Functional peroxisomes are required for β-cell integrity in mice

Peroxisomes play a crucial role in lipid and reactive oxygen species metabolism, but their importance for pancreatic β-cell functioning is presently unknown. To examine the contribution of peroxisomal metabolism to β-cell homeostasis in mice, we inactivated PEX5, the import receptor for peroxisomal matrix proteins, in an inducible and β-cell restricted manner (Rip-Pex5−/− mice). 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. 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 β-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 β-cell apoptosis in islets and a decrease in β-cell mass. Our data indicate that normal peroxisome metabolism in β-cells is crucial to preserve their structure and function. [Display omitted] •Pex5 deletion in β-cells impairs glucose tolerance and reduces β-cell mass.•Pex5-deficient β-cells display increased apoptosis.•Peroxisomal loss causes mitochondrial deterioration and cytoplasmic vacuolization.