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1.
PLoS Biol ; 22(6): e3002641, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38833481

RESUMEN

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.


Asunto(s)
Dieta Alta en Grasa , Ácidos Grasos , Hipotálamo , MicroARNs , Obesidad Materna , Animales , Femenino , Humanos , Masculino , Ratones , Embarazo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , MicroARNs/metabolismo , MicroARNs/genética , Neuronas/metabolismo , Obesidad/metabolismo , Obesidad/genética , Obesidad Materna/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/genética
2.
Bioessays ; 45(6): e2300026, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37042115

RESUMEN

Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals.


Asunto(s)
Metabolismo Basal , Animales , Humanos , Fenotipo
3.
Am J Physiol Heart Circ Physiol ; 327(1): H191-H220, 2024 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-38758127

RESUMEN

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.


Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Periodo Posparto , Embarazo , Humanos , Femenino , Animales , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Sistema Cardiovascular/fisiopatología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/diagnóstico
4.
FASEB J ; 37(6): e22887, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37132324

RESUMEN

Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off-target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg-1 ), Beta (0.1 mg kg-1 ), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO-dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin-1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system.


Asunto(s)
Betametasona , Glucocorticoides , Embrión de Pollo , Femenino , Embarazo , Animales , Betametasona/efectos adversos , Glucocorticoides/efectos adversos , Corazón , Arterias , Dexametasona/efectos adversos
5.
Diabetologia ; 66(12): 2320-2331, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37670017

RESUMEN

AIMS/HYPOTHESIS: Metformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta. METHODS: A cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated [Formula: see text]. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively. RESULTS: Complex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups. CONCLUSIONS/INTERPRETATION: In primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.


Asunto(s)
Metformina , Placenta , Humanos , Femenino , Embarazo , Metformina/farmacología , Metformina/uso terapéutico , Metformina/metabolismo , Trofoblastos/metabolismo , Cesárea , Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/metabolismo
6.
PLoS Genet ; 16(10): e1009069, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33057429

RESUMEN

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.


Asunto(s)
Factor II del Crecimiento Similar a la Insulina/genética , Mesodermo/crecimiento & desarrollo , Páncreas/crecimiento & desarrollo , Comunicación Paracrina/genética , Células Acinares/metabolismo , Células Acinares/patología , Aminoácidos/genética , Animales , Linaje de la Célula/genética , Cromo , Metilación de ADN/genética , Femenino , Citometría de Flujo , Regulación del Desarrollo de la Expresión Génica/genética , Impresión Genómica/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones , Ácidos Nicotínicos/genética , Páncreas/citología , Páncreas/metabolismo , Embarazo , ARN Largo no Codificante/genética
7.
Diabetologia ; 65(12): 2132-2145, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36112170

RESUMEN

AIMS/HYPOTHESIS: Metformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months. METHODS: C57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay). RESULTS: At 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring. CONCLUSIONS/INTERPRETATION: Maternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.


Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Hígado Graso , Metformina , Efectos Tardíos de la Exposición Prenatal , Humanos , Embarazo , Animales , Ratones , Niño , Masculino , Femenino , Adulto , Lactante , Metformina/farmacología , Metformina/uso terapéutico , Glucosa , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Composición Corporal , Hígado Graso/patología , Inflamación , Lípidos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Dieta Alta en Grasa/efectos adversos
8.
J Physiol ; 600(4): 903-919, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34505282

RESUMEN

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg kg-1  day-1 ) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669 ± 568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (P < 0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7 ± 125.4 nmol g-1 in the placenta and 2063 ± 2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk vs. benefits that are weighed in obstetric medical treatments. KEY POINTS: Maternal obesity and gestational diabetes mellitus have detrimental short- and long-term effects for mother and child. Metformin is commonly used to treat gestational diabetes mellitus in many populations worldwide but the effects on fetus and placenta are unknown. In a mouse model of diet-induced obesity and glucose intolerance in pregnancy we show reduced uterine artery compliance, placental structural changes and reduced fetal growth. Metformin treatment improved maternal metabolic health and uterine artery compliance but did not rescue obesity-induced changes in the fetus or placenta. Metformin crossed the placenta into the fetal circulation and entered fetal tissue. Metformin has beneficial effects on maternal health beyond glycaemic control. However, despite improvements in maternal physiology, metformin did not prevent fetal growth restriction or placental ageing. The high uptake of metformin into the placental and fetal circulation highlights the potential for direct immediate effects of metformin on the fetus with possible long-term consequences postnatally.


Asunto(s)
Intolerancia a la Glucosa , Metformina , Obesidad Materna , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Retardo del Crecimiento Fetal , Intolerancia a la Glucosa/metabolismo , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Metformina/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Placenta/metabolismo , Embarazo
9.
Physiol Rev ; 95(1): 47-82, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25540138

RESUMEN

Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease.


