Paternal high-fat diet elicits early-onset se-specific islet inflammation in rat progeny. Rattus norvegicus

Progressive β–cell failure and apoptosis, resultant of innate immune system activation1,2 is gaining traction as a converging point for type 1 (T1D) and type 2 (T2D). Islet inflammation (insulitis), a hallmark of T1D, occurs typically during the initiation phase of the disease, subsequently orchestrating an autoimmune assault against β–cells. Whether this is a primary event or a consequence of glucotoxicity or lipotoxicity is undetermined3 but metabolic stress is demonstrated to prompt islet inflammation1,2. Here we show that paternal consumption of high fat diet (HFD) invoked distinct immuno-inflammatory transcriptional response in the pancreatic islets of their weanling daughters, in contrast to compensatory changes in the sons. Importantly, these changes occurred in conjunction with transition in islet repertoire resembling the spectrum of T2D, along with progressive development of β–cell dysfunction4. Note, these females were lean, normolipidaemic and insulin sensitive4. These findings provide experimental support for the notion that islet inflammation could be an antecedent event in T2D, leading to β–cell secretory defect, repair/regeneration and apoptosis. Importantly, these effects were transmitted via paternal nutrient stress to offspring. Overall design: Male F0 Sprague Dawley founders were assigned to high fat diet (HFD) or control diet for 12 weeks, then mated with chow-fed female Sprague Dawley as previously decribed4. Litters from 8 control and 9 HFD fathers were included. Eligible litter size was 12-16 pups and litters were standardized to 12 pups at postnatal day-1 (P1). Additional animals were killed for post-mortem analysis. At P20, one cohort of animals was euthanized for pancreas histology and postmortem analyses. Littermates were weaned onto chow and islets harvested from another cohort killed at week-4 to -5. All animals were euthanized in a non-fasting state. Islet transcriptome data were extracted from Affymetrix GeneChip® Rat Gene ST 1.0 arrays [n = 10 controls and 10 HFD (5 females, 5 males), (Ramaciotti Centre for Genomics, UNSW)], representing one biological replicate per litter. Effects of paternal diets across both sexes were compared using two way ANOVA; data were also compared for each sex separately, based on robust multi-array average (RMA)3 normalized gene expression in log 2 space. Differentially expressed genes (P < 0.05, unadjusted) were then functionally annotated according to Gene Ontology (GO) terms and enriched terms were calculated using DAVID4,5. P < 0.05 was considered statistically significant. All experimental protocols were approved by the Animal Care and Ethics Committee, UNSW, Australia.