Functional peroxisomes are required for β-cell integrity in mice

Objectives: Peroxisomes play a crucial role in lipid and reactive oxygen species metabolism, but their importance for pancreatic beta-cell functioning is presently unknown. To examine the contribution of peroxisomal metabolism to beta-cell homeostasis in mice, we inactivated PEX5, the import receptor for peroxisomal matrix proteins, in an inducible and beta-cell restricted manner (Rip-Pex5(-/-) mice). Methods: After tamoxifen-induced recombination of the Pex5 gene at the age of 6 weeks, mice were fed either normal chow or a high-fat diet for 12 weeks and were subsequently phenotyped. Results: Increased levels of very long chain fatty acids and reduced levels of plasmalogens in islets confirmed impairment of peroxisomal fatty acid oxidation and ether lipid synthesis, respectively. The Rip-Pex5(-/-) mice fed on either diet exhibited glucose intolerance associated with impaired insulin secretion. Ultrastructural and biochemical analysis revealed a decrease in the density of mature insulin granules and total pancreatic insulin content, which was further accompanied by mitochondrial disruptions, reduced complex I activity and massive vacuole overload in beta-cells. RNAseq analysis suggested that cell death pathways were affected in islets from HFD-fed Rip-Pex5(-/-) mice. Consistent with this change we observed increased beta-cell apoptosis in islets and a decrease in beta-cell mass. Conclusions: Our data indicate that normal peroxisome metabolism in beta-cells is crucial to preserve their structure and function. (C) 2019 The Authors. Published by Elsevier GmbH.