RESUMEN
Although sheep have been widely adopted as an animal model for examining the timing of nutritional interventions through pregnancy on the short- and long-term outcomes, only modest programming effects have been seen. This is due in part to the mismatch in numbers of twins and singletons between study groups as well as unequal numbers of males and females. Placental growth differs between singleton and twin pregnancies which can result in different body composition in the offspring. One tissue that is especially affected is adipose tissue which in the sheep fetus is primarily located around the kidneys and heart plus the sternal/neck region. Its main role is the rapid generation of heat due to activation of the brown adipose tissue-specific uncoupling protein 1 at birth. The fetal adipose tissue response to suboptimal maternal food intake at defined stages of development differs between the perirenal abdominal and pericardial depots, with the latter being more sensitive. Fetal adipose tissue growth may be mediated in part by changes in leptin status of the mother which are paralleled in the fetus. Then, over the first month of life plasma leptin is higher in females than males despite similar adiposity, when fat is the fastest growing tissue with the sternal/neck depot retaining uncoupling protein 1, whereas other depots do not. Future studies should take into account the respective effects of fetal number and sex to provide more detailed insights into the mechanisms by which adipose and related tissues can be programmed in utero.
Asunto(s)
Adiposidad/fisiología , Reproducción/fisiología , Ovinos/fisiología , Animales , Femenino , Desarrollo Fetal , Masculino , EmbarazoRESUMEN
Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy.
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Salud Global , Trastornos de la Nutrición del Lactante/prevención & control , Fenómenos Fisiologicos Nutricionales Maternos , Modelos Biológicos , Política Nutricional , Cooperación del Paciente , Complicaciones del Embarazo/prevención & control , Adulto , Desarrollo Infantil , Femenino , Desarrollo Fetal , Humanos , Trastornos de la Nutrición del Lactante/epidemiología , Recién Nacido , Estado Nutricional , Embarazo , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo , Riesgo , Aumento de PesoRESUMEN
AIMS: To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans. METHODS: Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on (18)F-FDG PET/CT (n = 8) underwent a randomly allocated second (18)F-FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4). RESULTS: We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on (18)F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not. CONCLUSIONS: Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.
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Tejido Adiposo Pardo/metabolismo , Metabolismo Energético/efectos de los fármacos , Glucagón/farmacocinética , Adulto , Frío , Estudios Controlados Antes y Después , Fluorodesoxiglucosa F18 , Voluntarios Sanos , Humanos , Masculino , Tomografía de Emisión de Positrones/métodos , Distribución Aleatoria , Termogénesis/efectos de los fármacos , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
CONTEXT: Maternal obesity and gestational diabetes mellitus (GDM) can both contribute to adverse neonatal outcomes. The extent to which this may be mediated by differences in placental metabolism and nutrient transport remains to be determined. OBJECTIVE: Our objective was to examine whether raised maternal body mass index (BMI) and/or GDM contributed to a resetting of the expression of genes within the placenta that are involved in energy sensing, oxidative stress, inflammation, and metabolic pathways. METHODS: Pregnant women from Spain were recruited as part of the "Study of Maternal Nutrition and Genetics on the Foetal Adiposity Programming" survey at the first antenatal visit (12-20 weeks of gestation) and stratified according to prepregnancy BMI and the incidence of GDM. At delivery, placenta and cord blood were sampled and newborn anthropometry measured. RESULTS: Obese women with GDM had higher estimated fetal weight at 34 gestational weeks and a greater risk of preterm deliveries and cesarean section. Birth weight was unaffected by BMI or GDM; however, women who were obese with normal glucose tolerance had increased placental weight and higher plasma glucose and leptin at term. Gene expression for markers of placental energy sensing and oxidative stress, were primarily affected by maternal obesity as mTOR was reduced, whereas SIRT-1 and UCP2 were both upregulated. In placenta from obese women with GDM, gene expression for AMPK was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. CONCLUSIONS: Placental gene expression is sensitive to both maternal obesity and GDM which both impact on energy sensing and could modulate the effect of either raised maternal BMI or GDM on birth weight.
