title: L-Citrulline Supplementation Enhances Fetal Growth and Protein Synthesis in Rats with Intrauterine Growth Restriction.
abstract: BACKGROUND
  Intrauterine growth restriction (IUGR) results from either maternal undernutrition or impaired placental blood flow, exposing offspring to increased perinatal mortality and a higher risk of metabolic syndrome and cardiovascular disease during adulthood. l-Citrulline is a precursor of l-arginine and nitric oxide (NO), which regulates placental blood flow. Moreover, l-citrulline stimulates protein synthesis in other models of undernutrition.
  
  
  OBJECTIVE
  The aim of the study was to determine whether l-citrulline supplementation would enhance fetal growth in a model of IUGR induced by maternal dietary protein restriction.
  
  
  METHODS
  Pregnant rats were fed either a control (20% protein) or a low-protein (LP; 4% protein) diet. LP dams were randomly allocated to drink tap water either as such or supplemented with l-citrulline (2 g · kg(-1) · d(-1)), an isonitrogenous amount of l-arginine, or nonessential l-amino acids (NEAAs). On day 21 of gestation, dams received a 2-h infusion of l-[1-(13)C]-valine until fetuses were extracted by cesarean delivery. Isotope enrichments were measured in free amino acids and fetal muscle, liver, and placenta protein by GC-mass spectrometry.
  
  
  RESULTS
  Fetal weight was ∼29% lower in the LP group (3.82 ± 0.06 g) than in the control group (5.41 ± 0.10 g) (P < 0.001). Regardless of supplementation, fetal weight remained below that of control fetuses. Yet, compared with the LP group, l-citrulline and l-arginine equally increased fetal weight to 4.15 ± 0.08 g (P < 0.05) and 4.13 ± 0.1 g (P < 0.05 compared with LP), respectively, whereas NEAA did not (4.05 ± 0.05 g; P = 0.07). Fetal muscle protein fractional synthesis rate was 35% lower in the LP fetuses (41% ± 11%/d) than in the control (61% ± 13%/d) fetuses (P < 0.001) and was normalized by l-citrulline (56% ± 4%/d; P < 0.05 compared with LP, NS compared with control) and not by other supplements. Urinary nitrite and nitrate excretion was lower in the LP group (6.4 ± 0.8 μmol/d) than in the control group (17.9 ± 1.1 μmol/d; P < 0.001) and increased in response to l-citrulline or l-arginine (12.1 ± 2.2 and 10.6 ± 0.9 μmol/d; P < 0.05), whereas they did not in the LP + NEAA group.
  
  
  CONCLUSIONS
  l-Citrulline increases fetal growth in a model of IUGR, and the effect may be mediated by enhanced fetal muscle protein synthesis and/or increased NO production.
authors: National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France;
authors: Aurélie
authors: A
authors: Bourdon
authors: National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France;
authors: Patricia
authors: P
authors: Parnet
authors: National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France; Department of Gynecology and Obstetrics, University Medical Center of Nantes, Nantes, France; and.
authors: Christel
authors: C
authors: Nowak
authors: National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France;
authors: Nhat-Thang
authors: NT
authors: Tran
authors: National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France; Department of Gynecology and Obstetrics, University Medical Center of Nantes, Nantes, France; and.
authors: Norbert
authors: N
authors: Winer
authors: National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France; Nutrition Support Team, IMAD, University Medical Center of Nantes, Nantes, France ddarmaun@chu-nantes.fr.
authors: Dominique
authors: D
authors: Darmaun
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D002956:Citrulline / Q000008:administration & dosage*; D018753:Diet, Protein-Restricted / Q000009:adverse effects; D019587:Dietary Supplements; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000188:drug therapy*; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D039382:Maternal Nutritional Physiological Phenomena; D009569:Nitric Oxide / Q000378:metabolism; D009752:Nutritional Status; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine
keywords: amino acids; developmental origins of health and disease; l-arginine; muscle; nitric oxide; obstetrics; perinatal nutrition; placenta; protein metabolism; stable isotopes