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

Martínez, Nora; White, Verónica; Kurtz, M.; Higa, Romina; Capobianco, Evangelina; Jawerbaum, Alicia

doi:10.1002/dmrr.1151

Cited by 34 publications

(37 citation statements)

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“…The neonatal-induced streptozotocin-model of diabetes in the rat has been widely employed (14,15). We have characterized a neonatal streptozotocin-induced mild diabetic model during pregnancy in our laboratory and have demonstrated metabolic derangements and a pro-oxidative and pro-inflammatory intrauterine environment, which alters the embryo, the fetus and the placenta during their development (15,16). This model has maternal glycemia levels of 150-250 mg/dl and, thus, resembles the levels of hyperglycemia frequently seen in human diabetic pregnancies.…”

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confidence: 99%

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

et al. 2014

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Background: Diabetes in pregnancy affects fetal growth and development. The insulin/insulin-like growth factors (IGF) system comprising insulin, IGF, their receptors, and binding proteins, has been implicated in fetal growth regulation. This study tested the hypothesis that maternal diabetes alters the fetal insulin/IGF system in a tissue-specific manner. Methods: Wistar rats were rendered diabetic by neonatal administration of streptozotocin and mated with control rats. At day 21 of gestation, the weights of fetuses, placentas, and fetal organs (heart, lung, liver, stomach, intestine, and pancreas) were determined. Maternal and fetal plasma concentrations of insulin, IGF1, and IGF2 were measured by ELISA, and expression of IGF1, IGF2, IGF1R, IGF2R, IR, IGFBP1, BP2, and BP3 in placenta and fetal organs by qPCR. results: The well-known increase in fetal growth in this model of mild diabetes is accompanied by elevated insulin and IGF1 levels and alterations of the insulin/IGF system in the fetus and the placenta. These alterations were organ and gene specific. The insulin/IGF system was generally upregulated, especially in the fetal heart, while it was downregulated in fetal lung. conclusion: In our model of mild diabetes, the effect of maternal diabetes on fetal weight and fetal insulin/IGF system expression is organ specific with highly sensitive organs such as lung and heart, and organs that were less affected, such as stomach. d iabetes in pregnancy, i.e., the fetal exposure to hyperglycemia in utero, has become recognized as a risk factor for immediate adverse pregnancy outcome, and in having longterm effects on mother and offspring. Immediate outcomes include excessive fetal fat accretion as well as congenital malformations, such as cardiac, musco-skeletal, and central nervous system anomalies (1,2). Early evidence in Pima Indians and in animal models has clearly shown that long-term effects of growing in a diabetic environment in utero include a higher risk for the offspring to develop obesity, type 2 diabetes (T2D), the metabolic syndrome, and cardiovascular disease later in life (3). This was confirmed in further studies in which offspring from diabetic pregnancies were followed up into adolescence (4).One of the well-known effects of the diabetic environment on the offspring is its growth promoting action as reflected by weight increases of the fetus proper and of some fetal tissues (5,6). The insulin/IGF system is a potent regulator of development and growth, and elevated levels of cord blood insulin can be regarded as hallmark of fetal changes in the wake of maternal diabetes (7,8). This system comprises insulin, the insulin-like growth factors-1 (IGF1) and -2 (IGF2), the receptors for insulin (IR), IGF1 (IGF1R) and IGF2 (IGF2R) as well as a range of binding proteins (IGFBP1-6) for both IGFs, which regulate IGF bioavailability by modulating the half-life of IGFs and their site of action (9). Only a small proportion of IGFs circulates in a free form, the bulk is bound to IGFbinding proteins (IGFBPs). Am...

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

et al. 2014

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“…To induce diabetes, at 2 days of age, neonates were injected with streptozotocin (90 mg/kg, s.c., Sigma-Aldrich) diluted in citrate buffer (0.05 M, pH 4.5, Sigma-Aldrich), as previously described (Jawerbaum & White 2010, Martinez et al 2011a. The control animals were injected with citrate buffer alone.…”

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confidence: 99%

“…Lipid content was determined by thin layer chromatography, as described previously (Martinez et al 2011a). Briefly, hearts from three female or three male fetuses from each rat were pooled and homogenized (nZ9 rats in each experimental group) in 500 ml PBS and protein content in the homogenates was measured by the Bradford assay.…”

Section: Analysis Of Lipid Contentmentioning

confidence: 99%

“…Lipoperoxidation was assessed as described previously (Martinez et al 2011a), by measuring the concentrations of thiobarbituric acid reactive substances (TBARS), a method widely used to assess peroxidation of fatty acids (Ohkawa et al 1979). Briefly, hearts from two female or two male fetuses from each rat were pooled and homogenized (nZ9 rats in each experimental group) in 100 mM Tris-HCl buffer (0.1 mM, pH 7.4).…”

Section: Analysis Of Lipoperoxidationmentioning

confidence: 99%

“…In previous studies, in a mild diabetic rat model during pregnancy we have evaluated and found alterations in PPARa expression and signaling in different fetal organs such as the liver and the lungs (Jawerbaum & White 2010, Martinez et al 2011a). In the current study, we used the same diabetic rat model to address whether the fetal heart has altered expression of PPARa and lipid-oxidizing enzymes, lipid content, nitric oxide (NO) production, and lipid peroxidation.…”

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

Kurtz¹,

Capobianco²,

Martínez³

et al. 2014

Journal of Molecular Endocrinology

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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

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

Capobianco

Pelesson

Careaga

et al. 2015

Molecular Nutrition Food Res

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

Abstract: PPARα activation regulates the impaired foetal liver lipid metabolism, prevents hepatomegaly and reduces foetal overgrowth induced by maternal diabetes.

Cited by 34 publications

References 68 publications

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

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

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

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

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