Functional peroxisomes are required for β-cell integrity in mice

Ritesh Kumar Baboota, Abhijit Babaji Shinde, Katleen Lemaire, Marc Fransen, Stefan Vinckier, Paul P. Van Veldhoven, Frans Schuit, Myriam Baes

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.

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.