title: High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Thais
authors.initials: T
authors.lastname: de Castro Barbosa
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Lars R
authors.initials: LR
authors.lastname: Ingerslev
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Petter S
authors.initials: PS
authors.lastname: Alm
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Soetkin
authors.initials: S
authors.lastname: Versteyhe
authors.affiliation: Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Julie
authors.initials: J
authors.lastname: Massart
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Rasmussen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Donkin
authors.affiliation: Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Sjögren
authors.affiliation: Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Mudry
authors.affiliation: Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Laurène
authors.initials: L
authors.lastname: Vetterli
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, 1870 Frederiksberg, Denmark.
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: barres@sund.ku.dk.
authors.forename: Romain
authors.initials: R
authors.lastname: Barrès
keywords: DNA methylation; Epigenetics; Obesity; Spermatozoa; microRNA