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/genéticaRESUMEN
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/diagnósticoRESUMEN
Diet is integral to the healthy ageing process and certain diets can mitigate prolonged and deleterious inflammation. This review aims to assess the impact of diets high in sustainably sourced proteins on nutrient intake, gut, and age-related health in older adults. A systematic search of the literature was conducted on 5 September 2023 across multiple databases and sources. Studies assessing sustainably sourced protein consumption in community dwelling older adults (≥65 years) were included. Risk of bias (RoB) was assessed using 'RoB 2.0' and 'ROBINS-E'. Narrative synthesis was performed due to heterogeneity of studies. Twelve studies involving 12,166 older adults were included. Nine studies (n = 10,391) assessed habitual dietary intake and had some RoB concerns, whilst three studies (n = 1812), two with low and one with high RoB, conducted plant-based dietary interventions. Increased adherence to sustainably sourced diets was associated with improved gut microbial factors (n = 4640), healthier food group intake (n = 2142), and increased fibre and vegetable protein intake (n = 1078). Sustainably sourced diets positively impacted on gut microbiota and healthier intake of food groups, although effects on inflammatory outcomes and health status were inconclusive. Future research should focus on dietary interventions combining sustainable proteins and fibre to evaluate gut barrier function and consider inflammatory and body composition outcomes in older adults.
Asunto(s)
Proteínas en la Dieta , Microbioma Gastrointestinal , Humanos , Anciano , Microbioma Gastrointestinal/fisiología , Proteínas en la Dieta/administración & dosificación , Femenino , Masculino , Anciano de 80 o más Años , Dieta , Fibras de la Dieta/administración & dosificación , Dieta Saludable , Ingestión de Alimentos/fisiología , Vida IndependienteRESUMEN
Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P=0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG in both adipocyte differentiation and placental angiogenesis. NOS3, NRK, and ADAMTS8 (fetal and maternal-acting) have been implicated in both placental function and hypertension. Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors.
Asunto(s)
Complicaciones del Embarazo , Embarazo , Femenino , Humanos , Niño , Complicaciones del Embarazo/epidemiología , FamiliaRESUMEN
OBJECTIVE: We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. METHODS: Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity during pregnancy and ischemia-reperfusion on offspring cardiac miRNA expression and release. RESULTS: miR-15b-5p levels were increased in the sera of males born to mothers with higher BMI and in the hearts of adult mice born to obese dams. In an ex-vivo model of perfused mouse hearts, we demonstrated that cardiac tissue releases miR-15b-5p, and that some of the released miR-15b-5p was contained within small extracellular vesicles (EVs). We also demonstrated that release was higher from hearts exposed to maternal obesity following ischaemia/reperfusion. Over-expression of miR-15b-5p in vitro led to loss of outer mitochondrial membrane stability and to repressed fatty acid oxidation in cardiomyocytes. CONCLUSIONS: These findings suggest that miR-15-b could play a mechanistic role in the dysregulation of cardiac metabolism following exposure to an in utero obesogenic environment and that its release in cardiac EVs following ischaemic damage may be a novel factor contributing to inter-organ communication between the programmed heart and peripheral tissues.
Asunto(s)
Enfermedades Cardiovasculares , Vesículas Extracelulares , MicroARNs , Obesidad Materna , Daño por Reperfusión , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Embarazo , Enfermedades Cardiovasculares/metabolismo , Vesículas Extracelulares/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Obesidad Materna/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
OBJECTIVE: Obesity and excess adiposity are leading causes of metabolic and cardiovascular morbidity and mortality. Early identification of individuals at risk is key for preventive strategies. We examined the relationship between infant body composition (0-2 years of age) and later (>2 years) health outcomes using a systematic review. DESIGN: We preregistered the study on PROSPERO (ID 288013) and searched Embase, PubMed and Cochrane databases for English language publications using the Medical Subject Headings (MeSH) terms 'infant' and 'body composition' and 'risk' between January 1946 and February 2022. We included studies which assessed infant body composition using predetermined in vivo methods other than body mass index (BMI). RESULTS: We identified 6015 articles. After abstract screening to assess eligibility, we reviewed 130 full text publications. 30 were included in the final assessment and narrative synthesis. Meta-analysis was not possible due to heterogeneity of results. All 30 studies were of high quality and reported associations between infant body composition and 19 different health outcomes after 2 years of age. Outcome measurements ranged from 2 years to 16 years. The strongest associations were found between infant fat mass and later fat mass (7 studies), and later BMI (5 studies). For 11 of the outcomes assessed, there was no relationship to infant adiposity detected. CONCLUSIONS: Current evidence, from a small number of studies, suggests a positive association between infant adiposity and future adiposity or BMI, but the validity of infant body composition as a biomarker of future health remains inconclusive. Carefully designed, standardised studies are required to identify the value of infant body composition for predicting later health. TRIAL REGISTRATION: PROSPERO: 288013.
