RESUMEN

Limb muscle is responsible for physical activities and myogenic cell migration during embryogenesis is indispensable for limb muscle formation. Maternal obesity (MO) impairs prenatal skeletal muscle development, but the effects of MO on myogenic cell migration remain to be examined. C57BL/6 mice embryos were collected at E13.5. The GeoMx DSP platform was used to customize five regions along myogenic cell migration routes (myotome, dorsal/ventral limb, limb stroma, limb tip), and data were analyzed by GeomxTools 3.6.0. A total of 2224 genes were down-regulated in the MO group. The GO enrichment analysis showed that MO inhibited migration-related biological processes. The signaling pathways guiding myogenic migration such as hepatocyte growth factor signaling, fibroblast growth factor signaling, Wnt signaling and GTPase signaling were down-regulated in the MO E13.5 limb tip. Correspondingly, the expression levels of genes involved in myogenic cell migration, such as Pax3, Gab1, Pxn, Tln2 and Arpc, were decreased in the MO group, especially in the dorsal and ventral sides of the limb. Additionally, myogenic differentiation-related genes were down-regulated in the MO limb. MO impedes myogenic cell migration and differentiation in the embryonic limb, providing an explanation for the impairment of fetal muscle development and offspring muscle function due to MO.

Asunto(s)

Diferenciación Celular , Movimiento Celular , Desarrollo de Músculos , Obesidad Materna , Animales , Movimiento Celular/genética , Ratones , Femenino , Desarrollo de Músculos/genética , Diferenciación Celular/genética , Embarazo , Obesidad Materna/metabolismo , Obesidad Materna/genética , Ratones Endogámicos C57BL , Regulación del Desarrollo de la Expresión Génica , Transcriptoma , Desarrollo Embrionario/genética , Extremidades/embriología , Perfilación de la Expresión Génica , Transducción de Señal , Músculo Esquelético/metabolismo , Músculo Esquelético/embriología

RESUMEN

Placental growth is most rapid during the first trimester (FT) of pregnancy, making it vulnerable to metabolic and endocrine influences. Obesity, with its inflammatory and oxidative stress, can cause cellular damage. We hypothesized that maternal obesity increases DNA damage in the FT placenta, affecting DNA damage response and trophoblast turnover. Examining placental tissue from lean and obese non-smoking women (4-12 gestational weeks), we observed higher overall DNA damage in obesity (COMET assay). Specifically, DNA double-strand breaks were found in villous cytotrophoblasts (vCTB; semi-quantitative γH2AX immunostaining), while oxidative DNA modifications (8-hydroxydeoxyguanosine; FPG-COMET assay) were absent. Increased DNA damage in obese FT placentas did not correlate with enhanced DNA damage sensing and repair. Indeed, obesity led to reduced expression of multiple DNA repair genes (mRNA array), which were further shown to be influenced by inflammation through in vitro experiments using tumor necrosis factor-α treatment on FT chorionic villous explants. Tissue changes included elevated vCTB apoptosis (TUNEL assay; caspase-cleaved cytokeratin 18), but unchanged senescence (p16) and reduced proliferation (Ki67) of vCTB, the main driver of FT placental growth. Overall, obesity is linked to heightened non-oxidative DNA damage in FT placentas, negatively affecting trophoblast growth and potentially leading to temporary reduction in early fetal growth.

Asunto(s)

Daño del ADN , Obesidad , Placenta , Primer Trimestre del Embarazo , Trofoblastos , Humanos , Femenino , Embarazo , Trofoblastos/metabolismo , Placenta/metabolismo , Obesidad/metabolismo , Obesidad/genética , Obesidad/patología , Adulto , Estrés Oxidativo , Apoptosis , Reparación del ADN , Roturas del ADN de Doble Cadena , Proliferación Celular , Obesidad Materna/metabolismo , Obesidad Materna/genética

RESUMEN

OBJECTIVE: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. METHODS: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals. RESULTS: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance. CONCLUSIONS: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.

