| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RESEARCH |
activation regulates lipid metabolism in the feto-placental unit from diabetic ratsLaboratory of Reproduction and Metabolism, CEFYBO-CONICET-UBA, School of Medicine, University of Buenos Aires, Paraguay 2155, 17th floor, C1121ABG Buenos Aires, Argentina
Correspondence should be addressed to A Jawerbaum; Email: a.jawerbaum{at}abaconet.com.ar
 |
Abstract |
|---|
 Top Abstract IntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
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 PPAR (by Western blot) and its endogenous agonist leukotriene B4 (LTB4) (by enzyme immunoassay) were analysed. Placental explants and fetuses were cultured with LTB4 or clofibrate, and then lipid metabolism analysed (concentrations and synthesis from 14C-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. PPAR 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. PPAR 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 PPAR agonists. Maternal diabetes led to reductions in fetal and placental LTB4 concentrations and to increases in placental PPAR concentrations. Overall, these data support a novel role of PPAR as a regulator of lipid metabolism in the feto-placental unit, relevant in maternal diabetes where fetal and placental PPAR, LTB4 and lipid concentrations are altered. |
Introduction |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
Peroxisome proliferator-activated receptors (PPARs) are crucial nuclear receptors controlling transcription of a variety of genes involved in lipid metabolism and cellular differentiation (Desvergne et al. 2006). Three isoforms named PPAR, PPARβ/
and PPAR
, which exhibit different ligand specificities, functions and tissue distribution, have been identified in several tissues, including the placenta (Braissant & Wahli 1998, Fournier et al. 2007).
Both PPAR and PPARβ/ have essential roles in placental development, and their inactivation induces severe trophoblast differentiation defects that lead to fetal mortality after midgestation (Barak et al. 1999, 2002). However, although PPAR- null mice do not show placental developmental abnormalities, an increased abortion and neonatal mortality rate is observed in these mice, suggesting that PPAR may be involved in mother-to-fetus nutrient exchange (Peraza et al. 2006, Yessoufou et al. 2006). PPAR is mainly expressed in metabolically active tissues including the liver, heart and skeletal muscle, and is crucial in the regulation of lipid catabolism (Desvergne et al. 2006, Lefebvre et al. 2006). Also, PPAR is highly expressed both in the labyrinth and junctional zones of the rat placenta, and in human villous trophoblasts (Wang et al. 2002). In rat fetuses, PPAR transcripts are found from day 13 of gestation, and expressed in several tissues including the nervous system, digestive track, liver and heart (Braissant & Wahli 1998).
Fibrates are PPAR pharmacological agonists that efficiently lower triglyceridaemia in experimental models of obesity and diabetes, as well as in patients with hyperlipidaemia (Watts & Dimmitt 1999, Desvergne et al. 2004). PPAR endogenous ligands are lipophylic molecules such as long-chain polyunsaturated fatty acids and the eicosanoid leukotriene B4 (LTB4), which is synthesised in placenta and fetuses through the activity of lipoxygenases (Lin et al. 1999, Xu et al. 2007). Treatment of rats with pharmacological PPAR activators during pregnancy causes proliferation of peroxisomes and induction of peroxisomal enzyme activities in both maternal and fetal livers (Cibelli et al. 1988, Peraza et al. 2006). Reduction in maternal hypertriglyceridaemia has been found when rats are treated with fibrates during the whole pregnancy but not when treated only at term (Soria et al. 2002, Ringseis et al. 2007). These results suggest that PPAR is involved in the regulation of maternal lipid metabolism; however, direct effects of PPAR activation in lipid metabolism in the fetus and the placenta have not been reported yet and may be relevant in maternal diabetes.
We have previously characterised several embryonic and placental alterations in a mild experimental rat model of diabetes induced by neonatal administration of streptozotocin (Jawerbaum & Gonzalez 2006). In embryos and placentas from these diabetic rats, there are alterations in lipid metabolism, as well as in the protein expression of PPARβ/ and PPAR, PPAR isoforms that have specific regulatory roles in embryonic and placental lipid metabolism (Capobianco et al. 2005, Higa et al. 2007).
