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Maternal and fetal lipid metabolism under normal and gestational diabetic conditions

  • Emilio Herrera EMAIL logo and Gernot Desoye
Published/Copyright: August 18, 2015
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Hormone Molecular Biology and Clinical Investigation
From the journal Hormone Molecular Biology and Clinical Investigation Volume 26 Issue 2

Abstract

Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus (GDM) pregnancies. During early pregnancy, the increase in maternal fat depots is facilitated by insulin, followed by increased adipose tissue breakdown and subsequent hypertriglyceridemia, mainly as a result of insulin resistance (IR) and estrogen effects. The response to diabetes is variable as a result of greater IR but decreased estrogen levels. The vast majority of fatty acids (FAs) in the maternal circulation are esterified and associated with lipoproteins. These are taken up by the placenta and hydrolyzed by lipases. The released FAs enter various metabolic routes and are released into fetal circulation. Although these determinants are modified in maternal GDM, the fetus does not seem to receive more FAs than in non-GDM pregnancies. Long-chain polyunsaturated FAs are essential for fetal development and are obtained from the mother. Mitochondrial FA oxidation occurs in fetal tissue and in placenta and contributes to energy production. Fetal fat accretion during the last weeks of gestation occurs very rapidly and is sustained not only by FAs crossing the placenta, but also by fetal lipogenesis. Fetal hyperinsulinemia in GDM mothers promotes excess accretion of adipose tissue, which gives rise to altered adipocytokine profiles. Fetal lipoproteins are low at birth, but the GDM effects are unclear. The increase in body fat in neonates of GDM women is a risk factor for obesity in early childhood and later life.

Keywords: fatty acids; fetal lipids; gestational diabetes; human pregnancy; maternal lipids

Introduction

Maternal diabetes is still associated with excess maternal and fetal morbidity. Compared with normal pregnancy, women with poorly controlled diabetes have increased risk of preeclampsia, early delivery, cesarean section, and unfavorable intrauterine environment for fetus development, with increased risk of miscarriage, stillbirth, congenital malformations, placental dysfunction, fetus morbidity and mortality, and intrauterine malprograming [1, 2]. Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy [3–5] and still is a major risk factor for fetal macrosomia or obesity [6, 7]. It was initially proposed that overgrowth of the fetus in maternal diabetes is the result of increased delivery of glucose to the fetus, which consequently develops premature maturation of pancreatic insulin secretion and subsequent hyperinsulinemia, which together with the excess availability of glucose results in overgrowth of the fetus [8]. In fact, the association of high maternal glucose levels and fetus macrosomia has been well documented [9, 10]. However, the increased incidence of macrosomia in newborns is also observed in diabetic pregnancy with satisfactory glycemic control and in GDM mothers who have similar glycosylated hemoglobin (HbA1c) levels as non-diabetic women [11–13]. In diabetic pregnancy, a wide range of disturbances in lipid metabolism have been reported [14] and maternal lipids are thought to be strong determinants of fetal growth in GDM pregnancies [15].

Both maternal triacylglycerols (TAGs) and non-esterified fatty acids (NEFAs), rather than glucose, are positively correlated with neonatal weight and fat mass in well-controlled GDM women but not in normal pregnancies [15, 16]. This indicates that maternal dyslipemia in GDM actively enhances the availability of lipids to the fetus, contributing to fat depot accumulation and consequent risk of development of macrosomia.

Although lipids cross the placenta with difficulty, changes in placental function must contribute to the increased transfer of maternal lipids to the fetus under conditions of GDM hyperlipidemia. Moreover, it has been also shown that handling or metabolism of long-chain polyunsaturated fatty acids (LCPUFAs) is altered in the fetus of GDM women [17], suggesting that such a disturbance could also contribute to fat depot accumulation.

The purpose of this chapter is to review the overall changes in lipid metabolism that take place in pregnancy under normal and GDM conditions, analyzing both maternal and fetal size, as well as lipid placental transfer and its consequences for fetal growth.

Maternal lipid metabolism

Throughout pregnancy there are major changes in lipid metabolism. In the mother, there is an increase in adipose tissue mass and hyperlipidemia, whereas in the fetus there is a need for essential fatty acids (EFAs) and LCPUFAs, which are necessary for fetal growth and development.

Adipose tissue metabolism

During the first two thirds of gestation there is an increase in adipose tissue mass [18, 19], which represents most of the increase in maternal structures that takes place during pregnancy. This is the result of both hyperphagia [20] and increased lipid synthesis [21], which in rats is driven by the enhanced adipose tissue insulin responsiveness that occurs during early pregnancy [22]. During this early stage of pregnancy, there is unchanged [23] or even increased adipose tissue lipoprotein lipase (LPL) activity [24]. This enzyme is extrahepatic, being especially active in adipose tissue, and catalyzes the hydrolysis of circulating TAGs in TAG-rich lipoproteins (chylomicrons and very low density lipoproteins, VLDLs) [25]. The hydrolytic products, NEFAs and 2-monoacylglycerol or glycerol, are taken up by the subjacent tissue for re-synthesis of TAGs [26, 27] and these changes facilitate the accumulation of circulating lipids in maternal fat depots.

The increase in maternal fat depot accumulation stops during the third trimester of gestation as result of three main changes: (a) decreased adipose tissue fatty acid synthesis [22]; (b) decreased LPL activity [23], which causes a decline in the hydrolysis and tissue uptake of TAGs in TAG-rich lipoproteins and contributes to the development of maternal hypertriglyceridemia; and (c) increased adipose tissue lipolytic activity [28, 29]. Under normal conditions, the first two pathways are known to be stimulated by insulin whereas the third is inhibited. It is therefore proposed that the insulin-resistant condition present in the mother in the last trimester of pregnancy [30, 31] is responsible or actively contributes to these three changes. In fact, it has been shown that during late pregnancy there is resistance to the action of insulin in adipose tissue metabolism [32]. However, the regulation of adipose tissue lipolytic activity during late pregnancy deserves special attention. Lipolysis is under tight regulation by hormones, catecholamines and insulin being considered their major regulators in humans [33–35]. However, in addition to the insulin-resistant condition, other pregnancy hormones could contribute to such change. In fact, pregnancy-specific hormones have insulin-antagonistic and lipolytic effects [36].

In spite of the important role that increased adipose tissue lipolytic activity might play in maternal–fetal metabolic interactions during pregnancy, there is practically no data available regarding lipolysis during late pregnancy in normal women. There is, however, one report showing increased lipolysis in non-obese pregnant women in the third trimester and a significant negative correlation between insulin and the rate of glycerol production. However, no correlations were found between levels of glucagon, human placental GH (hPGH), estrogens, progesterone, or chromogranin A and the rate of glycerol production [37]. The reason for the lack of such correlation is not known although the mechanisms underlying insulin resistance in late pregnancy are well known. Placental hormones such as human placental lactogen and hPGH, as well as cortisol and estrogens, have been extensively studied as underlying the insulin resistance in late pregnancy. Recent studies have also implicated several factors derived from adipose tissue (collectively known as adipokines or adipocytokines) that mediate insulin resistance in pregnancy [38, 39]. A few of these adipocytokines are known to have increased plasma concentrations during late pregnancy and to decrease insulin sensitivity. Such factors include leptin [40], tumor necrosis factor-α (TNF-α) [41], interleukin-6 [42], visfatin [43], chemerin [44], retinol binding protein-4 (RBP4) [45], and resistin [46]. Other adipokines, such as adiponectin [47, 48] and apelin [49], are known to decrease during late pregnancy and to increase insulin sensitivity. These changes actively contribute to the maternal insulin-resistant condition during late pregnancy. Although these and other adipocytokines are derived from adipose tissue as well as other tissues such as liver, during pregnancy most of them are also produced by the placenta [50] and, therefore, actively contribute to insulin resistance and its effects, enhancing adipose tissue lipolytic activity during late pregnancy.

Increased levels of NEFAs as result of active adipose tissue lipolytic activity during late pregnancy can also contribute to insulin resistance [51]. In addition, the transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ), which is normally highly expressed in adipose tissue, is a regulator of adipogenesis and lipogenesis through binding to several genes [52, 53] and inducing synthesis of proteins such as adiponectin [54] and LPL [55]. It has been proposed that PPAR-γ coordinates the balance between fat deposition and mobilization through its effects on lipolysis [56]; it has also been implicated in the regulation of insulin sensitivity [57]. During late pregnancy, the levels of PPAR-γ mRNA and protein are lower in adipose tissue in both control and GDM women than in non-pregnant women [58].

The underlying pathophysiology of GDM is a function of two major metabolic disorders, pronounced peripheral resistance to insulin and inadequate β-cell function [31]. Accumulating evidence indicates that adipose tissue plays a key role in the development of GDM, not only because it is the main site of lipid storage but also because it is responsible for the synthesis and secretion of adipocytokines. Thus, those changes in maternal adipose tissue metabolism during late pregnancy known to be controlled by decreased insulin sensitivity become further affected in this condition, resulting in the increase in plasma NEFAs and ketone bodies seen in GDM pregnant women [59, 60]. Under these conditions, maternal adipocytokines associated with insulin resistance, such as adipocyte fatty acid-binding protein [AFABP) [61, 62], leptin [63], resistin [64, 65], and RBP4 [66] (among others), are higher whereas those associated with insulin sensitivity, such as adiponectin [47, 48], are lower in GDM than in control pregnant women [39, 67], contributing to the chronic insulin resistance seeing in GDM. Although the ability of insulin to inhibit lipolysis is reduced during late pregnancy [68], this is further reduced in GDM subjects [31, 58]. Furthermore, although the cellular mechanisms involved in its development are not yet completely understood, the pronounced resistance to insulin seems to actively contribute to the reduced insulin suppression of lipolysis present in GDM women with advancing gestation [58].

Maternal dyslipidemia

During late pregnancy, the net catabolic condition of maternal adipose tissue is associated with hyperlipidemia, which mainly corresponds to increases in TAG levels with smaller rises in phospholipids and cholesterol [23, 69]. The greatest increase in plasma TAGs corresponds to VLDLs as result of their increased production by the liver [70] and decreased removal from the circulation as a result of decreased LPL activity in adipose tissue [23]. Plasma lipoproteins of higher density than VLDLs, such as LDLs and HDLs that normally do not carry TAGs, also become enriched in TAGs during late pregnancy [23] as result of an increase in cholesteryl ester transfer protein (CETP) activity [71, 72] and a decrease in hepatic lipase activity [23]. This latter change also seems to be responsible for the proportional accumulation of TAGs in buoyant TAG-rich HDL2b subfractions at the expense of cholesterol-rich and TAG-poor HDL3 [23]. The increase in plasma estrogen levels during pregnancy probably contributes to these changes, because estrogens are known to stimulate hepatic VLDL production in pregnancy [69] and to decrease hepatic lipase activity [73, 74].

It is proposed that the two main hormonal factors responsible for the metabolic interactions that result in the development of maternal hypertriglyceridemia during late pregnancy are the high lipolytic activity and low LPL activity in adipose tissue caused by the insulin-resistant condition and the increased liver secretion of VLDLs [69] and decreased hepatic lipase activity caused by estrogen [75]. Figure 1 summarizes these metabolic interactions and the modulating effect of insulin resistance and estrogen on them.

Figure 1: Major lipid metabolic interactions during late pregnancy, showing control by the insulin-resistant condition (IR) and enhanced estrogen levels (EST) in specific steps: +, activated steps; –, inhibited steps; NEFA, non-esterified fatty acid; Glyc-3P, glycerol-3P; TAG, triacylglyceride; CE, cholesterol ester; LPL, lipoprotein lipase; HL, hepatic lipase; PUFA, polyunsaturated fatty acid; CETP, cholesterol ester transfer protein.
Figure 1:

Major lipid metabolic interactions during late pregnancy, showing control by the insulin-resistant condition (IR) and enhanced estrogen levels (EST) in specific steps: +, activated steps; –, inhibited steps; NEFA, non-esterified fatty acid; Glyc-3P, glycerol-3P; TAG, triacylglyceride; CE, cholesterol ester; LPL, lipoprotein lipase; HL, hepatic lipase; PUFA, polyunsaturated fatty acid; CETP, cholesterol ester transfer protein.

The dyslipidemic condition in diabetic pregnancy has been reported to be very variable. Some studies have found exaggerated hypertriglyceridemia in diabetic pregnancy compared with normal pregnancy in the three trimesters of gestation [76–78], but there are also studies showing no differences [59, 79, 80]. Plasma cholesterol, LDL-cholesterol, and HDL-cholesterol levels were also found to be higher or lower in GDM as compared with normal pregnancy (for a review see [14]]. However, small sized and dense LDL particles, which are characteristic of insulin-resistant conditions and have been associated with increased risk of coronary artery disease, have been consistently found in GDM women [80, 81].

The variations in the reported findings related to the dyslipidemic condition of diabetic pregnant women are not completely understood. As commented above, some of the changes occurring in lipid metabolism during late gestation of normal pregnancy are driven by both the insulin-resistant condition and increases in steroid hormones. Plasma levels of these hormones [59, 82] and of sex hormone-binding globulin [83] are decreased in pregnant diabetic women. Furthermore, plasma lipoprotein TAG levels have been shown to correlate with prolactin, estradiol, and progesterone in the course of gestation [59]. Because the degree of metabolic control can affect both the dyslipidemic condition and the level of sex hormones during pregnancy, it is proposed that the development or lack of development of exaggerated hypertriglyceridemia in diabetic pregnant women compared with the control condition depends on the balance between those two factors.