Asunto(s)
Metabolismo Energético/fisiología , Interacción Gen-Ambiente , Glucosa/metabolismo , Homeostasis/fisiología , Obesidad/genética , Animales , Diabetes Mellitus/etiología , Metabolismo Energético/genética , Ambiente , Predisposición Genética a la Enfermedad , Humanos , Plasticidad Neuronal/fisiología , Obesidad/etiología , Obesidad/metabolismo
10.
Int J Obes (Lond) ; 46(2): 269-278, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34663892

RESUMEN

OBJECTIVE: This study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA. METHODS: A mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring. RESULTS: Body weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 ± 0.8 g versus 10.4 ± 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 ± 2.1 g versus 12.9 ± 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgfß1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPKα, total AMPKα and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (-3p: 7.34 ± 1.35 versus 1.39 ± 0.50, p < 0.0001 and -5p: 4.66 ± 1.16 versus 1.63 ± 0.65, p < 0.05). CONCLUSION: Our findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny.


Asunto(s)
Conducta Alimentaria/psicología , Hígado/metabolismo , Enfermedades Metabólicas/dietoterapia , Factores de Edad , Animales , Modelos Animales de Enfermedad , Femenino , Expresión Génica/fisiología , Hígado/fisiopatología , Exposición Materna/efectos adversos , Exposición Materna/estadística & datos numéricos , Enfermedades Metabólicas/etiología , Ratones , Ratones Endogámicos C57BL/metabolismo , Obesidad/complicaciones , Obesidad/dietoterapia , ARN Mensajero
11.
FASEB J ; 35(5): e21477, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33891326

RESUMEN

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.


Asunto(s)
Ácido Ascórbico/uso terapéutico , Atrofia/tratamiento farmacológico , Hipoxia Fetal/complicaciones , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Animales , Animales Recién Nacidos , Antioxidantes/uso terapéutico , Atrofia/etiología , Atrofia/metabolismo , Atrofia/patología , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/tratamiento farmacológico , Retardo del Crecimiento Fetal/etiología , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/metabolismo , Complicaciones del Embarazo/patología , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Wistar
12.
FASEB J ; 35(5): e21446, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33788974

RESUMEN

Mitochondria-derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria-targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating functional experiments in vivo, with those at the isolated organ and molecular levels. Rats were randomized to normoxic or hypoxic (13%-14% O2 ) pregnancy ± MitoQ (500 µM day-1 ) in the maternal drinking water. At 4 months of age, one cohort of male offspring was chronically instrumented with vascular catheters and flow probes to test in vivo cardiovascular function. In a second cohort, the heart was isolated and mounted onto a Langendorff preparation. To establish mechanisms linking gestational hypoxia with cardiovascular dysfunction and protection by MitoQ, we quantified the expression of antioxidant system, ß-adrenergic signaling, and calcium handling genes in the fetus and adult, in frozen tissues from a third cohort. Maternal MitoQ in hypoxic pregnancy protected offspring against increased α1 -adrenergic reactivity of the cardiovascular system, enhanced reactive hyperemia in peripheral vascular beds, and sympathetic dominance, hypercontractility and diastolic dysfunction in the heart. Inhibition of Nfe2l2-mediated oxidative stress in the fetal heart and preservation of calcium regulatory responses in the hearts of fetal and adult offspring link molecular mechanisms to the protective actions of MitoQ treatment of hypoxic pregnancy. Therefore, these data show the efficacy of MitoQ in buffering mitochondrial stress through NADPH-induced oxidative damage and the prevention of programmed cardiovascular disease in adult offspring of hypoxic pregnancy.


Asunto(s)
Antioxidantes/farmacología , Enfermedades Cardiovasculares/prevención & control , Hipoxia Fetal/complicaciones , Mitocondrias/metabolismo , Estrés Oxidativo , Efectos Tardíos de la Exposición Prenatal/prevención & control , Animales , Animales Recién Nacidos , Calcio/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/patología , Femenino , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Wistar
13.
Int J Mol Sci ; 23(15)2022 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-35955948

