Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring

Nature. 2010 Oct 21;467(7318):963-6. doi: 10.1038/nature09491.


The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adiposity / drug effects
  • Aging / genetics
  • Animals
  • Apoptosis / genetics
  • Body Weight / drug effects
  • Cations / metabolism
  • Cell Cycle / genetics
  • Cytoskeleton / metabolism
  • DNA Methylation / drug effects
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diet / adverse effects*
  • Dietary Fats / administration & dosage*
  • Dietary Fats / adverse effects*
  • Epigenesis, Genetic / drug effects
  • Fathers*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glucose / pharmacology
  • Glucose Intolerance / etiology
  • Glucose Intolerance / pathology
  • Glucose Intolerance / physiopathology
  • Glucose Tolerance Test
  • Homeostasis / drug effects
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Litter Size
  • Male
  • Obesity / etiology
  • Obesity / pathology
  • Obesity / physiopathology
  • Paternal Exposure / adverse effects*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / genetics


  • Cations
  • Dietary Fats
  • Insulin
  • Adenosine Triphosphate
  • Glucose

Associated data

  • GEO/GSE19877