Placental lipid transfer in normal and GDM pregnancies

The placenta separates the maternal and fetal circulations, and any substance destined for fetal supply has to traverse this organ. Because of the rising incidence of newborns with excessive adiposity, lipid transfer across the placenta has received increasing interest in the past decade. Yet, the complexity of the organ and the processes involved, combined with a scarcity of relevant data, have hampered the development of a convincing concept about transfer mechanisms and their regulation. The current concept described below is thus mostly based on extrapolation of results from other tissues [84–88].

Concept of maternal–fetal lipid transfer and placental metabolism

Figure 2 depicts current understanding of maternal-to-fetal transfer of fatty acids. About 1%–3% of the fatty acids in the maternal circulation are non-esterified (i.e. the vast majority are in lipoproteins). LDL is the major lipoprotein in the maternal circulation and can be taken up into the syncytiotrophoblast (the placental tissue interfacing with maternal blood) by receptor-mediated endocytosis [89, 90]. After uptake, the LDL-TAG and LDL-cholesterol esters can become hydrolyzed by intracellular lipases and cholesterol-ester hydrolases and contribute to the intracellular fatty acid pool. Other lipoproteins such as VLDLs and HDLs bind to receptors on the syncytiotrophoblast surface and become hydrolyzed extracellularly. Endothelial lipase has been identified as the major extracellular placental lipase [91, 92], but this is not a uniform finding and there are claims about the presence of LPL [93]. Regardless of the molecular identity of the TAG hydrolase activity [94], the resulting NEFAs must be taken up by the syncytiotrophoblast to eventually contribute to the intracellular fatty acid pool. Uptake is accomplished by fatty acid transporters such as fatty acid transport proteins (FATB)-1, FATB-4, fatty acid translocase (FAT/CD36), and plasma membrane fatty acid binding protein (p-FABPm) [95]. These transporters have overlapping specificities for the various fatty acids, and their relative contribution to the uptake of distinct fatty acids is unknown.

Figure 2: Current concept of maternal-to-fetal transfer of fatty acids (FA).NEFA, non-esterified fatty acid; TAG, triacylglyceride, p-FABPm, plasma membrane fatty acid binding protein; FATP, fatty acid transport protein; FAT/CD36, fatty acid translocase; EL, endothelial lipase; FABP, fatty acid binding protein.
Figure 2:

Current concept of maternal-to-fetal transfer of fatty acids (FA).

NEFA, non-esterified fatty acid; TAG, triacylglyceride, p-FABPm, plasma membrane fatty acid binding protein; FATP, fatty acid transport protein; FAT/CD36, fatty acid translocase; EL, endothelial lipase; FABP, fatty acid binding protein.

Once inside the syncytiotrophoblast, the fatty acids must be bound to fatty acid binding proteins (FABP), of which the heart-type isoform appears to be the major FABP in the human placenta [96]. From there, fatty acids can enter the various metabolic routes, including β-oxidation, conversion into eicosanoids, and re-esterification to form phospholipids and triglycerides. The latter may then be stored in lipid droplets in the syncytiotrophoblast.

NEFAs can traverse the cytoplasm of the syncytiotrophoblast and are then released into the fetal circulation, where they bind to transport proteins such as α-fetoprotein. They are taken up in the fetal liver, esterified and metabolized or used to form lipoproteins, mostly HDL, which is the main cholesterol-carrying fetal lipoprotein in humans. The various fatty acids contribute differentially to fetal lipid pools (i.e. NEFA, TAG, phospholipids – mainly phosphatidylcholine, and cholesterol-esters) [97].

Interestingly, the human placenta has a preference for the transport of docosahexaenoic acid (DHA) over arachidonic acid (AA), α-linolenic acid (ALA), and linoleic acid (LA) [98]. This could explain the enrichment of LCPUFAs in fetal plasma and in particular of DHA [99, 100] and also reflect the high demand of the growing fetus for DHA, particularly to sustain brain and retinal development.

Challenges to this concept

This concept, which has been around for about a decade, suffers from several deficiencies (i.e. it is in contradiction to some important biochemical and biological principles).

Although fatty acid transfer proteins (FATPs) appear to be the main fatty acid transporters involved in the uptake of fatty acids, their conceptual involvement in the overall transfer process poses a problem. This is because FATPs are not only transporters, but also have acyl-CoA-ligase activity [101]. Thus, any fatty acid taken up by an FATP becomes an acyl-CoA immediately after having reached the cytoplasmic side of the FATP. Although this CoA-ligation is necessary to allow fatty acids to enter metabolic pathways, it poses a problem for fatty acid egress from the syncytiotrophoblast. No transporter molecule is known to date that accepts acyl-CoA. Thus, fatty acid-CoAs need to be hydrolyzed to release free fatty acids, a reaction catalyzed by acyl-CoA thioesterases. It is unclear whether these enzymes are present in the human placenta, although they have been found in BeWo cells, a choriocarcinoma cell line derived from the human syncytiotrophoblast [102]. This raises the question of whether FATPs account for the uptake of fatty acids destined for transfer to the fetus. Alternatively, simple diffusion could allow the passage of fatty acids across the syncytiotrophoblast to the fetal circulation.

The proportion of fatty acids on the maternal side of the syncytiotrophoblast that are transferred to the fetal circulation is entirely unknown; it is not even known whether it is most of the fatty acids or only a small fraction. Some information comes from in vivo studies using palmitic acid (PA, 16:0), oleic acid (OA, 18:1 n-9), LA (18:2 n-6), and DHA (22:6 n-3), all labeled with 13C-stable isotopes [103]. These were administered to the mother 12 h prior to delivery by cesarean section, at which time enrichment of the 13C-labeled fatty acids in cord blood was determined. Interestingly, only about 0.5% of the fatty acids administered to the mother were enriched in the fetal circulation. The exception was DHA, which was enriched by 3.5%. It is pertinent that the absolute transfer rate for PA and LA is in the range of 6–7 mmol/24 h. Extrapolation to the amount of fat stored in the fetus during the period of rapid development (i.e. the third trimester) demonstrated that maternal-to-fetal fatty acid transfer in normal pregnancies contributes to only about 20% of the neonatal fat stores (about 350 g) [104].

A further open question relates to the lipid droplets found in the syncytiotrophoblast. Although there is evidence that the droplets store fatty acids in TAGs, it is unknown whether they can also mobilize the TAGs or whether the released fatty acids contribute to the fatty acid pool destined for release to the fetal circulation or to the metabolic pool, or both.

The effect of GDM

There are multiple determinants of overall metabolite transport across the placenta, including that of fatty acids. At the level of the placenta, key roles are played by its structure, morphology, metabolism, and the number and activity of transporter molecules involved. If VLDL- and HDL-borne fatty acids contribute to overall transfer, then the lipase activity(ies) could be rate limiting. Also, thioesterase activity is relevant if the fatty acid-CoAs must be hydrolyzed to NEFAs and CoA. In addition, the utero-placental and umbilical blood flow, as well as the maternal-to-fetal concentration gradient, can become main determinants in the case of flow-limited nutrients. Each of these determinants could be modified by maternal GDM. Thus, the measurement of any single contributor to overall transfer does not allow conclusions to be made about potential GDM effects. Rather, methods have to be used that integrate each distinct GDM-associated change and provide an overall readout. This is why studies using stable isotopes are so powerful. Using this method it was demonstrated that the fetal enrichment of three maternally administered fatty acids (PA, OA, and LA) was similar in normal and GDM pregnancies, and that only DHA enrichment was reduced by about 50% [103]. Because fetal enrichment was measured in cord blood, this finding does not necessarily reflect the extent of transfer. An unknown proportion of fatty acids could have been incorporated into fatty acid ester pools (i.e. in TAGs, phospholipids and/or cholesterol esters) in fetal tissues and thus escaped measurement in cord blood. In addition, DHA and AA are retained in the placenta in GDM and integrated into phospholipids. This could also explain the lower DHA enrichment in cord blood in GDM [105].

The only study that used the ex vivo placental perfusion system (a method integrating the whole placental tissue and all its changes associated with a given condition) in diabetic pregnancies found increased placental uptake and release of AA into the fetal circulation [106]. However, this was in type 1 diabetes mellitus and, therefore, might not be representative of GDM.

Collectively, with all its limitations, the available evidence does not suggest that the fetus receives more fatty acids in a condition of maternal nutritional oversupply, such as GDM, than in non-GDM pregnancies.

Placental lipid metabolism in GDM

The GDM placenta contains more TAGs and phospholipids, but not cholesterol esters, than the normal placenta [107, 108]. These depots are almost exclusively stored in the syncytiotrophoblast as lipid droplets [109]. This location suggests that the build up of lipid droplets is fuelled mostly by maternally derived lipids.

In fact, in vitro experiments have demonstrated the key role of fatty acids in driving lipid droplet formation. Droplet formation is accompanied by increased expression of adipophilin (a lipid droplet-associated protein) and of fatty acids acting in concert with insulin [110, 111]. This process also requires proper activity of FABP-4 [112]. Because the maternal concentrations of both insulin and fatty acids are elevated in a medically managed GDM pregnancy, one could envisage their contribution to enhanced placental lipid storage in GDM. However, these results were obtained in trophoblast cells from normal pregnancies and, therefore, extrapolation to GDM has to be made with some caution. Thus, direct evidence is pending.

The energy requirements of the placenta are thought to be covered by maternal glucose sources. However, only about one third of maternal glucose taken up by the placenta is used to sustain placental activities, of which about 80% is channeled into the glycolytic pathway, resulting in lactate production [107]. Elevation of maternal glucose supply by higher circulating concentrations in GDM are unlikely to stimulate glycolysis because this pathway, at least in the normal placenta, is already saturated at low glucose concentrations (about 5–8 mmol/L) [110, 113]. Thus, the placenta probably depends on additional energy sources, and fatty acids are likely candidates. The presence of active enzymes involved in β-oxidation, predominantly in the syncytiotrophoblast (the metabolically most active placental cell type), provides the molecular basis [114, 115]. However, the proportion of fatty acids stored in lipid droplets or oxidized to cover the extra energy requirements of increased placental activity in GDM is unknown.

An important pathway for fatty acids, especially AA, is conversion into eicosanoids such as prostacyclin and thromboxane. In type 1 diabetes mellitus, AA conversion into thromboxane and prostacyclin is enhanced, with preferential formation of thromboxane B2 [116]. This imbalance of vasoactive eisoanoids with preference for the vasoconstricting thromboxane B2 could explain the reduced feto-placental (i.e. umbilical) blood flow in type 1 diabetic pregnancies. Because GDM is only rarely accompanied by a change in umbilical blood flow, this pathway has failed to receive attention in this condition and studies have not been conducted so far.

Fetal lipid metabolism

Role of LCPUFAs in fetal growth

Fatty acids are essentials for fetal development because they are used as structural components, as a source of energy, as precursors of bioactive compounds such as eicosanoids, and as regulators of transcription factors. Practically all fatty acids can provide energy, but structural and metabolic functions mainly require polyunsaturated fatty acids (PUFAs) of the n-3 or n-6 series. The fetus must obtain these PUFAs from the mother, who obtains them either from the diet or by supplementation [117]. Both ALA and LA are so-called essential fatty acids (EFAs) and must be present in the maternal diet, whereas their LCPUFA derivatives can be synthesized from EFAs through the n-3 and n-6 pathways, respectively, by the processes of elongation and desaturation. Metabolically important n-3 LCPUFAs are eicosapentaenoic acid (EPA, 20:5 n-3) and DHA; AA is an important n-6 LCPUFA. Although none of these three fatty acids are absolutely required in the maternal diet because they can be synthesized from EFA precursors, the fetus depends mainly on their exogenous supply as conversion of EFAs to LCPUFAs in term and preterm neonates is very limited. Thus, because production of EPA, DHA, and AA might be inadequate during periods of rapid intrauterine growth, they are considered essential for the fetus [118]. The major proportion of those LCPUFAs are found in the maternal circulation in their esterified form associated with plasma lipoproteins, with only a minor proportion in the form of NEFAs [119, 120]; therefore, the metabolic interactions summarized in Figure 1 are essential to ensure appropriate availability of those LCPUFAs to sustain fetal development.

During the first 8 weeks of intrauterine life, PUFAs are already required by gametes and embryo [121], but their net rate of utilization is small and does not represent an additional demand on the mother or her diet. Until around 25 weeks of gestation in humans the accumulation of lipids and specific fatty acids by the fetus is relatively small, but increases logarithmically with gestational age [86]. This period corresponds to the greatest accretion of individual fatty acids and it is crucial that there is sufficient supply of both AA and DHA for proper functions [122] such as retinal and cerebral function.

