Blocking TLR4-NF-κB pathway protects mouse islets from the combinatorial impact of high fat and fetuin-A mediated dysfunction and restores ability for insulin secretion. (15th July 2021)

• Record Type: Journal Article
• Authors: Mukhuty, Alpana; Fouzder, Chandrani; Kundu, Rakesh
• Is Part Of: Molecular and cellular endocrinology. Volume 532(2021)
• Publication Date: 2021-07-15
• Subjects: Fetuin-A -- Pancreatic β-cells -- Insulin -- TLR4 -- NF-κB -- FFA; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2021.111314
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Lipid mediated pancreatic β-cell dysfunction during Type 2 diabetes is known to be regulated by activation of TLR4 (Toll Like Receptor 4) and NF-κB (Nuclear factor kappa B). Recently we have reported that MIN6 cells (mouse insulinoma cells) secrete fetuin-A on stimulation by palmitate that aggravates β-cell dysfunction, but the mechanism involved in-vivo has not been demonstrated and thus remained unclear. Here we attempted to dissect the role of palmitate and fetuin-A on insulin secretion using high fat diet (HFD) fed mice model. HFD islets showed curtailed insulin secretion after 20 weeks of treatment with activated TLR4-NF-κB pathway. Further treatment of islets with palmitate raised fetuin-A expression by ~2.8 folds and cut down insulin secretion by ~1.4 folds. However, blocking the activity of TLR4, fetuin-A and NF-κB using specific inhibitors or siRNAs not only restored insulin secretion by ~2 folds in standard diet fed mice islets and MIN6 cells but also evoke insulin secretory ability by ~2.3 folds in HFD islets. Altogether this study demonstrated that blocking TLR4, fetuin-A and NF-κB protect pancreatic β-cells from the negative effects of free fatty acid and fetuin-A and restore insulin secretion. Graphical abstract: Image 1 Highlights: HFD deteriorates insulin secretion with concomitant increase in levels of fetuin-A and cytokines. Palmitate and fetuin-A activate TLR4 signalling in β-cells and affect insulin secretion while increasing fetuin-A secretion. Blocking TLR4 protects SD islets from the negative effects of palmitate and restores function of HFD islets. Blocking NF-κB inhibits fetuin-A secretion and restores insulin secretion from pancreatic islets.