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

作者：Cruciani Guglielmacci Celine; Bellini Lara; Denom Jessica; Oshima Masaya; Fernandez Neike; Normandie Levi Priscilla; Berney Xavier P; Kassis Nadim; Rouch Claude; Dairou Julien; Gorman Tracy; Smith David M; Marley Anna; Liechti Robin; Kuznetsov Dmitry; Wigger Leonore; Burdet Frederic; Lefevre Anne Laure; Wehrle Isabelle; Uphues Ingo; Hildebrandt Tobias; Rust Werner; Bernard Catherine; Ktorza Alain; Rutter Guy A; Scharfmann Raphael; Xenarios Ioannis; Le Stunff Herve

来源：Molecular Metabolism, 2017, 6(4): 340-351.

DOI：10.1016/j.molmet.2017.01.009

• Diabetes
• Pancreas
• Beta cell dysfunction
• Network analysis
• Molecular phenotyping
• Metabolic stress

Objective: In type 2 diabetes (T2D), pancreatic b 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 beta 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 beta cell failure under metabolic stress.

• 出版日期2017-4