Impact of PPAR natural agonists on the prevention of diabetic embryopathy

JAWERBAUM A

Buenos Aires

Congreso; ISPAD 2010; 2010

International Society for Pediatric and Adolescent Diabetes

Impact of PPAR natural agonists on the prevention of diabetic embryopathy: Maternal diabetes increases the risks of embryo malformations, and disturbs feto-placental development and growth. The increased metabolic substrates that reach the intrauterine compartment lead to a proinflammatory state evident in the embryo, the fetus and the placenta. Increased reactive oxygen species lead to a loss of essential fatty acids (EFAs), which are highly susceptible to peroxidation. EFAs have important functions as signaling molecules in embryo development. Arachidonic acid is the substrate for the synthesis of prostaglandin (PG) E2, highly needed in the process of neural tube closure. In addition, EFAs are ligands of peroxisome proliferators activated receptors (PPARs), and substrates for the synthesis of PGI2, 15deoxyD12,14PGJ2 and leukotriene B4, respective ligands of PPARd, PPARg and PPARa. PPARs are ligand activated transcription factors that regulate metabolic and anti-inflammatory pathways. Maternal diabetes alters the concentrations of PPARs and their endogenous ligands in embryos and placentas. By studying experimental models of diabetes and pregnancy, we found that PPARd is highly involved in the embryonic process of closure of the neural tube, PPARg mediates anti-inflammatory pathways in fetuses and placentas, and PPARa regulates feto-placental lipid metabolism. Interestingly, in pregnant diabetic rats, activation of the three PPAR isotypes with natural PPAR ligands regulates the synthesis of PGs and phospholipids needed in neural tube closure and reduces embryo resorptions and malformations. Besides, dietary activation of PPARs regulates lipid metabolic pathways and reduces matrix metalloproteinases overactivity in the placenta and prevents lipid accretion and reduces lipid peroxidation in the fetus. Summary: Maternal diabetes increases the risks of embryo malformations, and disturbs feto-placental development and growth. The increased metabolic substrates that reach the intrauterine compartment lead to a proinflammatory state evident in the embryo, the fetus and the placenta. Increased reactive oxygen species lead to a loss of essential fatty acids (EFAs), which are highly susceptible to peroxidation. EFAs have important functions as signaling molecules in embryo development. Arachidonic acid is the substrate for the synthesis of prostaglandin (PG) E2, highly needed in the process of neural tube closure. In addition, EFAs are ligands of peroxisome proliferators activated receptors (PPARs), and substrates for the synthesis of PGI2, 15deoxyD12,14PGJ2 and leukotriene B4, respective ligands of PPARd, PPARg and PPARa. PPARs are ligand activated transcription factors that regulate metabolic and anti-inflammatory pathways. Maternal diabetes alters the concentrations of PPARs and their endogenous ligands in embryos and placentas. By studying experimental models of diabetes and pregnancy, we found that PPARd is highly involved in the embryonic process of closure of the neural tube, PPARg mediates anti-inflammatory pathways in fetuses and placentas, and PPARa regulates feto-placental lipid metabolism. Interestingly, in pregnant diabetic rats, activation of the three PPAR isotypes with natural PPAR ligands regulates the synthesis of PGs and phospholipids needed in neural tube closure and reduces embryo resorptions and malformations. Besides, dietary activation of PPARs regulates lipid metabolic pathways and reduces matrix metalloproteinases overactivity in the placenta and prevents lipid accretion and reduces lipid peroxidation in the fetus. In conclusion, in maternal diabetes, dietary supplementation with natural PPAR ligands can help to prevent embryo dysmorphogenesis and loss, as well as to regulate proinflammatory and metabolic pathways during feto-placental development.