Asunto(s)

Intolerancia a la Glucosa , Células Madre Hematopoyéticas , Ratones Endogámicos C57BL , Animales , Intolerancia a la Glucosa/metabolismo , Femenino , Ratones , Masculino , Células Madre Hematopoyéticas/metabolismo , Embarazo , Obesidad Materna/metabolismo , Ratones Obesos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos

RESUMEN

The aim of this study was to examine the impact of maternal obesity on the reproductive capacity of the female offspring (F1) and on the early development of the second generation (F2). To this end, rats were fed either standard (SD) or cafeteria (CD) diet. CD rats and their offspring were divided into 2 groups: rats with 18% and ≥25% overweight (CD18 and CD25, respectively) and offspring from CD18 and CD25 rats (OCD18 and OCD25, respectively). Both OCD groups achieved greater weight gain than controls, without changes in the serum levels of glucose, cholesterol or triglycerides. However, they showed increased gonadal cholesterol concentration and fat content compared to controls. Female OCD groups showed a slight prolongation of the estrous cycle and different pattern of changes in the weight gain during pregnancy. The OCD25 group displayed an increased fertility index and preimplantation losses, and changes in some fetal measurements. Some OCD25 dams gave birth to a larger litter of pups and displayed a lower viability index and lactation rate than controls. OCD25 dams also showed an increase in estradiol and a decrease in testosterone and anti-Müllerian hormone. OCD25 rats showed increased mRNA levels of steroidogenenic enzymes. The offspring from OCD25 females (F2OCD25 offspring) showed early vaginal opening and higher ovulation rate in females, and lower ano-genital distances in males, compared to controls. In conclusion, these results reflect that maternal obesity impacts on the reproductive health of successive generations, probably as a result of epigenetic changes in different systems, including germ cells.

Asunto(s)

Obesidad Materna , Efectos Tardíos de la Exposición Prenatal , Reproducción , Animales , Femenino , Embarazo , Obesidad Materna/metabolismo , Ratas , Masculino , Dieta Alta en Grasa/efectos adversos , Testosterona/sangre , Ciclo Estral , Dieta/efectos adversos , Estradiol/sangre , Obesidad/metabolismo , Obesidad/etiología

RESUMEN

It has been widely reported that obesity adversely impacts reproductive performance of females. However, the effects of maternal obesity on fetal germ cells remain poorly understood. In the present study, by employing a high-fat diet (HFD)-based mouse model, it is discovered that maternal obesity disrupts the chromosomal synapsis and homologous recombination during fetal oogenesis. Moreover, transcriptomic profiling reveales the potential molecular network controlling this process. Of note, the global hypermethylation of genomic DNA in fetal oocytes from obese mouse is detected. Importantly, time-restricted feeding (TRF) of obese mice not only ameliorate the meiotic defects, but also partly restore the epigenetic remodeling in fetal oocytes. In sum, the evidence are provided showing the deficit fetal oogenesis in obese mother, implicating a mechanism underlying the intergenerational effects of environmental insults. TRF may represent a potentially effective approach for mitigating fertility issues in obese patients.

Asunto(s)

Modelos Animales de Enfermedad , Epigénesis Genética , Meiosis , Obesidad Materna , Oocitos , Animales , Femenino , Ratones , Oocitos/metabolismo , Meiosis/genética , Epigénesis Genética/genética , Obesidad Materna/metabolismo , Obesidad Materna/genética , Embarazo , Dieta Alta en Grasa/efectos adversos , Oogénesis/genética , Ratones Endogámicos C57BL , Metilación de ADN/genética , Obesidad/genética , Obesidad/metabolismo

RESUMEN

INTRODUCTION: Gestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity. METHODS: In a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters. RESULTS: We found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women. DISCUSSION: This study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes.