Asunto(s)
Peso Corporal , Diabetes Gestacional/fisiopatología , Placenta/fisiopatología , Resultado del Embarazo , Adolescente , Adulto , Antropometría , Peso al Nacer/genética , Índice de Masa Corporal , Diabetes Gestacional/genética , Ingestión de Energía/genética , Femenino , Expresión Génica/genética , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/genética , Humanos , Recién Nacido , Inflamación/genética , Inflamación/patología , Estudios Longitudinales , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/genética , Estrés Oxidativo , Placenta/metabolismo , Embarazo , España/epidemiología , Adulto JovenRESUMEN
Piglet neonatal mortality rates are high (~20%), so nutritional strategies to reduce this are highly desirable. Maternal fat substitution (FS) may promote the preweaning survival of piglets by improving their energy status. Therefore, the aim of the present study was to investigate the effects of FS throughout pregnancy on offspring viability, together with the gene expression of stress-related markers in the liver. Sixteen pregnant sows were randomly allocated to one of two isocaloric diets, control (C) or FS in the form of palm oil, fed from 0 to 110 days gestation. Glucose tolerance was examined on Day 108. Median and low birthweight offspring were allocated to tissue sampling at either 7 days or 6 months postnatal age. In response to a glucose tolerance test, FS sows exhibited a raised glucose area under the curve with no change in basal glucose. Average piglet mortality (up to Day 28) was increased fourfold in the FS group, with surviving median-sized piglets exhibiting significantly lower fatty acid binding protein 1 (FABP1) expression at 7 days. There were no effects on the abundance of any other stress- or metabolic-related genes examined. Thus, this study demonstrates that maternal FS throughout gestation causes maternal glucose intolerance that may be linked to the observed increase in piglet mortality. However, the surviving offspring do not exhibit any detectable differences in postnatal growth or hepatic gene profile in later life.
Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Dieta , Expresión Génica , Hígado/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Aceites de Plantas/administración & dosificación , Alimentación Animal/análisis , Animales , Animales Recién Nacidos , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Femenino , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Aceite de Palma , Embarazo , PorcinosRESUMEN
The 2013 Pennington Biomedical Research Center's Scientific Symposium focused on the treatment and management of pediatric obesity and was designed to (i) review recent scientific advances in the prevention, clinical treatment and management of pediatric obesity, (ii) integrate the latest published and unpublished findings and (iii) explore how these advances can be integrated into clinical and public health approaches. The symposium provided an overview of important new advances in the field, which led to several recommendations for incorporating the scientific evidence into practice. The science presented covered a range of topics related to pediatric obesity, including the role of genetic differences, epigenetic events influenced by in utero development, pre-pregnancy maternal obesity status, maternal nutrition and maternal weight gain on developmental programming of adiposity in offspring. Finally, the relative merits of a range of various behavioral approaches targeted at pediatric obesity were covered, together with the specific roles of pharmacotherapy and bariatric surgery in pediatric populations. In summary, pediatric obesity is a very challenging problem that is unprecedented in evolutionary terms; one which has the capacity to negate many of the health benefits that have contributed to the increased longevity observed in the developed world.
