Pre-natal undernutrition and post-natal overnutrition are associated with permanent changes in hepatic metabolism markers and fatty acid composition in sheep

AIM: Determine the impacts of pre- and early-post-natal nutrition on selected markers of hepatic glucose and fat metabolism.

METHODS: Twin-bearing ewes were fed 100% (NORM) or 50% (LOW) of protein and energy requirements during the last 6-weeks of gestation. Twin-lambs received either a high-carbohydrate high-fat (HCHF) or conventional (CONV) diet from 3 days to 6 months of age (around puberty), whereafter lambs from the four subgroups were slaughtered (16 males/3 females). Remaining lambs (19 females) were fed a moderate diet and slaughtered at 2 years of age (young adults).

RESULTS: Pre-natal LOW nutrition was associated with increased hepatic triglyceride, ceramide and free fatty acid content in adulthood (not observed in lambs), which was accompanied by up-regulated early-stage insulin signalling as reflected by increased INSRβ and PI3K-p110 protein expression. The HCHF diet increased hepatic triglyceride content in lambs, associated with down-regulated expressions of energy-metabolism-related genes (GLUT1, PPARα, SREBP1c, PEPCK). These post-natal effects were not observed in adult HCHF sheep, after they had received a moderate (body-fat correcting) diet for 1.5 years. Interestingly, pre-natal LOW nutrition induced permanent alterations in hepatic phospholipids' fatty acid composition. Thus, the amount of linoleic acid (C18 : 2 ∆(9,12)) was significantly increased and composition of rumen-derived fatty acids were altered, indicating changed composition of rumenal microbiota.

CONCLUSION: Hepatic insulin signalling and linoleic and microbial-derived fatty acid content in phospholipids are targets of foetal programming induced by late-gestation undernutrition. Future studies are required to explain their cause-effect associations with increased risks of developing hepatic steatosis and insulin insensitivity in adulthood.