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

Determine the impacts of pre‐ and early‐post‐natal nutrition on selected markers of hepatic glucose and fat metabolism. 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). 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. 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.