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male LPE when obese but not when lean (unpublished results).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.