Endocrine Abstracts

Introduction: Accumulating evidence has shown that not only maternal health during pregnancy, but also the paternal metabolic status at the time of conception may have an impact on the subsequent health of the offspring. Cholestatic liver diseases are metabolic conditions characterised by increased circulating serum bile acid and lipid levels. In this study we hypothesised that paternal cholestasis alters disease susceptibility in the offspring.

Methods: 7–9 week-old male mice were fed a Normal-Chow (NC) diet or 0.5% cholic acid supplemented diet (CA diet) for 10 weeks. At completion of feeding, males were mated to NC-fed females. Offspring were weaned onto NC diet and at 12 weeks old offspring were either kept on a NC diet or challenged with an obesogenic Western Diet (WD) for 8 weeks. Offspring groups were defined according to the paternal and offspring diet: NC NC, CA NC, NC WD and CA WD. Glucose and lipid homeostasis parameters were assessed in the offspring.

Results: Female offspring of cholestatic fathers showed a significant decrease in Respiratory Exchange Rate (RER) both in NC NC vs CA NC and NC WD vs CA WD comparisons (n=4–6, P-value ≤0.05). Moreover, hepatic free fatty acid (FFA) content was significantly increased in CA WD female offspring as compared to NC WD females (n=4–6, P-value ≤0.05). However, following a glucose tolerance test (GTT) challenge, female CA WD offspring showed a significant improvement in glucose levels at 30 min as compared to NC WD females.

Conclusions: Despite the increased levels of hepatic FFA and decreased RER in females from CA fathers, both features of metabolic syndrome, these mice had improved glucose tolerance. This may suggest a compromise of the lipid homeostatic set-points as a consequence of paternal cholestasis. In parallel, a homeostatic feedback response appears to be in place to counteract the metabolic imbalance.