Asunto(s)
Adiposidad , Investigación Biomédica , Obesidad Infantil/prevención & control , Salud Pública , Aumento de Peso , Adolescente , Adulto , Niño , Preescolar , Dieta , Epigenómica , Medicina Basada en la Evidencia , Ejercicio Físico , Conocimientos, Actitudes y Práctica en Salud , Promoción de la Salud , Humanos , Obesidad Infantil/epidemiología , Obesidad Infantil/genética , Vigilancia de la Población , Prevalencia , Factores de Riesgo , Aumento de Peso/genéticaRESUMEN
AIM: Hypothermia induced by cold exposure at birth is prevented in sheep by the rapid onset of non-shivering thermogenesis in brown adipose tissue (BAT). Changes in adipose tissue composition in early life are therefore essential for survival but also influence adiposity in later life and were thus examined in detail during early development. METHODS: Changes in adipose composition were investigated by immunohistochemistry and qRT-PCR between the period from the first appearance of adipose in the mid gestation foetus, through birth and up to 1 month of age. RESULTS: We identified four distinct phases of development, each associated with pronounced changes in tissue histology and in distribution of the BAT specific uncoupling protein (UCP)1. At mid gestation, perirenal adipose tissue exhibited a dense proliferative, structure marked by high expression of KI-67 but with no UCP1 or visible lipid droplets. By late gestation large quantities of UCP1 were present, lipid storage was evident and expression of BAT-related genes were abundant (e.g. prolactin and ß3 receptors). Subsequently, within 12 h of birth, the depot was largely depleted of lipid and expression of genes such as UCP1, PGC1α, CIDEA peaked. By 30 days UCP1 was undetectable and the depot contained large lipid droplets; however, genes characteristic of BAT (e.g. PRDM16 and BMP7) and most characteristic of white adipose tissue (e.g. leptin and RIP140) were still abundant. CONCLUSION: Adipose tissue undergoes profound compositional changes in early life, of which an increased understanding could offer potential interventions to retain BAT in later life.
Asunto(s)
Tejido Adiposo Pardo/enzimología , Tejido Adiposo Pardo/crecimiento & desarrollo , Adiposidad/fisiología , Envejecimiento/fisiología , Metabolismo de los Lípidos/fisiología , Ovinos/embriología , Ovinos/crecimiento & desarrollo , AnimalesRESUMEN
It is becoming increasingly recognized that early-life nutritional, metabolic and environmental factors can have a long-term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to their adult lifestyle and nutritional environment depends not only on their genetic susceptibility but also on their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to 'non- or epi-genetic' causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life course modelling and diet-induced foetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarize current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of foetal nutrition. Ultimately, we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues.
Asunto(s)
Tejido Adiposo/fisiopatología , Adiposidad/genética , Envejecimiento/genética , Epigénesis Genética/genética , Obesidad/genética , Proteínas/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Animales , Humanos , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Offspring of obese and diabetic mothers are at increased risk of being born with excess adiposity as a consequence of their intrauterine environment. Excessive fetal fat accretion reflects additional placental nutrient transfer, suggesting an effect of the maternal environment on placental function. High plasma levels of particular nutrients in obese and diabetic mothers are likely to be the important drivers of nutrient transfer to the fetus, resulting in excess fat accretion. However, not all offspring of obese and diabetic mothers are born large for gestational age and the explanation may involve the regulation of placental nutrient transfer required for fetal growth. The placenta integrates maternal and fetal signals across gestation in order to determine nutrient transfer rate. Understanding the nature of these signals and placental responses to them is key to understanding the pathology of both fetal growth restriction and macrosomia. The overall effects of the maternal environment on the placenta are the product of its exposures throughout gestation, the 'placental exposome'. Understanding these environmental influences is important as exposures early in gestation, for instance causing changes in the function of genes involved in nutrient transfer, may determine how the placenta will respond to exposures later in gestation, such as to raised maternal plasma glucose or lipid concentrations. Longitudinal studies are required which allow investigation of the influences on the placenta across gestation. These studies need to make full use of developing technologies characterising placental function, fetal growth and body composition. Understanding these processes will assist in the development of preventive strategies and treatments to optimise prenatal growth in those pregnancies at risk of either excess or insufficient nutrient supply and could also reduce the risk of chronic disease in later life.