Intervention trials have been conducted in different countries to determine the effects of marine oil or DHA and EPA supplementations in different periods of pregnancy. Although there were no clear differences in birth weight it was found that low n-3 LCPUFA levels were associated with dysfunctional brain and retinal development, suggesting that pregnant women should achieve an average intake of at least 200 mg/day of DHA to achieve a desirable outcome [123].

Arachidonic acid has been shown to be of particular importance for growth and development [124] and a linear regression between birth weight and plasma AA (but no other plasma fatty acid) has been found in premature infants [125]. Although not completely established, the growth-promoting effect of AA could be related to its function as a precursor of prostaglandins and other eicosanoids, or to its structural role in membrane phospholipids.

Fatty acids as source of energy for the fetus

The fetus has classically been considered to be primarily dependent on glucose oxidation for energy production [126]. However, several recent reports have re-evaluated the role of mitochondrial fatty acid oxidation (FAO) in human placental and fetal metabolism [114, 115, 127, 128]. The mRNA expression and activity of FAO enzymes in several human fetal tissues and in placenta [129] suggest that FAO actively contributes to fetal and placental energy production. Several recessive inherited disorders in genes of the FAO pathway have been reported to be associated with prematurity, intrauterine growth retardation, and other disorders that may progress to coma and death [130, 131].

Even in animal studies, despite the predominant role of glucose oxidation for energy production, disturbances of enzymes of the FAO pathway are associated with reduced fertility, fetal demise, and fetal growth restriction [132–134]. Furthermore, inactivation of genes encoding the transcription factors that regulate the FAO pathway, such as the peroxisome proliferator-activated receptors (PPARs), cause embryonic lethality and failure of the syncytiotrophoblast to develop and sustain pregnancy [135].

It is therefore suggested that, in contrast to the results obtained in animal studies, FAO plays an important role in the human fetus as a source of metabolic energy for placental function and fetal development. It is to be expected that there are differences in the proportion of each fatty acid being oxidized by the placental–fetal unit, LCPUFAs from maternal origin probably being the preferential substrate.

Lipid synthesis

From weeks 26–40 of gestation, human fetal weight increases more than fourfold, and beyond 30 weeks of gestation fat accumulation exceeds that of non-fat components [136]. In fact, the rate of fat accretion is approximately linear between 36 and 40 weeks of gestation [137]. By the end of pregnancy, fat accretion ranges from 1.6–3.4 g/kg/day [138] giving a total fetal body fat of approximately 14% of mean birth weight [139]. Although about half of that fat is derived from maternal sources passing across the placenta over the whole period of gestation [140], the remainder could be due to lipogenic activity within the fetus. It is known that as early as weeks 12–20 of gestation human fetal tissues are capable of incorporating different labeled substrates into lipids both in vitro [141–143] and in vivo [144]. It has even been shown that fatty acid synthesis from various precursors is higher in human fetuses than in their mothers, and that the rate of this synthesis decreases rapidly after birth, particularly in the liver [145]. Those lipids correspond to fatty acids, TAGs, phospholipids, and cholesterol. When palmitate is used as substrate, it is mainly incorporated into phospholipids and TAGs, whereas the synthesis of sterols is lower [146]. These data indicate that from an early embryonic stage, human tissues contain all the enzymatic machinery to synthesize lipids from carbohydrates. It should also be pointed out that there are differences in the rate of lipogenesis, not only between different species but also between different organs in the same species. An example is fatty acid synthesis in the brain of fetal rats, which is higher than in the liver [147].

Fetal adipose tissue development

White adipose tissue (WAT) appears in the second trimester of intrauterine life, and adipogenesis in different fat deposit sites begins at 14–15 weeks [148–150]. Adipogenesis begins with the accumulation of mesenchymal stem cells, which develop into adipocytes near the networks of capillaries [148, 149]. Then, early fat cell clusters develop into WAT, consisting of vascular structures and densely packed white adipocytes [151]. Thereafter, fat lobules slowly develop with predominating multilocular fat cells. After the 23rd week, the total number of fat lobules remains approximately constant and the growth of adipose tissue is determined mainly by an increase in size of the fat lobules. At the beginning of the third trimester, adipocytes are found in the characteristic fat depot areas but are still rather small [150]. After birth, the number of fat lobules remains constant, whereas their size continuously grows. This increase in fat mass is mainly the result of an enlargement in existing fat cell size [152, 153].

The process of adipogenesis implies the determination of preadipocytes from stem cells and the terminal differentiation of preadipocytes into mature adipocytes [149, 154]. Adipogenesis is a complex process that is not completely characterized and involves a cascade of gene activation processes, of which PPAR-γ is the master regulator [53, 155, 156], although its endogenous ligand is still unknown.

Several perinatal factors, including elevated insulin levels in amniotic fluid [157], have been associated with subsequent obesity development in offspring. Some studies suggest a direct relation between maternal prepregnancy body mass index (BMI) and/or maternal gestational weight gain and the newborn’s body fat mass [158–161]. Lifestyle intervention studies that comprise physical activity and dietary counseling seem to be effective strategies for reducing excessive gestational weight gain and improving maternal and neonatal outcomes [162–164]. Natural long-chain fatty acids act in preadipocytes as adipogenic hormones through their participation as transcriptional regulators of the expression of lipid-related genes such as those encoding PPARs, and thus promote adipogenesis [165, 166]. Evidence from animal and human studies suggests that changing the n-6:n-3 fatty acid ratio in the diet favors the possibility of altering the early stages of adipose tissue development during fetal life [167]. It was shown that the n-6 LCPUFA AA inhibits cell proliferation and promotes the differentiation of preadipocytes to adipocytes, whereas the n-3 LCPUFAs DHA and EPA seem to counteract this process [167, 168]. The effect of n-3 supplementation during pregnancy and lactation on infant body weight composition has only recently received attention. To date, results are inconclusive although there is no evidence that supplementation with n-3 fatty acids and reduction in dietary AA intake during pregnancy affects offspring fat mass [169, 170].

Newborns from well-controlled GDM mothers can have normal body weight but higher fat mass than those from healthy mothers [16, 171]. Enlargement of body fat mass in newborns of GDM mothers seems to be exclusively the result of an increase in the TAG content of single adipocytes rather than a change in the fat cell number [172]. Serum glucose levels and consequent insulin levels in cord blood of GDM women are augmented in comparison with control pregnancies [16]. Because neonatal plasma insulin levels have been shown to correlate with body fat mass and fat cell weight [173], such hyperinsulinemia in the fetus of GDM mothers would facilitate TAG synthesis, being responsible for increased storage in single adipocytes.

Adipose tissue is considered an endocrine organ, secreting adipocytokines. Given their importance in fetal growth and maturation for both survival at birth and overall health, adipocytokines have been studied in the human newborn of normal and complicated pregnancies [174–179]. There is a wealth of information on factors contributing to fetal growth, but we focus here on adipocyte fatty-acid binding protein (AFABP), leptin, adiponectin, retinol binding protein 4 (RBP4), and angiopoietin-like protein 4 (ANGPTL4). These factors have been studied in control and GDM conditions [67].

AFABP is responsible for intracellular fatty acid trafficking, which contributes to the regulation of hormone-sensitive lipase activity [180], one of the enzymes controlling adipose tissue lipolysis. In pregnant women it was found that AFABP serum concentration was higher in GDM than in control subjects, whereas in cord blood serum it was lower in GDM than in control subjects. AFABP concentration in cord serum of control subjects was higher than in the corresponding maternal serum; this was not the case in GDM, even though AFABP correlated with neonatal fat mass in these GDM fetuses [67], indicating a direct interaction between the two.

Leptin concentration in cord serum has a strong positive correlation with neonatal fat mass [181]. Higher leptin concentrations have been found in fetal plasma from women with either type I diabetes or GDM compared with non-diabetic controls [182, 183]. The relationship between fetal leptin and birth weight has not been clearly established and, although higher concentrations of leptin in cord plasma have been reported in diabetic pregnancies associated with fetal macrosomia [184–186], lower concentrations have also been reported [187].

RBP4 is another adipocytokine that, in addition to its role in the transport of retinol from liver to target tissues, regulates glucose metabolism and reduces insulin sensitivity in humans [183, 188]. Its concentration in GDM pregnant women and cord blood serum is higher than in controls [67, 189], which could contribute to the exaggerated insulin resistance in women with GDM and their newborns [16]. Maternal levels of RBP4 show a positive correlation with maternal fat mass [189], although the implications for fetal growth and development remain unknown.

In contrast to the above-mentioned adipocytokines, adiponectin increases insulin sensitivity and its levels in human pregnancies are lower in GDM than in controls [187]. Adiponectin is synthesized in several fetal tissues, which justifies its high concentrations in umbilical plasma [190]. Under normal conditions, cord blood adiponectin concentration increases with gestational age and correlates positively with birth weight [191], indicating that it contributes to fetal adiposity and development. However, in the cord blood of GDM pregnant women adiponectin levels are lower than in controls and no correlation was found with neonatal fat mass or body weight [67].

ANGPTL4 is secreted into serum from adipose tissue, liver, and placenta [192] and its overexpression in mice or treatment with it increase TAG levels as result of irreversible inhibition of LPL activity [193]. This protein has been recently studied in human pregnancy and newborns. It was found that GDM pregnant women who delivered newborns with high fat mass had high concentrations of both TAGs and NEFAs and low concentrations of ANGPTL4 [194]. Their neonates had lower concentrations of TAGs and no differences in NEFA and ANGPTL4 levels, but high insulin concentrations, which would contribute to their increased fat depots.

In addition to the adipocytokines mentioned above, there are several other factors that affect fat depot and lipid metabolism directly or indirectly in the fetus, therefore contributing to development. Potentially, they could affect fetal body composition and growth in both normal and diabetic pregnancies but their nature and involvement remain to be investigated.

Fetal lipoproteins

During early gestation [10–16 weeks post-conception) the cholesterol concentration in umbilical cord plasma is around 80 mg/dL and cyclically decreases to around 50 mg/dL at term [195, 196]. The cord serum TAG concentration averages 30–50 mg/dL [197–199]. LDL-cholesterol also declines during gestation in the human fetus, attaining values of 25–30 mg/dL at term [196, 200, 201]. However, HDL-cholesterol concentration is stable throughout gestation [200, 201], with values around 25 mg/dL. All these values for plasma lipoproteins are lower than in adults. In the case of HDL, which represents the main lipoprotein class in cord blood, plasma contains higher levels of large HDL2and a broader range of particle sizes [202, 203]. The plasma VLDL concentration of cord blood at term is also lower than in adults [204, 205], although it increases and the VLDLs become enriched in apoprotein E (apo E), apo CIII, and TAGs during the first week of life [205].

In agreement with the low levels of lipoproteins in the human fetus at birth, apolipoprotein B (apo B) and apolipoprotein A-I (apo A-I) concentrations are also low [205–207]. There are also some changes in the apoprotein content of certain particles. This is the case for HDL, which, despite maintaining a relatively stable concentration in the human fetus, shows an increase in its apo A-I concentration between weeks 20 and 40 of gestation, causing an increase in the ratio of apo A-I to HDL-cholesterol [208]. The main feature of fetal HDL is the high proportion of apo E [209], which is mainly associated with lower-density HDL classes. The concentration of apo E in cord plasma is close to or even higher than in adult plasma. Because fetal HDL and apo E have the ability to modulate placental gene expression, it has been proposed that the function of apo E-rich HDL in the fetal circulation is different to that of adult HDL with its higher proportion of apo A-I [210].

During gestation there is a progressive increase in hepatic LDL receptors in the human fetus, attaining higher activity at mid-gestation than in adult liver [200]. This change has an important role in lowering the concentration of LDL cholesterol, as commented above. After birth, cholesterol feeding decreases LDL receptor activity, as occurs in adults [211], therefore it is suggested that the absence of this regulatory process in the fetus contributes to the elevated LDL receptor activity and low LDL-cholesterol levels during late intrauterine life.

The human fetus has low activity of lecithin-cholesterol acyl-transferase activity [212, 213], causing a lower level of plasma cholesterol esterification [214] that could also contribute to the differences in lipoprotein composition compared with the adult.

Little is known about the effects of diabetes on lipoproteins in the fetus, although marked differences have been reported. An increase in LDL-cholesterol and decrease in HDL-cholesterol [215] and increases in NEFAs, total cholesterol, free cholesterol, esterified cholesterol, phospholipids, TAGs, apo A-I, and apo B in newborns of well-controlled type I diabetic mellitus mothers have been found [216]. Recently, HDL-proteome remodeling resulting in altered functionality of HDL was found to be associated with impaired cholesterol efflux capability and diminished anti-oxidative particle properties in newborns of GDM mothers [217].

Effects of altered maternal lipids in GDM women on fetal growth

It is well known that diabetic pregnancies are associated with a high incidence of fetal growth disorders and, although it was previously proposed to be the result of maternal hyperglycemia, it is now evident that control of fetal growth is far more complex than previously thought [218, 219]. Besides obvious disruptions to the control of glucose concentration and metabolism in diabetes, there is evidence that disturbances in maternal lipid metabolism could also contribute to these disorders [14, 220]. As expected, an altered maternal lipid profile affects the quantity and quality of lipids being transferred to the fetus. Increases in maternal plasma TAG levels in GDM women have been related to neonates that are either large or small for their gestational age [220, 221]. Circulating concentrations of TAGs in the third trimester of pregnancy in diabetic women have been considered a stronger predictor of birth weight than glucose concentrations [15, 221].

