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Mol Metab. 2015 Dec 25;5(3):184-197. doi: 10.1016/j.molmet.2015.12.002. eCollection 2016 Mar.

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

Author information

1
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.
2
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
3
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
4
Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden.
5
Department of Veterinary Disease Biology, University of Copenhagen, 1870 Frederiksberg, Denmark.
6
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.
7
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.

Abstract

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.

KEYWORDS:

DNA methylation; Epigenetics; Obesity; Spermatozoa; microRNA

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