Influence of Paternal Diabetes and Ketosis on Glucose Homeostasis in Offspring

Experience during fetal life is an important determinant of adult health. It is well established that maternal conditions such as gestational diabetes and starvation predispose offspring to metabolic syndrome, cardiovascular disease and type-2 diabetes. By contrast, paternal inheritance of metabolic disease remains controversial. It has been reported that paternal over-nutrition in humans predisposes to type-2 diabetes in offspring, and male mice receiving a low-protein diet give rise to progeny with altered glucose metabolism. These effects are presumably transmitted via epigenetic effects on the sperm, via DNA methylation or small RNAs.

We employ two mouse models to study physiologically-relevant metabolic stressors in fathers that can lead to metabolic alterations in progeny and to explore the underlying mechanisms. First, we use a transgenic mouse model for pancreatic beta-cell ablation causing severe, prolonged hyperglycemic in males, which are mated with healthy females and give rise to genetically normal progeny. Second, we test the impact of sustained ketosis as a model for chronic paternal starvation, by mating male mice fed a ketogenic diet with females fed normal chow. We monitor offspring of both groups for body weight, fasting and fed blood glucose levels, glucose tolerance and insulin sensitivity, liver and pancreas histology and gene expression to identify paternal transmission of metabolic states to offspring. These experiments are expected to provide reproducible models to clarify the involvement of paternal inheritance in metabolic health of progeny.