Asunto(s)
Adiposidad , Composición Corporal/fisiología , Feto/metabolismo , Placentación , Peso al Nacer , Epigénesis Genética , Femenino , Desarrollo Fetal , Humanos , Intercambio Materno-Fetal , Obesidad/metabolismo , Embarazo , Resultado del Embarazo , Factores de RiesgoRESUMEN
Reduced maternal food intake between early-to-mid gestation results in tissue-specific adaptations in the offspring following juvenile-onset obesity that are indicative of insulin resistance. The aim of the present study was to establish the extent to which renal ectopic lipid accumulation, as opposed to other markers of renal stress, such as iron deposition and apoptosis, is enhanced in obese offspring born to mothers nutrient restricted (NR) throughout early fetal kidney development. Pregnant sheep were fed either 100% (control) or NR (i.e. fed 50% of their total metabolisable energy requirement from 30-80 days gestation and 100% at all other times). At weaning, offspring were made obese and, at approximately 1 year, kidneys were sampled. Triglyceride content, HIF-1α gene expression and the protein abundance of the outer-membrane transporter voltage-dependent anion-selective channel protein (VDAC)-I on the kidney cortex were increased in obese offspring born to NR mothers compared with those born to controls, which exhibited increased iron accumulation within the tubular epithelial cells and increased gene expression of the death receptor Fas. In conclusion, suboptimal maternal nutrition coincident with early fetal kidney development results in enhanced renal lipid deposition following juvenile obesity and could accelerate the onset of the adverse metabolic, rather than cardiovascular, symptoms accompanying the metabolic syndrome.
Asunto(s)
Desarrollo Fetal/fisiología , Resistencia a la Insulina/fisiología , Riñón/embriología , Lípidos/análisis , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Obesidad/fisiopatología , Animales , Western Blotting , Cartilla de ADN/genética , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunohistoquímica , Riñón/química , Embarazo , Reacción en Cadena en Tiempo Real de la Polimerasa , Ovinos , Estadísticas no Paramétricas , Triglicéridos/análisis , Canal Aniónico 1 Dependiente del Voltaje/metabolismoRESUMEN
Adipose tissue function changes with development. In the newborn, brown adipose tissue (BAT) is essential for ensuring effective adaptation to the extrauterine environment, and its growth during gestation is largely dependent on glucose supply from the mother to the fetus. The amount, location and type of adipose tissue deposited can also determine fetal glucose homeostasis. Adipose tissue first appears at around mid-gestation. Total adipose mass then increases through late gestation, when it comprises a mixture of white and brown adipocytes. BAT possesses a unique uncoupling protein, UCP1, which is responsible for the rapid generation of large amounts of heat at birth. Then, during postnatal life some, but not all, depots are replaced by white fat. This process can be utilised to investigate the physiological conversion of brown to white fat, and how it is re-programmed by nutritional changes in pre- and postnatal environments. A reduction in early BAT deposition may perpetuate through the life cycle, thereby suppressing energy expenditure and ultimately promoting obesity. Normal fat development profiles in the offspring are modified by changes in maternal diet at defined stages of pregnancy, ultimately leading to adverse long-term outcomes. For example, excess macrophage accumulation and the onset of insulin resistance occur in an adipose tissue depot-specific manner in offspring born to mothers fed a suboptimal diet from early to mid-gestation. In conclusion, the growth of the different fetal adipose tissue depots varies according to maternal diet and, if challenged in later life, this can contribute to insulin resistance and impaired glucose homeostasis.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Desarrollo Fetal/fisiología , Tejido Adiposo Pardo/embriología , Tejido Adiposo Blanco/embriología , Animales , Femenino , Desarrollo Fetal/genética , Humanos , Resistencia a la Insulina , Modelos Biológicos , EmbarazoRESUMEN
The consequences of sub-optimal nutrition through alterations in the macronutrient content of the maternal diet will not simply be reflected in altered neonatal body composition and increased mortality, but are likely to continue into adulthood and confer greater risk of metabolic disease. One mechanism linking manipulations of the maternal environment to an increased risk of later disease is enhanced fetal exposure to glucocorticoids (GC). Tissue sensitivity to cortisol is regulated, in part, by the GC receptor and 11ß-hydroxysteroid dehydrogenase (11ß-HSD) types 1 and 2. Several studies have shown the effects of maternal undernutrition, particularly low-protein diets, on the programming of GC action in the offspring; however, dietary excess is far more characteristic of the diets consumed by contemporary pregnant women. This study investigated the programming effects of moderate protein supplementation in pigs throughout pregnancy. We have demonstrated an up-regulation of genes involved in GC sensitivity, such as GC receptor and 11ß-HSD, in the liver, but have yet to detect any other significant changes in these piglets, with no differences observed in body weight or composition. This increase in GC sensitivity was similar to the programming effects observed following maternal protein restriction or global undernutrition during pregnancy.
