Endocrine Abstracts

Background: The mechanistic basis of type 2 diabetes remission is challenging to model in humans. Insight into disease pathogenesis can be effectively studied in bespoke polygenic diabetes-susceptible models such as the NONcNZO10/ltJ mouse. We showed that this model develops impaired glucose tolerance and increased de novo lipogenesis (DNL) when fed a high sucrose diet (HSD) and that was reversed by calorie restriction (CR). Here, we provide a deeper molecular insight via comprehensive multi-omics analysis of the liver to elucidate molecular mechanisms underlying disease progression and remission.

Methods: NONcNZO10/ltJ mice (n = 12) were fed HSD for 12 weeks, after which half continued on HSD while the other half were switched to CR diet (30%) for 12 weeks. At 24 weeks, mice were euthanized, and liver tissues were snap-frozen at –80°C. Omics profiling—including transcriptomics, lipidomics, metabolomics, and kinomics—was performed using standardized protocols and analysed using in-house workflows.

Results: RNA-seq identified 334 differentially expressed genes (DEGs; 202↑,132↓) involved in many pathways including fatty acid metabolism (21 genes), neutral lipids storage (11 genes), long-chain fatty acid synthesis (9 genes), and regulation of lipid metabolic process (16 genes). Lipidomic and metabolomic analysis identified 44 lipids (19↑,25↓), and 58 compounds (33↑,25↓) significantly changed. Kinomic analysis identified 15 protein tyrosine kinases (PTKs; 10↑,5↓) and 19 serine/threonine kinases (STK; 16↓,3↓). Multi-omics data integration (transcriptomics, kinomics, and metabolomics) identified 38 enriched pathways, 10 of which were common across all three datasets. Notably, the sphingolipid signaling pathway emerged as a key shared pathway, involving critical targets such as Degs1l, Mapk12, Fyn, Pik3r1, and Pik3r3.

Conclusions: Our data identified several lipid-related hepatic targets significantly altered by CR in NONcNZO10/ltJ mice. These are currently being validated to clarify their roles in the DNL pathway and their potential as therapeutic targets.