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Maternal obesity, lipotoxicity and cardiovascular diseases in offspring
Journal of Molecular and Cellular Cardiology 55 (2013) 111–116
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Review article
Maternal obesity, lipotoxicity and cardiovascular diseases in offspring Maolong Dong a, b, 1, Qijun Zheng c, 1, Stephen P. Ford d, Peter W. Nathanielsz e, Jun Ren a, b, d,⁎ a
Department of Burn and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, 82071, USA c Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China d Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY 82071, USA e Center for Pregnancy and Newborn Research, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78299, USA b
a r t i c l e
i n f o
Article history: Received 23 June 2012 Received in revised form 28 August 2012 Accepted 28 August 2012 Available online 6 September 2012 Keywords: Maternal obesity Cardiovascular diseases Obesity Insulin resistance
a b s t r a c t Maternal obesity has risen dramatically over the past 20 years, by nearly 42% in African-Americans and 29% in Caucasians. Maternal obesity is afflicted with many maternal obstetric complications in the offspring including high blood pressure, obesity, gestational diabetes and increased perinatal morbidity. Maternal nutritional environment plays a rather important role in the programming of the health set-points in the offspring such as glucose and insulin metabolism, energy balance and predisposition to metabolic disorders. In particular, maternal obesity is associated with elevated prevalence of cardiovascular diseases in the offspring. Evidence from human and experimental studies including rodents and nonhuman primates has indicated that maternal obesity or overnutrition programs offspring for an increased risk of adult obesity. Maternal obesity or fat diet exposure predisposes the onset and development of obesity, insulin resistance, cardiac hypertrophy and myocardial contractile anomalies in the offspring. A number of mechanisms including elevated hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines have been postulated to play a key role in maternal obesity-induced postnatal cardiovascular sequelae. In addition, lipotoxicity (accumulation of lipid metabolites) resulting from maternal obesity is capable of activating a number of stress signaling cascades including pro-inflammatory cytokines and oxidative stress to exacerbate maternal obesity-induced cardiovascular complications later on in adult life. This mini-review summarizes the recent knowledge with regard to the role of lipotoxicity in maternal obesity-induced change in cardiovascular function in the offspring. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". © 2012 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . Fetal programming and cardiovascular function . . . Lipotoxicity and maternal obesity . . . . . . . . . 3.1. Oxidative stress . . . . . . . . . . . . . . 3.2. Adipokines . . . . . . . . . . . . . . . . 3.3. Insulin resistance . . . . . . . . . . . . . 3.4. Genetic disorders in lipid transport/metabolism 4. Conclusion . . . . . . . . . . . . . . . . . . . . Disclosure statement . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
⁎ Corresponding author at: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Tel.: + 1 307 766 6131; fax: + 1 307 766 2953. E-mail address: [email protected] (J. Ren). 1 Equal contribution. 0022-2828/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.yjmcc.2012.08.023
Obesity is a devastating epidemic medical problem in the United States and other parts of the world. Conservative estimate suggests a rise of ~ 50% in the prevalence of obesity during the last decade affecting all ages, ethnicities and genders [1]. While obesity is too complex to be attributed to a single factor, the dramatic rise in such a
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short time frame implicates a pivotal role of lifestyle and epigenetic factors including food intake and physical activity in the pathogenesis of obesity [2,3]. Uncorrected obesity is known as an independent risk factor for diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease. Sedentary lifestyle along with increased caloric intake has been deemed one of the main causes of obesity and metabolic syndrome [2,4,5]. Obesity imposes a substantial unfavorable effect on the heart as a consequence of autonomic stimulation and excess fat accumulation in and around the heart [4,6]. In particular, obesity leads to cardiac hypertrophy (remodeling), interstitial fibrosis and ventricular contractile dysfunction that are exacerbated by concomitant sympathetic overdrive resulting in the refractoriness to β-adrenergic stimulation [7]. Obesity-related myocardial dysfunction is characterized by an early increase in cardiac output and stroke volume associated with increased oxygen consumption and volume overload [8]. With sustained uncorrected obesity, the heart becomes decompensated and exhibits contractile dysfunction in association with cardiac hypertrophy [7]. Genetic models of obesity, such as the obese fa/fa rats and ob/ob mice, present contractile dysfunction reminiscent of human obesity [9]. The genetically obese Zucker rats and ob/ob mice demonstrate the phenotypical presentations of obesity including greater body mass, hyperlipidemia, hypertension and hyperglycemia along with compromised cardiac contractile function [9,10]. However, it is noteworthy that these obese rodents develop insulin resistance and mild hypertension which may confound the direct impact of obesity on myocardial geometry and function [9,10]. A number of scenarios including oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, autophagy and dyslipidemia have been implicated in obesity-related pathophysiological changes in the heart [1,7,11,12]. Recent evidence also indicated that cardiac fatty acid uptake and oxidation may not be balanced with uncorrected obesity. As a consequence, hearts accumulate lipid leading to cardiac lipotoxicity by acquiring fatty acids from the circulation to be later stored as triglyceride intracellularly [13]. Elevated peri- and epicardial fat accumulation may trigger a fetal pattern of myocardial energy utilization, which relies essentially on glucose, as opposed to fatty acid, as the main energy source. Moreover, lipid accumulation also induces a switch of the key intracellular molecular energy to upregulate levels of peroxisome proliferator-activated receptor γ coactivator (PGC) 1α, acetyl CoA carboxylase (ACC) and AMP-activated protein kinase (AMPK) [6,13,14]. Despite the harmful effect of lipid on the heart, low intake of n-3 polyunsaturated fatty acids has been shown to alter cardiac membrane phospholipid fatty acid composition, alleviate the onset of new heart failure, and retard the progression of established heart failure [6]. The beneficial effect of lipid on the heart is believed to be associated with decreased inflammation and improved resistance to mitochondrial permeability transition [6]. Given the complexity of lipid metabolism in the heart, a better and more thorough understanding is needed to elucidate the pros and cons of cardiac phospholipids, lipid metabolites, and metabolic flux in cardiac homeostasis. 2. Fetal programming and cardiovascular function Obesity afflicts nearly one-third of women at the child-bearing age [1] Obesity and other chronic diseases may be programmed during fetal life to permanently change the structure, homeostatic systems, and functions of the body [15–17]. Epidemiological studies demonstrated that maternal nutrient restriction or overnutrition during pregnancy predisposes offspring to a much higher prevalence of obesity, glucose intolerance, insulin resistance, hypertension, vascular dysfunction and heart disease [18–21]. This phenomenon is often referred to as “fetal programming” [22]. Epidemiological and animal studies indicate that the programmed effects operate within the normal range of growth and development, and influence the risk of chronic disease in adult life [23]. Many adult diseases may originate