RESUMEN

Sarcopenia is characterised by an age-related decrease in the number of muscle fibres and additional weakening of the remaining fibres, resulting in a reduction in muscle mass and function. Many studies associate poor maternal nutrition during gestation and/or lactation with altered skeletal muscle homeostasis in the offspring and the development of sarcopenia. The aim of this study was to determine whether the musculoskeletal physiology in offspring born to mouse dams fed a low-protein diet during pregnancy was altered and whether any physiological changes could be modulated by the nutritional protein content in early postnatal stages. Thy1-YFP female mice were fed ad libitum on either a normal (20%) or a low-protein (5%) diet. Newborn pups were cross-fostered to different lactating dams (maintained on a 20% or 5% diet) to generate three groups analysed at weaning (21 days): Normal-to-Normal (NN), Normal-to-Low (NL) and Low-to-Normal (LN). Further offspring were maintained ad libitum on the same diet as during lactation until 12 weeks of age, creating another three groups (NNN, NLL, LNN). Mice on a low protein diet postnatally (NL, NLL) exhibited a significant reduction in body and muscle weight persisting up to 12 weeks, unlike mice on a low protein diet only prenatally (LN, LNN). Muscle fibre size was reduced in mice from the NL but not LN group, showing recovery at 12 weeks of age. Muscle force was reduced in NLL mice, concomitant with changes in the NMJ site and changes in atrophy-related and myosin genes. In addition, µCT scans of mouse tibiae at 12 weeks of age revealed changes in bone mass and morphology, resulting in a higher bone mass in the NLL group than the control NNN group. Finally, changes in the expression of miR-133 in the muscle of NLL mice suggest a regulatory role for this microRNA in muscle development in response to postnatal diet changes. Overall, this data shows that a low maternal protein diet and early postnatal life low-protein intake in mice can impact skeletal muscle physiology and function in early life while postnatal low protein diet favours bone integrity in adulthood.


Asunto(s)
Lactancia , Sarcopenia , Animales , Dieta con Restricción de Proteínas , Femenino , Humanos , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Ratones , Músculo Esquelético/metabolismo , Proyectos Piloto , Embarazo , Sarcopenia/etiología , Sarcopenia/metabolismo
14.
Diabetologia ; 64(4): 890-902, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33501603

RESUMEN

AIMS/HYPOTHESIS: Levels of the microRNA (miRNA) miR-126-3p are programmed cell-autonomously in visceral adipose tissue of adult offspring born to obese female C57BL/6J mice. The spectrum of miR-126-3p targets and thus the consequences of its dysregulation for adipocyte metabolism are unknown. Therefore, the aim of the current study was to identify novel targets of miR-126-3p in vitro and then establish the outcomes of their dysregulation on adipocyte metabolism in vivo using a well-established maternal obesity mouse model. METHODS: miR-126-3p overexpression in 3T3-L1 pre-adipocytes followed by pulsed stable isotope labelling by amino acids in culture (pSILAC) was performed to identify novel targets of the miRNA. Well-established bioinformatics algorithms and luciferase assays were then employed to confirm those that were direct targets of miR-126-3p. Selected knockdown experiments were performed in vitro to define the consequences of target dysregulation. Quantitative real-time PCR, immunoblotting, histology, euglycaemic-hyperinsulinaemic clamps and glucose tolerance tests were performed to determine the phenotypic and functional outcomes of maternal programmed miR-126-3p levels in offspring adipose tissue. RESULTS: The proteomic approach confirmed the identity of known targets of miR-126-3p (including IRS-1) and identified Lunapark, an endoplasmic reticulum (ER) protein, as a novel one. We confirmed by luciferase assay that Lunapark was a direct target of miR-126-3p. Overexpression of miR-126-3p in vitro led to a reduction in Lunapark protein levels and increased Perk (also known as Eif2ak3) mRNA levels and small interference-RNA mediated knockdown of Lunapark led to increased Xbp1, spliced Xbp1, Chop (also known as Ddit3) and Perk mRNA levels and an ER stress transcriptional response in 3T3-L1 pre-adipocytes. Consistent with the results found in vitro, increased miR-126-3p expression in adipose tissue from adult mouse offspring born to obese dams was accompanied by decreased Lunapark and IRS-1 protein levels and increased markers of ER stress. At the whole-body level the animals displayed glucose intolerance. CONCLUSIONS/INTERPRETATION: Concurrently targeting IRS-1 and Lunapark, a nutritionally programmed increase in miR-126-3p causes adipose tissue insulin resistance and an ER stress response, both of which may contribute to impaired glucose tolerance. These findings provide a novel mechanism by which obesity during pregnancy leads to increased risk of type 2 diabetes in the offspring and therefore identify miR-126-3p as a potential therapeutic target.


Asunto(s)
Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Estrés del Retículo Endoplásmico , Proteínas de Homeodominio/metabolismo , MicroARNs/metabolismo , Obesidad Materna/metabolismo , Efectos Tardíos de la Exposición Prenatal , Células 3T3-L1 , Adipocitos/patología , Tejido Adiposo/patología , Animales , Glucemia/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Proteínas de Homeodominio/genética , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Obesidad Materna/genética , Obesidad Materna/patología , Fenotipo , Embarazo , Transducción de Señal
15.
FASEB J ; 34(9): 11844-11859, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32652768

