Peroxisome proliferator-activated receptor α activation regulates lipid metabolism in the feto-placental unit from diabetic rats

Abstract

Maternal diabetes promotes an overaccumulation of lipids in the feto-placental unit and impairs feto-placental development and growth. Here, we investigated the role played by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)a in lipid metabolism in fetuses and placentas from control and neonatal streptozotocin-induced diabetic rats. Placentas and fetuses were studied on day 13.5 of gestation. The concentrations of PPARa (by Western blot) and its endogenous agonist leukotriene B 4 (LTB 4 ) (by enzyme immunoassay) were analysed. Placental explants and fetuses were cultured with LTB 4 or clofibrate, and then lipid metabolism analysed (concentrations and synthesis from 14 C-acetate of triglycerides, phospholipids, cholesterol and cholesteryl esters; release of glycerol and free fatty acids (FFAs)).We found that maternal diabetes led to increases in placental concentrations of triglycerides and cholesteryl esters, and fetal concentrations of phospholipids. PPARa agonists downregulated fetal and placental lipid concentrations in control and diabetic rats. The synthesis of lipids was reduced in the diabetic placenta but increased in fetuses from diabetic animals. PPARa agonists reduced the synthesis of lipids in control placenta and in the fetuses from control and diabetic rats. Glycerol and FFA release was enhanced in the diabetic placenta and in control placenta cultured with PPARa agonists. Maternal diabetes led to reductions in fetal and placental LTB 4 concentrations and to increases in placental PPARa concentrations. Overall, these data support a novel role of PPARa as a regulator of lipid metabolism in the fetoplacental unit, relevant in maternal diabetes where fetal and placental PPARa, LTB 4 and lipid concentrations are altered.Reproduction (2008) 136 95-103

Activation of the nuclear receptor PPARα regulates lipid metabolism in foetal liver from diabetic rats: implications in diabetes‐induced foetal overgrowth

“…• C for PPARα determination or incubated for 3 h as previously [35] in a metabolic shaker under an atmosphere of 5% CO 2 and 95% O 2 at 37 • C, with or without the addition of either LTB 4 (0.1 µM) or clofibrate (20 µM). Thereafter, tissues were frozen at −80…”

“…PPARα concentrations were determined by Western blot, as previously [35]. Foetal liver tissues (100 mg) were homogenized in 300-µL ice-cold lysis buffer (pH 7.4, 20 mM Tris-HCl, 150 mM NaCl, 1% Triton-X-100) containing 1% protease inhibitor cocktail and then incubated on ice for 2 h. Tissues were centrifuged at 9600 g for 10 min at 4…”

Diabetes-associated changes in the fetal insulin/insulin-like growth factor system are organ specific in rats

“…This model has maternal glycemia levels of 150-250 mg/dl and, thus, resembles the levels of hyperglycemia frequently seen in human diabetic pregnancies. Moreover, the model is characterized by impaired maternal glucose and lipid metabolism, as well as placentomegalia and fetal macrosomia (17), typical outcomes of diabetic pregnancies in human (1,18) and is therefore a good model representing diabetes in humans and for studying the regulation of feto-placental growth.…”

The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development

“…42 for review). Contrary to Pparg and Ppard null mice, placental developmental abnormalities were not evident in Ppara null mice, showing that PPAR␣ does not play an essential role in placental development (90,150). However, PPAR␣ functions as a regulator of lipid metabolism, lipid peroxidation, and nitric oxide production in term rat placenta (Table 1) (91).…”