from suboptimal prenatal conditions such as maternal malnutrition, and poor gestational health [17,24,25]. Low birth weight and short body length at birth are associated with elevated risk of obesity, cardiovascular disease, and non-insulin-dependent diabetes in adult life [26]. Maternal nutrient restriction during pregnancy may trigger an increase in the tissue-specific glucocorticoid receptor in the newborn [27] which may subsequently compromise cardiovascular function in particular elevated blood pressure later in life [28]. Moreover, maternal nutritional environment is closely associated with fetal heart development and function [15]. Although fetal hearts from dam with maternal obesity display a normal cardiac contractile function during basal perfusion, they often exhibit an impaired heart-rate-leftventricular-developed pressure product following high workload stress [29]. Prenatal nutritional environment influences certain genes associated with cardiac development, structure and contractile function [29,30]. Given that cardiac hypertrophy is associated with suppressed insulin-dependent glucose transporter (GLUT) 4 expression, the cardiac isoform of fatty acid binding protein (FABP)3 and lipid accumulation [31,32], prenatal nutritional status may change the levels of proteins responsible for glucose and lipid metabolism. These changes in myocardial lipid and energy metabolism with altered maternal nutritional status may impact on other cardiac ‘nutrient sensors’ such as PGC-1α [33]. As a result of altered myocardial substrate supply and utilization, particularly fatty acids, obesity and metabolic disorder may initiate and develop in offspring later on in life [21]. Maternal obesity or overnutritioninduced rises in fetal hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines are believed to play a role [21] although the precise mechanisms behind cardiovascular sequelae of maternal dietary imbalance remain unknown. As nutritional excess is becoming a common socioeconomic issue world-wide, the imminent deleterious effects of maternal obesity on offspring health outcome has been the focus of much attention in recent years [34–36]. Although prenatal nutritional environment exhibits various effects on growth, development and physiology in multiple organ systems [15,17,24,30,36–39], ultimate physical presence of a ‘programmed’ end-point is dependent, in large part, upon perinatal, postnatal environment and life style such as food intake, physical activity, and energy consumption. Not surprisingly, the levels of exposure and active engagement in an ‘obesogenic’ lifestyle may ultimately govern the phenotype of cardiovascular system in adult offspring [40]. Although it is beyond the scope of this review, it is noteworthy that other contributing factors for heart disease such as hypertension and arrhythmia may also contribute to maternal overnutrition-induced cardiovascular sequelae in the offspring. For example, gestational hypertension, pre-eclampsia and placental abruption/infarction are more prevalent in women with metabolic syndrome, which may promote left ventricular impairment and sympathetic dominance after delivery [41]. Although our attention here will be focused on the impact of maternal overnutrition on postnatal cardiovascular health, it should be acknowledged that both fetal and neonatal periods are critical to the development and growth of organ systems pertinent to metabolic disease. The increased rates of hypertension, metabolic syndrome, type 2 diabetes, renal failure and heart failure in modern society may have resulted from discrepancy between the nutritional environment during fetal/early life and adulthood. Such discrepancy triggers a mismatch between the fetal programming of the subject and its adult circumstances being imposed on it later on in life [42]. Disregarding the adult circumstances being imposed later on in life, peripartum cardiomyopathy with multifactorial etiology may develop and be manifested as a rare form of dilated cardiomyopathy [43]. A number of maternal risk factors have been identified including advanced maternal age (>30), multiparity, twin pregnancy, African origin, obesity, pre-eclampsia, gestational hypertension, and prolonged tocolytic therapy [43]. To this end, certain caution should be taken to delineate the origin of cardiomyopathy in adult life (i.e., perinatal versus
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postnatal). Treatment of acute phase of peripartum cardiomyopathy is similar to that of acute systolic heart failure. However, maternal obesity may pose a diagnostic problem for the proper management of perinatal cardiomyopathy. For example, the incidence of conotruncal heart defects may be much higher due to epigenetic factors. As premature labor and delivery are frequent complications, perinatal management of cardiovascular function becomes rather challenging [43,44]. 3. Lipotoxicity and maternal obesity Maternal obesity increases the offspring's risk of juvenile obesity and metabolic diseases although the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Obese pregnancy triggers exaggerated metabolic adaptation, cardiovascular anomalies and adverse pregnancy outcome. Obesity is accompanied by hypertriglyceridemia, elevated total and LDL cholesterol as well as decreased HDL cholesterol levels. During normal pregnancy, levels of total, low-LDL-cholesterol and high-density lipoprotein (HDL) cholesterol, and triglycerides rise steadily and take months to fall postpartum. Triglycerides, which constitute the major storage of lipid intermediates, are usually employed as indicators of intracellular lipid accumulation. Not surprisingly, triglyceride levels are closely corroborated maternal pregravid weight and excessive fetal growth [45,46]. Elevated lipid levels prompt a state of lipotoxicity to suppress glucose and lipid metabolism [47,48]. Lipotoxicity imposes significant effect on the heart, for its high caloric requirement and robust oxidation of fatty acids. Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation lose their balance to promote cardiac lipotoxicity. Experimental evidence has indicated that lipid accumulation causes overt heart dysfunction [13]. A number of theories have been speculated for lipid accumulation-induced cardiac toxicity. For example, intracellular fatty acids (FAs) and long-chain fatty acyl-CoAs may suppress hexokinase and glycogen synthase [49]. On the other hand, diacylglycerols are capable of interrupting insulin signaling through protein kinase C-dependent serine/threonine phosphorylation of IRS-1 [50]. The sphingolipid ceramide dephosphorylated Akt to compromise insulin signaling [51]. Excess free FAs or lipotoxicity may also produce an unfavorable effect on fetal development. In a recent study, Jungheim and colleagues exposed murine blastocysts with excess palmitic acid (PA), the most abundant saturated FFA in human serum. Their observations demonstrated that PA-exposed blastocysts displayed altered IGF-1 receptor level, increased glutamic pyruvate transaminase activity, and decreased nuclei number. Cells displayed increased apoptosis and decreased proliferation following sustained PA exposure. Blastocysts cultured for 30 h in PA were then transferred into foster mice, and pregnancies followed through embryonic day 14.5 (ED14.5) or delivery. Fetuses from PA-exposed blastocysts (ED14.5) and delivered pups were much smaller although they demonstrated a catch-up growth and ultimately surpassed control pups in weight. Their findings suggest that brief fatty acid exposure during gestation alters embryonic metabolism and growth, with lasting adverse effects on offspring, providing further insight into the pathophysiology of maternal obesity [36]. Along the same line, lipid accumulation during gestation may suppress trophoblast invasion and placental development, lipid metabolism and transport in the fetus [34]. Excess lipid supply in utero metabolic environment has been demonstrated to affect placental gene expression, inflammation and metabolism which may ultimately promote the risk of obesity in the offspring. Obesity or fat dietary exposure during pregnancy is associated with fatty acid excess and ectopic fat deposition in the heart, liver, pancreas and placenta. Chronic maternal high fat diet consumption, independent of maternal obesity or diabetes, significantly increased the risk of nonalcoholic fatty liver disease (NAFLD) in the developing nonhuman primate fetus that persisted into the postnatal period. The evidence for NAFLD includes a 3-fold increase in liver triglyceride levels, activation of several markers of oxidative stress, and premature activation of genes in the gluconeogenic pathway [35]. Presence of lipotoxicity
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(accumulation of lipid metabolites) may in turn activate a number of cell stress cascades including pro-inflammatory cytokines and oxidative stress to exacerbate insulin resistance at a later stage of postnatal life [52]. These stress signaling mechanisms (which will be discussed in greater detail below) may predispose obese women who are pregnant to lipotoxicity, metabolic dysregulation and inflammation. To this end, reducing ectopic lipid accumulation in maternal life is expected to represent a useful therapeutic strategy in the management of maternal obesity-induced increase in postnatal metabolic disorders. 3.1. Oxidative stress Oxidative stress plays a pivotal role in lipotoxicity-induced alterations in cardiovascular function. Obesity is known to be associated with oxidative stress and high levels of ROS [7,11]. Oxidative stress may arise from intracellular accumulation of triglycerides to suppress mitochondrial efficiency and electron transport chain. Consistently, proteomic analysis of placenta reveals differential expression of proteins responsible for oxidative stress, inflammation, coagulation and apoptosis in obese pregnant women. These disturbances are expected to possess significant implications for fetal growth and development [53]. It is expected that oxidative stress oxidizes LDL which binds with scavenger receptors on the surface of macrophages to facilitate influx of lipoproteins resulting in foam cell formation and local inflammation. Three types of oxidized lipid product may be generated with concurrent oxidative stress and lipid accumulation, namely lipid peroxides, oxidized lipoproteins and oxysterols. To examine the role of oxidative stress in maternal obesity, Sen and Simmons administered an antioxidant supplement to pregnant Western diet-fed rats before evaluation of adiposity in the offspring. Their data revealed that offspring from dams fed the Western diet had significantly increased adiposity with impaired glucose tolerance. Inflammation and oxidative stress were increased in preimplantation embryos, fetuses, and newborns of Western diet-fed rats. Gene expression of proadipogenic and lipogenic genes was altered in fat tissue of rats. Addition of an antioxidant supplement decreased adiposity and normalized glucose tolerance [54]. These data suggest that oxidative stress appears to play a pivotal role in the development of increased adiposity in the offspring of Western diet-fed pregnant dams. More importantly, these findings revealed that therapeutic benefit of antioxidants in the management of postnatal adiposity with maternal fat dietary exposure. 3.2. Adipokines An adverse prenatal environment often triggers long-term metabolic consequences, in particular obesity and metabolic syndrome. Such “'fetal programming” has generally been considered an irreversible process in developmental trajectory with the release of adipocytokines (adipokines) from adipose tissue, together with insulin resistance, to promote inflammation [55]. This is supported by a higher prevalence of obesity in genetic polymorphisms of adipokine genes including leptin, leptin receptor, resistin, adiponectin, interleukin-1β (IL-1β), IL-6 (IL-6), and tumor necrosis factor-α (TNF-α) [56]. Obesity is accompanied by elevated plasma adipokines including leptin, adiponectin, resistin, IL-6, C-reactive protein (CRP) and TNF-α [57,58]. Accumulating evidence indicates that obesity causes chronic low-grade inflammation en route to systemic metabolic dysfunction. Adipose tissue functions as a key endocrine organ by releasing multiple adipose-derived secreted factors or adipokines, with either pro- or anti-inflammatory activities [57]. Similarly, obesity in pregnancy is characterized by elevations in adipokines and inflammatory markers [39,59,60]. A higher physical mass during gestation (or maternal obesity) represents a significant risk for metabolic syndrome in offspring [61]. In particular, levels of the pro-inflammatory cytokine TNFα and leptin are elevated in maternal obesity and may underline the negative inotropic effect on the heart
