High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring

作者：Barbosa, Thais de Castro; Ingerslev, Lars R.; Alm, Petter S.; Versteyhe, Soetkin; Massart, Julie; Rasmussen, Morten; Donkin, Ida; Sjogren, Rasmus; Mudry, Jonathan M.; Vetterli, Laurene; Gupta, Shashank; Krook, Anna; Zierath, Juleen R.; Barres, Romain^*

来源：Molecular Metabolism, 2016, 5(3): 184-197.

DOI：10.1016/j.molmet.2015.12.002

• Epigenetics
• Obesity
• Spermatozoa
• DNA methylation
• microRNA

Objectives: Chronic and high consumption of fat constitutes an environmental stress that leads to metabolic diseases. We hypothesized that high-fat diet (HFD) transgenerationally remodels the epigenome of spermatozoa and metabolism of the offspring. @@@ Methods: FO-male rats fed either HFD or chow diet for 12 weeks were mated with chow-fed dams to generate F1 and F2 offspring. Motile spermatozoa were isolated from FO and F1 breeders to determine DNA methylation and small non-coding RNA (sncRNA) expression pattern by deep sequencing. @@@ Results: Newborn offspring of HFD-fed fathers had reduced body weight and pancreatic beta -cell mass. Adult female, but not male, offspring of HFD-fed fathers were glucose intolerant and resistant to HFD-induced weight gain. This phenotype was perpetuated in the F2 progeny, indicating transgenerational epigenetic inheritance. The epigenome of spermatozoa from HFD-fed FO and their F1 male offspring showed common DNA methylation and small non-coding RNA expression signatures. Altered expression of sperm miRNA let-7c was passed down to metabolic tissues of the offspring, inducing a transcriptomic shift of the let-7c predicted targets. @@@ Conclusion: Our results provide insight into mechanisms by which HFD transgenerationally reprograms the epigenome of sperm cells, thereby affecting metabolic tissues of offspring throughout two generations.

• 出版日期2016-3