Asunto(s)
Dieta , Proteínas en la Dieta/farmacología , Desarrollo Fetal/efectos de los fármacos , Glucocorticoides/metabolismo , Complicaciones del Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal , Desnutrición Proteico-Calórica/complicaciones , Animales , Suplementos Dietéticos , Femenino , Desarrollo Fetal/fisiología , Hidroxiesteroide Deshidrogenasas/metabolismo , Hígado/metabolismo , Enfermedades Metabólicas/etiología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Receptores de Glucocorticoides/metabolismo , Porcinos , Regulación hacia ArribaRESUMEN
Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood.
Asunto(s)
Restricción Calórica/efectos adversos , Metabolismo Energético , Retardo del Crecimiento Fetal/etiología , Mucosa Gástrica/metabolismo , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Abomaso/crecimiento & desarrollo , Abomaso/metabolismo , Abomaso/patología , Adiposidad , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Proliferación Celular , Femenino , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Retardo del Crecimiento Fetal/fisiopatología , Mucosa Gástrica/crecimiento & desarrollo , Mucosa Gástrica/patología , Regulación de la Expresión Génica , Resistencia a la Insulina , Leptina/sangre , Leptina/genética , Leptina/metabolismo , Masculino , Embarazo , ARN Mensajero/metabolismo , Distribución Aleatoria , Ovinos , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Aumento de PesoRESUMEN
Epidemiological and animal studies have demonstrated that early-life nutrition alters the metabolic responses and generates structural changes in complex tissues, such as the kidneys, which may lead to a reduction in the offspring lifespan. Independently, obesity induces a spontaneous low-grade chronic inflammatory response by modulating several of the major metabolic pathways that ultimately compromise long-term renal health. However, the combined effects of maternal nutrition and early-life obesity in the development of renal diseases are far from conclusive. Previous results, using the ovine model, demonstrated that the combination of a reduction in fetal nutrition and juvenile obesity induced a series of adaptations associated with severe metabolic syndrome in the heart and adipose tissue. Surprisingly, exposure to an obesogenic environment in the kidney of those offspring produced an apparent reduction in glomerulosclerosis in relation to age- and weight-matched controls. However, this reduction in cellular apoptosis was accompanied by a rise in glomerular filtration rate and blood pressure of equal intensity when compared with obese controls. The intention of this review is to explain the adaptive responses observed in this model, based on insights into the mechanism of renal fetal programming, and their potential interactions with some of the metabolic changes produced by obesity.
