Adult-Onset Obesity Reveals Prenatal Programming of Glucose-Insulin Sensitivity in Male Sheep Nutrient Restricted during Late Gestation

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

A low protein diet during early gestation in sheep detrimentally impacts hepatic glucose metabolism in the adult offspring

Differences in maternal diet can account for variation in the metabolic competence of the subsequent individual as an adult. ‘Developmental programming’ may impair fetal organ development leading to a limitation in function as an adult and/or increase the rate of age-related organ decline for example under conditions of obesity. Here, we have tested the interaction between prenatal nutritional ‘thrift’ and postnatal nutritional excess on gluco-regulatory functions in an ovine model. Seventy-four Scottish Blackface ewes were randomly assigned to receive either a control protein diet with adequate energy (18% protein; CP, n 20) or low protein diet (9% protein) fed during early gestation (0–65 d, term ~147 d; LPE, n 37) or late gestation (65–147 d; LPL, n 17). At 65 d a proportion of ewes was euthanised for fetal sampling. At term, remaining ewes lambed naturally, were weaned at 10 weeks and a random sample of offspring studied longitudinally when lean (1.5 years of age) and after 6 months exposure to an obesogenic environment. Body composition was determined by dual-energy absorptiometry and glucose and insulin tolerance tests were conducted with appropriate sampling intervals. At post mortem, muscle and hepatic tissues were sampled for expression and abundance of relevant gluco-regulatory genes. The diets had little effect on maternal weight and body composition through gestation or on fetal weights at 65 d. Term weight was reduced by ~500 g (P = 0.001) in LPL v. other groups but, by weaning, body weight was similar between groups and growth rate to adulthood was not different. Homeostasis model assessment of baseline glucose and insulin concentrations indicated relative insulin resistance in male LPE . Indeed, when challenged with a GTT, the incremental insulin AUC was significantly greater in male LPE when obese but not when lean (unpublished results). Molecular quantification of glucose-insulin pathways in muscle and liver indicated specific down-regulation of the hepatic insulin, but not lipid, pathways in male liver only. Muscle insulin-signalling pathways were unaffected as determined by microarray (Affymetrix, U133 chip; www.arraymining.net). The data suggest that a maternal, low protein, diet during early gestation specifically impacts upon the function of the resulting adult liver, such that the offspring appear more susceptible to large excursions in plasma insulin during gluco-regulatory challenges. The insulin sensitivity of offspring muscle, the largest single source of insulin-stimulated glucose uptake, was largely unaffected. Thus, obesity appears to exacerbate any functional deficits inherent in low protein exposed offspring in sheep, but those offspring born of low birth weight were largely unaffected, illustrating that nutritional quality is far more important than nutritional quantity especially during sensitive developmental phases of growth

DNA replication checkpoint promotes G1-S transcription by inactivating the MBF repressor Nrm1

The cell cycle transcriptional program imposes order on events of the cell-cycle and is a target for signals that regulate cell-cycle progression, including checkpoints required to maintain genome integrity. Neither the mechanism nor functional significance of checkpoint regulation of the cell-cycle transcription program are established. We show that Nrm1, an MBF-specific transcriptional repressor acting at the transition from G1 to S phase of the cell cycle, is at the nexus between the cell cycle transcriptional program and the DNA replication checkpoint in fission yeast. Phosphorylation of Nrm1 by the Cds1 (Chk2) checkpoint protein kinase, which is activated in response to DNA replication stress, promotes its dissociation from the MBF transcription factor. This leads to the expression of genes encoding components that function in DNA replication and repair pathways important for cell survival in response to arrested DNA replication