Asunto(s)

Diabetes Gestacional , Kisspeptinas , Obesidad , Placenta , Receptores de Kisspeptina-1 , Transducción de Señal , Humanos , Femenino , Embarazo , Kisspeptinas/metabolismo , Placenta/metabolismo , Placenta/patología , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patología , Adulto , Sudáfrica/epidemiología , Obesidad/metabolismo , Obesidad/patología , Receptores de Kisspeptina-1/metabolismo , Receptores de Kisspeptina-1/genética , Obesidad Materna/metabolismo

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

RESUMEN

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide insights into fetal brain microglial programs and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders.

Asunto(s)

Encéfalo , Feto , Microglía , Microglía/metabolismo , Microglía/patología , Animales , Femenino , Embarazo , Encéfalo/metabolismo , Encéfalo/patología , Ratones , Humanos , Macrófagos/metabolismo , Obesidad Materna/metabolismo , Transcriptoma/genética , Masculino , Placenta/metabolismo , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Obesidad/patología , Obesidad/metabolismo

RESUMEN

Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven, in part, by the dysregulation of the early life microbiome. Here, using a mouse model of WD-induced maternal obesity, we demonstrate that exposure to a disordered microbiome from WD-fed dams suppressed circulating levels of endogenous ligands of the aryl hydrocarbon receptor (AHR; indole, indole-3-acetate) and TMAO (a product of AHR-mediated transcription), as well as hepatic expression of Il10 (an AHR target), in offspring at 3 weeks of age. This signature was recapitulated by fecal microbial transfer from WD-fed pregnant dams to chow-fed germ-free (GF) lactating dams following parturition and was associated with a reduced abundance of Lactobacillus in GF offspring. Further, the expression of Il10 was downregulated in liver myeloid cells and in LPS-stimulated bone marrow-derived macrophages (BMDM) in adult offspring, suggestive of a hypo-responsive, or tolerant, innate immune response. BMDMs from adult mice lacking AHR in macrophages exhibited a similar tolerogenic response, including diminished expression of Il10. Overall, our study shows that exposure to maternal WD alters microbial metabolites in the offspring that affect AHR signaling, potentially contributing to innate immune hypo-responsiveness and progression of MASLD, highlighting the impact of early life gut dysbiosis on offspring metabolism. Further investigations are warranted to elucidate the complex interplay between maternal diet, gut microbial function, and the development of neonatal innate immune tolerance and potential therapeutic interventions targeting these pathways.

Asunto(s)

Dieta Occidental , Microbioma Gastrointestinal , Inmunidad Innata , Receptores de Hidrocarburo de Aril , Triptófano , Animales , Femenino , Embarazo , Dieta Occidental/efectos adversos , Triptófano/metabolismo , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Ratones Endogámicos C57BL , Interleucina-10/metabolismo , Efectos Tardíos de la Exposición Prenatal , Obesidad Materna/metabolismo , Hígado/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Masculino , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de Enfermedad

RESUMEN

INTRODUCTION: Obesity and metabolic-associated fatty liver disease (MAFLD) during pregnancy constitute significant problems for routine antenatal care, with increasing prevalence globally. Similar to obesity, MAFLD is associated with a higher risk for maternal complications (e.g. pre-eclampsia and gestational diabetes) and long-term adverse health outcomes for the offspring. However, MAFLD during pregnancy is often under-recognized, with limited management/treatment options. AREAS COVERED: PubMed/MEDLINE, EMBASE, and Scopus were searched based on a search strategy for obesity and/or MAFLD in pregnancy to identify relevant papers up to 2024. This review summarizes the pertinent evidence on the relationship between maternal obesity and MAFLD during pregnancy. Key mechanisms implicated in the underlying pathophysiology linking obesity and MAFLD during pregnancy (e.g. insulin resistance and dysregulated adipokine secretion) are highlighted. Moreover, a diagnostic approach for MAFLD diagnosis during pregnancy and its complications are presented. Finally, promising relevant areas for future research are covered. EXPERT OPINION: Research progress regarding maternal obesity, MAFLD, and their impact on maternal and fetal/offspring health is expected to improve the relevant diagnostic methods and lead to novel treatments. Thus, routine practice could apply more personalized management strategies, incorporating individualized algorithms with genetic and/or multi-biomarker profiling to guide prevention, early diagnosis, and treatment.