Asunto(s)
Desarrollo Fetal , Enfermedades Renales/etiología , Riñón/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Síndrome Metabólico/complicaciones , Obesidad/complicaciones , Efectos Tardíos de la Exposición Prenatal , Tejido Adiposo/metabolismo , Animales , Femenino , Humanos , Inflamación , Riñón/embriología , Riñón/metabolismo , Miocardio/metabolismo , Obesidad/metabolismo , EmbarazoRESUMEN
Maternal nutrition during the period of early organ development can modulate the offspring's ability to metabolise excess fat as young adults when exposed to an obesogenic environment. This study examined the hypothesis that exposing offspring to nutrient restriction coincident with early hepatogenesis would result in endocrine and metabolic adaptations that subsequently lead to increased ectopic lipid accumulation within the liver. Pregnant sheep were fed either 50 or 100% of total metabolisable energy requirements from 30 to 80 days gestation and 100% thereafter. At weaning, offspring were made obese, and at ~1 year of age livers were sampled. Lipid infiltration and molecular indices of gluconeogenesis, lipid metabolism and mitochondrial function were measured. Although hepatic triglyceride accumulation was not affected by obesity per se, it was nearly doubled in obese offspring born to nutrient-restricted mothers. This adaptation was accompanied by elevated gene expression for peroxisome proliferator-activated receptor γ (PPARG) and its co-activator PGC1α, which may be indicative of changes in the rate of hepatic fatty acid oxidation. In contrast, maternal diet had no influence on the stimulatory effect of obesity on gene expression for a range of proteins involved in glucose metabolism and energy balance including glucokinase, glucocorticoid receptors and uncoupling protein 2. Similarly, although gene expressions for the insulin and IGF1 receptors were suppressed by obesity they were not influenced by the prenatal nutritional environment. In conclusion, excess hepatic lipid accumulation with juvenile obesity is promoted by suboptimal nutrition coincident with early development of the fetal liver.
Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales , Hígado Graso/metabolismo , Hígado/metabolismo , Desnutrición/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/metabolismo , Efectos Tardíos de la Exposición Prenatal , Factores de Edad , Animales , Modelos Animales de Enfermedad , Hígado Graso/embriología , Hígado Graso/genética , Hígado Graso/patología , Hígado Graso/fisiopatología , Femenino , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Gluconeogénesis/genética , Metabolismo de los Lípidos/genética , Hígado/embriología , Hígado/patología , Hígado/fisiopatología , Desnutrición/embriología , Desnutrición/genética , Desnutrición/fisiopatología , Mitocondrias Hepáticas/metabolismo , Obesidad/embriología , Obesidad/genética , Obesidad/patología , Obesidad/fisiopatología , PPAR gamma/genética , Embarazo , Ovinos , Triglicéridos/metabolismoRESUMEN
Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality; it may also predispose the mother and fetus to increased risks of adult cardiovascular disease. The selenoprotein glutathione peroxidases (GPxs) have critical roles in regulating antioxidant status. OBJECTIVES, STUDY DESIGN AND MAIN OUTCOME MEASURES: Immunohistochemical measurements of GPx1, GPx3 and GPx4 protein expression were performed on samples taken from three standardised sampling sites between the cord insertion and the periphery of the placenta from 12 normotensive, and 12 preeclamptic women to establish if their expression differed between sampling sites. Total GPx activities were also examined from the three sampling sites of these placentae. RESULTS: There were highly significant reductions in overall immunohistochemical staining of all 3 GPxs in the preeclampsia compared to normotensive placentae (GPx1: P=0.016; GPx3: P=0.003; GPx4: P<0.001). Furthermore, graded differences in expression between the standardised placental sampling sites were also found for GPx3 (higher in the inner region, P=0.05) and GPx4 (higher in the periphery, P=0.02) but not GPx1. Placental GPx enzyme activity was also significantly reduced in tissue from preeclamptic women as compared to normotensive women (P=0.007; the difference was more pronounced nearest the cord insertion). CONCLUSIONS: We have shown highly significant reductions in expression of all three major classes of GPx in placentae from women with preeclampsia, and distribution gradients in activity, which may relate to the differential oxygenation of regions of the placenta.
Asunto(s)
Glutatión Peroxidasa/metabolismo , Placenta/enzimología , Preeclampsia/enzimología , Adulto , Femenino , Humanos , Inmunohistoquímica , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Placenta/patología , Preeclampsia/patología , Embarazo , Glutatión Peroxidasa GPX1RESUMEN
The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11ß-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring.