The aim of the present study was to evaluate whether PPAR agonists regulate lipid metabolism in the feto-placental unit from control and diabetic rats after placentation. In addition, we analysed whether maternal diabetes alters the protein expression of PPAR and the levels of LTB4, its endogenous agonist, in both fetuses and placentas.
|
Results |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
agonist LTB4 and the protein expression of PPAR were analysed in placentas and fetuses from control and diabetic rats on day 13.5 of gestation. LTB4 concentrations were reduced in both the placentas and the fetuses from diabetic animals when compared with controls (Table 1). PPAR protein expression was enhanced in the placenta from diabetic rats in comparison with controls, while there were no changes in PPAR concentrations in the fetuses from diabetic animals when compared with controls (Fig. 1).
|
|
agonists on placental and fetal lipid concentrations agonists LTB4 (0.1 µM) or clofibrate (20 µM), and placental and fetal lipid concentrations were analysed. We found an increase in triglycerides and cholesteryl esters, but no differences in the levels of phospholipids and cholesterol in the placenta from diabetic animals when compared with controls without additions (Fig. 2).
|
agonists was analysed in the placenta from control and diabetic rats, we found that the pharmacological agonist clofibrate led to a reduction in all lipid species analysed in diabetic tissues and to a reduction in the levels of triglycerides, phospholipids and cholesteryl esters in control tissues (Fig. 2). On the other hand, although the endogenous agonist LTB4 did not significantly change any lipid species analysed in the placenta from control rats, in the placenta from diabetic rats LTB4 specifically reduced the concentrations of phospholipids and cholesterol, those lipid species that were not overaccumulated in these tissues (Fig. 2).
When lipid mass was analysed in the fetuses (Fig. 3), we found that phospholipids were the lipid species overaccumulated in the fetuses from diabetic animals, whereas no changes in the concentrations of triglycerides, cholesteryl esters and cholesterol were found when fetuses from diabetic rats were compared with controls. When the effects of PPAR agonists were analysed in the fetuses from control and diabetic rats, we found that both clofibrate and LTB4 had similar effects, and were able to reduce the concentrations of triglycerides, cholesteryl esters and cholesterol in the fetuses from both the control and diabetic animals. In contrast, neither clofibrate nor LTB4 was able to modify the concentrations of phospholipids, the only lipid species that was overaccumulated in the fetuses from diabetic animals (Fig. 3).
|
agonists on placental and fetal lipid syntheses agonists on the de novo lipid synthesis was analysed in the placenta from control rats (Fig. 4), a reduction in the synthesis of triglycerides, cholesteryl esters and cholesterol was found in the presence of LTB4, while the synthesis of all lipid species analysed was decreased in the presence of clofibrate. In contrast, there were no effects of either LTB4 or clofibrate on the synthesis of the lipids analysed in the placenta from diabetic rats, which showed reduced de novo synthesis of all lipid species studied when compared with controls (Fig. 4).
|
|
agonists on placental release of glycerol and FFAs agonists, glycerol and FFAs were analysed in the media where placentas and fetuses from control and diabetic rats on day 13.5 of gestation were cultured for 3 h in the presence or absence of the PPAR agonists studied. Glycerol and FFAs were below the limit of detection of the employed techniques in the culture media of the fetuses. When the effects of PPAR agonists on glycerol and FFA release were analysed in the placenta from control rats, we found an increase in glycerol and FFA concentrations in the presence of LTB4 and clofibrate, when compared with the controls without additions (Fig. 6). In contrast, PPAR agonists were devoid of effect in the placenta from diabetic animals, in which both glycerol and FFA concentrations were increased when compared with controls (Fig. 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
as a regulator of lipid metabolism in the fetuses and placentas from healthy and diabetic rats. PPAR agonists lead to a reduction in the concentrations of several lipid species in the fetuses and the placenta as a result of their effects on both lipid catabolism and lipid synthesis. The observed effects of PPAR agonists may contribute to the understanding of the impairments in lipid metabolism in fetuses and placentas from diabetic rats, which showed alterations in the concentrations of PPAR and its endogenous agonist LTB4.
