Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity

Bandyopadhyay, Gautam; Mahata, Sushil K.

doi:10.3389/fendo.2017.00020

Cited by 39 publications

(33 citation statements)

References 130 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our molecular studies in EndoC-βH1 cells confirm that CgA is a substrate for PAM amidation in beta cells (34). CgA is a granular packaging protein known to influence vesicle composition in other neuroendocrine cell types by facilitating the condensation of secreted proteins within nascent secretory vesicles (28)(29)(30)(35)(36)(37). Previous studies using global Chga knockout mouse models have attempted to investigate a role for CgA in pancreatic islets, but have been confounded by compensatory increases in other granin proteins including Chromogranin B (CgB) (38,39).…”

Section: Discussionsupporting

confidence: 62%

Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

Raimondo

Thomsen

Hastoy

et al. 2017

Preprint

View full text Add to dashboard Cite

149Word count: 4500Number of tables and figures: 5 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/158642 doi: bioRxiv preprint first posted online Jul. 3, 2017; 2 ABSTRACT Molecular mechanisms underpinning the genetic risk for type 2 diabetes (T2D) remain poorly understood, hindering translation into new therapies. Recently, genome-wide studies identified two coding variants in Peptidylglycine Alpha-amidating Monooxygenase (PAM) associated with T2D risk and measures of beta cell dysfunction. Here, we demonstrate that both risk alleles impact negatively on overall PAM activity, but via distinct effects on expression and catalytic function. In a human beta cell model, PAM silencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cells from cadaveric donors confirmed an effect on exocytosis in carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein Chromogranin A is a PAM substrate and a strong candidate for mediating downstream effects on insulin secretion. Taken together, our results establish a role for PAM in beta cell function, and uncover a novel mechanism for T2D-associated PAM alleles.

show abstract

Section: Discussionsupporting

confidence: 62%

Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

Raimondo

Thomsen

Hastoy

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…As a proprotein, CgA gives rise to several peptides of biological importance: catestatin (CST: hCgA352-372) 18 , pancreastatin (PST: hCgA250-301) 19 , WE14 20 , vasostatin 21 , and serpinin 22 ; we show that CST is abundantly processed in the gut. Unexpectedly, we found, that CgA regulates the gut permeability via the antagonistic actions of its two peptides, PST and CST; while PST is a pro-inflammatory, proobesigenic and anti-insulin peptide 23 which loosens the barrier, CST acts as antiinflammatory, antiobesigenic, anti-microbial, and proinsulin peptide 15,[24][25][26][27] that appears to be necessary and sufficient to neutralize the actions of PST and tighten the barrier. Using knockout (KO) mice in conjunction with recombinant proteins, we show that CST exerts its actions via counteracting PST.…”

Section: Introductionmentioning

confidence: 72%

Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides

Muntjewerff

Tang

Lutter

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Some authors assume that the peptide may contribute to the development of metabolic syndrome and diabetes mellitus. Its possible use as a future treatment for obesity and hypertension was also considered [130].…”

Section: The Presumed Role Of Catestatin In Carbohydrate Metabolismmentioning

confidence: 99%

Chromogranina A i jej rola w patogenezie cukrzycy

Herold

Doleschall²,

Kövesdi

et al. 2018

Endokrynologia Polska

View full text Add to dashboard Cite

Chromogranin A is a member of the granin glycoprotein family that is expressed by the endocrine and neuroendocrine cells of different organs. Intracellularly, Chromogranin A contributes to the regulation of secretion, and gives several cleavage products after secretion. Some of its cleavage products modify the hormone functions in autocrine and paracrine ways, while the functions of others have not been fully understood yet. Serum Chromogranin A level is most prominently used in neuroendocrine tumor diagnostics. In addition, recent studies have suggested that Chromogranin A and some of its cleavage products, pancreastatin and WE-14, also play important roles in the pathogenesis of the various forms of diabetes mellitus, but their exact mechanisms still need to be clarified. Higher Chromogranin A, pancreastatin and WE-14 levels have been reported in type 1, type 2 and gestational diabetic patients compared to healthy controls. A notable connection has been inferred through the observation that type 1 diabetes mellitus is not at all or rarely developed in Chromogranin A gene-knockout, non-obese diabetic model mice compared to non-knockout, non-obese diabetic mice. Pancreastatin inhibits insulin release in various cell and animal models, and WE-14 serves as an autoantigen for both CD4+ and CD8+ beta cell-destructive diabetogenic T-cell clones in type 1 diabetes. Chromogranin A contributes to the pathogenesis of diabetes mellitus according to the available literature. The current findings facilitate further investigation to unravel the deeper relationships between this glycoprotein and diabetes.

show abstract

Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity

Cited by 39 publications

References 130 publications

Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides

Chromogranina A i jej rola w patogenezie cukrzycy

Contact Info

Product

Resources

About