In GDM pregnant women having normal levels of serum glucose, insulin, and glycerol as well as normal insulin resistance values (as assessed by the homeostasis model, HOMA), the neonatal fat mass was found to be higher than in controls [15, 16]. In these same GDM women, but not in controls, at a time close to delivery, maternal plasma TAG and NEFA concentrations correlated with all neonatal anthropometric measures (i.e. birth weight, BMI, and fat mass). These findings indicate that in GDM, but not in controls, maternal lipids are strong predictors of fetal growth. Comparing maternal lipids (i.e. TAGs, NEFAs, and cholesterol) in GDM and control pregnant women, similar concentrations were found but there were higher NEFA concentrations in the cord blood serum of GDM women [16].

An altered intrauterine fatty acid metabolism could also contribute to the elevated fat depots in neonates of GDM women. Such a possibility is suggested by the finding of a lower proportion of DHA and lower total n-6 and n-3 PUFAs in umbilical arterial plasma, but not in umbilical vein plasma, in GDM subjects compared with controls [17]. Whereas umbilical vein blood comes from the placental capillaries, umbilical artery blood arrives from fetal tissues. Therefore, the decreased proportion of those PUFAs in the umbilical arteries of GDM fetuses indicates their enhanced utilization by fetal tissues, which would also contribute to the tendency for increased fat depot accumulation.

In a literature review related to the fetal origins of obesity, it was reported that most studies showed a positive correlation between birth weight and childhood obesity (for a review see [222]). Recently, a significant correlation between the percentage of body fat at birth and child body fat at follow-up was found in offspring of lean and obese women with normal glucose tolerance and GDM [223]. Therefore, the increase in body fat in neonates of GDM women seems to be a significant risk factor for obesity in early childhood and possibly in later life.

Expert opinion

Although human maternal and fetal lipid metabolism under normal conditions is well understood, there are still several open questions regarding the process of placental fatty acid transfer. It has been studied by several authors and using different methodological systems, but as most PUFAs in maternal plasma are esterified and associated with lipoproteins, the system is quite complex and not completely known. Most functional studies on human placenta have been carried out at the end of pregnancy using ex-vivo perfusion systems or by analyzing components contributing to transfer. However, full elucidation of the order and interaction of intracellular events, their control, and how these events are modified at different stages of pregnancy still needs additional information. Maternal dyslipidemia is quite variable under gestational diabetic conditions and depends on the degree of maternal insulin resistance and steroid hormone levels. Concerning fetal lipid metabolism, the role of maternally derived LCPUFAs on fetal development and specific functions is now well known. Although glucose oxidation is regarded as the primary route for energy production, the important role of mitochondrial fatty acid oxidation for placental and fetal metabolism has recently been recognized. Early studies demonstrate an active contribution of human fetal lipogenesis to fetal adipose tissue development. The rapid accumulation of fetal fat depots during the last weeks of intrauterine life call for additional studies to determine the factors controlling fetal lipogenesis under normal and pathological conditions such as GDM. These studies seem imperative, especially in view of newborn fat rather than birth weight being an important risk factor for later obesity.

Outlook

The important role of maternal nutrition on fetal epigenetic characteristics has now been established. It is expected that in the next 5–10 years additional efforts will be made to identify the most appropriate nutritional conditions during pregnancy and lactation to prevent the risk of long-term pathologies, with a focus on those associated with the highest mortality risk such as obesity and diabetes and their subsequent increased incidence of cardiovascular diseases. Additional research on the dynamics of placental function and the molecular biology of placental cells would provide a better understanding of placental lipid transfer under normal and diabetic conditions.

Highlights

  • Glucose plays a key role in the development of neonatal fat mass and maternal dyslipidemia in GDM, enhances the availability of lipids to the fetus, and thereby actively contributes to increased fetal adipose tissue mass.

  • During early pregnancy, maternal insulin resistance is not yet developed, but the maternal pancreas is more responsive to feeding. The resulting hyperinsulinemia stimulates adipose tissue LPL activity and lipogenesis, causing an accumulation of maternal fat depots.

  • The third trimester of pregnancy is characterized by increased catabolism in maternal adipose tissue, which contributes to the development of hypertrigyceridemia. Insulin resistance, estrogens, and adipocytokines are responsible for these changes. They are further altered in diabetic pregnancy, although maternal dyslipidemia appears quite variable.

  • The vast majority of fatty acids in the maternal circulation are esterified and associated with lipoproteins. Their placental transfer requires the associated lipoproteins to be recognized by specific receptors and the TAG and cholesterol esters to be hydrolyzed after uptake. Released NEFAs participate in placental intrinsic metabolism and a proportion is finally released to fetal circulation. These interactions are modified in GDM.

  • The fetus needs PUFAs from the maternal circulation, especially DHA and AA, which are crucial for intrauterine development and specific functions such as retinal and cerebral development. The fetus also uses fatty acids for energy production through the mitochondrial fatty acid oxidation pathway.

  • During the last weeks of intrauterine life there is a rapid increase in fetal fat accumulation. Although around half of the fat is derived from maternal sources, fetal lipogenesis from different substrates is quite active and greatly contributes to adipose tissue development. This process seems to be further enhanced under GDM conditions, contributing to the risk of excessive fetal fat accumulation.

  • The fetal lipoprotein profile is different to that of adults, and there are also changes in the apolipoprotein content in specific particles (e.g. enrichment of apo E in HDL).

  • In GDM women close to delivery, but not in controls, maternal plasma TAG and NEFA concentrations correlate with neonatal anthropometric measures, indicating that maternal lipids are strong predictors of fetal growth in GDM.

  • The increase in body fat in neonates of GDM women is a significant risk factor for later development of obesity.

Corresponding author: Emilio Herrera, University San Pablo CEU, Ctra. Boadilla del Monte km 5.300, 28668 Boadilla del Monte, Madrid, Spain, Phone: +34 913724730, Fax: +34 913510496, E-mail: ; and Department of Chemistry and Biochemistry, University San Pablo CEU, Madrid, Spain

Acknowledgments

The authors thank pp-science-editing.com for editing and linguistic revision of the manuscript. This article was written under the sponsorship of research grants from Fundación Ramón Areces of Spain (CIVP16A1835) to EH and from the European Union’s Seventh Framework Programme (FP7/2007-2013), project Early Nutrition under grant agreement number 289346 to GD. The authors declare that there is not a conflict of financial and/or other interest between them.

References

1. Balsells M, Garcia-Patterson A, Gich I, Corcoy R. Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab 2009;94:4284–91.10.1210/jc.2009-1231Search in Google Scholar

2. Melamed N, Hod M. Perinatal mortality in pregestational diabetes. Int J Gynaecol Obstet 2009;104:Suppl 1:S20–4.10.1016/j.ijgo.2008.11.024Search in Google Scholar

3. Expert Committee on the D, Classification of Diabetes M. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26:Suppl 1:S5–20.10.2337/diacare.26.2007.S5Search in Google Scholar

4. Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care 1998;21:Suppl 2:B161–7.Search in Google Scholar

5. American Diabetes A. Gestational diabetes mellitus. Diabetes Care 2004;27:Suppl 1:S88–90.10.2337/diacare.27.2007.S88Search in Google Scholar

6. Spellacy WN, Miller S, Winegar A, Peterson PQ. Macrosomia–maternal characteristics and infant complications. Obstet Gynecol 1985;66:158–61.Search in Google Scholar

7. Najafian M, Cheraghi M. Occurrence of fetal macrosomia rate and its maternal and neonatal complications: a 5-year cohort study. ISRN Obstet Gynecol 2012;2012:353791.10.5402/2012/353791Search in Google Scholar

8. Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh) 1954;16:330–42.10.1530/acta.0.0160330Search in Google Scholar

9. Jimenez-Moleon JJ, Bueno-Cavanillas A, Luna-del-Castillo Jde D, Garcia-Martin M, Lardelli-Claret P, Galvez-Vargas R. Impact of different levels of carbohydrate intolerance on neonatal outcomes classically associated with gestational diabetes mellitus. Eur J Obstet Gynecol Reprod Biol 2002;102:36–41.10.1016/S0301-2115(01)00575-9Search in Google Scholar

10. Sameshima H, Kamitomo M, Kajiya S, Kai M, Furukawa S, Ikenoue S. Early glycemic control reduces large-for-gestational-age infants in 250 Japanese gestational diabetes pregnancies. Am J Perinatol 2000;17:371–6.10.1055/s-2000-13450Search in Google Scholar PubMed

11. Fraser D, Weitzman S, Leiberman JR, Eschwege E. Factors influencing birth weight in newborns of diabetic and non-diabetic women. A population based study. Eur J Epidemiol 1990;6:427–31.10.1007/BF00151720Search in Google Scholar PubMed

12. Evers IM, de Valk HW, Mol BW, ter Braak EW, Visser GH. Macrosomia despite good glycaemic control in Type I diabetic pregnancy; results of a nationwide study in The Netherlands. Diabetologia 2002;45:1484–9.10.1007/s00125-002-0958-7Search in Google Scholar PubMed

13. Schwartz R, Gruppuso PA, Petzold K, Brambilla D, Hiilesmaa V, Teramo KA. Hyperinsulinemia and macrosomia in the fetus of the diabetic mother. Diabetes Care 1994;17:640–8.10.2337/diacare.17.7.640Search in Google Scholar

14. Herrera E, Ortega-Senovilla H. Disturbances in lipid metabolism in diabetic pregnancy – Are these the cause of the problem? Best Pract Res Clin Endocrinol Metab 2010;24:515–25.10.1016/j.beem.2010.05.006Search in Google Scholar

15. Schaefer-Graf UM, Graf K, Kulbacka I, Kjos SL, Dudenhausen J, Vetter K, Herrera E. Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus. Diabetes Care 2008;31:1858–63.10.2337/dc08-0039Search in Google Scholar

16. Schaefer-Graf UM, Meitzner K, Ortega-Senovilla H, Graf K, Vetter K, Abou-Dakn M, Herrera E. Differences in the implications of maternal lipids on fetal metabolism and growth between gestational diabetes mellitus and control pregnancies. Diabet Med 2011;28:1053–9.10.1111/j.1464-5491.2011.03346.xSearch in Google Scholar

17. Ortega-Senovilla H, Alvino G, Taricco E, Cetin I, Herrera E. Gestational diabetes mellitus upsets the proportion of fatty acids in umbilical arterial but not venous plasma. Diabetes Care 2009;32:120–2.10.2337/dc08-0679Search in Google Scholar

18. Hytten FE, Leitch I. The gross composition of the components of weight gain. In: Hytten FE, Leitch I, editors. The Physiology of Human Pregnancy, 2nd ed. Oxford: Blackwell, 1971:370–87.Search in Google Scholar

19. Villar J, Cogswell M, Kestler E, Castillo P, Menendez R, Repke JT. Effect of fat and fat-free mass deposition during pregnancy on birth weight. Am J Obstet Gynecol 1992;167:1344–52.10.1016/S0002-9378(11)91714-1Search in Google Scholar

20. Murphy SP, Abrams BF. Changes in energy intakes during pregnancy and lactation in a national sample of US women. Am J Public Health 1993;83:1161–3.10.2105/AJPH.83.8.1161Search in Google Scholar

21. Andersen O, Kuhl C. Adipocyte insulin receptor binding and lipogenesis at term in normal pregnancy. Eur J Clin Invest 1988;18:575–81.10.1111/j.1365-2362.1988.tb01270.xSearch in Google Scholar

22. Ramos MP, Crespo-Solans MD, del Campo S, Cacho J, Herrera E. Fat accumulation in the rat during early pregnancy is modulated by enhanced insulin responsiveness. Am J Physiol Endocrinol Metab 2003;285:E318–28.10.1152/ajpendo.00456.2002Search in Google Scholar

23. Alvarez JJ, Montelongo A, Iglesias A, Lasuncion MA, Herrera E. Longitudinal study on lipoprotein profile, high density lipoprotein subclass, and postheparin lipases during gestation in women. J Lipid Res 1996;37:299–308.10.1016/S0022-2275(20)37617-3Search in Google Scholar

24. Rebuffe-Scrive M, Enk L, Crona N, Lonnroth P, Abrahamsson L, Smith U, Bjorntorp P. Fat cell metabolism in different regions in women. Effect of menstrual cycle, pregnancy, and lactation. J Clin Invest 1985;75:1973–6.10.1172/JCI111914Search in Google Scholar PubMed PubMed Central

25. Mead JR, Irvine SA, Ramji DP. Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med (Berl) 2002;80:753–69.10.1007/s00109-002-0384-9Search in Google Scholar PubMed

26. Lasuncion MA, Herrera E. “In Vitro” utilization of labelled esterified fatty acids and glyceride glycerol from triglyceride-rich lipoproteins in rat adipose tissue. Horm Metab Res 1981;13:335–9.10.1055/s-2007-1019260Search in Google Scholar PubMed