Asunto(s)

Obesidad Materna , Complicaciones del Embarazo , Humanos , Embarazo , Femenino , Obesidad Materna/complicaciones , Obesidad Materna/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología

RESUMEN

Diet-induced obesity reduces oocyte quality mainly by impacting oocyte mitochondrial functions. Moreover, maternal obesity is associated with mitochondrial dysfunction in oocytes of their adult offspring. However, these effects were reported only in fully grown oocytes, mainly in the form of abnormal mitochondrial ultrastructure. It is unknown if obesogenic (OB) diets or maternal obesity already impact the primordial and preantral follicles. Considering the long duration and dynamics of folliculogenesis, determining the stage at which oocytes are affected and the extent of the damage is crucial for optimal reproductive management of obese patients and their daughters. Potential interaction between maternal and offspring diet effects are also not described, yet pivotal in our contemporary society. Therefore, here we examined the impact of OB diets on oocyte mitochondrial ultrastructure in primordial and activated preantral follicles in offspring from diet-induced obese or lean mothers. We used an outbred Swiss mouse model to increase the pathophysiological relevance to humans. Female mice were fed control or OB diets for 7 weeks, then mated with control males. Their female offspring were fed control or OB diets after weaning for 7 weeks (2-by-2 factorial design). Adult offspring ovarian sections were examined using transmission electron microscopy. We characterised and classified unique features of oocyte mitochondrial ultrastructure in the preantral follicles. An increase in mitochondrial matrix density was the most predominant change during follicle activation in secondary follicles, a feature that is linked with a higher mitochondrial activity. Maternal obesity increased mitochondrial density already in the primordial follicles suggesting an earlier increase in bioenergetic capacity. Maternal obesity did not induce abberant ultrastructure (abnormalities and defects) in primordial or preantral follicles. In contrast, offspring OB diet increased mitochondrial abnormalities in the primordial follicles. Further investigation of the consequences of these changes on oocyte metabolic regulation and stress levels during folliculogenesis is needed.

Asunto(s)

Mitocondrias , Oocitos , Folículo Ovárico , Animales , Oocitos/ultraestructura , Oocitos/metabolismo , Femenino , Folículo Ovárico/metabolismo , Folículo Ovárico/ultraestructura , Folículo Ovárico/patología , Ratones , Mitocondrias/ultraestructura , Mitocondrias/metabolismo , Embarazo , Obesidad/etiología , Obesidad/patología , Obesidad/metabolismo , Masculino , Obesidad Materna/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Dieta Alta en Grasa/efectos adversos

RESUMEN

BACKGROUND: Maternal obesity (MO) has been shown to adversely affect metabolic, oxidative, reproductive, and cognitive function in offspring. However, it is unclear whether lifestyle modification can ameliorate the metabolic and organ dysfunction programmed by MO and prevent the effects of metabolic syndrome in adulthood. This study aimed to evaluate whether moderate voluntary exercise in the offspring of rats born to obese mothers can ameliorate the adverse effects of MO programming on metabolism and liver function in mid-adulthood. METHODS: Offspring of control (CF1) and MOF1 mothers were fed with a control diet from weaning. Adult males and females participated in 15 min exercise sessions five days/week. Metabolic parameters were analyzed before and after the exercise intervention. Liver oxidative stress biomarkers and antioxidant enzymes were analyzed before and after the intervention. RESULTS: Males showed that CF1ex ran more than MOF1ex and increased the distance covered. In contrast, females in both groups ran similar distances and remained constant but ran more distance than males. At PND 300 and 450, male and female MOF1 had higher leptin, triglycerides, insulin, and HOMA-IR levels than CF1. However, male MOF1ex had lower triglycerides, insulin, and HOMA-IR levels than MOF1. Improvements in liver fat and antioxidant enzymes were observed in CF1ex and MOF1ex males and females compared to their respective CF1 and MOF1 groups. CONCLUSION: These findings suggest that moderate voluntary exercise, even when started in mid-adulthood, can improve metabolic outcomes and delay accelerated metabolic aging in MO-programmed rats in a sex-dependent manner.

