Spatial Transcriptomics Analysis: Maternal Obesity Impairs Myogenic Cell Migration and Differentiation during Embryonic Limb Development.

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.

Obesity-associated non-oxidative genotoxic stress alters trophoblast turnover in human first-trimester placentas.

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.

Maternal Obesity Induces the Meiotic Defects and Epigenetic Alterations During Fetal Oocyte Development.

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.

Adult rats sired by obese fathers present learning deficits associated with epigenetic and neurochemical alterations linked to impaired brain glutamatergic signaling.

AIM: Offspring of obese mothers are at high risk of developing metabolic syndrome and cognitive disabilities. Impaired metabolism has also been reported in the offspring of obese fathers. However, whether brain function can also be affected by paternal obesity has barely been examined. This study aimed to characterize the learning deficits resulting from paternal obesity versus those induced by maternal obesity and to identify the underlying mechanisms. METHODS: Founder control and obese female and male Wistar rats were mated to constitute three first-generation (F1) experimental groups: control mother/control father, obese mother/control father, and obese father/control mother. All F1 animals were weaned onto standard chow and underwent a learning test at 4 months of age, after which several markers of glutamate-mediated synaptic plasticity together with the expression of miRNAs targeting glutamate receptors and the concentration of kynurenic and quinolinic acids were quantified in the hippocampus and frontal cortex. RESULTS: Maternal obesity induced a severe learning deficit by impairing memory encoding and memory consolidation. The offspring of obese fathers also showed reduced memory encoding but not impaired long-term memory formation. Memory deficits in offspring of obese fathers and obese mothers were associated with a down-regulation of genes encoding NMDA glutamate receptors subunits and several learning-related genes along with impaired expression of miR-296 and miR-146b and increased concentration of kynurenic acid. CONCLUSION: Paternal and maternal obesity impair offspring's learning abilities by affecting different processes of memory formation. These cognitive deficits are associated with epigenetic and neurochemical alterations leading to impaired glutamate-mediated synaptic plasticity.

Dilemma of Epigenetic Changes Causing or Reducing Metabolic Disorders in Offsprings of Obese Mothers.

Maternal obesity is associated with fetal complications predisposing later to the development of metabolic syndrome during childhood and adult stages. High-fat diet seems to influence individuals and their subsequent generations in mediating weight gain, insulin resistance, obesity, high cholesterol, diabetes, and cardiovascular disorder. Research evidence strongly suggests that epigenetic alteration is the major contributor to the development of metabolic syndrome through DNA methylation, histone modifications, and microRNA expression. In this review, we have discussed the outcome of recent studies on the adverse and beneficial effects of nutrients and vitamins through epigenetics during pregnancy. We have further discussed about the miRNAs altered during maternal obesity. Identification of new epigenetic modifiers such as mesenchymal stem cells condition media (MSCs-CM)/exosomes for accelerating the reversal of epigenetic abnormalities for the development of new treatments is yet another aspect of the present review.

Maternal obesity increases DNA methylation and decreases RNA methylation in the human placenta.

Maternal obesity is associated with increased risk of adverse pregnancy and birth outcomes. While increasing body of evidence supports that the etiology is related to fetal and placental hypoxia, molecular signaling changes in response to this pathophysiological condition in human placenta have remained elusive. Here by using varied approaches including immunocytochemistry staining, Western blot, RT-qPCR, and ELISA, we aimed to investigate the changes in epigenetic markers in placentas from obese pregnant women following delivery by Caesarean-section at term. Our results revealed that the levels of 5-methylcytosine (5mC), a methylated form commonly occurring in CpG dinucleotides and an important repressor of gene transcription in the genome, were significantly increased coupled with decreased activity of Ten-Eleven Translocation (TETs) enzymes that principally function by oxidizing 5mC in the obese placenta, consistent with hypoxia-induced genome-wide DNA hypermethylation observed in varied types of cells and tissues. N6-methyladenosine (m6A) represents the most abundant and conserved modification of gene transcripts, especially within mRNAs, which is stalled by m6A methyltransferases or "writers" including METTL-3/-14, WTAP, RBM15B, and KIAA1429. We further showed that obese placentas demonstrated significantly down-regulated levels of m6A along with reduced gene expression of WTAP, RBM15B, and KIAA1429. Our data support that maternal obesity-induced hypoxia may play an important role in triggering genome-wide DNA hypermethylation in the human placenta, and in turn leading to transcriptome-wide inhibition of RNA modifications. Our results further suggest that selectively modulating these pathways may facilitate development of novel therapeutic approaches for controlling and managing maternal obesity-associated adverse clinical outcomes.

Imprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance.

Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT). We find that MO impairs fetal BAT development, which persistently suppresses BAT thermogenesis and primes female offspring to metabolic dysfunction. In fetal BAT, MO enhances expression of Dio3, which encodes deiodinase 3 (D3) to catabolize triiodothyronine (T3), while a maternally imprinted long noncoding RNA, Dio3 antisense RNA (Dio3os), is inhibited, leading to intracellular T3 deficiency and suppression of BAT development. Gain and loss of function shows Dio3os reduces D3 content and enhances BAT thermogenesis, rendering female offspring resistant to high fat diet-induced obesity. Attributing to Dio3os inactivation, its promoter has higher DNA methylation in obese dam oocytes which persists in fetal and adult BAT, uncovering an oocyte origin of intergenerational obesity. Overall, our data uncover key features of Dio3os activation in BAT to prevent intergenerational obesity and metabolic dysfunctions.

Aberrant DNA Methylation Mediates the Transgenerational Risk of Metabolic and Chronic Disease Due to Maternal Obesity and Overnutrition.

Maternal obesity is a rapidly evolving universal epidemic leading to acute and long-term medical and obstetric health issues, including increased maternal risks of gestational diabetes, hypertension and pre-eclampsia, and the future risks for offspring's predisposition to metabolic diseases. Epigenetic modification, in particular DNA methylation, represents a mechanism whereby environmental effects impact on the phenotypic expression of human disease. Maternal obesity or overnutrition contributes to the alterations in DNA methylation during early life which, through fetal programming, can predispose the offspring to many metabolic and chronic diseases, such as non-alcoholic fatty liver disease, obesity, diabetes, and chronic kidney disease. This review aims to summarize findings from human and animal studies, which support the role of maternal obesity in fetal programing and the potential benefit of altering DNA methylation to limit maternal obesity related disease in the offspring.

Effect of Polyphenols Intake on Obesity-Induced Maternal Programming.

Excess caloric intake and body fat accumulation lead to obesity, a complex chronic disease that represents a significant public health problem due to the health-related risk factors. There is growing evidence showing that maternal obesity can program the offspring, which influences neonatal phenotype and predispose offspring to metabolic disorders such as obesity. This increased risk may also be epigenetically transmitted across generations. Thus, there is an imperative need to find effective reprogramming approaches in order to resume normal fetal development. Polyphenols are bioactive compounds found in vegetables and fruits that exert its anti-obesity effect through its powerful anti-oxidant and anti-inflammatory activities. Polyphenol supplementation has been proven to counteract the prejudicial effects of maternal obesity programming on progeny. Indeed, some polyphenols can cross the placenta and protect the fetal predisposition against obesity. The present review summarizes the effects of dietary polyphenols on obesity-induced maternal reprogramming as an offspring anti-obesity approach.

Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency, and diastolic function early in life.

