Obesity-induced overexpression of miR-802 impairs insulin transcription and secretion

Abstract

B cell dysfunction due to obesity can be associated with alterations in the levels of micro-RNAs (miRNAs). However, the role of miRNAs in these processes remains elusive. Here, we show that miR-802 is increased in the pancreatic islets of obese mouse models and demonstrate that inducible transgenic overexpression of miR-802 in mice causes impaired insulin transcription and secretion. We identify Foxo1 as a transcription factor of miR-802 promoting its transcription, and NeuroD1 and Fzd5 as targets of miR-802-dependent silencing. Repression of NeuroD1 in β cell and primary islets impairs insulin transcription and reduction of Fzd5 in β cell, which, in turn, impairs Ca 2+ signaling, thereby repressing calcium influx and decreasing insulin secretion. We functionally create a novel network between obesity and β cell dysfunction via miR-802 regulation. Elucidation of the impact of obesity on microRNA expression can broaden our understanding of pathophysiological development of diabetes.

Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young

“…INS1 cells were cotransfected with plasmids encoding Cys354Phe-KLF11 and WT-KLF11 to investigate insulin secretion and insulin contents, as described previously [ 10 ]. Insulin secretion was determined using a static incubation method under conditions of 5% CO 2 and 95% air at 37°C, as previously described [ 11 , 12 ]. Cells were seeded at a density of 2 × 10 5 cells in 24-well plates and cultured in 1 mL of Dulbecco's Modified Eagle Medium (DMEM, 25 mmol/L glucose).…”

Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression

“…5E), supporting the inference of a functional increase of Sox6 in the Sirt6 KO mice. Since CREB is a negative regulator of Sox6 23 and given our prior observation that Sirt6 enhanced CREB expression (Fig. 4), we measured whether CREB occupancy on Sox6 promoter was altered in Sirt6 KO muscle.…”

Emerging roles of Sox6 in the renal and cardiovascular system

“…The miRNA-802 is highly upregulated in islets of the pancreas of obese mouse models. Using knockout and knock-in approaches Zhang et al (2020), showed that miRNA-802 regulates synthesis of insulin. In this study, they revealed that increased expression of miRNA-802 downregulates phosphorylation of CREB, that results into overexpression of Sox6 and dysregulation of insulin secretion and synthesis (Zhang et al, 2020).…”

“…Sox6 binds and degrades the β‐catenin that further leads to reduced WNT signaling causing the adipocyte multiplication (Leow et al., 2016). The miR‐802 increases Sox6 expression by inhibiting the p‐CREB expression leading to reduced insulin secretion (Zhang et al., 2020). Lower expression of all the miRs with asterisk (*) results into the overexpression of Sox6 causing the reduction in the number of insulins producing cells and synthesis/secretion of insulin.…”

“…Type 1 and/or T2DM are one of the main contributors of microvascular complications during diabetic kidney disease (DKD) which is the main cause of end‐stage renal disease (ESRD; Lu et al., 2017). Using a DKD model, and mouse renal mesangial cells (MCs), Jiang and colleagues studied the miRNA‐342 mediated regulation of Sox6 and impacts on interstitial fibrosis during diabetic nephropathy (Zhang et al., 2020). They showed that miRNA‐342 binds to the 3’‐UTR of Sox6 and inhibits its expression.…”