Abstract
Chromogranin A (CHGA/Chga), a proprotein, widely distributed in endocrine and neuroendocrine tissues (not expressed in muscle, liver, and adipose tissues), generates at least four bioactive peptides. One of those peptides, pancreastatin (PST), has been reported to interfere with insulin action. We generated a Chga knock-out (KO) mouse by the targeted deletion of the Chga gene in neuroendocrine tissues. KO mice displayed hypertension, higher plasma catecholamine, and adipokine levels and lower IL-6 and lipid levels compared with wild type mice. Liver glycogen content was elevated, but the nitric oxide (NO) level was diminished. Glucose, insulin, and pyruvate tolerance tests and hyperinsulinemic-euglycemic clamp studies established increased insulin sensitivity in liver but decreased glucose disposal in muscle. Despite higher catecholamine and ketone body levels and muscle insulin resistance, KO mice maintained euglycemia due to increased liver insulin sensitivity. Suppressed mRNA abundance of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase) in KO mice further support this conclusion. PST administration in KO mice stimulated phosphoenolpyruvate carboxykinase and G6Pase mRNA abundance and raised the blood glucose level. In liver cells transfected with G6Pase promoter, PST caused transcriptional activation in a protein kinase C (PKC)- and NO synthase-dependent manner. Thus, PST action may be mediated by suppressing IRS1/2-phosphatidylinositol 3-kinase-Akt-FOXO-1 signaling and insulin-induced maturation of SREBP1c by PKC and a high level of NO. The combined effects of conventional PKC and endothelial NO synthase activation by PST can suppress insulin signaling. The rise in blood PST level with age and in diabetes suggests that PST is a negative regulator of insulin sensitivity and glucose homeostasis.
Highlights
Chromogranin A (CHGA/Chga), a proprotein, widely distributed in endocrine and neuroendocrine tissues, generates at least four bioactive peptides
Because IL-6 was shown to be elevated in patients with Type 2 diabetes mellitus [19] and adiponectin was shown to improve insulin sensitivity [20, 21], these findings correlate well with the data on hypertensive KO mice, suggesting increased insulin sensitivity
Consistent with the antagonistic effect of the CHGA peptide PST on insulin action in adipocytes [8, 30, 37] and hepatocytes [32, 38], the current studies demonstrated that Chga KO mice display increased insulin sensitivity as confirmed by glucose tolerance test (GTT) (Fig. 2D), insulin tolerance test (ITT)
Summary
Chromogranin A (CHGA/Chga), a proprotein, widely distributed in endocrine and neuroendocrine tissues (not expressed in muscle, liver, and adipose tissues), generates at least four bioactive peptides One of those peptides, pancreastatin (PST), has been reported to interfere with insulin action. To further delineate the role of PST in metabolism, we tested whether removal of PST, a negative regulator of insulin action, stabilizes glucose levels in knock-out (KO) mice and protects against metabolic disorders. To this end, we characterized more extensively the phenotype of the global Chga KO mouse [12], which we had found to be hypertensive (resulting from elevation in catecholamine release) and hyperadrenergic [12]. Contrary to what is found in hypertension [13], hypertensive KO mice exhibited a high plasma adiponectin level
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
