8116 Paternal Metabolism Modulates Lipid Metabolism in Offspring Liver

Abstract Disclosure: B. Ozturk: None. R. Ferraz-Bannitz: None. V. Efthymiou: None. M. Patti: Consulting Fee; Self; AstraZeneca, Hamni, MBX Biosciences. Grant Recipient; Self; Dexcom. Other; Self; data and safety monitoring board for Fractyl Health. Introduction: Paternal metabolic phenotypes prior to conception can influence metabolic health of offspring. We previously demonstrated treatment of mice with diet-induced obesity with canagliflozin (SGLT2i) or caloric restriction prior to breeding reduces adiposity, glucose intolerance, and hepatic steatosis in adult male offspring (9 months). To identify potential molecular contributors to this paternally-mediated intergenerational disease risk in later life, we analyzed the liver transcriptome and lipidome of young adult offspring. Method: C57BL/6J male mice, age 8 weeks, were treated with low fat (10% fat) or high fat diet (HFD, 60%) to induce obesity/hyperglycemia; after 5 weeks, HFD mice were randomized to HFD, HFD with canagliflozin (25 mg/kg/day) (HFD-CANA) or 15-30% caloric restriction (HFD-CR). HFD-CANA and HFD-CR had lower weight and glucose vs. HFD (P0.05). After 5 weeks of treatment, males were bred with chow-fed females, yielding 4 groups of F1 generation offspring (pLFD, pHFD, pHFD-CANA, pHFD-CR). F1 were fed chow at weaning and sacrificed at 4 months. Results: pHFD offspring have greater hepatic steatosis vs. pLFD, partially reversed in pHFD CANA and pHFD-CR, as determined by histology and total lipid weight. To identify potential molecular mediators of differential steatosis, we analyzed the liver transcriptome (RNA-seq) in offspring. Gene ontology analysis (ClusterFinder, padj0.05) revealed genes downregulated in pHFD vs. pLFD (n=495) were enriched for lipid localization/transport and phospholipid and carbohydrate metabolism. Strikingly, genes upregulated in pHFD-CANA (n=449) and pHFD CR (n=875) vs. pHFD were also enriched for lipid localization/transport and fatty acid and steroid metabolism. 20% and 33% of genes downregulated in pHFD vs. pLFD were reversed in pHFD-CANA and pHFD-CR, respectively. Reversed genes were enriched for lipid and mitochondrial/peroxisomal fatty acid metabolism. ChIP Enrichment Analysis of reversed genes indicated Ppara, Lxr and Rxr as potential upstream regulators. Parallel lipidomic analysis using mass-spectrometry revealed upregulation of multiple ceramide species in pHFD vs. pLFD, with downregulation in pHFD-CANA and pHFD-CR vs. p-HFD. Top lipids altered in pHFD were reversed in pHFD-CANA or pHFD-CR. Conclusion: Paternal diet-induced obesity modulates offspring hepatic transcriptome and lipidome, with dominant impact on genes regulating lipid metabolism and increased ceramide species. Moreover, treatment of obese males prior to conception with canagliflozin or caloric restriction yields substantial reversal of these patterns. Taken together, these data suggest that perturbations in offspring lipid metabolism may be an early phenotype altered in response to paternal obesity. Interventions to improve paternal health may interrupt nongenetic intergenerational transmission of metabolic disease risk. Presentation: 6/1/2024