Dataset Information

Adult-onset obesity reveals prenatal programming of glucose-insulin sensitivity in male sheep nutrient restricted during late gestation.

ABSTRACT:

Background

Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese.

Methods/principal findings

Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1-65 days; LEE, n = 6) or late (65-128 days; LEL, n = 7) gestation (term approximately 147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6-7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were 'lean' (1.5 years). Obesity revealed generalised metabolic 'inflexibility' and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulin(AUC) (from 133 to 341 [s.e.d. 26] ng.ml(-1).120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml(-1)) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml(-1); LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism.

Conclusions

This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and 'reveals' programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young prenatally 'programmed' animals so long as weight is adequately controlled. Nutritional excess in adulthood exacerbates any programmed phenotype, indicating greater vigilance over weight control is required for those individuals exposed to nutritional thrift during gestation.

SUBMITTER: Rhodes P

PROVIDER: S-EPMC2756957 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundMaternal nutrient restriction during pregnancy causes a metabolic disorder that threatens the offspring's health in humans and animals. However, the molecular mechanism of how undernutrition affecting hepatic metabolism of fetal or postnatal offspring is still unclear. We aimed to investigate transcriptomic changes of fetal livers in response to maternal malnutrition in goats during mid-gestation and to explore whether these changes would disappear when the nutrition was recovered to normal level during mid-gestation using goats (Capra hircus) as the experimental animals.MethodsFifty-three pregnant goats were subjected to a control (100% of the maintenance requirements, CON) or a restricted (60% of the maintenance requirements on day 45 to day 100 of gestation and then realimentation, RES) diet. A total of 16 liver samples were collected from fetal goats on day 100 of gestation and goat kids of postnatal day 90 to obtain hepatic transcriptional profiles using RNA-Seq.ResultsPrincipal component analysis of the hepatic transcriptomes presented a clear separation by growth phase (fetus and kid) rather than treatment. Maternal undernutrition up-regulated 86 genes and down-regulated 76 genes in the fetal liver of the FR group as compared to the FC group. KEGG pathway analysis showed the DEGs mainly enriched in protein digestion and absorption, steroid biosynthesis, carbohydrate digestion and absorption and bile secretion. A total of 118 significant DEGs (fold change > 1.2 and FDR < 0.1) within KR vs. KC comparison was identified with 79 up-regulated genes and down-regulated 39 genes, and these DEGs mainly enriched in the biosynthesis of amino acids, citrate cycle, valine, leucine and isoleucine biosynthesis and carbon metabolism.ConclusionHepatic transcriptome analysis showed that maternal undernutrition promoted protein digestion and absorption in the fetal livers, while which restrained carbohydrate metabolism and citric acid cycle in the livers of kid goats after realimentation. The results indicate that maternal undernutrition during mid-gestation causes hepatic metabolism programming in kid goats on a molecular level.

Project description:Prenatal testosterone (T)-treated sheep, similar to polycystic ovarian syndrome women, manifest reduced cyclicity, functional hyperandrogenism, and polycystic ovary (PCO) morphology. The PCO morphology results from increased follicular recruitment and persistence of antral follicles, a consequence of reduced follicular growth and atresia, and is driven by cell-specific gene expression changes that are poorly understood. Therefore, using RNA sequencing, cell-specific transcriptional changes were assessed in laser capture microdissection isolated antral follicular granulosa and theca cells from age 21 months control and prenatal T-treated (100 mg intramuscular twice weekly from gestational day 30 to 90; term: 147 days) sheep. In controls, 3494 genes were differentially expressed between cell types with cell signaling, proliferation, extracellular matrix, immune, and tissue development genes enriched in theca; and mitochondrial, chromosomal, RNA, fatty acid, and cell cycle process genes enriched in granulosa cells. Prenatal T treatment 1) increased gene expression of transforming growth factor β receptor 1 and exosome component 9, and decreased BCL6 corepressor like 1, BCL9 like, and MAPK interacting serine/threonine kinase 2 in both cells, 2) induced differential expression of 92 genes that included increased mitochondrial, ribosome biogenesis, ribonucleoprotein, and ubiquitin, and decreased cell development and extracellular matrix-related pathways in granulosa cells, and 3) induced differential expression of 56 genes that included increased noncoding RNA processing, ribosome biogenesis, and mitochondrial matrix, and decreased transcription factor pathways in theca cells. These data indicate that follicular function is affected by genes involved in transforming growth factor signaling, extracellular matrix, mitochondria, epigenetics, and apoptosis both in a common as well as a cell-specific manner and suggest possible mechanistic pathways for prenatal T treatment-induced PCO morphology in sheep.