We found that LTB4 production was reduced in the placenta and the fetuses from diabetic animals, an alteration that may impair feto-placental development and growth. Consistent with this hypothesis, murine pregnancies predisposed to spontaneous abortion have reduced LTB4 levels in the feto-placental unit (Gendron et al. 1992). Interestingly, increased abortion and neonatal mortality rates have also been observed in control and diabetic Ppara- null mice, in which an altered balance in Th1/Th2 cytokine response is observed (Yessoufou et al. 2006). On the other hand, mice that overexpress PPAR show defects in cardiac development and metabolism (Finck et al. 2002), and fetuses from rats treated with fibrates do not show malformations but present metabolic alterations (Soria et al. 2002, Peraza et al. 2006), suggesting that proper concentrations of PPAR and their ligands are needed for a proper development and growth. In this work, we found that PPAR concentrations were similar in fetuses from control and diabetic rats, but were increased in the placenta from diabetic animals, an alteration that may be related to a disregulated lipid utilisation in the feto-placental unit.
Alterations in the feto-placental lipid metabolism associated with maternal diabetes depend on the type and severity of the diabetic condition, and also on the developmental stage (Desoye & Shafrir 1996, Grissa et al. 2007). We have previously shown that during early organogenesis lipid synthesis is decreased in embryos from mild and severe diabetic rats whereas triglycerides are overaccumulated in embryos obtained from severe diabetic rats (Jawerbaum et al. 2002, Sinner et al. 2003). However, in this work, we identified phospholipids as the lipid species overaccumulated in the fetuses from mild diabetic rats on day 13.5 of gestation, together with an increase in the de novo lipid synthesis that is likely to contribute to the increased fetal lipid mass. These differences probably reflect developmental changes occurring after mid-pregnancy in the rat, when the efficient mother-to-fetus nutrient exchange through the chorioallantoic placenta is initiated (Ain et al. 2003).
On the other hand, overaccumulation of triglycerides and cholesteryl esters was found in the diabetic placenta, despite the compensatory reduction in the de novo lipid synthesis observed. Our previous studies performed in term placenta in the same diabetic model have shown reductions in the de novo lipid synthesis but no changes in lipid mass, supporting the concept that the capacity of accretion of lipids in the placenta depends on the developmental stage, and is reduced at term (Capobianco et al. 2005).
There is little evidence of PPAR-mediated regulation of lipid metabolism in the placenta (Xu et al. 2007). PPAR has been found to regulate uptake of FFAs, formation of lipid droplets and the de novo lipid synthesis in rat trophoblasts and placental tissues (Capobianco et al. 2005, Schaiff et al. 2007).
In this work, we focused on PPAR, a major regulator of lipid metabolism that regulates the transcription of multiple genes involved in the catabolism and the synthesis of lipids mainly in the liver and also in other tissues (Lefebvre et al. 2006). The degree of induction of these genes is specific for each tissue and depends on the levels of PPAR and its different ligands and co-activators (Desvergne et al. 2006). Some differences were observed in this work between the effects of PPAR agonists clofibrate and LTB4 on the regulation of feto-placental lipid metabolism, which suggests that clofibrate effects are more potent, while those of LTB4 are more specific. Indeed, although both PPAR agonists were able to reduce lipid concentrations in the placenta and the fetuses from control and diabetic rats, LTB4 was able to reduce only those lipid species that are not overproduced in both the placenta and fetuses from diabetic animals. We speculate that overaccumulation of lipids might be specific for triglycerides and cholesteryl esters in the diabetic placenta and for phospholipids in the fetuses from diabetic rats due to the lack of LTB4 catabolic effects on them.