27. Lasuncion MA, Herrera E. Changes with starvation in the rat of the lipoprotein lipase activity and hydrolysis of triacylglycerols from triacylglycerol-rich lipoproteins in adipose tissue preparations. Biochem J 1983;210:639–43.10.1042/bj2100639Search in Google Scholar PubMed PubMed Central

28. Williams C, Coltart TM. Adipose tissue metabolism in pregnancy: the lipolytic effect of human placental lactogen. Br J Obstet Gynaecol 1978;85:43–6.10.1111/j.1471-0528.1978.tb15824.xSearch in Google Scholar PubMed

29. Elliott JA. The effect of pregnancy on the control of lipolysis in fat cells isolated from human adipose tissue. Eur J Clin Invest 1975;5:159–63.10.1111/j.1365-2362.1975.tb02282.xSearch in Google Scholar

30. Dahlgren J. Pregnancy and insulin resistance. Metab Syndr Relat Disord 2006;4:149–52.10.1089/met.2006.4.149Search in Google Scholar PubMed

31. Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care 2007;30:Suppl 2:S112–9.10.2337/dc07-s202Search in Google Scholar PubMed

32. Sivan E, Homko CJ, Chen XH, Reece EA, Boden G. Effect of insulin on fat metabolism during and after normal pregnancy. Diabetes 1999;48:834–8.10.2337/diabetes.48.4.834Search in Google Scholar PubMed

33. Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol 2007;293:G1–4.10.1152/ajpgi.00554.2006Search in Google Scholar PubMed PubMed Central

34. Langin D. Adipose tissue lipolysis revisited (again!): lactate involvement in insulin antilipolytic action. Cell metabolism 2010;11:242–3.10.1016/j.cmet.2010.03.003Search in Google Scholar PubMed

35. Lafontan M. Historical perspectives in fat cell biology: the fat cell as a model for the investigation of hormonal and metabolic pathways. Am J Physiol Cell Physiol 2012;302:C327–59.10.1152/ajpcell.00168.2011Search in Google Scholar PubMed

36. Ryan EA, Enns L. Role of gestational hormones in the induction of insulin resistance. J Clin Endocrinol Metab 1988;67:341–7.10.1210/jcem-67-2-341Search in Google Scholar PubMed

37. Diderholm B, Stridsberg M, Ewald U, Lindeberg-Norden S, Gustafsson J. Increased lipolysis in non-obese pregnant women studied in the third trimester. BJOG 2005;112:713–8.10.1111/j.1471-0528.2004.00534.xSearch in Google Scholar PubMed

38. Boyadzhieva M, Atanasova I, Zacharieva S, Kedikova S. Adipocytokines during pregnancy and postpartum in women with gestational diabetes and healthy controls. J Endocrinol Invest 2013;36:944–9.Search in Google Scholar

39. Wojcik M, Chmielewska-Kassassir M, Grzywnowicz K, Wozniak L, Cypryk K. The relationship between adipose tissue-derived hormones and gestational diabetes mellitus (GDM). Endokrynol Pol 2014;65:134–42.10.5603/EP.2014.0019Search in Google Scholar

40. Tessier DR, Ferraro ZM, Gruslin A. Role of leptin in pregnancy: consequences of maternal obesity. Placenta 2013;34:205–11.10.1016/j.placenta.2012.11.035Search in Google Scholar PubMed

41. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, Kalhan SC, Catalano PM. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes 2002;51:2207–13.10.2337/diabetes.51.7.2207Search in Google Scholar PubMed

42. Jahromi AS, Zareian P, Madani A. Association of Insulin Resistance with Serum Interleukin-6 and TNF-alpha Levels During Normal Pregnancy. Biomark Insights 2011;6:1–6.10.4137/BMI.S6150Search in Google Scholar PubMed PubMed Central

43. Fasshauer M, Bluher M, Stumvoll M, Tonessen P, Faber R, Stepan H. Differential regulation of visfatin and adiponectin in pregnancies with normal and abnormal placental function. Clin Endocrinol (Oxf) 2007;66:434–9.10.1111/j.1365-2265.2007.02751.xSearch in Google Scholar PubMed

44. Kasher-Meron M, Mazaki-Tovi S, Barhod E, Hemi R, Haas J, Gat I, Zilberberg E, Yinon Y, Karasik A, Kanety H. Chemerin concentrations in maternal and fetal compartments: implications for metabolic adaptations to normal human pregnancy. J Perinat Med 2014;42:371–8.10.1515/jpm-2013-0166Search in Google Scholar PubMed

45. Ueland T, Dalsoren T, Voldner N, Godang K, Henriksen T, Bollerslev J. Retinol-binding protein-4 is not strongly associated with insulin sensitivity in normal pregnancies. Eur J Endocrinol 2008;159:49–54.10.1530/EJE-07-0682Search in Google Scholar PubMed

46. Nien JK, Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Gotsch F, Pineles BL, Friel LA, Espinoza J, Goncalves L, Santolaya J, Gomez R, Hong JS, Edwin S, Soto E, Richani K, Mazor M, Hassan SS. Resistin: a hormone which induces insulin resistance is increased in normal pregnancy. J Perinat Med 2007;35:513–21.10.1515/JPM.2007.122Search in Google Scholar

47. Cseh K, Baranyi E, Melczer Z, Kaszas E, Palik E, Winkler G. Plasma adiponectin and pregnancy-induced insulin resistance. Diabetes Care 2004;27:274–5.10.2337/diacare.27.1.274Search in Google Scholar

48. Skvarca A, Tomazic M, Blagus R, Krhin B, Janez A. Adiponectin/leptin ratio and insulin resistance in pregnancy. J Int Med Res 2013;41:123–8.10.1177/0300060513476409Search in Google Scholar

49. Kourtis A, Gkiomisi A, Mouzaki M, Makedou K, Anastasilakis AD, Toulis KA, Gerou S, Gavana E, Agorastos T. Apelin levels in normal pregnancy. Clin Endocrinol (Oxf) 2011;75:367–71.10.1111/j.1365-2265.2011.04061.xSearch in Google Scholar

50. Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care 2007;30:Suppl 2:S120–6.10.2337/dc07-s203Search in Google Scholar

51. Sivan E, Homko CJ, Whittaker PG, Reece EA, Chen X, Boden G. Free fatty acids and insulin resistance during pregnancy. J Clin Endocrinol Metab 1998;83:2338–42.10.1210/jc.83.7.2338Search in Google Scholar

52. Brun RP, Kim JB, Hu E, Spiegelman BM. Peroxisome proliferator-activated receptor gamma and the control of adipogenesis. Curr Opin Lipidol 1997;8:212–8.10.1097/00041433-199708000-00004Search in Google Scholar

53. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611–7.10.1016/S1097-2765(00)80211-7Search in Google Scholar

54. Qiao L, Maclean PS, Schaack J, Orlicky DJ, Darimont C, Pagliassotti M, Friedman JE, Shao J. C/EBPalpha regulates human adiponectin gene transcription through an intronic enhancer. Diabetes 2005;54:1744–54.10.2337/diabetes.54.6.1744Search in Google Scholar PubMed

55. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 1996;15:5336–48.10.1002/j.1460-2075.1996.tb00918.xSearch in Google Scholar

56. Rodriguez-Cuenca S, Carobbio S, Velagapudi VR, Barbarroja N, Moreno-Navarrete JM, Tinahones FJ, Fernandez-Real JM, Oresic M, Vidal-Puig A. Peroxisome proliferator-activated receptor gamma-dependent regulation of lipolytic nodes and metabolic flexibility. Mol Cell Biol 2012;32:1555–65.10.1128/MCB.06154-11Search in Google Scholar PubMed PubMed Central

57. Zeghari N, Vidal H, Younsi M, Ziegler O, Drouin P, Donner M. Adipocyte membrane phospholipids and PPAR-gamma expression in obese women: relationship to hyperinsulinemia. Am J Physiol Endocrinol Metab 2000;279:E736–E43.10.1152/ajpendo.2000.279.4.E736Search in Google Scholar PubMed

58. Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab 2002;282:E522–33.10.1152/ajpendo.00124.2001Search in Google Scholar PubMed

59. Montelongo A, Lasuncion MA, Pallardo LF, Herrera E. Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes 1992;41:1651–9.10.2337/diab.41.12.1651Search in Google Scholar PubMed

60. Jovanovic L, Metzger BE, Knopp RH,Conley MR, Park E, Lee YJ, Simpson JL, Holmes L, Aarons JH, Mills JL. The Diabetes in Early Pregnancy Study: beta-hydroxybutyrate levels in type 1 diabetic pregnancy compared with normal pregnancy. NICHD-Diabetes in Early Pregnancy Study Group (DIEP). National Institute of Child Health and Development. Diabetes Care 1998;21:1978–84.10.2337/diacare.21.11.1978Search in Google Scholar PubMed

61. Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, Wat NM, Wong WK, Lam KS. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006;52:405–13.10.1373/clinchem.2005.062463Search in Google Scholar PubMed

62. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, Cheung BM, Janus ED, Lam KS. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care 2007;30:2667–72.10.2337/dc07-0413Search in Google Scholar PubMed

63. Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta 2013;417:80–4.10.1016/j.cca.2012.12.007Search in Google Scholar PubMed

64. Gharibeh MY, Al Tawallbeh GM, Abboud MM, Radaideh A, Alhader AA, Khabour OF. Correlation of plasma resistin with obesity and insulin resistance in type 2 diabetic patients. Diabetes Metab 2010;36(6 Pt 1):443–9.10.1016/j.diabet.2010.05.003Search in Google Scholar PubMed

65. Tsiotra PC, Tsigos C, Anastasiou E, Yfanti E, Boutati E, Souvatzoglou E, Kyrou I, Raptis SA. Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women. Mediators Inflamm 2008;2008:892864.10.1155/2008/892864Search in Google Scholar PubMed PubMed Central

66. Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, Kiernan UA, Phillips DA, Maruyama H, Kraus BJ, Usheva A, Davis RJ, Smith U, Kahn BB. Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol 2012;32:2010–9.10.1128/MCB.06193-11Search in Google Scholar

67. Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, Abou-Dakn M, Graf K, Kintscher U, Herrera E. Gestational diabetes mellitus causes changes in the concentrations of adipocyte fatty acid-binding protein and other adipocytokines in cord blood. Diabetes Care 2011;34:2061–6.10.2337/dc11-0715Search in Google Scholar

68. Homko CJ, Sivan E, Reece EA, Boden G. Fuel metabolism during pregnancy. Semin Reprod Endocrinol 1999;17:119–25.10.1055/s-2007-1016219Search in Google Scholar

69. Knopp RH, Bonet B, Lasunción MA, Montelongo A, Herrera E. Lipoprotein metabolism in pregnancy. In: Herrera E, Knopp RH, editors. Perinatal Biochemistry. Boca Raton: CRC Press, 1992:19–51.10.1201/9781003068624-2Search in Google Scholar

70. Wasfi I, Weinstein I, Heimberg M. Increased formation of triglyceride from oleate in perfused livers from pregnant rats. Endocrinology 1980;107:584–96.10.1210/endo-107-2-584Search in Google Scholar

71. Iglesias A, Montelongo A, Herrera E, Lasuncion MA. Changes in cholesteryl ester transfer protein activity during normal gestation and postpartum. Clin Biochem 1994;27:63–8.10.1016/0009-9120(94)90013-2Search in Google Scholar

72. Silliman K, Tall AR, Kretchmer N, Forte TM. Unusual high-density lipoprotein subclass distribution during late pregnancy. Metabolism 1993;42:1592–9.10.1016/0026-0495(93)90156-ISearch in Google Scholar

73. Kinnunen PK, Unnerus HA, Ranta T, Ehnholm C, Nikkila EA, Seppala M. Activities of post-heparin plasma lipoprotein lipase and hepatic lipase during pregnancy and lactation. Eur J Clin Invest 1980;10:469–74.10.1111/j.1365-2362.1980.tb02087.xSearch in Google Scholar PubMed

74. Brinton EA. Oral estrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate. Arterioscler Thromb Vasc Biol 1996;16:431–40.10.1161/01.ATV.16.3.431Search in Google Scholar

75. Perret B, Mabile L, Martinez L, Terce F, Barbaras R, Collet X. Hepatic lipase: structure/function relationship, synthesis, and regulation. J Lipid Res 2002;43:1163–9.10.1194/jlr.R100020-JLR200Search in Google Scholar

76. Sanchez-Vera I, Bonet B, Viana M, Quintanar A, Martin MD, Blanco P, Donnay S, Albi M. Changes in plasma lipids and increased low-density lipoprotein susceptibility to oxidation in pregnancies complicated by gestational diabetes: consequences of obesity. Metabolism 2007;56:1527–33.10.1016/j.metabol.2007.06.020Search in Google Scholar PubMed

77. Hollingsworth DR, Grundy SM. Pregnancy-associated hypertriglyceridemia in normal and diabetic women. Differences in insulin-dependent, non-insulin-dependent, and gestational diabetes. Diabetes 1982;31:1092–7.10.2337/diacare.31.12.1092Search in Google Scholar

78. Koukkou E, Watts GF, Lowy C. Serum lipid, lipoprotein and apolipoprotein changes in gestational diabetes mellitus: a cross-sectional and prospective study. J Clin Pathol 1996;49:634–7.10.1136/jcp.49.8.634Search in Google Scholar

