Maternal dietary citrulline supplementation increases fetal growth and programs pancreatic development in the lambs

Intrauterine growth restriction (IUGR), caused by maternal undernutrition, impairs fetal growth and increases the risk for postnatal metabolic dysfunction. L-arginine can mitigate these effects; however, its use in sheep is limited by ruminal microbial degradation. Interestingly, L-citrulline, the precursor for arginine synthesis, bypasses ruminal catabolism and may be a practical alternative. This study evaluated if maternal L-citrulline supplementation to nutrient restricted ewes from gestational days (GD) 28 to 140 (term = 147) enhances fetal growth in lambs. Gestating ewes were fed 50% of National Research Council (NRC) nutritional recommendations to induce IUGR and received either L-citrulline (0.40% of diet) or an isonitrogenous alanine control (0.61% of diet). Birth weight and pre-suckling blood samples were collected, and lambs remained with dams until postnatal day 60 (PND60) (citrulline: n = 13; alanine: n = 10). Lambs from L-citrulline treated ewes were heavier at birth (P = 0.05) and PND60 (P < 0.05), with greater (P < 0.05) absolute weights of the pancreas, brain, liver, and small intestine. Pancreatic mass per gram of body weight was greater (P < 0.05) in citrulline lambs. The relative proportion of endocrine and exocrine pancreas were not different between treatments. Circulating insulin concentrations were greater (P = 0.05) at birth and circulating glucose concentrations were increased (P < 0.05) in the citrulline lambs on PND60. These results suggest that maternal L-citrulline supplementation is a viable alternative to arginine for improving fetal growth during maternal malnutrition, with benefits persisting through weaning.