Asunto(s)

Envejecimiento , Obesidad Materna , Condicionamiento Físico Animal , Animales , Femenino , Masculino , Ratas , Embarazo , Envejecimiento/metabolismo , Obesidad Materna/metabolismo , Estrés Oxidativo , Ratas Wistar , Hígado/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Obesidad/metabolismo , Obesidad/terapia , Obesidad/fisiopatología

RESUMEN

Maternal obesity is a well-known risk factor for developing premature obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes in the progeny. The development of white adipose tissue is a dynamic process that starts during prenatal life: fat depots laid down in utero are associated with the proportion of fat in children later on. How early this programming takes place is still unknown. However, recent evidence shows that mesenchymal stem cells (MSC), the embryonic adipocyte precursor cells, show signatures of the early setting of an adipogenic committed phenotype when exposed to maternal obesity. This review aims to present current findings on the cellular adaptations of MSCs from the offspring of women with obesity and how the metabolic environment of MSCs could affect the early commitment towards adipocytes. In conclusion, maternal obesity can induce early programming of fetal adipose tissue by conditioning MSCs. These cells have higher expression of adipogenic markers, altered insulin signalling and mitochondrial performance, compared to MSCs of neonates from lean pregnancies. Fetal MSCs imprinting by maternal obesity could help explain the increased risk of childhood obesity and development of further noncommunicable diseases.

Asunto(s)

Células Madre Mesenquimatosas , Obesidad Materna , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Embarazo , Obesidad Materna/metabolismo , Tejido Adiposo , Obesidad Infantil , Adipogénesis/fisiología , Recién Nacido , Adipocitos

RESUMEN

Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.

Asunto(s)

Ansiedad , Conducta Animal , Cannabidiol , Hipocampo , Obesidad Materna , Corteza Prefrontal , Efectos Tardíos de la Exposición Prenatal , Ratas Wistar , Animales , Femenino , Cannabidiol/farmacología , Embarazo , Ratas , Masculino , Obesidad Materna/metabolismo , Ansiedad/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Conducta Social , Obesidad/metabolismo , Endocannabinoides/metabolismo

RESUMEN

OBJECTIVE: Maternal obesity affects 39.7% of reproductive-age women in the United States. Emerging research has suggested that in utero exposure to maternal obesity is associated with adverse neurodevelopmental outcomes, but knowledge of underlying mechanisms in human samples is lacking. METHODS: A matched case-control study was performed in women with singleton fetuses who were undergoing elective pregnancy termination at gestational ages 15 to 21 weeks. Maternal adiponectin levels from plasma were measured using ELISA kits. RNA was extracted from fetal brain tissue using RNeasy Mini Kit (QIAGEN). mRNA expression from ADIPOR1, ADIPOR2, MTOR, ATG5, ATG7, BECN1, and MAP1LC3B was quantified through the ΔΔCt method and using GAPDH as a housekeeping gene. RESULTS: We have identified transcription patterns associated with inhibition of autophagy in male fetal brain tissue exposed to maternal obesity (↑MTOR, ↓ATG5, ↓ATG7, and ↓MAP1LC3B), with female fetuses demonstrating either no change in transcription or nonsignificant changes associated with increased autophagy. There was significant downregulation of the autophagy-associated gene BECN1 in both male and female individuals who were exposed to obesity in utero. CONCLUSIONS: We present novel evidence suggesting that in utero exposure to maternal obesity in humans may significantly affect neurodevelopment, especially in male fetuses, through alterations in normal autophagy molecular mechanisms and with adiponectin as a potential mediator.