79. Marseille-Tremblay C, Ethier-Chiasson M, Forest JC, Giguere Y, Masse A, Mounier C, Lafond J. Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta. Mol Reprod Dev 2008;75:1054–62.10.1002/mrd.20842Search in Google Scholar

80. Rizzo M, Berneis K, Altinova AE, Toruner FB, Akturk M, Ayvaz G, Rini GB, Spinas GA, Arslan M. Atherogenic lipoprotein phenotype and LDL size and subclasses in women with gestational diabetes. Diabet Med 2008;25:1406–11.10.1111/j.1464-5491.2008.02613.xSearch in Google Scholar

81. Qiu C, Rudra C, Austin MA, Williams MA. Association of gestational diabetes mellitus and low-density lipoprotein (LDL) particle size. Physiol Res 2007;56:571–8.10.33549/physiolres.931073Search in Google Scholar

82. Jovanovic L, Peterson CM, Saxena BB, Dawood MY, Saudek CD. Feasibility of maintaining normal glucose profiles in insulin-dependent pregnant diabetic women. Am J Med 1980;68:105–12.10.1016/0002-9343(80)90179-5Search in Google Scholar

83. Thadhani R, Wolf M, Hsu-Blatman K, Sandler L, Nathan D, Ecker JL. First-trimester sex hormone binding globulin and subsequent gestational diabetes mellitus. Am J Obstet Gynecol 2003;189:171–6.10.1067/mob.2003.343Search in Google Scholar PubMed

84. Cetin I, Parisi F, Berti C, Mando C, Desoye G. Placental fatty acid transport in maternal obesity. J Dev Orig Health Dis 2012;3:409–14.10.1017/S2040174412000414Search in Google Scholar PubMed

85. Gil-Sanchez A, Koletzko B, Larque E. Current understanding of placental fatty acid transport. Curr Opin Clin Nutr Metab Care 2012;15:265–72.10.1097/MCO.0b013e3283523b6eSearch in Google Scholar PubMed

86. Haggarty P. Fatty acid supply to the human fetus. Annu Rev Nutr 2010;30:237–55.10.1146/annurev.nutr.012809.104742Search in Google Scholar PubMed

87. Duttaroy AK. Transport of fatty acids across the human placenta: a review. Prog Lipid Res 2009;48:52–61.10.1016/j.plipres.2008.11.001Search in Google Scholar

88. Cunningham P, McDermott L. Long chain PUFA transport in human term placenta. J Nutr 2009;139:636–9.10.3945/jn.108.098608Search in Google Scholar

89. Winkel CA, MacDonald PC, Simpson ER. The role of receptor-mediated low-density lipoprotein uptake and degradation in the regulation of progesterone biosynthesis and cholesterol metabolism by human trophoblasts. Placenta Suppl 1981;3:133–43.Search in Google Scholar

90. Winkel CA, Gilmore J, MacDonald PC, Simpson ER. Uptake and degradation of lipoproteins by human trophoblastic cells in primary culture. Endocrinology 1980;107:1892–8.10.1210/endo-107-6-1892Search in Google Scholar

91. Gauster M, Hiden U, Blaschitz A, Frank S, Lang U, Alvino G, Cetin I, Desoye G, Wadsack C. Dysregulation of placental endothelial lipase and lipoprotein lipase in intrauterine growth-restricted pregnancies. J Clin Endocrinol Metab 2007;92:2256–63.10.1210/jc.2006-2403Search in Google Scholar

92. Gauster M, Hiden U, van Poppel M, Frank S, Wadsack C, Hauguel-de Mouzon S, Desoye G. Dysregulation of placental endothelial lipase in obese women with gestational diabetes mellitus. Diabetes 2011;60:2457–64.10.2337/db10-1434Search in Google Scholar

93. Lindegaard ML, Olivecrona G, Christoffersen C, Kratky D, Hannibal J, Petersen BL, Zechner R, Damm P, Nielsen LB. Endothelial and lipoprotein lipases in human and mouse placenta. J Lipid Res 2005;46:2339–46.10.1194/jlr.M500277-JLR200Search in Google Scholar

94. Magnusson AL, Waterman IJ, Wennergren M, Jansson T, Powell TL. Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes. J Clin Endocrinol Metab 2004;89:4607–14.10.1210/jc.2003-032234Search in Google Scholar

95. Abumrad N, Coburn C, Ibrahimi A. Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm. Biochim Biophys Acta 1999;1441:4–13.10.1016/S1388-1981(99)00137-7Search in Google Scholar

96. Larque E, Demmelmair H, Klingler M, De Jonge S, Bondy B, Koletzko B. Expression pattern of fatty acid transport protein-1 (FATP-1), FATP-4 and heart-fatty acid binding protein (H-FABP) genes in human term placenta. Early Hum Dev 2006;82:697–701.10.1016/j.earlhumdev.2006.02.001Search in Google Scholar PubMed

97. Lewis RM, Hanson MA, Burdge GC. Umbilical venous-arterial plasma composition differences suggest differential incorporation of fatty acids in NEFA and cholesteryl ester pools. Br J Nutr 2011;106:463–7.10.1017/S0007114511000377Search in Google Scholar PubMed

98. Haggarty P, Ashton J, Joynson M, Abramovich DR, Page K. Effect of maternal polyunsaturated fatty acid concentration on transport by the human placenta. Biol Neonate 1999;75:350–9.10.1159/000014115Search in Google Scholar

99. Innis SM. Essential fatty acid transfer and fetal development. Placenta 2005;26:Suppl A:S70–5.10.1016/j.placenta.2005.01.005Search in Google Scholar

100. Gil-Sanchez A, Larque E, Demmelmair H, Acien MI, Faber FL, Parrilla JJ, Koletzko B. Maternal-fetal in vivo transfer of [13C]docosahexaenoic and other fatty acids across the human placenta 12 h after maternal oral intake. Am J Clin Nutr 2010;92:115–22.10.3945/ajcn.2010.29589Search in Google Scholar

101. Kazantzis M, Stahl A. Fatty acid transport proteins, implications in physiology and disease. Biochim Biophys Acta 2012;1821:852–7.10.1016/j.bbalip.2011.09.010Search in Google Scholar

102. Duttaroy AK, Crozet D, Taylor J, Gordon MJ. Acyl-CoA thioesterase activity in human placental choriocarcinoma (BeWo), cells: effects of fatty acids. Prostaglandins Leukot Essent Fatty Acids 2003;68:43–8.10.1016/S0952-3278(02)00234-XSearch in Google Scholar

103. Pagan A, Prieto-Sanchez MT, Blanco-Carnero JE, Gil-Sanchez A, Parrilla JJ, Demmelmair H, Koletzko B, Larque E. Materno-fetal transfer of docosahexaenoic acid is impaired by gestational diabetes mellitus. Am J Physiol Endocrinol Metab 2013;305:E826–33.10.1152/ajpendo.00291.2013Search in Google Scholar

104. Dancis J, Jansen V, Kayden HJ, Schneider H, Levitz M. Transfer across perfused human placenta. II. Free fatty acids. Pediatr Res 1973;7:192–7.10.1203/00006450-197304000-00022Search in Google Scholar

105. Bitsanis D, Ghebremeskel K, Moodley T, Crawford MA, Djahanbakhch O. Gestational diabetes mellitus enhances arachidonic and docosahexaenoic acids in placental phospholipids. Lipids 2006;41:341–6.10.1007/s11745-006-5104-8Search in Google Scholar

106. Kuhn DC, Crawford MA, Stuart MJ, Botti JJ, Demers LM. Alterations in transfer and lipid distribution of arachidonic acid in placentas of diabetic pregnancies. Diabetes 1990;39:914–8.10.2337/diab.39.8.914Search in Google Scholar

107. Desoye G, Shafrir E. Placental metabolism and its regulation in health and diabetes. Mol Aspects Med 1994;15:505–682.10.1016/0098-2997(94)90004-3Search in Google Scholar

108. Diamant YZ, Metzger BE, Freinkel N, Shafrir E. Placental lipid and glycogen content in human and experimental diabetes mellitus. Am J Obstet Gynecol 1982;144:5–11.10.1016/0002-9378(82)90385-4Search in Google Scholar

109. Jones CJ, Fox H. Ultrastructure of the normal human placenta. Electron Microsc Rev 1991;4:129–78.10.1016/0892-0354(91)90019-9Search in Google Scholar

110. Pathmaperuma AN, Mana P, Cheung SN, Kugathas K, Josiah A, Koina ME, Broomfield A, Delghingaro-Augusto V, Ellwood DA, Dahlstrom JE, Nolan CJ. Fatty acids alter glycerolipid metabolism and induce lipid droplet formation, syncytialisation and cytokine production in human trophoblasts with minimal glucose effect or interaction. Placenta 2010;31:230–9.10.1016/j.placenta.2009.12.013Search in Google Scholar

111. Elchalal U, Schaiff WT, Smith SD, Rimon E, Bildirici I, Nelson DM, Sadovsky Y. Insulin and fatty acids regulate the expression of the fat droplet-associated protein adipophilin in primary human trophoblasts. Am J Obstet Gynecol 2005;193:1716–23.10.1016/j.ajog.2005.04.012Search in Google Scholar

112. Scifres CM, Chen B, Nelson DM, Sadovsky Y. Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. J Clin Endocrinol Metab 2011;96:E1083–91.10.1210/jc.2010-2084Search in Google Scholar

113. Hauguel S, Desmaizieres V, Challier JC. Glucose uptake, utilization, and transfer by the human placenta as functions of maternal glucose concentration. Pediatr Res 1986;20:269–73.10.1203/00006450-198603000-00015Search in Google Scholar

114. Rakheja D, Bennett MJ, Foster BM, Domiati-Saad R, Rogers BB. Evidence for fatty acid oxidation in human placenta, and the relationship of fatty acid oxidation enzyme activities with gestational age. Placenta 2002;23:447–50.10.1053/plac.2002.0808Search in Google Scholar

115. Shekhawat P, Bennett MJ, Sadovsky Y, Nelson DM, Rakheja D, Strauss AW. Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases. Am J Physiol Endocrinol Metab 2003;284:E1098–105.10.1152/ajpendo.00481.2002Search in Google Scholar

116. Kuhn DC, Botti JJ, Cherouny PH, Demers LM. Eicosanoid production and transfer in the placenta of the diabetic pregnancy. Prostaglandins 1990;40:205–15.10.1016/0090-6980(90)90084-9Search in Google Scholar

117. Muskiet FA, Fokkema MR, Schaafsma A, Boersma ER, Crawford MA. Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr 2004;134:183–6.10.1093/jn/134.1.183Search in Google Scholar PubMed

118. Le HD, Meisel JA, de Meijer VE, Gura KM, Puder M. The essentiality of arachidonic acid and docosahexaenoic acid. Prostaglandins Leukot Essent Fatty Acids 2009;81:165–70.10.1016/j.plefa.2009.05.020Search in Google Scholar

119. Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 2002;19:43–55.10.1385/ENDO:19:1:43Search in Google Scholar

120. Herrera E, Amusquivar E, Lopez-Soldado I, Ortega H. Maternal lipid metabolism and placental lipid transfer. Horm Res 2006;65:Suppl 3:59–64.10.1159/000091507Search in Google Scholar PubMed

121. Matorras R, Ruiz JI, Mendoza R, Ruiz N, Sanjurjo P, Rodriguez-Escudero FJ. Fatty acid composition of fertilization-failed human oocytes. Hum Reprod 1998;13:2227–30.10.1093/humrep/13.8.2227Search in Google Scholar PubMed

122. Uauy R, Treen M, Hoffman DR. Essential fatty acid metabolism and requirements during development. Semin Perinatol 1989;13:118–30.Search in Google Scholar

123. Koletzko B, Cetin I, Brenna JT, Perinatal Lipid Intake Working Group; Child Health Foundation; Diabetic Pregnancy Study Group; European Association of Perinatal Medicine; European Association of Perinatal Medicine; European Society for Clinical Nutrition and Metabolism; European Society for Paediatric Gastroenterology, Hepatology and Nutrition, Committee on Nutrition; International Federation of Placenta Associations; International Society for the Study of Fatty Acida and Lipids.. Dietary fat intakes for pregnant and lactating women. Br J Nutr 2007;98:873–7.10.1017/S0007114507764747Search in Google Scholar PubMed

124. Carlson SE, Werkman SH, Peeples JM, Cooke RJ, Tolley EA. Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci USA 1993;90:1073–7.10.1073/pnas.90.3.1073Search in Google Scholar PubMed PubMed Central

125. Woltil HA, van Beusekom CM, Schaafsma A, Muskiet FA, Okken A. Long-chain polyunsaturated fatty acid status and early growth of low birth weight infants. Eur J Pediatr 1998;157:146–52.10.1007/s004310050787Search in Google Scholar PubMed

126. Girard J, Ferre P, Pegorier JP, Duee PH. Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiol Rev 1992;72:507–62.10.1152/physrev.1992.72.2.507Search in Google Scholar PubMed