On the other hand, the observed capacity of PPAR agonists to reduce the de novo lipid synthesis in control placentas was not observed in the diabetic placenta probably due to the reduced synthesis of all lipid species found in these diabetic tissues. Whether or not the upregulation of PPAR concentrations observed in the diabetic placenta is involved in the reduced lipid synthesis found in these tissues remains to be established.
The de novo lipid synthesis in the fetuses from diabetic animals was highly elevated, an alteration that probably contributes to their increased lipid accumulation (Kasser et al. 1981), and that was reduced through the activation of PPAR. Similar effects of PPAR agonists on the de novo lipid synthesis were observed in the fetuses from control and diabetic animals, consistent with a similar PPAR protein expression. Nevertheless, the degree of activation of PPAR by its agonists will require further research as they may have PPAR-independent effects (Cui et al. 2001, Miyahara et al. 2006).
Most enzymes required for FFA oxidation are highly expressed in the placenta, an organ capable of both transporting fatty acids to the fetus and using them as metabolic fuels (Shekhawat et al. 2003). The capacity of releasing glycerol as an index of lipid catabolism in placental explants has previously been reported (Ramsay et al. 1991). In this work, we found that both pharmacological and endogenous PPAR agonists stimulated glycerol and FFA release in the control placenta. In addition, both glycerol and FFA release was elevated in the diabetic placenta, a catabolic pathway that seems to occur despite the low concentrations of LTB4 and probably as a result of the increased PPAR concentrations. By contrast, PPAR agonists did not change glycerol and FFA release in the diabetic placenta, probably due to a further oxidation of FFAs and glycerol as it occurs in different tissues as a result of the stimulation of the increased PPAR concentrations (Patsouris et al. 2004, Desvergne et al. 2006).
In conclusion, here we demonstrate an important role of PPAR in fetal and placental lipid metabolism, as PPAR agonists reduce lipid concentrations through the regulation of both a reduction in the de novo lipid synthesis and an increase in lipid catabolism in these intrauterine tissues. These PPAR signalling pathways are disregulated and appear to be especially relevant in maternal diabetes, where several alterations in feto-placental lipid metabolism are found, probably as a response to the excess lipids derived from maternal circulation.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
Tissue preparations
Animals were killed by cervical dislocation on day 13.5 of gestation, after the initiation of mother-to-fetus circulation through the placenta (Ain et al. 2003) and when PPAR is expressed in both placental and fetal tissues (Braissant & Wahli 1998). Placentas and fetuses were removed and placed in Petri dishes containing Krebs–Ringer bicarbonate solution (KRB, ionic composition: 5.5 mM glucose, 145 mM Na+, 2.2 mM Ca++, 1.2 mM Mg++, 127 mM Cl–, 25 mM 
, 1.2 mM 
and 1.2 mM 
). Placentas and fetuses were either frozen at –70 °C for further analyses of LTB4 and PPAR concentrations or prepared for the evaluation of the effect of PPAR agonists on lipid concentrations, the de novo lipid synthesis and lipid catabolism, as follows. Two fetuses or one placenta selected at random from each animal (n=8 or 9 animals in each experimental group) were incubated for 3 h as previously done to evaluate regulation of lipid metabolism (White et al. 2004, Capobianco et al. 2005) in a metabolic shaker under an atmosphere of 5% CO2 and 95% O2 at 37 °C, with or without the addition of either LTB4 (0.1 µM; Cayman Chemical Co., Ann Arbor, MI, USA) or clofibrate (20 µM; Sigma–Aldrich). Thereafter, tissues were frozen at –70 °C for further analysis of lipid concentrations, and aliquots of incubation medium were frozen at –20 °C for further determination of glycerol and FFA concentrations.
To analyse the de novo lipid synthesis, fetuses and placentas were incubated as described above, with the addition of 1 µCi 14C-acetate (53 mCi/mmol; Amersham Biosciences), and then stored at –70 °C until determination of the newly formed radioactive lipids, as described below.