RESUMEN
The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Fenómenos Fisiologicos Nutricionales Maternos , Sobrepeso/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Proteínas/genética , Envejecimiento/metabolismo , Animales , ADN Complementario/química , Femenino , Peso Fetal , Hipotálamo/metabolismo , Masculino , Obesidad/prevención & control , Tamaño de los Órganos , Especificidad de Órganos , Placenta/metabolismo , Embarazo , Proteínas/química , Proteínas/metabolismo , ARN Mensajero/metabolismo , Alineación de Secuencia , Oveja Doméstica , Delgadez/metabolismoRESUMEN
Maternal parity influences size at birth, postnatal growth and body composition with firstborn infants being more likely to be smaller with increased fat mass, suggesting that adiposity is set in early life. The precise effect of parity on fat mass and its endocrine sensitivity remains unclear and was, therefore, investigated in the present study. We utilised an established sheep model in which perirenal-abdominal fat mass (the major fat depot in the neonatal sheep) increases approximately 10-fold over the first month of life and focussed on the impact of parity on glucocorticoid sensitivity and adipokine expression in the adipocyte. Twin-bearing sheep of similar body weight and adiposity that consumed identical diets were utilised, and maternal blood samples were taken at 130 days of gestation. One offspring from each twin pair was sampled at 1 day of age, coincident with the time of maximal recruitment of uncoupling protein 1 (UCP1), whilst its sibling was sampled at 1 month, when UCP1 had disappeared. Plasma leptin was lower in nulliparous mothers than in multiparous mothers, and offspring of nulliparous mothers possessed more adipose tissue with increased mRNA abundance of leptin, glucocorticoid receptor and UCP2, adaptations that persisted up to 1 month of age when gene expression for interleukin-6 and adiponectin was also raised. The increase in fat mass associated with firstborn status is therefore accompanied by a resetting of the leptin and glucocorticoid axis within the adipocyte. Our findings emphasise the importance of parity in determining adipose tissue development and that firstborn offspring have an increased capacity for adipogenesis which may be critical in determining later adiposity.
Asunto(s)
Tejido Adiposo/metabolismo , Hormonas/sangre , Paridad , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Adipoquinas/genética , Adipoquinas/metabolismo , Animales , Animales Recién Nacidos , Peso Corporal , Femenino , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Canales Iónicos/metabolismo , Proteínas Mitocondriales/metabolismo , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Embarazo , ARN Mensajero/metabolismo , Receptor de Insulina/metabolismo , Receptores de Glucocorticoides/metabolismo , Ovinos , Proteína Desacopladora 1 , Proteína Desacopladora 2RESUMEN
Nutrient restriction (NR) during critical windows of pregnancy has differential effects on placento-fetal growth and development. Our study, therefore, investigated developmental and metabolic adaptations within the ovine placenta following NR at different critical windows during the first 110 days of gestation (term=147 days). Thus, the effects of NR on cell proliferation, glucocorticoid sensitivity, IGF1 and 2 receptor, peroxisome proliferator-activated receptor gamma (PPARG), and uncoupling protein (UCP)2 gene expression in the placenta were examined. Singleton bearing sheep (n=4-8 per group) were fed either 100% of their total metabolizable energy requirements throughout the study or 50% of this amount between 0-30, 31-65, 66-110, and 0-110 days gestation. A significant reduction in cell proliferation and increased gene expression for the glucocorticoid and IGF2 receptors, PPARG, and UCP2 were detected in placentae sampled from mothers who were nutrient restricted between days 66 and 110 of gestation, only, relative to controls. This window of gestation coincides with the maximum placental growth and the start of exponential growth of the fetus when there are substantially increased metabolic demands on the placenta compared with earlier in gestation. Consequently, increased glucocorticoid sensitivity and suppressed IGF2 action could contribute to a switch in the placenta from proliferation to differentiation, thereby improving its nutrient transfer capacity. Upregulation of PPARG and UCP2 would promote placental fatty acid metabolism thereby limiting glucose utilization. These compensatory placental responses may serve to maintain fetal growth but could result in adverse adaptations such as the early onset of the metabolic syndrome in later life.