PPAR ligands improve impaired metabolic pathways in fetal hearts of diabetic rats

Abstract

In maternal diabetes, the fetal heart can be structurally and functionally affected. Maternal diets enriched in certain unsaturated fatty acids can activate the nuclear receptors peroxisome proliferator-activated receptors (PPARs) and regulate metabolic and anti-inflammatory pathways during development. Our aim was to investigate whether PPARa expression, lipid metabolism, lipoperoxidation, and nitric oxide (NO) production are altered in the fetal hearts of diabetic rats, and to analyze the putative effects of in vivo PPAR activation on these parameters. We found decreased PPARa expression in the hearts of male but not female fetuses of diabetic rats when compared with controls. Fetal treatments with the PPARa ligand leukotriene B 4 upregulated the expression of PPARa and target genes involved in fatty acid oxidation in the fetal hearts. Increased concentrations of triglycerides, cholesterol, and phospholipids were found in the hearts of fetuses of diabetic rats. Maternal treatments with diets supplemented with 6% olive oil or 6% safflower oil, enriched in unsaturated fatty acids that can activate PPARs, led to few changes in lipid concentrations, but up-regulated PPARa expression in fetal hearts. NO production, which was increased in the hearts of male and female fetuses in the diabetic group, and lipoperoxidation, which was increased in the hearts of male fetuses in the diabetic group, was reduced by the maternal treatments supplemented with safflower oil. In conclusion, impaired PPARa expression, altered lipid metabolism, and increased oxidative and nitridergic pathways were evidenced in hearts of fetuses of diabetic rats and were regulated in a genderdependent manner by treatments enriched with PPAR ligands. Key Words" diabetes in pregnancy " fetus " heart " nitric oxide " PPAR

Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction

“…Epidemiological studies demonstrate that circulating maternal triglyceride levels independently and temporally correlate with both fetal overgrowth and ventricular hypertrophy in offspring of diabetic mothers (1,19,33,53,56), which suggests a strong lipid-mediated influence. Although previous studies have reported individual effects of maternal diabetes or a HF diet on cardiovascular disease risk (7,13,14,33,35), our study adds evidence that a maternal HF diet in combination with diabetes is especially detrimental for the developing fetal heart. 5.…”

Intrauterine programming of lipid metabolic alterations in the heart of the offspring of diabetic rats is prevented by maternal diets enriched in olive oil

“…Sex differences in the intrauterine programming of metabolic and cardiovascular diseases have been observed in different experimental models of intrauterine growth restriction, obesity, and diabetes . Experimentally, we have previously demonstrated that diets enriched in 6% olive oil (highly enriched in oleic acid, an unsaturated fatty acid that activates PPARα) are able to regulate lipid‐metabolic pathways as well as oxidative and nitrative pathways in different fetal organs of diabetic rats, including the fetal heart . In this work, we hypothesize that maternal diabetes leads to gender‐dependent alterations in lipid metabolism in the heart of offspring from diabetic rats, and that these alterations are prevented by maternal diets enriched in 6% olive oil.…”

“…Damage in the offspring's heart has also been found in severe models of pregestational diabetes . In a pregestational but mild experimental model of diabetes, we have previously found that the fetus accumulates lipids in different fetal organs, including the liver, lung, and heart; organs in which the activation of PPARα regulates the expression of genes involved in lipid metabolism . This mild diabetic model is neonatally induced by streptozotocin, has been thoroughly characterized during pregnancy, and is particularly relevant as its glycemia ranging 150–230 mg/dL resembles the levels of glycemia often seen in human diabetic pregnancies .…”

“…On this day, both control and diabetic animals were randomized into two different groups: (Group 1) Animals fed with a standard diet ( n = 8 control mothers and n = 8 diabetic mothers), and (Group 2) animals fed until parturition with a standard diet supplemented with 6% olive oil (a supplemented diet that is 354% enriched in oleic acid, a PPAR activator, when compared to the standard diet; n = 8 control mothers and n = 8 diabetic mothers). The composition of the diets was as follows: (i) standard diet (g/100g): proteins (25); carbohydrates (50); fat (5); major fatty acids 16:0 (0.58), 18:0 (0.16), 18:1 (1.27), 18:2 (1.99), 18:3 (0.73) and (ii) olive oil supplemented diet (g/100g): proteins (24); carbohydrates (48); fat (11); major fatty acids 16:0 (1.55), 18:0 (0.26), 18:1 (5.77), 18:2 (2.41), 18:3 (0.57) . Food intake did not change in the control and diabetic olive oil supplemented groups when respectively compared to the control and diabetic nonsupplemented groups (control: 66 ± 3 g/kg/day, control supplemented with olive oil: 67.5 ± 2.5 g/kg/day, diabetic: 76.6 ± 3.5 g/kg/day ( p < 0.05 versus control), and diabetic supplemented with olive oil: 72.5 ± 2.7 g/kg/day).…”

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

“…PPAR␥ activation resulted in suppression of placental NO levels (62). Furthermore, in rat offspring exposed to maternal diabetes, PPAR ligands beneficially modulated lipid composition and metabolic enzyme expression in lungs and led to a reduction in NO production and lipoperoxidation in hearts (78,79).…”