LTB4 concentrations analysis
LTB4 concentrations were measured in control and diabetic fetuses and placentas by employing a commercial enzyme immunoassay kit (Cayman Chemical Co). One fetus or one placenta from each rat (n=8 rats in each experimental group) was selected at random. Eicosanoids were extracted twice in absolute ethanol. The extracts were dried in a Savant Speed-Vac concentrator (Savant, Hicksville, NY, USA) and reconstituted with 200 µl assay buffer provided by the commercial kit. Briefly, the kit uses a polyclonal antibody against LTB4 that binds in a competitive manner the eicosanoid in the sample or an acetylcholinesterase molecule, which has LTB4 covalently attached to it. After a simultaneous incubation, a p-nitrophenyl phosphate substrate was added, and the yellow colour generated was evaluated on a microplate reader at 405 nm.
PPAR protein expression assessment
Two fetuses or one placenta from each rat (n=8 rats in each experimental group) were selected at random for the determination of PPAR protein expression by Western blot, as previously performed for other PPAR isoforms (Jawerbaum et al. 2004, Higa et al. 2007). The tissues were homogenised 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 7200 g for 10 min at 4 °C and the supernatant removed. Protein concentrations were determined by Bradford method using a protein assay reagent (Bio-Rad, Inc). Equal amounts of protein samples were separated with the use of 15% SDS-PAGE. Proteins were then transferred into nitrocellulose membranes, which were blocked overnight with 1% BSA and then incubated with a polyclonal rabbit IgG antibody either against PPAR (1:200; Santa Cruz Biotechnology, Santa Cruz, CA, USA) or actin (Sigma–Aldrich) at 4 °C overnight. After washing with Tris buffer saline and Tween 0.05%, the blots were treated with horseradish peroxidase-conjugated secondary antibody for 1 h and washed several times. The specific signals were visualised using the enhanced chemiluminescence system (Amersham Biosciences). The identity of PPAR was established by the use of molecular weight standards, which allow the identification of the band revealed at the expected size of 50 kDa, which was absent in the negative control experiments performed in the absence of primary antibody. Actin reactivity was detected with a phosphatase alkaline-conjugated secondary antibody. The relative intensity of protein signals was quantified by densitometry using the Sigma Gel Program (Sigma–Aldrich).
Lipid concentrations assessment
Lipid concentrations were determined by thin layer chromatography (TLC), as previously described (Capobianco et al. 2005). Briefly, placental and fetal lipids were extracted in methanol–chloroform in the ratio of 2:1 (v/v) and then concentrated in a Savant Speed-Vac concentrator. Total lipids were chromatographed with a solvent system consisting of hexane:ethyl ether:acetic acid in the ratio of 80:20:2 (v/v). After development, the TLC plate was dried for 5 min under an N2 stream and the lipids were stained with iodine vapours. Lipid species levels were quantified by comparison with known amounts of pure lipid standards run on the same plate. The plates were scanned and analysed by densitometry using the Sigma Gel Program (Sigma–Aldrich).
Determination of de novo lipid synthesis
Fetal and placental lipid syntheses from 14C-acetate were evaluated as previously (Higa et al. 2007). Briefly, following the incubations performed in the presence of 14C-acetate (53 mCi/mmol) either with or without the addition of LTB4 (0.1 µM) or clofibrate (20 µM), lipids were separated by TLC as described above. Thereafter, the radioactive spots corresponding to the different 14C-labelled lipid species were scrapped into vials and counted in a liquid scintillation counter.
