Elsevier

Molecular Metabolism

Volume 6, Issue 4, April 2017, Pages 340-351
Molecular Metabolism

Original Article
Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

https://doi.org/10.1016/j.molmet.2017.01.009Get rights and content
Under a Creative Commons license
open access

Highlights

  • High fat and normal chow fed mice from six common strains were studied over 3 months.

  • Islet RNA-Seq and phenotype data were integrated in a network-based analysis.

  • Elovl2 was identified as a hub in a network module related to insulin secretion.

  • Elovl2 silencing decreased insulin secretion in mouse and human β cell lines.

Abstract

Objective

In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress.

Methods

Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis.

Results

A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines.

Conclusion

Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.

Keywords

Diabetes
Pancreas
Beta cell dysfunction
Network analysis
Molecular phenotyping
Metabolic stress

Cited by (0)

10

Co-first authors.