Asunto(s)
Salud del Adolescente , Obesidad , Adolescente , Niño , Humanos , Lactante , Adiposidad , Composición Corporal , Índice de Masa Corporal , Recién Nacido , PreescolarRESUMEN
The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.
Asunto(s)
Dieta con Restricción de Proteínas , Proteostasis , Femenino , Masculino , Animales , Ratones , Dieta con Restricción de Proteínas/efectos adversos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Proteínas/metabolismo , Mitocondrias/metabolismoRESUMEN
BACKGROUND: Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus. METHODS: We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions. RESULTS: There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis. CONCLUSIONS: Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.
Gestational diabetes (GDM) is high blood sugar first detected during pregnancy. Normalizing blood sugar levels quickly is important to avoid pregnancy complications. Many women achieve this with lifestyle changes, such as to diet, but some need to inject insulin or take tablets. We did two thorough reviews of existing research to see if we could predict which women need medication. Firstly we looked for ways to identify the characteristics of women who benefit most from changing their lifestyles to treat GDM, but found very limited research on this topic. We secondly searched for characteristics that help identify women who need medication to treat GDM. We found some useful characteristics that are obtained during routine pregnancy care. Further studies are needed to test if additional information could provide even better information about how we could make GDM treatment more tailored for individuals during pregnancy.
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/metabolismoRESUMEN
Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations in the UK Biobank study (Nâ¼420,000). We identified genes in which rare heterozygous loss-of-function increases adult BMI in women (DIDO1, PTPRG, and SLC12A5) and in men (SLTM), with effect sizes up to â¼8 kg/m2. This is complemented by analyses implicating rare variants in OBSCN and MADD for recalled childhood adiposity. The known functions of these genes, as well as findings of common variant genome-wide pathway enrichment analyses, suggest a role for neuron death, apoptosis, and DNA damage response mechanisms in the susceptibility to obesity across the life-course. These findings highlight the importance of considering sex-specific and life-course effects in the genetic regulation of obesity.
RESUMEN
The number of pregnancies complicated by obesity is increasing in line with the worldwide obesity crisis; recent estimates suggest that in developed countries more than 50% of pregnancies are in women who are overweight or have obesity. Maternal obesity is associated with an increased risk of many adverse outcomes for both the mother and baby during pregnancy and birth. In addition to these immediate outcomes, maternal obesity before and during pregnancy is associated with an increased risk of offspring cardio-metabolic disease later in life. Studies comparing siblings discordant for in utero exposure to maternal obesity suggest this is not simply due to transmission of 'obesogenic genes' between mother and child or current lifestyle factors, but reflects a direct impact of the obese intrauterine environment on fetal development. This review will describe the long-term consequences of exposure to maternal obesity during development for the cardio-metabolic health of the offspring. It will also discuss the potential molecular mechanisms that underlie the increased risk of metabolic disease in offspring of mothers with obesity, and explore interventions that may be implemented during pregnancy to limit the impact of obesity on offspring long-term health. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.
