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

TY - JOUR

T1 - High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring

AU - de Castro Barbosa, Thais

AU - Ingerslev, Lars R

AU - Alm, Petter S

AU - Versteyhe, Soetkin

AU - Massart, Julie

AU - Rasmussen, Morten

AU - Donkin, Ida

AU - Sjögren, Rasmus

AU - Mudry, Jonathan M

AU - Vetterli, Laurène

AU - Gupta, Shashank

AU - Krook, Anna

AU - Zierath, Juleen R

AU - Barrès, Romain

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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: F0-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 F0 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 F0 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.

AB - 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: F0-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 F0 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 F0 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.

U2 - 10.1016/j.molmet.2015.12.002

DO - 10.1016/j.molmet.2015.12.002

M3 - Journal article

C2 - 26977389

SN - 2212-8778

VL - 5

SP - 184

EP - 197

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 3

ER -