Asunto(s)

Adiponectina , Autofagia , Beclina-1 , Encéfalo , Proteínas Asociadas a Microtúbulos , Obesidad Materna , Serina-Treonina Quinasas TOR , Humanos , Femenino , Embarazo , Masculino , Estudios de Casos y Controles , Obesidad Materna/metabolismo , Encéfalo/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adiponectina/metabolismo , Adiponectina/sangre , Beclina-1/metabolismo , Adulto , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/genética , Feto/metabolismo , ARN Mensajero/metabolismo , Factores Sexuales , Edad Gestacional , Regulación hacia Abajo , Obesidad/metabolismo

RESUMEN

Although obesity is recognized as a risk factor for cardiorenal and metabolic diseases, the impact of parental obesity on the susceptibility of their offspring to renal injury at adulthood is unknown. We examined the impact of parental obesity on offspring kidney function, morphology, and markers of kidney damage after acute kidney injury (AKI). Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were fed N (HN) or H diet (HH) after weaning. All offspring groups were submitted to bilateral AKI by clamping the left and right renal pedicles for 30 min. Compared with male NH and NN offspring from lean parents, male HH and HN offspring from obese parents exhibited higher kidney injury markers such as urinary, renal osteopontin, plasma creatinine, urinary albumin excretion, and neutrophil gelatinase-associated lipocalin (NGAL) levels, and worse histological injury score at 22 wk of age. Only albumin excretion and NGAL were elevated in female HH offspring from obese parents compared with lean and obese offspring from lean parents. We also found an increased mortality rate and worse kidney injury scores after AKI in male offspring from obese parents, regardless of the diet consumed after weaning. Female offspring were protected from major kidney injury after AKI. These results indicate that parental obesity leads to increased kidney injury in their offspring after ischemia-reperfusion in a sex-dependent manner, even when their offspring remain lean.NEW & NOTEWORTHY Offspring from obese parents are more susceptible to kidney injury and worse outcomes following an acute ischemia-reperfusion insult. Male, but not female, offspring from obese parents exhibit increased blood pressure early in life. Female offspring are partially protected against major kidney injury induced by ischemia-reperfusion.

Asunto(s)

Lesión Renal Aguda , Riñón , Ratones Endogámicos C57BL , Daño por Reperfusión , Animales , Masculino , Femenino , Daño por Reperfusión/patología , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/patología , Riñón/fisiopatología , Riñón/patología , Riñón/metabolismo , Factores Sexuales , Obesidad/complicaciones , Obesidad/fisiopatología , Dieta Alta en Grasa , Embarazo , Lipocalina 2/metabolismo , Obesidad Materna/metabolismo , Obesidad Materna/complicaciones , Obesidad Materna/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Ratones , Factores de Riesgo , Modelos Animales de Enfermedad , Biomarcadores/sangre

RESUMEN

Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17% kJ as fat) or a high-fat diet (HF, 49% kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n = 10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, principal component analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.

Asunto(s)

Dieta Alta en Grasa , Suplementos Dietéticos , Hipotálamo , Inflamación , Melatonina , Ratones Endogámicos C57BL , Obesidad Materna , Termogénesis , Animales , Termogénesis/efectos de los fármacos , Femenino , Melatonina/farmacología , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Masculino , Embarazo , Obesidad Materna/metabolismo , Inflamación/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Fenómenos Fisiologicos Nutricionales Maternos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética

RESUMEN

The prevalence of maternal obesity rapidly increases, which represents a major public health concern worldwide. Maternal obesity is characteristic by metabolic dysfunction and chronic inflammation. It is associated with health problems in both mother and offspring. Increasing evidence indicates that the placenta is an axis connecting maternal obesity with poor outcomes in the offspring. In this brief review, we have summarized the current data regarding deregulated placental function in maternal obesity. The data show that maternal obesity induces numerous placental defects, including lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics. These placental defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus. Further investigations are required to explore the exact molecular alterations in the placenta in maternal obesity, which may pave the way to develop specific interventions for preventing epigenetic and metabolic programming in the fetus.