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of the offspring [62–64]. Recent evidence highlights the importance of leptin in postnatal metabolic disorders as a consequence of developmental fetal programming [55] and offers exciting new strategies for therapeutic intervention, whether it be maternal or neonatal intervention or targeted nutritional manipulation in postnatal life. 3.3. Insulin resistance Excess cardiac lipid accumulation is associated with high plasma FFAs and triglyceride levels, fostering glucose intolerance, insulin resistance and cardiomyopathy [35,36]. Consistent with elevated plasma TG levels, recent data from our group revealed markedly lipid accumulation and elevated levels of stearoyl-CoA desaturase (SCD1), the rate-limiting enzyme for fatty acid synthesis and fat deposition hearts from offspring with chronic pre- and postnatal fat exposure, indicating a potential contribution of lipotoxicity to maternal dietary fat exposure-induced exacerbation of cardiac morphology and function following postnatal dietary fat intake [65]. Transmission electron micrographs found regular myofilament alignment and mitochondria with electron dense matrix in the longitudinal sections from mouse hearts without maternal or postnatal fat diet intake. Postnatal high fat diet feeding (45% of calories) resulted in variations in mitochondria size and vacuolization (shown in arrowheads). Moreover, combined maternal and postnatal high fat diet exposure triggers a more prominent mitochondrial damage characterized by swelling, disruption of double membrane and reduction of electron-dense matrix (arrowheads), indicating severe mitochondrial damage (Fig. 1). Further scrutiny of Akt and AMPK, two signaling molecules governing cell survival, glycolysis and TG synthesis, revealed a robust decline in phosphorylation of Akt,
MLPL
AMPK and the AMPK target ACC. AMPK inhibits glycerol-3-phosphate acyltransferase (GPAT), the initial step in de novo TG synthesis and fatty acid oxidation. Depressed AMPK signaling in offspring exposed to pre-and postnatal fat diet may impede fatty acid oxidation and promote TG synthesis. One of the interesting findings from our group is the severely dampened post-receptor insulin signaling (IRS-1 serine phosphorylation) and glucose handling in offspring exposed to preand post-natal fat diet. IRS-1 dissociation away from insulin receptor following Ser307 phosphorylation of IRS-1 suppresses PI3K/Akt pathway in obesity (38). Excessive serine phosphorylation of IRS blunts insulin sensitivity and reduces insulin-stimulated myocardial glucose uptake (39). Moreover, data from our laboratory indicated elevated Ser307 phosphorylation of IRS-1 in hearts from fetus born to obese sheep, en route to impaired insulin sensitivity and myocardial function (41). These data suggest a possible contribution of compromised insulin sensitivity to the unfavorable changes in cardiac morphology and function following maternal and/or postnatal fat exposure. 3.4. Genetic disorders in lipid transport/metabolism Maternal hyperlipidemia is associated with premature birth. Genetic predisposition in lipid transport/metabolism in women with pregnancy may affect postnatal life outcomes although convincing evidence is still elusive. Women with heterozygous familial hypercholesterolemia (FH) who become pregnant display rather high levels of LDL-cholesterol early in pregnancy (260 mg/dl) that rise to even higher levels near term (330 mg/dl), thus predisposing mother and fetus to high lipid levels and risks of pregnancy. Familial hypercholesterolemia, with a prevalence of 1:500 in general population, is caused by mutations in
MLPH
M
MHPL
MHPH
Fig. 1. Myocardial ultrastructure in adult offspring of mice fed a low fat (LF) or high fat (HF) diet during gestation and lactation. Weaning male offspring were placed on either LF or HF for 4 months prior to assessment of morphology: Transmission electron micrographs displayed regular myofilament alignment and mitochondria with electron dense matrix in longitudinal sections from MLPL hearts. High fat diet feeding resulted in variation in mitochondria size and vacuolization (arrowheads) in MLPH group. Hearts from MHPH group demonstrated prominent mitochondrial damage characterized by swelling, disruption of double membrane and reduction of electron-dense matrix (arrowheads) in addition to structural abnormalities found in MLPH hearts, indicating more severe mitochondrial damage. Maternal high fat diet exposure itself exhibited similar myocardial structure to that of MLPL group. Scale bar = 1 μm.
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Scheme 1. Schematic diagram depicting possible mechanisms involved in maternal overnutrition-induced changes in fetal hearts. It is likely that changes in mitochondrial integrity may promote apoptosis, cardiac remodeling and myocardial contractile dysfunction.
the low-density lipoprotein receptor. In a study linking the Medical Birth Registry of Norway (1967–2006) and the Medical Genetics Laboratory at Oslo University Hospital, the children of mothers with FH were no more likely than the general population to be born prematurely, with low birth weight, or congenital malformations. Although this is a retrospective, registry-based study, the data likely reflect the birth outcomes of a representative cohort of childbearing FH women [66]. Although the mechanism of action responsible for the discrepant findings between this familial hypercholesterolemia study and the known lipotoxicity outcome in maternal obesity is still elusive, certain caution should be taken with regard to a given patient population of genetic mutations for lipid metabolism/transport. It is noteworthy that a significant increase was noted in many lipid transport and TG synthesis genes including PPAR δ (peroxisome proliferator-activated receptor delta), Slc27a1 (fatty acid transport protein 1; also known as Fatp1), Cd36 (cluster of differentiation 36; also known as fatty acid translocation [22]), Lipin1, and Lipin3 under maternal obesity [67]. 4. Conclusion In conclusion, maternal obesity and/or high fat diet feeding may predispose offspring to a higher prevalence of postnatal fat diet-induced metabolic diseases including changes in cardiac geometry and function. Lipid accumulation and subsequently lipotoxicity appear to play a pivotal role in the observed metabolic and cardiovascular anomalies in the offspring from obese mothers during pregnancy. These findings, which are summarized in Scheme 1, should shed some lights towards a better management of obesity and obesity-associated heart diseases. Nonetheless, it is noteworthy that drug usage during pregnancy may also alter nutritional status and significantly impact the health outcome in the offspring. For example, polypharmacy is capable of triggering loss of appetite, nausea, diarrhea, weight changes, taste alterations, decrease in saliva secretion, modifications in lipid profile, alterations in electrolyte balance, and changes in glucose metabolism. Malnutrition may also lead to decreased amount of serum protein, meaning a higher unbound drug fraction [68]. Caution needs to be taken for drug-induced change in nutritional status during pregnancy. As maternal obesity and fat dietary exposure are commonplace and rapidly increasing, the future generations will be at an increased risk for metabolic and
cardiovascular disorders. Therefore, it is pertinent to identify effective therapeutic strategies for preventing maternal obesity-induced unfavorable fetal programming.
Disclosure statement None.
