1847-P: SGLT2 Inhibition Reduces Paternal Intergenerational Transmission of Metabolic Disease in Mice with Dietary Obesity

Risk for metabolic disease can be transmitted via both the maternal and paternal lineage, potentially through both genetic and non-genetic mechanisms. This may contribute to the exponential rise in obesity and type 2 diabetes worldwide. We hypothesized that preconception interventions to improve paternal metabolism could improve offspring health and reduce adult offspring metabolic disease. We have developed a model of glucolipotoxicity, induced by chronic overnutrition, and its reversal by SGLT2 inhibitors (SGLT2i). Male C57BL/6J mice fed a 60% high fat diet (HFD) were subjected to (1) continued HFD ad libitum (HFD), or (2) HFD ad libitum, supplemented with canagliflozin (CANA, 30mg/kg/day) for 4 weeks. CANA significantly (1) reduced body weight and hepatic steatosis, (2) improved glucose tolerance and (3) reprogrammed hepatic transcription to favor catabolism in adult males. HFD and CANA males were bred with control females, and offspring were fed chow diet ad libitum throughout life. At 13 months male offspring of CANA-treated fathers had 18% lower body weight and 32% lower fat mass (all p<0.05, vs. offspring of HFD fathers). Improved glucose tolerance and improved insulin sensitivity were also observed at age 9-12 months (26% and 18% lower AUC respectively, P<0.05). Remarkably, at 13 months all male offspring of HFD-exposed fathers had mild to severe liver steatosis; however, 57% of CANA-treated fathers were free of liver steatosis. At a transcriptional level, expression of genes encoding key lipogenic enzymes (e.g., Fasn, Pkl and Scd1) were reduced in offspring of CANA-treated males Together these data demonstrate that improvement of paternal metabolism prior to conception protects against obesity, hepatic steatosis, and diabetes risk later in life in offspring.