Determination of FFA and glycerol release
FFAs and glycerol generated during the hydrolysis of triglycerides and phospholipids and released to the culture media of the placental tissues were determined. FFAs were determined by employing a colorimetric commercial kit (Randox Laboratories, Antrim, UK). Glycerol was determined by an enzymatic method as described previously (Young et al. 1988, White et al. 2006). Briefly, 0.2 ml placental explant incubation medium was allowed to react with 1 ml assay solution containing glycine (15 mg/ml), MgCl2 (0.4 mg/ml), ATP (0.75 mg/ml), NAD+(0.36 mg/ml), hydrazine hydrate (0.2 ml/ml), glycerokinase (0.42 units/ml) and glycerol-3-phosphate dehydrogenase (2.5 units/ml; Roche Diagnostics Corporation). After 45 min, optical density was read at 340 nm in a microtitre plate using calibration curves of glycerol standards.
Statistical analysis
Results are expressed as means±S.E.M. Comparisons between groups were performed employing either one-way ANOVA in conjunction with Tukey's test or Student's t-test, where appropriate. The statistical level of significance was defined as P<0.05.
|
Acknowledgements |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
Received 16 January 2008
First decision 3 April 2008
Revised manuscript received 13 February 2008
Accepted 15 April 2008
|
References |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
Ain R, Canham LN & Soares MJ 2003 Gestation stage-dependent intrauterine trophoblast cell invasion in the rat and mouse: novel endocrine phenotype and regulation. Developmental Biology 260 176–190.[CrossRef][Web of Science][Medline]
Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A & Evans RM 1999 PPAR gamma is required for placental, cardiac, and adipose tissue development. Molecular Cell 4 585–595.[CrossRef][Web of Science][Medline]
Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R & Evans RM 2002 Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. PNAS 99 303–308.
Braissant O & Wahli W 1998 Differential expression of peroxisome proliferator-activated receptor-alpha, -beta, and -gamma during rat embryonic development. Endocrinology 139 2748–2754.
Capobianco E, Jawerbaum A, Romanini MC, White V, Pustovrh C, Higa R, Martinez N, Mugnaini MT, Sonez C & Gonzalez E 2005 15-Deoxy-Delta(12,14)-prostaglandin J2 and peroxisome proliferator-activated receptor gamma (PPAR) levels in term placental tissues from control and diabetic rats: modulatory effects of a PPAR agonist on nitridergic and lipid placental metabolism. Reproduction, Fertility, and Development 17 423–433.[CrossRef][Medline]
Cibelli A, Stefanini S & Ceru MP 1988 Peroxisomal beta-oxidation and catalase activities in fetal rat liver: effect of maternal treatment with clofibrate. Cellular and Molecular Biology 34 191–205.[Web of Science][Medline]
Cui X, Kawashima H, Barclay TB, Peters JM, Gonzalez FJ, Morgan ET & Strobel HW 2001 Molecular cloning and regulation of expression of two novel mouse CYP4F genes: expression in peroxisome proliferator-activated receptor alpha-deficient mice upon lipopolysaccharide and clofibrate challenges. Journal of Pharmacology and Experimental Therapeutics 296 542–550.
Desoye G & Shafrir E 1996 The human placenta in diabetic pregnancy. Diabetes Reviews 4 70–89.
Desvergne B, Michalik L & Wahli W 2004 Be fit or be sick: peroxisome proliferator-activated receptors are down the road. Molecular Endocrinology 18 1321–1332.
Desvergne B, Michalik L & Wahli W 2006 Transcriptional regulation of metabolism. Physiological Reviews 86 465–514.