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Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 2012;125:2844-53. [48] Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies. Diabet Med 2009;26:1185-92. [49] Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, et al. Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol Endocrinol Metab 2000;279:E554-60. [50] Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002;277:50230-6. [51] Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 1999;274:24202-10. [52] Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 2005;54:3458-65. [53] Oliva K, Barker G, Riley C, Bailey MJ, Permezel M, Rice GE, et al. The effect of pre-existing maternal obesity on the placental proteome: two-dimensional difference gel electrophoresis coupled with mass spectrometry. J Mol Endocrinol 2012;48:139-49. [54] Sen S, Simmons RA. Maternal antioxidant supplementation prevents adiposity in the offspring of Western diet-fed rats. Diabetes 2010;59:3058-65. [55] Vickers MH. Developmental programming and adult obesity: the role of leptin. Curr Opin Endocrinol Diabetes Obes 2007;14:17-22. [56] Yu Z, Han S, Cao X, Zhu C, Wang X, Guo X. 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Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Review article
Maternal obesity, lipotoxicity and cardiovascular diseases in offspring Maolong Dong a, b, 1, Qijun Zheng c, 1, Stephen P. Ford d, Peter W. Nathanielsz e, Jun Ren a, b, d,⁎ a
Department of Burn and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, 82071, USA c Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China d Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY 82071, USA e Center for Pregnancy and Newborn Research, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78299, USA b
a r t i c l e
i n f o
Article history: Received 23 June 2012 Received in revised form 28 August 2012 Accepted 28 August 2012 Available online 6 September 2012 Keywords: Maternal obesity Cardiovascular diseases Obesity Insulin resistance
a b s t r a c t Maternal obesity has risen dramatically over the past 20 years, by nearly 42% in African-Americans and 29% in Caucasians. Maternal obesity is afflicted with many maternal obstetric complications in the offspring including high blood pressure, obesity, gestational diabetes and increased perinatal morbidity. Maternal nutritional environment plays a rather important role in the programming of the health set-points in the offspring such as glucose and insulin metabolism, energy balance and predisposition to metabolic disorders. In particular, maternal obesity is associated with elevated prevalence of cardiovascular diseases in the offspring. Evidence from human and experimental studies including rodents and nonhuman primates has indicated that maternal obesity or overnutrition programs offspring for an increased risk of adult obesity. Maternal obesity or fat diet exposure predisposes the onset and development of obesity, insulin resistance, cardiac hypertrophy and myocardial contractile anomalies in the offspring. A number of mechanisms including elevated hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines have been postulated to play a key role in maternal obesity-induced postnatal cardiovascular sequelae. In addition, lipotoxicity (accumulation of lipid metabolites) resulting from maternal obesity is capable of activating a number of stress signaling cascades including pro-inflammatory cytokines and oxidative stress to exacerbate maternal obesity-induced cardiovascular complications later on in adult life. This mini-review summarizes the recent knowledge with regard to the role of lipotoxicity in maternal obesity-induced change in cardiovascular function in the offspring. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". © 2012 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . Fetal programming and cardiovascular function . . . Lipotoxicity and maternal obesity . . . . . . . . . 3.1. Oxidative stress . . . . . . . . . . . . . . 3.2. Adipokines . . . . . . . . . . . . . . . . 3.3. Insulin resistance . . . . . . . . . . . . . 3.4. Genetic disorders in lipid transport/metabolism 4. Conclusion . . . . . . . . . . . . . . . . . . . . Disclosure statement . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
⁎ Corresponding author at: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Tel.: + 1 307 766 6131; fax: + 1 307 766 2953. E-mail address: [email protected] (J. Ren). 1 Equal contribution. 0022-2828/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.yjmcc.2012.08.023
Obesity is a devastating epidemic medical problem in the United States and other parts of the world. Conservative estimate suggests a rise of ~ 50% in the prevalence of obesity during the last decade affecting all ages, ethnicities and genders [1]. While obesity is too complex to be attributed to a single factor, the dramatic rise in such a
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short time frame implicates a pivotal role of lifestyle and epigenetic factors including food intake and physical activity in the pathogenesis of obesity [2,3]. Uncorrected obesity is known as an independent risk factor for diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease. Sedentary lifestyle along with increased caloric intake has been deemed one of the main causes of obesity and metabolic syndrome [2,4,5]. Obesity imposes a substantial unfavorable effect on the heart as a consequence of autonomic stimulation and excess fat accumulation in and around the heart [4,6]. In particular, obesity leads to cardiac hypertrophy (remodeling), interstitial fibrosis and ventricular contractile dysfunction that are exacerbated by concomitant sympathetic overdrive resulting in the refractoriness to β-adrenergic stimulation [7]. Obesity-related myocardial dysfunction is characterized by an early increase in cardiac output and stroke volume associated with increased oxygen consumption and volume overload [8]. With sustained uncorrected obesity, the heart becomes decompensated and exhibits contractile dysfunction in association with cardiac hypertrophy [7]. Genetic models of obesity, such as the obese fa/fa rats and ob/ob mice, present contractile dysfunction reminiscent of human obesity [9]. The genetically obese Zucker rats and ob/ob mice demonstrate the phenotypical presentations of obesity including greater body mass, hyperlipidemia, hypertension and hyperglycemia along with compromised cardiac contractile function [9,10]. However, it is noteworthy that these obese rodents develop insulin resistance and mild hypertension which may confound the direct impact of obesity on myocardial geometry and function [9,10]. A number of scenarios including oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, autophagy and dyslipidemia have been implicated in obesity-related pathophysiological changes in the heart [1,7,11,12]. Recent evidence also indicated that cardiac fatty acid uptake and oxidation may not be balanced with uncorrected obesity. As a consequence, hearts accumulate lipid leading to cardiac lipotoxicity by acquiring fatty acids from the circulation to be later stored as triglyceride intracellularly [13]. Elevated peri- and epicardial fat accumulation may trigger a fetal pattern of myocardial energy utilization, which relies essentially on glucose, as opposed to fatty acid, as the main energy source. Moreover, lipid accumulation also induces a switch of the key intracellular molecular energy to upregulate levels of peroxisome proliferator-activated receptor γ coactivator (PGC) 1α, acetyl CoA carboxylase (ACC) and AMP-activated protein kinase (AMPK) [6,13,14]. Despite the harmful effect of lipid on the heart, low intake of n-3 polyunsaturated fatty acids has been shown to alter cardiac membrane phospholipid fatty acid composition, alleviate the onset of new heart failure, and retard the progression of established heart failure [6]. The beneficial effect of lipid on the heart is believed to be associated with decreased inflammation and improved resistance to mitochondrial permeability transition [6]. Given the complexity of lipid metabolism in the heart, a better and more thorough understanding is needed to elucidate the pros and cons of cardiac phospholipids, lipid metabolites, and metabolic flux in cardiac homeostasis. 