycin‐insensitive complex) activities. Conclusions: CST directly promotes the glycogenic pathway by (a) reducing glucose production, (b) increasing glycogen synthesis from UDPG, (c) reducing glycogenolysis and (d) enhancing downstream insulin signalling. [ABSTRACT FROM AUTHOR]

Catestatin (CST) is a bioactive cleavage product of the neuroendocrine prohormone chromogranin A (CgA). Recent findings show that CST can exert anti-inflammatory and antiadrenergic effects by suppressing the inflammatory actions of mammalian macrophages. However, recent findings also suggest that macrophages themselves are major CST producers. Here, we hypothesize that macrophages produce CST in an inflammation-dependent manner and thereby might self-regulate inflammation in an autocrine fashion. CST is associated with pathological conditions hallmarked by chronic inflammation, including autoimmune, cardiovascular, and metabolic disorders. Since intraperitoneal injection of CST in mouse models of diabetes and inflammatory bowel disease has been reported to be beneficial for mitigating disease, we posit that CST should be further investigated as a candidate target for treating certain inflammatory diseases. Catestatin (CST), a 21-amino acid peptide derived from proteolytic cleavage of the prohormone chromogranin A, has been reported to have anti-inflammatory and antiadrenergic functions in mice. CST is thought to be mainly co-released with catecholamines by neuroendocrine cells. Recent studies suggest that macrophages are also a source of CST and that the anti-inflammatory effects of CST might be attributable to CST produced by macrophages, at least in mice. We propose that CST produced by macrophages might suppress neuronal and neuroendocrine activity, in an inflammation-dependent manner. [ABSTRACT FROM AUTHOR]

Aim: A "leaky" gut barrier has been implicated in the initiation and progression of a multitude of diseases, for example, inflammatory bowel disease (IBD), irritable bowel syndrome and celiac disease. Here we show how pro‐hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352‐372), the most abundant CgA‐derived proteolytic peptide, affect the gut barrier. Methods: Colon tissues from region‐specific CST‐knockout (CST‐KO) mice, CgA‐knockout (CgA‐KO) and WT mice were analysed by immunohistochemistry, western blot, ultrastructural and flowcytometry studies. FITC‐dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250‐301). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients. Results: Plasma levels of CST were elevated in IBD patients. CST‐KO mice displayed (a) elongated tight, adherens junctions and desmosomes similar to IBD patients, (b) elevated expression of Claudin 2, and (c) gut inflammation. Plasma FITC‐dextran measurements showed increased intestinal paracellular permeability in the CST‐KO mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST‐KO mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA‐KO mice supplementation with CST and/or PST in CgA‐KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability. Conclusion: The pro‐hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts by antagonizing PST. [ABSTRACT FROM AUTHOR]

We have previously shown that the chromogranin A (CgA)-derived peptide catestatin (CST: hCgA352–372) inhibits nicotine-induced secretion of catecholamines from the adrenal medulla and chromaffin cells. In the present study, we seek to determine whether CST regulates dense core (DC) vesicle (DCV) quanta (catecholamine and chromogranin/secretogranin proteins) during acute (0.5-h treatment) or chronic (24-h treatment) cholinergic (nicotine) or peptidergic (PACAP, pituitary adenylyl cyclase activating polypeptide) stimulation of PC12 cells. In acute experiments, we found that both nicotine (60 μM) and PACAP (0.1 μM) decreased intracellular norepinephrine (NE) content and increased 3H‐NE secretion, with both effects markedly inhibited by co-treatment with CST (2 μM). In chronic experiments, we found that nicotine and PACAP both reduced DCV and DC diameters and that this effect was likewise prevented by CST. Nicotine or CST alone increased expression of CgA protein and together elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate CgA expression. In contrast, PACAP increased expression of CgB and SgII proteins, with a further potentiation by CST. CST augmented the expression of tyrosine hydroxylase (TH) but did not increase intracellular NE levels, presumably due to its inability to cause post-translational activation of TH through serine phosphorylation. Co-treatment of CST with nicotine or PACAP increased quantal size, plausibly due to increased synthesis of CgA, CgB and SgII by CST. We conclude that CST regulates DCV quanta by acutely inhibiting catecholamine secretion and chronically increasing expression of CgA after nicotinic stimulation and CgB and SgII after PACAPergic stimulation. [ABSTRACT FROM AUTHOR]