Catestatin improves insulin sensitivity by attenuating endoplasmic reticulum stress: In vivo and in silico validation

Dasgupta, Abhijit; Bandyopadhyay, Gautam; I, Ray; Bandyopadhyay, Keya; Chowdhury, Nirmalya; De, Rajat K.; Mahata, Sushil K.

doi:10.1016/j.csbj.2020.02.005

Cited by 24 publications

(25 citation statements)

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“…This phenotype was reversed upon CST treatment ( Fig. 5H-J), reinforcing CST as an insulin-sensitizing peptide in the heart, which is consistent with previous studies in liver (23,37).…”

Section: Cst-ko Mice Display a Cardiometabolic Shift: Glucose Utilizasupporting

confidence: 91%

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

Ying

Tang

Avolio

et al. 2020

Preprint

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38Objective: Hypertension (HTN) is a global pandemic, affecting more than one billion people. 39Although catestatin (CST), a chromogranin A (CgA)-derived peptide, decreases blood pressure 40 (BP) in rodent models of HTN, the mechanisms underlying its hypotensive action is yet to be 41 established. Here we generated CST knockout (CST-KO) mice to pinpoint the mechanism of the 42 hypotensive action of CST. 44Methods and Results: CST-KO mice were hypertensive; their serum cytokines were elevated, 45 anti-inflammatory genes were downregulated, and their hearts showed marked infiltration with 46 macrophages. CST replenishment reversed all these phenotypes -it normalized BP, reduced 47 serum cytokines, upregulated anti-inflammatory genes, and reduced the cardiac infiltrates by 48 ~30%, as determined by FACS. Pre-conditioning-induced cardioprotection was also abolished in 49 CST-KO mice. We hypothesize that CST's anti-hypertensive and cardioprotective effects may be 50 caused by suppressed trafficking of macrophages to the heart and reduced inflammation. Such 51 cause-and-effect relationship is supported by the fact that CST-KO mice became normotensive 52 when they were depleted of macrophages using chlodronate, or when they received bone marrow 53 transplant from wild-type littermates. Mechanistically, cardiac tissue transcriptomes revealed 54 multiple altered gene expression programs in CST-KO mice that are commonly encountered in 55 human cardiomyopathies. Among others, a prominent reduction of Glo1 gene was seen in CST-56 KO mice; supplementation with CST increased it expression by >7-fold. Because Glo1 in 57 macrophages metabolizes methylglyoxal, an inflammatory agent whose accumulation promotes 58 vascular damage in HTN and T2DM, this could be one of the means by which CST attenuates 59 inflammation and improves cardiovascular health. Repletion of CST also improved glucose 60 metabolism and increased the surface area of mitochondrial cristae and decreased the secretion 61 of catecholamines; the latter explains the anti-hypertensive actions of CST. 63Conclusions: We conclude that the anti-hypertensive effects of CST is mediated at least in part 64 via CST's anti-inflammatory actions; in the absence of CST, macrophages are more reactive, they 65 infiltrate the heart and alter the ultrastructure, physiologic and molecular makeup of the 66 myocardium. These studies implicate CST as a key mediator of the observed crosstalk between 67 systemic and cardiac inflammation in HTN.68 69 70 71 3 Abbreviations 72 2DG: 2-deoxy-glucose 73 Actc1: cardiac muscle actin alpha 74 Atp5j: mitochondrial ATP synthase subunit F6 75 BRS: baroreflex sensitivity 76 Cd36: cluster of differentiation 36 77 Cers2: ceramide synthase 2 78 CgA: chromogranin A 79 CST: catestatin 80 CST-KO: CST knockout Introduction 122 123 Hypertension (HTN) is an important risk factor for cardiovascular disease (CVD) and mortality 1 .124 The burden of HTN and the estimated HTN-associated deaths have increased substantially over 125 the past 25 years 2 .126 The role o...

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“…This phenotype was reversed upon CST treatment ( Fig. 5H-J), reinforcing CST as an insulin-sensitizing peptide in the heart, which is consistent with previous studies in liver (23,37).…”

Section: Cst-ko Mice Display a Cardiometabolic Shift: Glucose Utilizasupporting

confidence: 91%

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

Ying

Tang

Avolio

et al. 2020

Preprint

Self Cite

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“…Antagonistic effects of PST and CST determine gut permeability. CgA is unique in having peptide domains that antagonize several functions including inflammation (CST suppresses while PST promotes) 23,26 , obesity (CST inhibits while PST stimulates) 23,26 and sensitivity to insulin (CST increases while PST diminishes) 23,26,70,71 . Since CgA-KO mice lack both CST and PST, and we observed increased permeability in CST-KO mice and decreased permeability in CgA-KO mice, we reasoned that these opposing phenotypes are probably caused by the lack of PST in the CgA-KO mice.…”