2. Fetal programming and cardiovascular function Obesity afflicts nearly one-third of women at the child-bearing age [1] Obesity and other chronic diseases may be programmed during fetal life to permanently change the structure, homeostatic systems, and functions of the body [15–17]. Epidemiological studies demonstrated that maternal nutrient restriction or overnutrition during pregnancy predisposes offspring to a much higher prevalence of obesity, glucose intolerance, insulin resistance, hypertension, vascular dysfunction and heart disease [18–21]. This phenomenon is often referred to as “fetal programming” [22]. Epidemiological and animal studies indicate that the programmed effects operate within the normal range of growth and development, and influence the risk of chronic disease in adult life [23]. Many adult diseases may originate
from suboptimal prenatal conditions such as maternal malnutrition, and poor gestational health [17,24,25]. Low birth weight and short body length at birth are associated with elevated risk of obesity, cardiovascular disease, and non-insulin-dependent diabetes in adult life [26]. Maternal nutrient restriction during pregnancy may trigger an increase in the tissue-specific glucocorticoid receptor in the newborn [27] which may subsequently compromise cardiovascular function in particular elevated blood pressure later in life [28]. Moreover, maternal nutritional environment is closely associated with fetal heart development and function [15]. Although fetal hearts from dam with maternal obesity display a normal cardiac contractile function during basal perfusion, they often exhibit an impaired heart-rate-leftventricular-developed pressure product following high workload stress [29]. Prenatal nutritional environment influences certain genes associated with cardiac development, structure and contractile function [29,30]. Given that cardiac hypertrophy is associated with suppressed insulin-dependent glucose transporter (GLUT) 4 expression, the cardiac isoform of fatty acid binding protein (FABP)3 and lipid accumulation [31,32], prenatal nutritional status may change the levels of proteins responsible for glucose and lipid metabolism. These changes in myocardial lipid and energy metabolism with altered maternal nutritional status may impact on other cardiac ‘nutrient sensors’ such as PGC-1α [33]. As a result of altered myocardial substrate supply and utilization, particularly fatty acids, obesity and metabolic disorder may initiate and develop in offspring later on in life [21]. Maternal obesity or overnutritioninduced rises in fetal hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines are believed to play a role [21] although the precise mechanisms behind cardiovascular sequelae of maternal dietary imbalance remain unknown. As nutritional excess is becoming a common socioeconomic issue world-wide, the imminent deleterious effects of maternal obesity on offspring health outcome has been the focus of much attention in recent years [34–36]. Although prenatal nutritional environment exhibits various effects on growth, development and physiology in multiple organ systems [15,17,24,30,36–39], ultimate physical presence of a ‘programmed’ end-point is dependent, in large part, upon perinatal, postnatal environment and life style such as food intake, physical activity, and energy consumption. Not surprisingly, the levels of exposure and active engagement in an ‘obesogenic’ lifestyle may ultimately govern the phenotype of cardiovascular system in adult offspring [40]. Although it is beyond the scope of this review, it is noteworthy that other contributing factors for heart disease such as hypertension and arrhythmia may also contribute to maternal overnutrition-induced cardiovascular sequelae in the offspring. For example, gestational hypertension, pre-eclampsia and placental abruption/infarction are more prevalent in women with metabolic syndrome, which may promote left ventricular impairment and sympathetic dominance after delivery [41]. Although our attention here will be focused on the impact of maternal overnutrition on postnatal cardiovascular health, it should be acknowledged that both fetal and neonatal periods are critical to the development and growth of organ systems pertinent to metabolic disease. The increased rates of hypertension, metabolic syndrome, type 2 diabetes, renal failure and heart failure in modern society may have resulted from discrepancy between the nutritional environment during fetal/early life and adulthood. Such discrepancy triggers a mismatch between the fetal programming of the subject and its adult circumstances being imposed on it later on in life [42]. Disregarding the adult circumstances being imposed later on in life, peripartum cardiomyopathy with multifactorial etiology may develop and be manifested as a rare form of dilated cardiomyopathy [43]. A number of maternal risk factors have been identified including advanced maternal age (>30), multiparity, twin pregnancy, African origin, obesity, pre-eclampsia, gestational hypertension, and prolonged tocolytic therapy [43]. To this end, certain caution should be taken to delineate the origin of cardiomyopathy in adult life (i.e., perinatal versus
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postnatal). Treatment of acute phase of peripartum cardiomyopathy is similar to that of acute systolic heart failure. However, maternal obesity may pose a diagnostic problem for the proper management of perinatal cardiomyopathy. For example, the incidence of conotruncal heart defects may be much higher due to epigenetic factors. As premature labor and delivery are frequent complications, perinatal management of cardiovascular function becomes rather challenging [43,44]. 3. Lipotoxicity and maternal obesity Maternal obesity increases the offspring's risk of juvenile obesity and metabolic diseases although the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Obese pregnancy triggers exaggerated metabolic adaptation, cardiovascular anomalies and adverse pregnancy outcome. Obesity is accompanied by hypertriglyceridemia, elevated total and LDL cholesterol as well as decreased HDL cholesterol levels. During normal pregnancy, levels of total, low-LDL-cholesterol and high-density lipoprotein (HDL) cholesterol, and triglycerides rise steadily and take months to fall postpartum. Triglycerides, which constitute the major storage of lipid intermediates, are usually employed as indicators of intracellular lipid accumulation. Not surprisingly, triglyceride levels are closely corroborated maternal pregravid weight and excessive fetal growth [45,46]. Elevated lipid levels prompt a state of lipotoxicity to suppress glucose and lipid metabolism [47,48]. Lipotoxicity imposes significant effect on the heart, for its high caloric requirement and robust oxidation of fatty acids. Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation lose their balance to promote cardiac lipotoxicity. Experimental evidence has indicated that lipid accumulation causes overt heart dysfunction [13]. A number of theories have been speculated for lipid accumulation-induced cardiac toxicity. For example, intracellular fatty acids (FAs) and long-chain fatty acyl-CoAs may suppress hexokinase and glycogen synthase [49]. On the other hand, diacylglycerols are capable of interrupting insulin signaling through protein kinase C-dependent serine/threonine phosphorylation of IRS-1 [50]. The sphingolipid ceramide dephosphorylated Akt to compromise insulin signaling [51]. Excess free FAs or lipotoxicity may also produce an unfavorable effect on fetal development. In a recent study, Jungheim and colleagues exposed murine blastocysts with excess palmitic acid (PA), the most abundant saturated FFA in human serum. Their observations demonstrated that PA-exposed blastocysts displayed altered IGF-1 receptor level, increased glutamic pyruvate transaminase activity, and decreased nuclei number. Cells displayed increased apoptosis and decreased proliferation following sustained PA exposure. Blastocysts cultured for 30 h in PA were then transferred into foster mice, and pregnancies followed through embryonic day 14.5 (ED14.5) or delivery. Fetuses from PA-exposed blastocysts (ED14.5) and delivered pups were much smaller although they demonstrated a catch-up growth and ultimately surpassed control pups in weight. Their findings suggest that brief fatty acid exposure during gestation alters embryonic metabolism and growth, with lasting adverse effects on offspring, providing further insight into the pathophysiology of maternal obesity [36]. Along the same line, lipid accumulation during gestation may suppress trophoblast invasion and placental development, lipid metabolism and transport in the fetus [34]. Excess lipid supply in utero metabolic environment has been demonstrated to affect placental gene expression, inflammation and metabolism which may ultimately promote the risk of obesity in the offspring. Obesity or fat dietary exposure during pregnancy is associated with fatty acid excess and ectopic fat deposition in the heart, liver, pancreas and placenta. Chronic maternal high fat diet consumption, independent of maternal obesity or diabetes, significantly increased the risk of nonalcoholic fatty liver disease (NAFLD) in the developing nonhuman primate fetus that persisted into the postnatal period. The evidence for NAFLD includes a 3-fold increase in liver triglyceride levels, activation of several markers of oxidative stress, and premature activation of genes in the gluconeogenic pathway [35]. Presence of lipotoxicity
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(accumulation of lipid metabolites) may in turn activate a number of cell stress cascades including pro-inflammatory cytokines and oxidative stress to exacerbate insulin resistance at a later stage of postnatal life [52]. These stress signaling mechanisms (which will be discussed in greater detail below) may predispose obese women who are pregnant to lipotoxicity, metabolic dysregulation and inflammation. To this end, reducing ectopic lipid accumulation in maternal life is expected to represent a useful therapeutic strategy in the management of maternal obesity-induced increase in postnatal metabolic disorders. 3.1. Oxidative stress Oxidative stress plays a pivotal role in lipotoxicity-induced alterations in cardiovascular function. Obesity is known to be associated with oxidative stress and high levels of ROS [7,11]. Oxidative stress may arise from intracellular accumulation of triglycerides to suppress mitochondrial efficiency and electron transport chain. Consistently, proteomic analysis of placenta reveals differential expression of proteins responsible for oxidative stress, inflammation, coagulation and apoptosis in obese pregnant women. These disturbances are expected to possess significant implications for fetal growth and development [53]. It is expected that oxidative stress oxidizes LDL which binds with scavenger receptors on the surface of macrophages to facilitate influx of lipoproteins resulting in foam cell formation and local inflammation. Three types of oxidized lipid product may be generated with concurrent oxidative stress and lipid accumulation, namely lipid peroxides, oxidized lipoproteins and oxysterols. To examine the role of oxidative stress in maternal obesity, Sen and Simmons administered an antioxidant supplement to pregnant Western diet-fed rats before evaluation of adiposity in the offspring. Their data revealed that offspring from dams fed the Western diet had significantly increased adiposity with impaired glucose tolerance. Inflammation and oxidative stress were increased in preimplantation embryos, fetuses, and newborns of Western diet-fed rats. Gene expression of proadipogenic and lipogenic genes was altered in fat tissue of rats. Addition of an antioxidant supplement decreased adiposity and normalized glucose tolerance [54]. These data suggest that oxidative stress appears to play a pivotal role in the development of increased adiposity in the offspring of Western diet-fed pregnant dams. More importantly, these findings revealed that therapeutic benefit of antioxidants in the management of postnatal adiposity with maternal fat dietary exposure. 3.2. Adipokines An adverse prenatal environment often triggers long-term metabolic consequences, in particular obesity and metabolic syndrome. Such “'fetal programming” has generally been considered an irreversible process in developmental trajectory with the release of adipocytokines (adipokines) from adipose tissue, together with insulin resistance, to promote inflammation [55]. This is supported by a higher prevalence of obesity in genetic polymorphisms of adipokine genes including leptin, leptin receptor, resistin, adiponectin, interleukin-1β (IL-1β), IL-6 (IL-6), and tumor necrosis factor-α (TNF-α) [56]. Obesity is accompanied by elevated plasma adipokines including leptin, adiponectin, resistin, IL-6, C-reactive protein (CRP) and TNF-α [57,58]. Accumulating evidence indicates that obesity causes chronic low-grade inflammation en route to systemic metabolic dysfunction. Adipose tissue functions as a key endocrine organ by releasing multiple adipose-derived secreted factors or adipokines, with either pro- or anti-inflammatory activities [57]. Similarly, obesity in pregnancy is characterized by elevations in adipokines and inflammatory markers [39,59,60]. A higher physical mass during gestation (or maternal obesity) represents a significant risk for metabolic syndrome in offspring [61]. In particular, levels of the pro-inflammatory cytokine TNFα and leptin are elevated in maternal obesity and may underline the negative inotropic effect on the heart
