Biology subjects

Bandyopadhyay, G. K.

Publications and source records attributed to Bandyopadhyay, G. K..

3 recordsLinked to original sources

bioRxiv2020

Catestatin reduces hyperglycemia in insulin-resistant mice by redirecting glucose-6-phosphate from the gluconeogenic to the glycogenic pathway

AimDefects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372) has been shown to improve glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis. MethodsWe determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG), and glycogen synthase (GYS2) activities; plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI) levels in fed and fasted liver of lean and obese mice as well as in CST knockout (CST-KO) mice after treatments with saline, CST, or insulin. We also determined glycogen synthesis and glycogenolysis in primary hepatocytes. In addition, we analyzed phosphorylation signals of Insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3{beta} (GSK-3{beta}), AKT (an enzyme in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mTOR (mammalian/mechanistic target of rapamycin) by immunoblotting. ResultsCST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma NE and EPI levels, suggesting that CST promotes glycogenesis by inhibiting catecholamine-induced glycogenolysis. CST also directly stimulated glycogenesis and inhibited NE and EPI-induced glycogenolysis in hepatocytes. CST elevated the levels of UDPG and increased GYS2 activity, thus redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST can improve insulin signals downstream of insulin receptor IR and IRS-1 by enhancing phospho-AKT signals through stimulation of PDK-1 and mTORC2 (mTOR complex 2) activities. ConclusionsWe conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production, (ii) increasing glycogen synthesis from UDPG, and (iii) reducing glycogenolysis. This is achieved by enhancing downstream insulin signaling.

physiology↗

bioRxiv2020

Catestatin (CST) is a key mediator of the immunoendocrine regulation of cardiovascular function

Hypertension (HTN) is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of Catestatin (CST), a bioactive cleavage product of the prohormone Chromogranin A (CgA). In mouse models, HTN symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with knockout (KO) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted, but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of pro-inflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic pre-conditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone-marrow transfer showed that macrophages produce CST and that the anti-hypertensive effects of CST are mediated in part via CSTs immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in HTN by reducing macrophage inflammation.

physiology↗

bioRxiv2019

Catestatin improves insulin sensitivity in diet-induced obese mice: in vivo and in silico validation

Obesity is characterized by a state of chronic, unresolved inflammation in insulin-targeted tissues. Obesity-induced inflammation accumulates proinflammatory macrophages in adipose tissue and liver. Proinflammatory cytokines released from tissue macrophages inhibits insulin sensitivity. Chromogranin A (CgA) peptide catestatin (CST: hCgA352-372) improves obesity-induced hepatic insulin resistance by reducing inflammation and inhibiting proinflammatory macrophage infiltration. Obesity leads to inflammation-induced endoplasmic reticulum (ER) stress and insulin resistance. We reasoned that the anti-inflammatory effects of CST would alleviate ER stress. CST decreased obesity-induced ER dilation in hepatocytes and macrophages. CST reduced phosphorylation of UPR signaling molecules and increased phosphorylation of insulin signaling molecules. We developed an in silico state space model mimicking dynamics of integrated ER stress and insulin pathways. Proportional-Integral-Derivative (PID) controllers helped in checking whether the reduction of phosphorylated PERK resulting in attenuation of ER stress, resembling CST effect, could enhance insulin sensitivity. The simulation results showed CST not only decreased ER stress but also enhanced insulin sensitivity. Simulation results also revealed that enhancement of AKT phosphorylation overcame effects of high ER stress to achieve insulin sensitivity.

systems biology↗