Asunto(s)

Obesidad Materna , Placenta , Humanos , Embarazo , Femenino , Placenta/metabolismo , Obesidad Materna/metabolismo , Epigénesis Genética , Intercambio Materno-Fetal , Inflamación/metabolismo , Enfermedades Placentarias/fisiopatología , Enfermedades Placentarias/metabolismo , Complicaciones del Embarazo/metabolismo , Complicaciones del Embarazo/fisiopatología , Obesidad/metabolismo , Obesidad/fisiopatología

RESUMEN

The aim of this study was to analyse the expression of genes related to the regulation of energy metabolism in skeletal muscle tissue by comparing male offspring in two age groups [at 110 and 245 postnatal days (pnd)] from a mother with obesity induced by a high-fat diet and (-)-epicatechin (Epi) administration. Four groups of six male offspring from different litters were randomly selected for the control groups [C and offspring of mothers with maternal obesity (MO)] or Epi intervention groups. We evaluated the effect of Epi on gastrocnemius tissue by analysing the mRNA and protein expression levels of Fndc5/irisin, Pgc-1α, Ucp3, and Sln. Epi significantly increased the Pgc-1α protein in the MO group of offspring at 110 pnd (p < 0.036, MO vs. MO+Epi), while at 245 pnd, Epi increased Fndc5/irisin mRNA expression in the MO+Epi group versus the MO group (p = 0.006).No differences were detected in Fndc5/irisin, Ucp3 or Sln mRNA or protein levels (including Pgc-1α mRNA) in the offspring at 110 pnd or in Pgc-1α, Ucp3, or Sln mRNA or protein levels (including Fndc5/irisin protein) at 245 pnd among the experimental groups. In conclusion, (-)-epicatechin treatment increased Fndc5/irisin mRNA expression and Pgc-α protein levels in the gastrocnemius muscle of offspring at postnatal days 110 and 245. Furthermore, it is suggested that the flavonoid effect in a model of obesity and its impact on thermogenesis in skeletal muscle are regulated by a different pathway than Fndc5/irisin.

Asunto(s)

Catequina , Obesidad Materna , Humanos , Embarazo , Ratas , Masculino , Femenino , Animales , Catequina/farmacología , Fibronectinas/genética , Fibronectinas/metabolismo , Fibronectinas/farmacología , Músculo Esquelético/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/farmacología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad Materna/metabolismo , ARN Mensajero/genética

RESUMEN

During inguinal adipose tissue (iWAT) ontogenesis, beige adipocytes spontaneously appear between postnatal 10 (P10) and P20 and their ablation impairs iWAT browning capacity in adulthood. Since maternal obesity has deleterious effects on offspring iWAT function, we aimed to investigate its effect in spontaneous iWAT browning in offspring. Female C57BL/6 J mice were fed a control or obesogenic diet six weeks before mating. Male and female offspring were euthanized at P10 and P20 or weaned at P21 and fed chow diet until P60. At P50, mice were treated with saline or CL316,243, a ß3-adrenoceptor agonist, for ten days. Maternal obesity induced insulin resistance at P60, and CL316,243 treatment effectively restored insulin sensitivity in male but not female offspring. This discrepancy occurred due to female offspring severe browning impairment. During development, the spontaneous iWAT browning and sympathetic nerve branching at P20 were severely impaired in female obese dam's offspring but occurred normally in males. Additionally, maternal obesity increased miR-22 expression in the iWAT of male and female offspring during development. ERα, a target and regulator of miR-22, was concomitantly upregulated in the male's iWAT. Next, we evaluated miR-22 knockout (KO) offspring at P10 and P20. The miR-22 deficiency does not affect spontaneous iWAT browning in females and, surprisingly, anticipates iWAT browning in males. In conclusion, maternal obesity impairs functional iWAT development in the offspring in a sex-specific way that seems to be driven by miR-22 levels and ERα signaling. This impacts adult browning capacity and glucose homeostasis, especially in female offspring.

Asunto(s)

Adipocitos Beige , MicroARNs , Obesidad Materna , Animales , Femenino , Masculino , Ratones , Embarazo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Obesidad/genética , Obesidad/metabolismo , Obesidad Materna/metabolismo