127. Oey NA, den Boer ME, Ruiter JP, Wanders RJ, Duran M, Waterham HR, Boer K, van der Post JA, Wijburg FA. High activity of fatty acid oxidation enzymes in human placenta: implications for fetal-maternal disease. J Inherit Metab Dis 2003;26:385–92.10.1023/A:1025163204165Search in Google Scholar

128. Strauss AW. Surprising? Perhaps not. Long-chain fatty acid oxidation during human fetal development. Pediatr Res 2005;57:753–4.10.1203/01.PDR.0000161412.24792.55Search in Google Scholar PubMed

129. Oey NA, den Boer ME, Wijburg FA, Vekemans M, Auge J, Steiner C, Wanders RJ, Waterham HR, Ruiter JP, Attie-Bitach T. Long-chain fatty acid oxidation during early human development. Pediatr Res 2005;57:755–9.10.1203/01.PDR.0000161413.42874.74Search in Google Scholar

130. Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol 2002;64:477–502.10.1146/annurev.physiol.64.082201.154705Search in Google Scholar

131. Bennett MJ, Rinaldo P, Strauss AW. Inborn errors of mitochondrial fatty acid oxidation. Crit Rev Clin Lab Sci 2000;37:1–44.10.1080/10408360091174169Search in Google Scholar

132. Ibdah JA, Paul H, Zhao Y, Binford S, Salleng K, Cline M, Matern D, Bennett MJ, Rinaldo P, Strauss AW. Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death. J Clin Invest 2001;107:1403–9.10.1172/JCI12590Search in Google Scholar

133. Kurtz DM, Rinaldo P, Rhead WJ, Tian L, Millington DS, Vockley J, Hamm DA, Brix AE, Lindsey JR, Pinkert CA, O’Brien WE, Wood PA. Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation. Proc Natl Acad Sci USA 1998;95:15592–7.10.1073/pnas.95.26.15592Search in Google Scholar

134. Cox KB, Hamm DA, Millington DS, Matern D, Vockley J, Rinaldo P, Pinkert CA, Rhead WJ, Lindsey JR, Wood PA. Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse. Hum Mol Genet 2001;10:2069–77.10.1093/hmg/10.19.2069Search in Google Scholar

135. Kompare M, Rizzo WB. Mitochondrial fatty-acid oxidation disorders. Semin Pediatr Neurol 2008;15:140–9.10.1016/j.spen.2008.05.008Search in Google Scholar

136. Hahn P, Novak M. Development of brown and white adipose tissue. Journal of lipid research 1975;16:79–91.10.1016/S0022-2275(20)36732-8Search in Google Scholar

137. Van Aerde JE, Wilke MS, Feldman M, Clandinin MT. Accretion of lipid in the fetus and newborn, 4th ed. Philadelphia: Elsevier, Saunders, 2011.10.1016/B978-1-4160-3479-7.10042-4Search in Google Scholar

138. Heim T. Energy and lipid requirements of the fetus and the preterm infant. J Pediatr Gastroenterol Nutr 1983;2:Suppl 1:S16–41.10.1097/00005176-198300201-00004Search in Google Scholar PubMed

139. Catalano PM, Kirwan JP. Maternal factors that determine neonatal size and body fat. Current diabetes reports 2001;1:71–7.10.1007/s11892-001-0013-ySearch in Google Scholar

140. Desoye G, Hauguel-de Mouzon S, Shafrir E. The placenta in diabetic pregnancy: placental transfer of nutrients, 2nd ed. London: Informa Healthcare, 2003.Search in Google Scholar

141. Villee CA, Loring JM. Alternative pathways of carbohydrate metabolism in foetal and adult tissues. Biochem J 1961;81:488–94.10.1042/bj0810488Search in Google Scholar

142. Villee CA, Hagerman DD, Holmberg N, Lind J, Vilee DB. The effects of anoxia on the metabolism of human fetal tissues. Pediatrics 1958;22:953–71.10.1542/peds.22.5.953Search in Google Scholar

143. Dunlop M, Court JM. Lipogenesis in developing human adipose tissue. Early Hum Dev 1978;2:123–30.10.1016/0378-3782(78)90004-XSearch in Google Scholar

144. Coltart TM. Effect on fetal liver lipids of 14 C glucose administered intravenously to the mother. J Obstet Gynaecol Br Commonw 1972;79:639–43.10.1111/j.1471-0528.1972.tb14214.xSearch in Google Scholar PubMed

145. Villee CA, Hagerman DD. Effect of oxygen deprivation on the metabolism of fetal and adult tissues. Am J Physiol 1958;194:457–64.10.1152/ajplegacy.1958.194.3.457Search in Google Scholar PubMed

146. Yoshioka T, Roux JF. In vitro metabolism of palmitic acid in human fetal tissue. Pediatr Res 1972;6:675–81.10.1203/00006450-197208000-00005Search in Google Scholar PubMed

147. Volpe JJ, Kishimoto Y. Fatty acid synthetase of brain: development, influence of nutritional and hormonal factors and comparison with liver enzyme. J Neurochem 1972;19:737–53.10.1111/j.1471-4159.1972.tb01389.xSearch in Google Scholar PubMed

148. Ailhaud G, Grimaldi P, Negrel R. Cellular and molecular aspects of adipose tissue development. Annu Rev Nutr 1992;12:207–33.10.1146/annurev.nu.12.070192.001231Search in Google Scholar PubMed

149. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006;7:885–96.10.1038/nrm2066Search in Google Scholar PubMed

150. Poissonnet CM, Burdi AR, Bookstein FL. Growth and development of human adipose tissue during early gestation. Early Hum Dev 1983;8:1–11.10.1016/0378-3782(83)90028-2Search in Google Scholar

151. Feng B, Zhang T, Xu H. Human adipose dynamics and metabolic health. Ann N Y Acad Sci 2013;1281:160–77.10.1111/nyas.12009Search in Google Scholar

152. Ailhaud G, Hauner H. Development of white adipose tissue, 2nd ed. New York, N.Y.: Marcel Dekker, 2004.Search in Google Scholar

153. Sjostrom L, William-Olsson T. Prospective studies on adipose tissue development in man. Int J Obes 1981;5:597–604.Search in Google Scholar

154. Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 2011;12:722–34.10.1038/nrm3198Search in Google Scholar

155. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 2008;77:289–312.10.1146/annurev.biochem.77.061307.091829Search in Google Scholar

156. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994;79:1147–56.10.1016/0092-8674(94)90006-XSearch in Google Scholar

157. Weiss PA, Scholz HS, Haas J, Tamussino KF, Seissler J, Borkenstein MH. Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors. Diabetes Care 2000;23:905–11.10.2337/diacare.23.7.905Search in Google Scholar PubMed

158. Sewell MF, Huston-Presley L, Super DM, Catalano P. Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J Obstet Gynecol 2006;195:1100–3.10.1016/j.ajog.2006.06.014Search in Google Scholar PubMed

159. Hull HR, Dinger MK, Knehans AW, Thompson DM, Fields DA. Impact of maternal body mass index on neonate birthweight and body composition. Am J Obstet Gynecol 2008;198: 416 e1–6.10.1016/j.ajog.2007.10.796Search in Google Scholar PubMed

160. Estampador AC, Pomeroy J, Renstrom F, Nelson SM, Mogren I, Persson M, Sattar N, Domellof M, Franks PW. Infant body composition and adipokine concentrations in relation to maternal gestational weight gain. Diabetes Care 2014;37:1432–8.10.2337/dc13-2265Search in Google Scholar PubMed PubMed Central

161. Carlsen EM, Renault KM, Norgaard K, Nilas L, Jensen JE, Hyldstrup L, Michaelsen KF, Cortes D, Pryds O. Newborn regional body composition is influenced by maternal obesity, gestational weight gain and the birthweight standard score. Acta Paediatr 2014;103:939–45.10.1111/apa.12713Search in Google Scholar PubMed

162. Streuling I, Beyerlein A, von Kries R. Can gestational weight gain be modified by increasing physical activity and diet counseling? A meta-analysis of interventional trials. Am J Clin Nutr 2010;92:678–87.10.3945/ajcn.2010.29363Search in Google Scholar

163. Tanentsapf I, Heitmann BL, Adegboye AR. Systematic review of clinical trials on dietary interventions to prevent excessive weight gain during pregnancy among normal weight, overweight and obese women. BMC Pregnancy Childbirth 2011;11:81.10.1186/1471-2393-11-81Search in Google Scholar

164. Thangaratinam S, Rogozinska E, Jolly K, Glinkowski S, Roseboom T, Tomlinson JW, Kunz R, Mol BW, Coomarasamy A, Khan KS. Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence. Br Med J 2012;344:e2088.10.1097/OGX.0b013e31826f78d9Search in Google Scholar

165. Amri EZ, Ailhaud G, Grimaldi PA. Fatty acids as signal transducing molecules: involvement in the differentiation of preadipose to adipose cells. J Lipid Res 1994;35:930–7.10.1016/S0022-2275(20)39187-2Search in Google Scholar

166. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999;3:397–403.10.1016/S1097-2765(00)80467-0Search in Google Scholar

167. Ailhaud G, Massiera F, Weill P, Legrand P, Alessandri JM, Guesnet P. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 2006;45:203–36.10.1016/j.plipres.2006.01.003Search in Google Scholar

168. Azain MJ. Role of fatty acids in adipocyte growth and development. J Anim Sci 2004;82:916–24.10.2527/2004.823916xSearch in Google Scholar

169. Hauner H, Much D, Vollhardt C, Brunner S, Schmid D, Sedlmeier EM, Heimberg E, Schuster T, Zimmermann A, Schneider KT, Bader BL, Amann-Gassner U. Effect of reducing the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on infant adipose tissue growth within the first year of life: an open-label randomized controlled trial. Am J Clin Nutr 2012;95:383–94.10.3945/ajcn.111.022590Search in Google Scholar

170. Hauner H, Brunner S, Amann-Gassner U. The role of dietary fatty acids for early human adipose tissue growth. Am J Clin Nutr 2013;98:549S–55S.10.3945/ajcn.112.040733Search in Google Scholar

171. Catalano PM, Thomas A, Huston-Presley L, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol 2003;189:1698–704.10.1016/S0002-9378(03)00828-7Search in Google Scholar

172. Enzi G, Inelmen EM, Caretta F, Villani F, Zanardo V, DeBiasi F. Development of adipose tissue in newborns of gestational-diabetic and insulin-dependent diabetic mothers. Diabetes 1980;29:100–4.10.2337/diab.29.2.100Search in Google Scholar PubMed

173. Enzi G, Inelmen EM, Caretta F, Rubaltelli F, Grella P, Baritussio A. Adipose tissue development “in utero”. Relationships between some nutritional and hormonal factors and body fat mass enlargement in newborns. Diabetologia 1980;18:135–40.10.1007/BF00290490Search in Google Scholar PubMed

174. Cortelazzi D, Corbetta S, Ronzoni S, Pelle F, Marconi A, Cozzi V, Cetin I, Cortelazzi R, Beck-Peccoz P, Spada, A. Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies. Clin Endocrinol (Oxf) 2007;66:447–53.10.1111/j.1365-2265.2007.02761.xSearch in Google Scholar PubMed

175. Christou H, Serdy S, Mantzoros CS. Leptin in relation to growth and developmental processes in the fetus. Semin Reprod Med 2002;20:123–30.10.1055/s-2002-32503Search in Google Scholar PubMed

176. Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Schiff E, Sivan E. Cord blood adiponectin in large-for-gestational age newborns. Am J Obstet Gynecol 2005;193(3 Pt 2):1238–42.10.1016/j.ajog.2005.05.049Search in Google Scholar PubMed

177. Briana DD, Malamitsi-Puchner A. Reviews: adipocytokines in normal and complicated pregnancies. Reprod Sci 2009;16:921–37.10.1177/1933719109336614Search in Google Scholar PubMed

178. Briana DD, Malamitsi-Puchner A. Intrauterine growth restriction and adult disease: the role of adipocytokines. Eur J Endocrinol 2009;160:337–47.10.1530/EJE-08-0621Search in Google Scholar PubMed

179. Briana DD, Malamitsi-Puchner A. The role of adipocytokines in fetal growth. Ann N Y Acad Sci 2010;1205:82–7.10.1111/j.1749-6632.2010.05650.xSearch in Google Scholar PubMed

180. Smith AJ, Thompson BR, Sanders MA, Bernlohr DA. Interaction of the adipocyte fatty acid-binding protein with the hormone-sensitive lipase: regulation by fatty acids and phosphorylation. J Biol Chem 2007;282:32424–32.10.1074/jbc.M703730200Search in Google Scholar PubMed

181. Okereke NC, Uvena-Celebrezze J, Hutson-Presley L, Amini SB, Catalano PM. The effect of gender and gestational diabetes mellitus on cord leptin concentration. Am J Obstet Gynecol 2002;187:798–803.10.1067/mob.2002.125887Search in Google Scholar PubMed

182. Gross GA, Solenberger T, Philpott T, Holcomb WL, Jr., Landt M. Plasma leptin concentrations in newborns of diabetic and nondiabetic mothers. Am J Perinatol 1998;15:243–7.10.1055/s-2007-993935Search in Google Scholar PubMed