Eriksson UJ, Cederberg J & Wentzel P 2003 Congenital malformations in offspring of diabetic mothers-animal and human studies. Reviews in Endocrine and Metabolic Disorders 4 79–93.[CrossRef]
Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD et al. 2002 The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. Journal of Clinical Investigation 109 121–130.[CrossRef][Web of Science][Medline]
Fournier T, Tsatsaris V, Handschuh K & Evain-Brion D 2007 PPARs and the placenta. Placenta 28 65–76.[CrossRef][Web of Science][Medline]
Gendron RL, Farookhi R & Baines MG 1992 Murine pregnancies predisposed to spontaneous resorption show alterations in the concentrations of leukotriene B4 and prostaglandin E2. Biology of Reproduction 47 72–75.[Abstract]
Grissa O, Ategbo JM, Yessoufou A, Tabka Z, Miled A, Jerbi M, Dramane KL, Moutairou K, Prost J, Hichami A et al. 2007 Antioxidant status and circulating lipids are altered in human gestational diabetes and macrosomia. Translational Research 150 164–171.[CrossRef][Web of Science][Medline]
Herrera E & Amusquivar E 2000 Lipid metabolism in the fetus and the newborn. Diabetes/Metabolism Research and Reviews 16 202–210.[CrossRef]
Herrera E, Amusquivar E, Lopez-Soldado I & Ortega H Maternal lipid metabolism and placental lipid transfer Hormone Research 65 Suppl_3 2006 59–64.[CrossRef][Medline]
Higa R, Gonzalez E, Pustovrh MC, White V, Capobianco E, Martinez N & Jawerbaum A 2007 PPAR and its activator PGI2 are reduced in diabetic embryopathy: involvement of PPAR activation in lipid metabolic and signalling pathways in rat embryo early organogenesis. Molecular Human Reproduction 13 103–110.
Jansson T, Cetin I, Powell TL, Desoye G, Radaelli T, Ericsson A & Sibley CP Placental transport and metabolism in fetal overgrowth – a workshop report Placenta 27 Supplement A 2006 S109–S113.[Web of Science][Medline]
Jawerbaum A & Gonzalez E 2005 The role of alterations in arachidonic acid metabolism and nitric oxide homeostasis in rat models of diabetes during early pregnancy. Current Pharmaceutical Design 11 1327–1342.[CrossRef][Web of Science][Medline]
Jawerbaum A & Gonzalez E 2006 Diabetic pregnancies: the challenge of developing in a pro-inflammatory environment. Current Medicinal Chemistry 13 2127–2138.[CrossRef][Web of Science][Medline]
Jawerbaum A, Sinner D, White V, Pustovrh C, Capobianco E & Gonzalez E 2002 Modulation of nitric oxide concentration and lipid metabolism by 15-deoxy Delta12,14prostaglandin J2 in embryos from control and diabetic rats during early organogenesis. Reproduction 124 625–631.[Abstract]
Jawerbaum A, Capobianco E, Pustovrh C, White V, Baier M, Salzberg S, Pesaresi M & Gonzalez E 2004 Influence of peroxisome proliferator-activated receptor gamma activation by its endogenous ligand 15-deoxy Delta12,14 prostaglandin J2 on nitric oxide production in term placental tissues from diabetic women. Molecular Human Reproduction 10 671–676.
Kasser TR, Martin RJ & Allen CE 1981 Effect of gestational alloxan diabetes and fasting on fetal lipogenesis and lipid deposition in pigs. Biology of the Neonate 40 105–112.[Web of Science][Medline]
Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H & Van Allen MI 1986 Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biology of the Neonate 50 297–317.[Web of Science][Medline]
Lefebvre P, Chinetti G, Fruchart JC & Staels B 2006 Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. Journal of Clinical Investigation 116 571–580.[CrossRef][Web of Science][Medline]
Lin Q, Ruuska SE, Shaw NS, Dong D & Noy N 1999 Ligand selectivity of the peroxisome proliferator-activated receptor alpha. Biochemistry 38 185–190.[CrossRef][Web of Science][Medline]
Lindegaard ML, Damm P, Mathiesen ER & Nielsen LB 2006 Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression. Journal of Lipid Research 47 2581–2588.
Miyahara N, Miyahara S, Takeda K & Gelfand EW 2006 Role of the LTB4/BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation. Allergology International 55 91–97.[CrossRef][Medline]
Patsouris D, Mandard S, Voshol PJ, Escher P, Tan NS, Havekes LM, Koenig W, Marz W, Tafuri S, Wahli W et al. 2004 PPAR governs glycerol metabolism. Journal of Clinical Investigation 114 94–103.[CrossRef][Web of Science][Medline]
Peraza MA, Burdick AD, Marin HE, Gonzalez FJ & Peters JM 2006 The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicological Sciences 90 269–295.
