Deletion of Bmal1 Impairs Pancreatic β-Cell Function via Mitochondrial Signaling Pathway

Lu Ye,Weihong Xu,Huaxiang Wu

doi:10.1155/2020/9803024

Abstract

Several studies have demonstrated that brain and muscle Arnt-like protein-1 (Bmal1) acts as a core clock gene for maintaining normal cell function, including hepatocytes and cardiomyocytes. Loss of Bmal1 is associated with type 2 diabetes due to pancreatic β-cell failure. However, little information is available about its role and mechanism in pancreatic β-cell. To address this, we investigated the consequences of Bmal1 inhibition in an insulinoma cell line (INS-1) by using small interfering RNA (siRNA). We observed that knockout of Bmal1 impaired glucose-stimulated insulin secretion in β-cell. Meanwhile, the depletion of Bmal1 in β-cell caused an adverse change in mitochondrial membrane potential and mitochondrial architecture. Deletion of Bmal1 attenuated mRNA and protein expression of mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) and enhanced the expression of fission 1 (Fis1). In summary, the deletion of Bmal1 impaired β-cell function may be via the mitochondrial signaling pathway in INS-1 cells.

Highlights

Type 2 diabetes, a disease characterized by hyperglycaemia, has become one of the major chronic diseases that seriously endanger human health
Circadian clocks regulate various aspects of behavioral and metabolic processes in mammals [2]. This circadian system, composed of a master clock that locates in the hypothalamic suprachiasmatic nucleus (SCN) and various peripheral tissue clocks, is generated by a feedback loop formed by core clock genes including brain and muscle Arnt-like protein-1 (Bmal1), circadian locomotor output cycles kaput (Clock), Period (Per), and Cryptochrome (Cry)
To investigate the effect of Bmal1 on membrane potential (MMP), we examined the alteration of MMP in βcells with or without Bmal1 inhibition by the JC-1 assay

Summary

Introduction

Type 2 diabetes, a disease characterized by hyperglycaemia, has become one of the major chronic diseases that seriously endanger human health. Pancreatic β-cell dysfunction is a key factor in the development of type 2 diabetes [1]. Circadian clocks regulate various aspects of behavioral and metabolic processes in mammals [2]. It has been reported that mitochondrial dysfunction could impair glucose utilization and insulin secretion in β-cells [12, 16]. Circadian clocks have been reported to regulate mitochondrial acetylation and various essential proteins involved in metabolic pathways [18]. Mitochondrial deacetylation is demonstrated as Bmal dependent [19] These data indicate that mitochondrial function is under circadian clock control. Our results suggest that the deletion of Bmal could impair β-cell function via the mitochondrial signaling pathway

Materials and Methods

Results

Discussion