RESUMEN

Lactation-induced bone loss occurs due to high calcium requirements for fetal growth but skeletal recovery is normally achieved promptly postweaning. Dietary protein is vital for fetus and mother but the effects of protein undernutrition on the maternal skeleton and skeletal muscles are largely unknown. We used mouse dams fed with normal (N, 20%) or low (L, 8%) protein diet during gestation and lactation and maintained on the same diets (NN, LL) or switched from low to normal (LN) during a 28 d skeletal restoration period post lactation. Skeletal muscle morphology and neuromuscular junction integrity was not different between any of the groups. However, dams fed the low protein diet showed extensive bone loss by the end of lactation, followed by full skeletal recovery in NN dams, partial recovery in LN and poor bone recovery in LL dams. Primary osteoblasts from low protein diet fed mice showed decreased in vitro bone formation and decreased osteogenic marker gene expression; promoter methylation analysis by pyrosequencing showed no differences in Bmpr1a, Ptch1, Sirt1, Osx, and Igf1r osteoregulators, while miR-26a, -34a, and -125b expression was found altered in low protein fed mice. Therefore, normal protein diet is indispensable for maternal musculoskeletal health during the reproductive period.


Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Enfermedades Óseas Metabólicas/fisiopatología , Dieta con Restricción de Proteínas , Lactancia/fisiología , Músculo Esquelético/fisiología , Reproducción/fisiología , Animales , Animales Recién Nacidos , Peso Corporal , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones Transgénicos , MicroARNs/genética , Músculo Esquelético/metabolismo , Osteoblastos/metabolismo , Osteogénesis/genética , Destete
16.
FASEB J ; 34(7): 9664-9677, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32502311

RESUMEN

Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off-target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the chicken embryo, a model system in which the effects on the developing heart and circulation of therapy can be investigated, independent of effects on the mother and/or the placenta. Fertilized chicken eggs were incubated and divided randomly into control (C) or dexamethasone (Dex) treatment at day 14 out of the 21-day incubation period. Combining functional experiments at the isolated organ, cellular and molecular levels, embryos were then studied close to term. Chicken embryos exposed to dexamethasone were growth restricted and showed systolic and diastolic dysfunction, with an increase in cardiomyocyte volume but decreased cardiomyocyte nuclear density in the left ventricle. Underlying mechanisms included a premature switch from tissue accretion to differentiation, increased oxidative stress, and activated signaling of cellular senescence. These findings, therefore, demonstrate that dexamethasone treatment can have direct detrimental off-target effects on the cardiovascular system in the developing embryo, which are independent of effects on the mother and/or placenta.


Asunto(s)
Senescencia Celular , Dexametasona/toxicidad , Fibrosis/patología , Glucocorticoides/toxicidad , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Animales , Embrión de Pollo , Pollos , Fibrosis/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos
17.
Adv Exp Med Biol ; 1327: 215-223, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34279842

RESUMEN

There have been recent encouraging reports about the development of vaccines for COVID-19. Given the scale and effects of this pandemic on public health and economies worldwide, there has been an unprecedented approach across the globe, leading to the emergence of vaccine candidates many times faster than the normal process would allow. This review gives up-to-date information as of November 28, 2020, on the latest developments in this area and covers the plans to roll out the most promising vaccines across the entire world to halt the spread of this devastating virus.


Asunto(s)
COVID-19 , Vacunas Virales , Vacunas contra la COVID-19 , Humanos , Pandemias , SARS-CoV-2
18.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-34299070

RESUMEN

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams' systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.


Asunto(s)
Diabetes Gestacional/patología , Metabolismo de los Lípidos , Lipidómica/métodos , Lípidos/análisis , Obesidad/fisiopatología , Animales , Glucemia/análisis , Diabetes Gestacional/etiología , Diabetes Gestacional/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Ratones , Embarazo
19.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-34360870

RESUMEN

BACKGROUND: Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white adipose tissue (WAT) of 8-week-old male and female mouse offspring. METHODS: C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR. RESULTS: Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (p < 0.05), exaggerated adipocyte hyperplasia (p < 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (p < 0.05) and the mRNA expression of F4/80 (p < 0.05). These changes were not observed in female Ob-Met offspring. CONCLUSIONS: Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT.


Asunto(s)
Animales Recién Nacidos/metabolismo , Diabetes Gestacional , Metformina/farmacología , Obesidad Materna , Efectos Tardíos de la Exposición Prenatal , Adiposidad , Animales , Diabetes Gestacional/tratamiento farmacológico , Diabetes Gestacional/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad Materna/tratamiento farmacológico , Obesidad Materna/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Factores Sexuales
20.
Diabetologia ; 63(2): 324-337, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31773193

RESUMEN

AIMS/HYPOTHESIS: Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. METHODS: Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. RESULTS: Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- (p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Islotes Pancreáticos/metabolismo , Obesidad Materna/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Apoptosis/fisiología , Western Blotting , ADN Mitocondrial/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Consumo de Oxígeno/fisiología , Embarazo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres Sexuales
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