Section: Discussionmentioning

confidence: 99%

Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides

Muntjewerff

Tang

Lutter

et al. 2020

Preprint

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Background and AimsA ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we asked how Chromogranin A (CgA), a major hormone produced by the enteroendocrine cells, and Catestatin (CST), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.Methods and ResultsUltrastructural studies on the colons from Catestatin (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology of tight (TJ) and adherens (AJ) junctions and desmosomes, indicative of junctional stress and (ii) an increased infiltration of immune cells compared to controls. Flow cytometry studies confirmed these cells to be macrophages and CD4+ T cells. Gene expression studies confirmed that multiple TJ-markers were reduced, with concomitant compensatory elevation of AJ and desmosome markers. Consistently, the levels of plasma FITC-dextran were elevated in the CST-KO mice, confirming leakiness’ of the gut. Leaky gut in CST-KO mice correlated with inflammation and a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in a multitude of diseases. Supplementation of CST-KO mice with recombinant CST reversed this leakiness and key phenotypes. Supplementation of CgA-KO mice with either CST alone, or with the pro-inflammatory proteolytic CgA fragment pancreastatin (PST: CgA250-301) showed that gut permeability is regulated by the antagonistic roles of these two peptide hormones: CST reduces and PST increases leakiness.ConclusionWe conclude that the enteroendocrine cell-derived hormone, CgA regulates gut permeability. CST is both necessary and sufficient to reduce the leakiness. CST acts primarily via antagonizing the effects of PST.What you need to knowBackground and ContextThe intestinal barrier is disrupted in many intestinal diseases such as Crohn’s disease. Chromogranin A (CgA) is produced by enteroendocrine cells in the gut. CgA is proteolytically cleaved into bioactive peptides including catestatin (CST) and pancreastatin (PST). The role of CgA in the gut is unknown.New findingsCgA is efficiently processed to CST in the gut and this processing might be decreased during active Crohn’s disease. CST promotes epithelial barrier function and reduces inflammation by counteracting PST.LimitationsThe complete mechanism of intestinal barrier regulation by CST likely involves a complex interplay between the enteroendocrine system, metabolism, the epithelium, the immune system and the gut microbiota.ImpactOur findings indicate that CST is a key modulator of the intestinal barrier and immune functions that correlates with disease severity of Crohn’s disease. CST could be a target for therapeutic interventions in Crohn’s disease.

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“…In the past 15 years of type 1 diabetes (T1D) research, in-silico clinical trials (ISCTs), performed using simulators relying on mathematical models of glucose-insulin system dynamics, have accelerated the development of new treatments 1 - 4 and drugs, 5 - 7 and have facilitated the design of clinical studies. 8 - 11 ISCTs allow investigators to carry out a vast number of experiments quickly, in order to evaluate, for example, new algorithms in high-risk scenarios, and so offer considerable economic and human resource savings.…”

Section: Introductionmentioning

confidence: 99%

Mathematical Models of Meal Amount and Timing Variability With Implementation in the Type-1 Diabetes Patient Decision Simulator

Camerlingo

Vettoretti

Favero

et al. 2020

J Diabetes Sci Technol

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Background: In type 1 diabetes (T1D) research, in-silico clinical trials (ISCTs) have proven effective in accelerating the development of new therapies. However, published simulators lack a realistic description of some aspects of patient lifestyle which can remarkably affect glucose control. In this paper, we develop a mathematical description of meal carbohydrates (CHO) amount and timing, with the aim to improve the meal generation module in the T1D Patient Decision Simulator (T1D-PDS) published in Vettoretti et al. Methods: Data of 32 T1D subjects under free-living conditions for 4874 days were used. Univariate probability density function (PDF) parametric models with different candidate shapes were fitted, individually, against sample distributions of: CHO amounts of breakfast (CHOB), lunch (CHOL), dinner (CHOD), and snack (CHOS); breakfast timing (TB); and time between breakfast-lunch (TBL) and between lunch-dinner (TLD). Furthermore, a support vector machine (SVM) classifier was developed to predict the occurrence of a snack in future fixed-length time windows. Once embedded inside the T1D-PDS, an ISCT was performed. Results: Resulting PDF models were: gamma (CHOB, CHOS), lognormal (CHOL, TB), loglogistic (CHOD), and generalized-extreme-values (TBL, TLD). The SVM showed a classification accuracy of 0.8 over the test set. The distributions of simulated meal data were not statistically different from the distributions of the real data used to develop the models (α = 0.05). Conclusions: The models of meal amount and timing variability developed are suitable for describing real data. Their inclusion in modules that describe patient behavior in the T1D-PDS can permit investigators to perform more realistic, reliable, and insightful ISCTs.

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Catestatin improves insulin sensitivity by attenuating endoplasmic reticulum stress: In vivo and in silico validation

Cited by 24 publications

References 100 publications

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides

Mathematical Models of Meal Amount and Timing Variability With Implementation in the Type-1 Diabetes Patient Decision Simulator

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