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of the offspring [62–64]. Recent evidence highlights the importance of leptin in postnatal metabolic disorders as a consequence of developmental fetal programming [55] and offers exciting new strategies for therapeutic intervention, whether it be maternal or neonatal intervention or targeted nutritional manipulation in postnatal life. 3.3. Insulin resistance Excess cardiac lipid accumulation is associated with high plasma FFAs and triglyceride levels, fostering glucose intolerance, insulin resistance and cardiomyopathy [35,36]. Consistent with elevated plasma TG levels, recent data from our group revealed markedly lipid accumulation and elevated levels of stearoyl-CoA desaturase (SCD1), the rate-limiting enzyme for fatty acid synthesis and fat deposition hearts from offspring with chronic pre- and postnatal fat exposure, indicating a potential contribution of lipotoxicity to maternal dietary fat exposure-induced exacerbation of cardiac morphology and function following postnatal dietary fat intake [65]. Transmission electron micrographs found regular myofilament alignment and mitochondria with electron dense matrix in the longitudinal sections from mouse hearts without maternal or postnatal fat diet intake. Postnatal high fat diet feeding (45% of calories) resulted in variations in mitochondria size and vacuolization (shown in arrowheads). Moreover, combined maternal and postnatal high fat diet exposure triggers a more prominent mitochondrial damage characterized by swelling, disruption of double membrane and reduction of electron-dense matrix (arrowheads), indicating severe mitochondrial damage (Fig. 1). Further scrutiny of Akt and AMPK, two signaling molecules governing cell survival, glycolysis and TG synthesis, revealed a robust decline in phosphorylation of Akt,
MLPL
AMPK and the AMPK target ACC. AMPK inhibits glycerol-3-phosphate acyltransferase (GPAT), the initial step in de novo TG synthesis and fatty acid oxidation. Depressed AMPK signaling in offspring exposed to pre-and postnatal fat diet may impede fatty acid oxidation and promote TG synthesis. One of the interesting findings from our group is the severely dampened post-receptor insulin signaling (IRS-1 serine phosphorylation) and glucose handling in offspring exposed to preand post-natal fat diet. IRS-1 dissociation away from insulin receptor following Ser307 phosphorylation of IRS-1 suppresses PI3K/Akt pathway in obesity (38). Excessive serine phosphorylation of IRS blunts insulin sensitivity and reduces insulin-stimulated myocardial glucose uptake (39). Moreover, data from our laboratory indicated elevated Ser307 phosphorylation of IRS-1 in hearts from fetus born to obese sheep, en route to impaired insulin sensitivity and myocardial function (41). These data suggest a possible contribution of compromised insulin sensitivity to the unfavorable changes in cardiac morphology and function following maternal and/or postnatal fat exposure. 3.4. Genetic disorders in lipid transport/metabolism Maternal hyperlipidemia is associated with premature birth. Genetic predisposition in lipid transport/metabolism in women with pregnancy may affect postnatal life outcomes although convincing evidence is still elusive. Women with heterozygous familial hypercholesterolemia (FH) who become pregnant display rather high levels of LDL-cholesterol early in pregnancy (260 mg/dl) that rise to even higher levels near term (330 mg/dl), thus predisposing mother and fetus to high lipid levels and risks of pregnancy. Familial hypercholesterolemia, with a prevalence of 1:500 in general population, is caused by mutations in
MLPH
M
MHPL
MHPH
Fig. 1. Myocardial ultrastructure in adult offspring of mice fed a low fat (LF) or high fat (HF) diet during gestation and lactation. Weaning male offspring were placed on either LF or HF for 4 months prior to assessment of morphology: Transmission electron micrographs displayed regular myofilament alignment and mitochondria with electron dense matrix in longitudinal sections from MLPL hearts. High fat diet feeding resulted in variation in mitochondria size and vacuolization (arrowheads) in MLPH group. Hearts from MHPH group demonstrated prominent mitochondrial damage characterized by swelling, disruption of double membrane and reduction of electron-dense matrix (arrowheads) in addition to structural abnormalities found in MLPH hearts, indicating more severe mitochondrial damage. Maternal high fat diet exposure itself exhibited similar myocardial structure to that of MLPL group. Scale bar = 1 μm.
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Scheme 1. Schematic diagram depicting possible mechanisms involved in maternal overnutrition-induced changes in fetal hearts. It is likely that changes in mitochondrial integrity may promote apoptosis, cardiac remodeling and myocardial contractile dysfunction.
the low-density lipoprotein receptor. In a study linking the Medical Birth Registry of Norway (1967–2006) and the Medical Genetics Laboratory at Oslo University Hospital, the children of mothers with FH were no more likely than the general population to be born prematurely, with low birth weight, or congenital malformations. Although this is a retrospective, registry-based study, the data likely reflect the birth outcomes of a representative cohort of childbearing FH women [66]. Although the mechanism of action responsible for the discrepant findings between this familial hypercholesterolemia study and the known lipotoxicity outcome in maternal obesity is still elusive, certain caution should be taken with regard to a given patient population of genetic mutations for lipid metabolism/transport. It is noteworthy that a significant increase was noted in many lipid transport and TG synthesis genes including PPAR δ (peroxisome proliferator-activated receptor delta), Slc27a1 (fatty acid transport protein 1; also known as Fatp1), Cd36 (cluster of differentiation 36; also known as fatty acid translocation [22]), Lipin1, and Lipin3 under maternal obesity [67]. 4. Conclusion In conclusion, maternal obesity and/or high fat diet feeding may predispose offspring to a higher prevalence of postnatal fat diet-induced metabolic diseases including changes in cardiac geometry and function. Lipid accumulation and subsequently lipotoxicity appear to play a pivotal role in the observed metabolic and cardiovascular anomalies in the offspring from obese mothers during pregnancy. These findings, which are summarized in Scheme 1, should shed some lights towards a better management of obesity and obesity-associated heart diseases. Nonetheless, it is noteworthy that drug usage during pregnancy may also alter nutritional status and significantly impact the health outcome in the offspring. For example, polypharmacy is capable of triggering loss of appetite, nausea, diarrhea, weight changes, taste alterations, decrease in saliva secretion, modifications in lipid profile, alterations in electrolyte balance, and changes in glucose metabolism. Malnutrition may also lead to decreased amount of serum protein, meaning a higher unbound drug fraction [68]. Caution needs to be taken for drug-induced change in nutritional status during pregnancy. As maternal obesity and fat dietary exposure are commonplace and rapidly increasing, the future generations will be at an increased risk for metabolic and
cardiovascular disorders. Therefore, it is pertinent to identify effective therapeutic strategies for preventing maternal obesity-induced unfavorable fetal programming.
Disclosure statement None.
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