Intergenerational effects of high fat diet: exploring mechanisms in germ cells

Abstract

The prevalence of obesity is increasing each year, likely due to altered diet and a sedentary lifestyle. However, some epidemiological data suggests that parental and grandparental environments may also impact upon weight gain, metabolic health and mortality. This non-genetic inheritance has been reproduced in some experimental animal studies. The mechanisms are, however, unknown. One hypothesis has been that environmental exposures perturb germ cell development. Changes to the germ cell epigenome are an example of one such alteration.

In this thesis, epigenetic mechanisms are explored in rodent and primate male germ cells throughout development. The conservation of global methylation patterns, expression of DNA methyltransferases and of key histone modifications is demonstrated in rat, marmoset and human tissue demonstrating mechanisms are in place that might be disrupted by environmental exposures either in utero or during post-natal development.

A rat model of parental high fat diet (HFD) exposure is established and phenotype explored in two generations of offspring. Maternal HFD results in weight gain in male and female offspring and paternal HFD in weight gain in just female offspring. Grandpaternal exposure to HFD via the maternal line has the greatest impact on the second generation where, in males, increased weight, adiposity, reduced insulin sensitivity and an increased luteinising hormone to testosterone ratio were found. Given that postnatal exposure in males resulted in adverse metabolic health in grand offspring, the exposed germ cells were interrogated by RNA and smallRNA-sequencing. HFD exposure did not alter the germline transcriptome suggesting an alternative mechanism to be responsible for the intergenerational effects observed. Thus, HFD perturbs metabolic health in two generations of rats in a grand-parent and sex specific manner but does not affect the germ cell transcriptome.