183. Lepercq J, Cauzac M, Lahlou N, Timsit J, Girard J, Auwerx J, Hauguel-de Mouzon S. Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes 1998;47:847–50.10.2337/diabetes.47.5.847Search in Google Scholar PubMed

184. Maffei M, Volpe L, Di Cianni G, Bertacca A, Ferdeghini M, Murru S, Teti G, Casadidio I, Cecchetti P, Navalesi R, Benzi L. Plasma leptin levels in newborns from normal and diabetic mothers. Horm Metab Res 1998;30:575–80.10.1055/s-2007-978936Search in Google Scholar PubMed

185. Marchini G, Fried G, Ostlund E, Hagenas L. Plasma leptin in infants: relations to birth weight and weight loss. Pediatrics 1998;101(3 Pt 1):429–32.10.1542/peds.101.3.429Search in Google Scholar PubMed

186. Wolf HJ, Ebenbichler CF, Huter O, Bodner J, Lechleitner M, Foger B, Patsch JR, Desoye G. Fetal leptin and insulin levels only correlate inlarge-for-gestational age infants. Eur J Endocrinol 2000;142:623–9.10.1530/eje.0.1420623Search in Google Scholar PubMed

187. Ategbo JM, Grissa O, Yessoufou A, Hichami A, Dramane KL, Moutairou K, Miled A, Grissa A, Jerbi M, Tabka Z, Khan NA. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. J Clin Endocrinol Metab 2006;91:4137–43.10.1210/jc.2006-0980Search in Google Scholar PubMed

188. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 2006;354:2552–63.10.1056/NEJMoa054862Search in Google Scholar PubMed

189. Choi SH, Kwak SH, Youn BS, Lim S, Park YJ, Lee H, Kim YB, Park KS, Jang HC. High plasma retinol binding protein-4 and low plasma adiponectin concentrations are associated with severity of glucose intolerance in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 2008;93:3142–8.10.1210/jc.2007-1755Search in Google Scholar PubMed

190. Corbetta S, Bulfamante G, Cortelazzi D, Barresi V, Cetin I, Mantovani G, Bondioni S, Beck-Peccoz P, Spada A. Adiponectin expression in human fetal tissues during mid- and late gestation. J Clin Endocrinol Metab 2005;90:2397–402.10.1210/jc.2004-1553Search in Google Scholar PubMed

191. Kadowaki K, Waguri M, Nakanishi I, Miyashita Y, Nakayama M, Suehara N, Funahashi T, Shimomura I, Fujita T. Adiponectin concentration in umbilical cord serum is positively associated with the weight ratio of fetus to placenta. J Clin Endocrinol Metab 2006;91:5090–4.10.1210/jc.2005-2846Search in Google Scholar PubMed

192. Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH, Cohen JC. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest 2009;119:70–9.10.1172/JCI37118Search in Google Scholar

193. Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Frase, CC, Yang DD, Heuer JG, Jaskunas SR, Eacho P. Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 2005;146:4943–50.10.1210/en.2005-0476Search in Google Scholar

194. Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, Abou-Dakn M, Herrera E. Decreased concentrations of the lipoprotein lipase inhibitor angiopoietin-like protein 4 and increased serum triacylglycerol are associated with increased neonatal fat mass in pregnant women with gestational diabetes mellitus. J Clin Endocrinol Metab 2013;98:3430–7.10.1210/jc.2013-1614Search in Google Scholar

195. Johnson HJ Jr, Simpson ER, Carr BR, MacDonald PC, Parker RC Jr. The levels of plasma cholesterol in the human fetus throughout gestation. Pediatr Res 1982;16:682–3.10.1203/00006450-198208000-00021Search in Google Scholar

196. Donega S, Oba J, Maranhao RC. [Concentration of serum lipids and apolipoprotein B in newborns]. Arq Bras Cardiol 2006;86:419–24.10.1590/S0066-782X2006000600003Search in Google Scholar

197. Mott GE. Lipoprotein metabolism and nutritional programming in the fetus and neonate, 4th ed. Philadelphia: Elsevier Saunders, 2011.10.1016/B978-1-4160-3479-7.10047-3Search in Google Scholar

198. Chow SN, Chen HY, Ouyang PC, Lee TY, Wei PY, Chen JS. Serum triglyceride levels in newborns and mothers at parturition. Int J Biol Res Pregnancy 1982;3:30–2.Search in Google Scholar

199. Alvino G, Cozzi V, Radaelli T, Ortega H, Herrera E, Cetin I. Maternal and fetal fatty acid profile in normal and intrauterine growth restriction pregnancies with and without preeclampsia. Pediatr Res 2008;64:615–20.10.1203/PDR.0b013e31818702a2Search in Google Scholar

200. Cai HJ, Xie CL, Chen Q, Chen XY, Chen YH. The relationship between hepatic low-density lipoprotein receptor activity and serum cholesterol level in the human fetus. Hepatology 1991;13:852–7.10.1002/hep.1840130509Search in Google Scholar

201. Parker CR Jr, Carr BR, Simpson ER, MacDonald PC. Decline in the concentration of low-density lipoprotein-cholesterol in human fetal plasma near term. Metabolism 1983;32:919–23.10.1016/0026-0495(83)90207-XSearch in Google Scholar

202. Davis PA, Forte TM, Nichols AV, Blum CB. Umbilical cord blood lipoproteins. Isolation and characterization of high density lipoproteins. Arteriosclerosis 1983;3:357–65.10.1161/01.ATV.3.4.357Search in Google Scholar

203. Nichols AV, Blanche PJ, Genzel-Boroviczeny O, Forte TM, Gong EL. Apolipoprotein-specific populations in high density lipoproteins of human cord blood. Biochim Biophys Acta 1991;1085:306–4.10.1016/0005-2760(91)90134-4Search in Google Scholar

204. Winkler L, Schlag B, Goetze E. Concentration and composition of the lipoprotein classes in human umbilical cord serum. Clin Chim Acta 1977;76:187–91.10.1016/0009-8981(77)90095-XSearch in Google Scholar

205. van Biervliet JP, Rosseneu M, Bury J, Caster H, Stul MS, Lamote R. Apolipoprotein and lipid composition of plasma lipoproteins in neonates during the first month of life. Pediatr Res 1986;20:324–8.10.1203/00006450-198604000-00009Search in Google Scholar

206. Averna MR, Barbagallo CM, Di Paola G, Labisi M, Pinna G, Marino G, Dimita U, Notarbartolo A. Lipids, lipoproteins and apolipoproteins AI, AII, B, CII, CIII and E in newborns. Biol Neonate 1991;60:187–92.10.1159/000243407Search in Google Scholar

207. McConathy WJ, Lane DM. Studies on the apolipoproteins and lipoproteins of cord serum. Pediatr Res 1980;14:757–61.10.1203/00006450-198005000-00009Search in Google Scholar

208. Parker CR Jr, Fortunato SJ, Carr BR, Owen J, Hankins GD, Hauth JC. Apolipoprotein A-1 in umbilical cord blood of newborn infants: relation to gestational age and high-density lipoprotein cholesterol. Pediatr Res 1988;23:348–51.10.1203/00006450-198804000-00002Search in Google Scholar

209. Blum CB, Davis PA, Forte TM. Elevated levels of apolipoprotein E in the high density lipoproteins of human cord blood plasma. J Lipid Res 1985;26:755–60.10.1016/S0022-2275(20)34333-9Search in Google Scholar

210. Augsten M, Hackl H, Ebner B, Chemelli A, Glatter O, Marsche G, Lang U, Desoye G, Wadsack C. Fetal HDL/apoE: a novel regulator of gene expression in human placental endothelial cells. Physiol Genomics 2011;43:1255–62.10.1152/physiolgenomics.00109.2011Search in Google Scholar PubMed

211. Packard CJ, McKinney L, Carr K, Shepherd J. Cholesterol feeding increases low density lipoprotein synthesis. J Clin Invest 1983;72:45–51.10.1172/JCI110983Search in Google Scholar

212. Amr S, Chowdhry P, Hamosh P, Hamosh M. Low levels of apolipoprotein A1 are not contributors to the low lecithin-cholesterol acyl transferase activity in premature newborn infants. Pediatr Res 1988;24:191–3.10.1203/00006450-198808000-00010Search in Google Scholar PubMed

213. Lacko AG, Rutenberg HL, Soloff LA. On the rate of cholesterol esterification in cord blood serum. Lipids 1972;7:426–9.10.1007/BF02531515Search in Google Scholar PubMed

214. Dolphin PJ, Breckenridge WC, Dolphin MA, Tan MH. The lipoproteins of human umbilical cord blood apolipoprotein and lipid levels. Atherosclerosis 1984;51:109–22.10.1016/0021-9150(84)90147-3Search in Google Scholar

215. Fordyce MK, Duncan R, Chao R, Christakis M, Hsia SL, Robertson E, Kafatos A, Christakis G. Cord blood serum in newborns of diabetic mothers. J Chronic Dis 1983;36:263–8.10.1016/0021-9681(83)90061-9Search in Google Scholar

216. Kilby MD, Neary RH, Mackness MI, Durrington PN. Fetal and maternal lipoprotein metabolism in human pregnancy complicated by type I diabetes mellitus. J Clin Endocrinol Metab 1998;83:1736–41.10.1210/jc.83.5.1736Search in Google Scholar

217. Sreckovic I, Birner-Gruenberger R, Besenboeck C, Miljkovic M, Stojakovic T, Scharnagl H, Marsche G, Lang U, Kotur-Stevuljevic J, Jelic-Ivanovic Z, Desoye G, Wadsack C. Gestational diabetes mellitus modulates neonatal high-density lipoprotein composition and its functional heterogeneity. Biochim Biophys Acta 2014;1841:1619–27.10.1016/j.bbalip.2014.07.021Search in Google Scholar

218. Higgins M, Mc Auliffe F. A review of maternal and fetal growth factors in diabetic pregnancy. Curr Diabetes Rev 2010;6:116–25.10.2174/157339910790909431Search in Google Scholar

219. Chex N, Scholl TO. Glucose, foetal growth and pregnancy. In: Pertry CJ, editor. Gestational diabetes: origins, complications and treatment. Boca Raton: CRC Press, 2014:3–32.10.1201/b16474-3Search in Google Scholar

220. Simeonova-Krstevska S, Krstevska B, Velkoska-Nakova V, Hadji Lega M, Samardjiski I, Serafimoski V, Livrinova V, Todorovska I, Sima A. Effect of lipid parameters on foetal growth in gestational diabetes mellitus pregnancies. Prilozi 2014;35:131–6.10.2478/prilozi-2014-0017Search in Google Scholar

221. Kitajima M, Oka S, Yasuhi I, Fukuda M, Rii Y, Ishimaru T. Maternal serum triglyceride at 24–32 weeks’ gestation and newborn weight in nondiabetic women with positive diabetic screens. Obstet Gynecol 2001;97(5 Pt 1):776–80.10.1016/S0029-7844(01)01328-XSearch in Google Scholar

222. Oken E, Gillman MW. Fetal origins of obesity. Obes Res 2003;11:496–506.10.1038/oby.2003.69Search in Google Scholar PubMed

223. Catalano PM, Farrell K, Thomas A, Huston-Presley L, Mencin P, de Mouzon SH, Amini SB. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr 2009; 90:1303–13.10.3945/ajcn.2008.27416Search in Google Scholar PubMed PubMed Central

Received: 2015-6-25
Accepted: 2015-7-8
Published Online: 2015-8-18
Published in Print: 2016-5-1

©2016 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Topic B: Pathophysiology of Diabetes on Metabolic, Reproductive and Other Disorders: Endocrine Aspects
  3. Mini-Review Article
  4. Hyperglycemic memory in metabolism and cancer
  5. Review Articles
  6. Molecular mechanisms redirecting the GLP-1 receptor signalling profile in pancreatic β-cells during type 2 diabetes
  7. Pathophysiology of obesity on knee joint homeostasis: contributions of the infrapatellar fat pad
  8. Maternal and fetal lipid metabolism under normal and gestational diabetic conditions
  9. Male gonadal axis function in patients with type 2 diabetes
  10. Original Article
  11. Ingestion of a natural mineral-rich water in an animal model of metabolic syndrome: effects in insulin signalling and endoplasmic reticulum stress
https://doi.org/10.1515/hmbci-2015-0025
Keywords for this article
fatty acids; fetal lipids; gestational diabetes; human pregnancy; maternal lipids

Articles in the same Issue

  1. Frontmatter
  2. Topic B: Pathophysiology of Diabetes on Metabolic, Reproductive and Other Disorders: Endocrine Aspects
  3. Mini-Review Article
  4. Hyperglycemic memory in metabolism and cancer
  5. Review Articles
  6. Molecular mechanisms redirecting the GLP-1 receptor signalling profile in pancreatic β-cells during type 2 diabetes
  7. Pathophysiology of obesity on knee joint homeostasis: contributions of the infrapatellar fat pad
  8. Maternal and fetal lipid metabolism under normal and gestational diabetic conditions
  9. Male gonadal axis function in patients with type 2 diabetes
  10. Original Article
  11. Ingestion of a natural mineral-rich water in an animal model of metabolic syndrome: effects in insulin signalling and endoplasmic reticulum stress
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