EXCESS FETAL ADIPOSITY IS ASSOCIATED WITH PROGRAMMING OF PLACENTAL LIPID GENES

EXCESS FETAL ADIPOSITY IS

ASSOCIATED WITH PROGRAMMING OF PLACENTAL LIPID GENES

Tatjana Radaelli

, Ali Varastehpour

, Patrick Catalano

, Sylvie Hauguel-de Mouzon

1

Dept of Obstetrics and Gynecology ‘L.Magiagalli’, University of Milan, Milan, Italy,

2

Dept of Reproductive Biology, CWRU at

2

MetroHealth Medical Center, Cleveland,

Ohio, US

Introduction. Increased adiposity in fetuses of women with abnormal glucose tolerance has been associated with an increased risk to develop obesity and type-2 diabetes in later life. Maternal anthropometric and metabolic parameters can explain only part of the fetal fat mass variance, suggesting that other factors may be involved. As the primary interface between maternal and fetal circulation, the placenta is a major determinant of nutrient flux from mother to fetus. However the role of placental genes in controlling nutrient availability has not been widely studied. Knowledge is even more limited in understanding diabetes-induced modifications of placental functions. To gain insight into the molecular mechanisms that alter placental metabolic pathways, we have constructed the gene expression profile of placenta from women with normal glucose tolerance and with gestational diabetes (GDM).

Methods. Global gene screening was performed by oligonucleotide microarray analysis (Human U133 Affymetrix) of placenta obtained at term from lean controls, obese controls and women with gestational diabetes (GDM).

Anthropometric data were obtained in the neonates within 48 hours from the delicery; neonatal body composition was estimated by total body electrical conductivity (TOBEC) and macrosomia was defined as % body fat > 14.

Results. A four-step selection criteria was applied to identify significantly modified genes in relation to fetal macrosomia. 136 genes encoding proteins for glucose and lipid metabolism were expressed in normal placenta. 38.2 % of these genes were significantly regulated in placenta of macrosomic neonates d from GDM patients and only 5.1 % were modified in placenta of macrosomic neonates from obese women. In GDM, about half of the regulated genes were t related to lipid metabolism, primarily encoding rate-limiting enzymes for fatty acid transport, triglycerides and cholesterol synthesis. Genes for leptin and leptin receptor were also up-regulated while lipoprotein lipase and NPY receptor were the only genes down-regulated in the lipid cluster. Despite the diabetic milieu, no genes were modified in relation to glucose transport but, the expression of glycogenin 2, a self initiator of glycogen synthesis was increased.

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Conclusion. Using microarray technology we have identified major modifications of gene profiles in placentas of macrosomic fetuses of GDM mothers. These genes do not control glucose but primarily lipid metabolism pointing to a placental programming of lipid genes. We propose that the increase in placental lipid biosynthetic pathways have functional significance for fetal fat accretion as a step towards enhanced placental transfer of FFA.

Key words: fetal body composition; gestational diabetes; lipid metabolism, gene chips.