Asunto(s)
Obesidad Materna , Lactante , Niño , Humanos , Femenino , Embarazo , Obesidad , Desarrollo Fetal , Madres , Estilo de VidaRESUMEN
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 adversosRESUMEN
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 , FenotipoRESUMEN
BACKGROUND/PURPOSE: Litter size is a biological variable that strongly influences adult physiology in rodents. Despite evidence from previous decades and recent studies highlighting its major impact on metabolism, information about litter size is currently underreported in the scientific literature. Here, we urge that this important biological variable should be explicitly stated in research articles. RESULTS/CONCLUSION: Below, we briefly describe the scientific evidence supporting the impact of litter size on adult physiology and outline a series of recommendations and guidelines to be implemented by investigators, funding agencies, editors in scientific journals, and animal suppliers to fill this important gap.
Asunto(s)
Roedores , Embarazo , Animales , Femenino , Tamaño de la Camada/fisiologíaRESUMEN
AIMS: Precision medicine has revolutionized our understanding of type 1 diabetes and neonatal diabetes but has yet to improve insight into gestational diabetes mellitus (GDM), the most common obstetric complication and strongly linked to obesity. Here we explored if patterns of glycaemia (fasting, 1 hour, 2 hours) during the antenatal oral glucose tolerance test (OGTT), reflect distinct pathophysiological subtypes of GDM as defined by insulin secretion/sensitivity or lipid profiles. METHODS: 867 pregnant women with obesity (body mass index ≥ 30 kg/m2) from the UPBEAT trial (ISRCTN 89971375) were assessed for GDM at 28 weeks' gestation (75 g oral glucose tolerance test OGTT; World Health Organization criteria). Lipid profiling of the fasting plasma OGTT sample was undertaken using direct infusion mass spectrometry and analyzed by logistic/linear regression, with and without adjustment for confounders. Insulin secretion and sensitivity were characterized by homeostatic model assessment 2b and 2s, respectively. RESULTS: In women who developed GDM (n = 241), patterns of glycaemia were associated with distinct clinical and biochemical characteristics and changes to lipid abundance in the circulation. Severity of glucose derangement, rather than pattern of postload glycaemia, was most strongly related to insulin action and lipid abundance/profile. Unexpectedly, women with isolated postload hyperglycemia had comparable insulin secretion and sensitivity to euglycemic women, potentially indicative of a novel mechanistic pathway. CONCLUSIONS: Patterns of glycemia during the OGTT may contribute to a precision approach to GDM as assessed by differences in insulin resistance/secretion. Further research is indicated to determine if isolated postload hyperglycemia reflects a different mechanistic pathway for targeted management.
Asunto(s)
Diabetes Gestacional , Hiperglucemia , Resistencia a la Insulina , Recién Nacido , Femenino , Embarazo , Humanos , Mujeres Embarazadas , Glucemia/análisis , Medicina de Precisión , Insulina/metabolismo , Obesidad/complicaciones , LípidosRESUMEN
Enhancing pregnancy health is known to improve the mother's and offspring's life-long well-being. The maternal environment, encompassing genetic factors, impacts of social determinants, the nutritional/metabolic milieu, and infections and inflammation, have immediate consequences for the in utero development of the fetus and long-term programming into childhood and adulthood. Moreover, adverse pregnancy outcomes such as preterm birth or preeclampsia, often attributed to the maternal environmental factors listed above, have been associated with poor maternal cardiometabolic health after pregnancy. In this BMC Medicine article collection, we explore a broad spectrum of maternal characteristics across pregnancy and postnatal phenotypes, anticipating substantial cross-fertilization of new understanding and shared mechanisms around diverse outcomes. Advances in the ability to leverage 'omics across different platforms (genome, transcriptome, proteome, metabolome, microbiome, lipidome), large high-dimensional population databases, and unique cohorts are generating exciting new insights: The first articles in this collection highlight the role of placental biomarkers of preterm birth, metabolic influences on fetal and childhood growth, and the impact of common pre-existing maternal disorders, obesity and smoking on pregnancy outcomes, and the child's health. As the collection grows, we look forward to seeing the connections emerge across maternal, fetal, and childhood outcomes that will foster new insights and preventative strategies for women.