Format

Send to

Choose Destination
Front Genet. 2019 Jul 29;10:693. doi: 10.3389/fgene.2019.00693. eCollection 2019.

Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus.

Author information

1
Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.
2
Mie University Zebrafish Drug Screening Center, Tsu, Japan.
3
Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan.
4
Department of Bioinformatics, University Advanced Science Research Promotion Centre, Tsu, Mie, Japan.
5
Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.
6
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
7
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Japan.
8
Department of Research Support Platform, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is influenced by genetic and environmental factors. Optimum T2DM management involves early diagnosis and effective glucose-lowering therapies. Further research is warranted to improve our understanding of T2DM pathophysiology and reveal potential roles of genetic predisposition. We have previously developed an obesity-induced diabetic zebrafish model that shares common pathological pathways with humans and may be used to identify putative pharmacological targets of diabetes. Additionally, we have previously identified several candidate genes with altered expression in T2DM zebrafish. Here, we performed a small-scale zebrafish screening for these genes and discovered a new therapeutic target, centromere protein X (CENPX), which was further validated in a T2DM mouse model. In zebrafish, cenpx knockdown by morpholino or knockout by CRISPR/Cas9 system ameliorated overfeeding-induced hyperglycemia and upregulated insulin level. In T2DM mice, small-interfering RNA-mediated Cenpx knockdown decreased hyperglycemia and upregulated insulin synthesis in the pancreas. Gene expression analysis revealed insulin, mechanistic target of rapamycin, leptin, and insulin-like growth factor 1 pathway activation following Cenpx silencing in pancreas tissues. Thus, CENPX inhibition exerted antidiabetic effects via increased insulin expression and related pathways. Therefore, T2DM zebrafish may serve as a powerful tool in the discovery of new therapeutic gene targets.

KEYWORDS:

CRISPR/Cas9; centromere protein X; gene silencing; insulin; therapeutic gene target; type 2 diabetes mellitus; zebrafish model

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center