Peroxisomes are still enigmatic organelles six decades after their discovery. Their importance for pancreatic β-cell function remains largely unexplored. Baboota, Shinde, and colleagues assessed the abundance of peroxisomes in the endocrine pancreas and used an in vivo loss-of-function approach to investigate the role of peroxisomes in pancreatic β-cells. They provide evidence that peroxisomal metabolism plays an essential role in the preservation of β-cell integrity. This suggests that enhancing peroxisome activity is a potential avenue to support β-cell function in metabolic stress conditions.
Functional peroxisomes are required for β-cell integrity in mice
Objective: 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).
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 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.
Conclusions: Our data indicate that normal peroxisome metabolism in β-cells is crucial to preserve their structure and function.