Adiponectin improves local lipid metabolism in regenerating pancreatic islets after ß-cell ablation

Pathways that stimulate ß-cell regeneration remain of great clinical interest, yet effective therapeutic avenues that promote survival or reconstitution of ß-cell mass remain elusive. Utilizing a mouse model with inducible ß-cell apoptosis followed by adiponectin-mediated regeneration, we aimed to identify key molecules boosting ß-cell viability. Within the regenerating pancreatic islets, we examined changes within the transcriptome, and observed an extensive upregulation of genes encoding proteins involved in lipid transport and metabolism. The most prominent targets were further confirmed by quantitative PCR and immunofluorescence. Among the upstream regulators predicted by pathway analysis of the transcriptome, we detected enhanced levels of two key transcription factors, HNF4a and PPARa. Enhanced leptin levels in circulation may also contribute to the anti-lipotoxic program in islets. In summary, our data suggest that improving local lipid metabolism as an important anti-lipotoxic phenomenon to boost ß-cell regeneration, primarily mediated by adiponectin’s action on the ß-cells directly as well as on the adipocyte. Overall design: RNA profiles of pancreatic islets isolated from PANIC-ATTAT mice crossed with adiponectin wild-type (P-Adn+/+) or the overexpressing transgene (P-AdnTg/+) at 5 weeks after initial dimerizer administration.

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Ye R, Wang M, Wang QA, Scherer PE