373-OR: Paternal SGLT2 Inhibition Upregulates Hepatic Expression of Oxidative Phosphorylation Genes in Both Fetal and Adult Offspring

Paternal obesity has a detrimental impact on metabolic health of his offspring, suggesting an opportunity for preventive strategies prior to conception. Indeed, treatment of male mice with the SGLT2 inhibitor canagliflozin (CANA, 25mg/kg/d) for 4 weeks prior to breeding reduces obesity, hepatic steatosis, and glycemia in offspring. To identify molecular mediators, we analyzed mRNA-seq in fetal and adult liver from male offspring of fathers treated with chow (pCHOW), 60% high-fat diet (pHFD), or HFD+CANA (pCANA). Differentially expressed genes were identified using Limma (R). In adult offspring, paternal SGLT2 inhibition altered the expression of 213 genes (FDR<0.05, 137 upregulated, 67 downregulated with FC ≥|1.5|, vs. paternal HFD, n=5/group). Pathway analysis revealed enrichment of oxidative phosphorylation and ribosome in upregulated genes, including 11 subunits of complex IV (Cox6b2), complex III (Uqcrq, Uqcr10), complexI(Ndufs7, Ndufa1, Ndufa2/3/7/11) and complex V(Atp5mpl, Atp5e), with similar trend for complex II Sdhb (FC=1.32, FDR=0.07). Mitochondrial DNA (quantitated by NADH dehydrogenase 1 relative to β-globin DNA) did not differ between pCANA and pHFD. To determine whether this pattern was present early in life, before emergence of offspring metabolic phenotypes, we analyzed E16.5 fetal liver. 95 genes were differentially expressed in pCANA vs. pHFD (p<0.05, 55 upregulated, 40 downregulated with FC ≥|1.5|, n=5 vs. n=3); of these, 99% were also inversely regulated by pHFD vs. pChow. 16 OXPHOS genes were downregulated by pHFD but upregulated by pCANA (FC≥|1.2|). ETFB was downregulated by pHFD (FC -1.6), but upregulated by pCANA in both fetal (FC 1.3) and adult (FC 1.5) liver.

In summary, paternal CANA modulates liver mitochondrial gene expression in his offspring during both embryonic and adult life, suggesting that improvements in oxidative capacity may mediate the protective effects of paternal SGLT2 inhibition.