title: Maternal Calorie Restriction Causing Uteroplacental Insufficiency Differentially Affects Mammalian Placental Glucose and Leucine Transport Molecular Mechanisms.
abstract: We examined the effect of mild (Mi; ∼25%) and moderate (Mo; ∼50%) maternal calorie restriction (MCR) vs ad libitum-fed controls on placental glucose and leucine transport impacting fetal growth potential. We observed in MiMCR a compensatory increase in transplacental (TP) glucose transport due to increased placental glucose transporter isoform (GLUT)-3 but no change in GLUT1 protein concentrations. This change was paralleled by increased glut3 mRNA and 5-hydroxymethylated cytosines with enhanced recruitment of histone 3 lysine demethylase to the glut3 gene locus. To assess the biologic relevance of placental GLUT1, we also examined glut1 heterozygous null vs wild-type mice and observed no difference in placental GLUT3 and TP or intraplacental glucose and leucine transport. Both MCR states led to a graded decrease in TP and intraplacental leucine transport, with a decline in placental L amino acid transporter isoform 2 (LAT2) concentrations and increased microRNA-149 (targets LAT2) and microRNA-122 (targets GLUT3) expression in MoMCR alone. These changes were accompanied by a step-wise reduction in uterine and umbilical artery Doppler blood flow with decreased fetal left ventricular ejection fraction and fractional shortening. We conclude that MiMCR transactivates placental GLUT3 toward preserving TP glucose transport in the face of reduced leucine transport. This contrasts MoMCR in which a reduction in placental GLUT3 mediated glucose transport with a reciprocal increase in miR-122 expression was encountered. A posttranscriptional reduction in LAT2-mediated leucine transport also occurred with enhanced miR-149 expression. Both MCR states, although not affecting placental GLUT1, resulted in uteroplacental insufficiency and fetal growth restriction with compromised cardiovascular health.
authors: Department of Pediatrics (A.G., M.T., S.T., S.U.D.), Division of Neonatology and Developmental Biology, and Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; and Department of Neurology (D.C.D.V.), Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors: Amit
authors: A
authors: Ganguly
authors: Department of Pediatrics (A.G., M.T., S.T., S.U.D.), Division of Neonatology and Developmental Biology, and Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; and Department of Neurology (D.C.D.V.), Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors: Marlin
authors: M
authors: Touma
authors: Department of Pediatrics (A.G., M.T., S.T., S.U.D.), Division of Neonatology and Developmental Biology, and Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; and Department of Neurology (D.C.D.V.), Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors: Shanthie
authors: S
authors: Thamotharan
authors: Department of Pediatrics (A.G., M.T., S.T., S.U.D.), Division of Neonatology and Developmental Biology, and Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; and Department of Neurology (D.C.D.V.), Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors: Darryl C
authors: DC
authors: De Vivo
authors: Department of Pediatrics (A.G., M.T., S.T., S.U.D.), Division of Neonatology and Developmental Biology, and Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; and Department of Neurology (D.C.D.V.), Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors: Sherin U
authors: SU
authors: Devaskar
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction / Q000009:adverse effects*; D047108:Embryonic Development; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000378:metabolism; D027301:Fusion Regulatory Protein 1, Light Chains / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D021041:Placental Circulation; D010927:Placental Insufficiency / Q000209:etiology* / Q000378:metabolism; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena
chemical_list: D027182:Amino Acid Transport System y+; D027301:Fusion Regulatory Protein 1, Light Chains; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; C518286:SLC7A8 protein, mouse; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse; D007930:Leucine; D005947:Glucose