A Novel Pathway of Insulin Sensitivity in Chromogranin A Null Mice

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.Chromogranin A (CHGA/Chga), 2 the index member of the chromogranin/secretogranin protein family (1, 2), is a proprotein that gives rise to biologically active peptides such as the dysglycemic hormone pancreastatin (PST; human CHGA-(250 -301)) (3), the vascular smooth muscle vasodilator vasostatin (human CHGA-(1-76)) (4), and a catecholamine release inhibitory peptide, catestatin (human CHGA-(352-372); bovine Chga-(344 -364)) (5). Several studies, including in vivo analyses of experimental animals (6, 7), showed that PST inhibits insulin release in response to glucose (3), reduces glucose uptake in adipocytes and hepatocytes (8), and triggers glycogenolysis (6). Genetic analysis in humans supports a role for PST in decreasing glucose uptake by ϳ50% (9) while increasing the spillover of free fatty acids but not amino acids. Moreover the PST level is elevated in patients with Type 2 diabetes mellitus (9 -11). Taken together, the data suggest that PST is an important player in metabolism.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 t...

Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo

“…Consistent with an enhanced metabolic burden of ATP-dependent vesicular transport in Chga -KO mice, we found evidence for profound alteration in subcellular morphology of organelles involved in energy metabolism, including mitochondria, ER and GC. The ultrastructural findings correlate well with the pathophysiological findings reported earlier in Chga -KO mice (Bandyopadhyay et al 2015; Gayen et al 2009a, b; Mahapatra et al 2005). We also observed greatly enhanced glucose uptake and utilization in Chga -KO mice, consistent with increased metabolic burden on the chromaffin cell in the absence of CgA expression in the adrenal medulla.…”

“…One of the main functions of insulin is to stimulate glycogenesis and inhibit glycogenolysis. We have previously reported Chga -KO mice as being hypertensive, hyperadrenergic and sensitive to insulin (Bandyopadhyay et al 2015; Gayen et al 2009a, b; Mahapatra et al 2005). Therefore, increased glycogen granules in the adrenal medulla of Chga -KO mice may be a reflection of heightened insulin sensitivity in Chga -KO mice (Bandyopadhyay et al 2015; Gayen et al 2009b).…”

“…The extracellular function of CgA includes the generation of bioactive peptides, such as the insulin-regulatory hormone pancreastatin (Bandyopadhyay et al 2015; Gayen et al 2009b; Sanchez-Margalet et al 2010; Tatemoto et al 1986), the vasodilating and cardioprotective vasostatin (Aardal et al 1993; Tota et al 2008), the anti-adrenergic (Mahata et al 2003; Mahata, et al 2010; Mahata et al 1997), anti-hypertensive (Mahapatra et al 2005), anti-obesity (Bandyopadhyay et al 2012), proangiogenic (Theurl et al 2010) and cardioprotective catestatin (Angelone et al 2008; Mahata et al 2010) and the pro-adrenergic serpinin (Tota et al 2012). The intracellular function of CgA includes the initiation and regulation of DCV biogenesis and sequestration of hormones in neuroendocrine cells (Elias et al 2012; Iacangelo and Eiden 1995; Kim et al 2001; Taupenot et al 2002).…”

Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas

“…Gayen et al [52] observed an inverse relationship between pancreastatin and insulin. This CgA-derived peptide might antagonize the effect of insulin via the Akt/FOXO-1 and, administration of insulin could result in low plasma levels of pancreastatin in mice (the basal pancreastatin level dropped significantly following insulin injection).…”

Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice

“…It should be pointed out that Chga -KO mice are unique showing increased insulin sensitivity in the face of persistent hypertension (Mahapatra et al . 2005, Gayen et al . 2009, Biswas et al .…”