Portha B, Picon L & Rosselin G 1979 Chemical diabetes in the adult rat as the spontaneous evolution of neonatal diabetes. Diabetologia 17 371–377.[CrossRef][Web of Science][Medline]
Ramsay TG, Karousis J, White ME & Wolverton CK 1991 Fatty acid metabolism by the porcine placenta. Journal of Animal Science 69 3645–3654.[Abstract]
Ringseis R, Gutgesell A, Dathe C, Brandsch C & Eder K 2007 Feeding oxidized fat during pregnancy up-regulates expression of PPAR-responsive genes in the liver of rat fetuses. Lipids in Health and Disease 6 6.[CrossRef]
Schaiff WT, Knapp FF Jr, Barak Y, Biron-Shental T, Nelson DM & Sadovsky Y 2007 Ligand-activated peroxisome proliferator activated receptor gamma alters placental morphology and placental fatty acid uptake in mice. Endocrinology 148 3625–3634.
Schwartz R & Teramo KA 2000 Effects of diabetic pregnancy on the fetus and newborn. Seminars in Perinatology 24 120–135.[CrossRef][Web of Science][Medline]
Shekhawat P, Bennett MJ, Sadovsky Y, Nelson DM, Rakheja D & Strauss AW 2003 Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases. American Journal of Physiology. Endocrinology and Metabolism 284 E1098–E1105.
Sinner D, Caviglia JM, Jawerbaum A, Igal RA & Gonzalez E 2003 Lipid metabolism in the embryos of diabetic rats during early organogenesis: modulatory effect of prostaglandin E2. Reproduction, Fertility, and Development 15 75–80.[CrossRef][Medline]
Soria A, Bocos C & Herrera E 2002 Opposite metabolic response to fenofibrate treatment in pregnant and virgin rats. Journal of Lipid Research 43 74–81.
Wang Q, Fujii H & Knipp GT 2002 Expression of PPAR and RXR isoforms in the developing rat and human term placentas. Placenta 23 661–671.[CrossRef][Web of Science][Medline]
Watts GF & Dimmitt SB 1999 Fibrates, dyslipoproteinaemia and cardiovascular disease. Current Opinion in Lipidology 10 561–574.[CrossRef][Web of Science][Medline]
White V, Gonzalez E, Capobianco E, Pustovrh C, Sonez C, Romanini MC & Jawerbaum A 2004 Modulatory effect of leptin on nitric oxide production and lipid metabolism in term placental tissues from control and streptozotocin-induced diabetic rats. Reproduction, Fertility, and Development 16 363–372.[CrossRef][Medline]
White V, Gonzalez ET, Capobianco E, Pustovrh C, Martinez N, Higa R, Baier M & Jawerbaum A 2006 Leptin modulates nitric oxide production and lipid metabolism in human placenta. Reproduction, Fertility, and Development 18 425–432.[CrossRef][Medline]
Xu Y, Wang Q, Cook TJ & Knipp GT 2007 Effect of placental fatty acid metabolism and regulation by peroxisome proliferator activated receptor on pregnancy and fetal outcomes. Journal of Pharmaceutical Sciences 96 2582–2606.[CrossRef][Web of Science][Medline]
Yessoufou A, Hichami A, Besnard P, Moutairou K & Khan NA 2006 Peroxisome proliferator-activated receptor alpha deficiency increases the risk of maternal abortion and neonatal mortality in murine pregnancy with or without diabetes mellitus: modulation of T cell differentiation. Endocrinology 147 4410–4418.
Young DA, King DS, Chen M, Norris B & Nemeth PM 1988 A novel method for measurement of triglyceride lipase activity: suitable for microgram and nanogram quantities of tissue. Journal of Lipid Research 29 527–532.[Abstract]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