Previous studies suggest that parental obesity may adversely impact long-term metabolic health of the offspring. We tested the hypothesis that parental (paternal + maternal) obesity impairs cardiac function in the offspring early in life. Within 1-3 days after weaning, offspring from obese rats fed a high-fat diet (HFD-Offs) and age-matched offspring from lean rats (ND-Offs) were submitted to echocardiography and cardiac catheterization for assessment of pressure-volume relationships. Then, hearts were digested and isolated cardiomyocytes were used to determine contractile function, calcium transients, proteins related to calcium signaling, and mitochondrial bioenergetics. Female and male HFD-Offs were heavier (72 ± 2 and 61 ± 4 g vs. 57 ± 2 and 49 ± 1 g), hyperglycemic (112 ± 8 and 115 ± 12 mg/dL vs. 92 ± 10 and 96 ± 8 mg/dL) with higher plasma insulin and leptin concentrations compared with female and male ND-Offs. When compared with male controls, male HFD-Offs exhibited similar systolic function but impaired diastolic function as indicated by increased IVRT (22 ± 1 vs. 17 ± 1 ms), E/E' ratio (29 ± 2 vs. 23 ± 1), and tau (5.7 ± 0.2 vs. 4.8 ± 0.2). The impaired diastolic function was associated with reduced resting free Ca2+ levels and phospholamban protein expression, increased activated matrix metalloproteinase 2, and reduced SIRT3 protein expression, mitochondrial ATP reserve, and ATP-linked respiration. These results indicate that male and female Offs from obese parents have multiple metabolic abnormalities early in life (1-3 days after weaning) and that male, but not female, Offs have impaired diastolic function as well as reductions in cardiac SIRT3, resting free Ca2+ levels, and mitochondrial biogenesis.NEW & NOTEWORTHY Parental obesity contributes to diastolic dysfunction in young offspring (1-3 days after weaning) in a sex-dependent manner, as well as reduced cardiac SIRT3 expression and altered mitochondrial bioenergetics, resting Ca2+ levels, and reduced phospholamban protein levels.

Maternal Socs3 knockdown attenuates postnatal obesity caused by an early life environment of maternal obesity and intrauterine overnutrition in progeny mice.

Pathological states in the early life environment of mammalian offspring, including maternal obesity and intrauterine overnutrition, can induce obesity and metabolic disorder later in life. Leptin resistance caused by upregulation of Socs3 in the hypothalamus of offspring was believed to be the main mechanism of this effect. In this study, obese mother (OM) and lean mother (LM) models were generated by feeding C57BL/6N female mice a high-fat diet or standard lean diet, respectively. Additionally, an obese mother with intervention (OMI) model was generated by injecting the high-fat diet group with Socs3-shRNA lentivirus during early pregnancy. The offspring of the groups was correspondingly named OM-F1 , LM-F1 , and OMI-F1 , representing progeny mouse models of different early life environments. The offspring were fed a high-fat diet to test their propensity for obesity. The body weight, food intake and fat accumulation were higher, while glucose intolerance and insulin resistance were worse in the OM-F1 group than LM-F1 group. By contrast, the obesity phenotype, hyperphagia and metabolic disorder were alleviated in the OMI-F1 group compared with the OM-F1 group. The mechanism was identified that downregulation of hypothalamic SOCS3 resulted in an increased level of p-STAT3 and p-JAK2, which ameliorated the leptin resistance and restored the lean expression of appetite regulatory genes (Pomc and Agrp) in hypothalamus of OMI-F1 group. Taken together, these results indicate that reducing maternal Socs3 expression during pregnancy can attenuate obesity caused by the early life environment in mice, which may inspire therapies that enable obese mothers to bear metabolically healthy children.

Maternal obesity reverses the resistance to LPS-induced adverse pregnancy outcome and increases female offspring metabolic alterations in cannabinoid receptor 1 knockout mice.

Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a "nutritional programming" of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.

Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus.

Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, but few studies have focused on obese pregnant women with GDM. Antioxidant and macro/chaperone-mediated autophagy (CMA)-related gene expressions were evaluated herein in obese and GDM placentas. A total of 47 women with singleton pregnancies delivered by elective cesarean section were enrolled: 16 normal weight (NW), 18 obese with no comorbidities (OB GDM(-)), 13 obese with GDM (OB GDM(+)). Placental gene expression was assessed by real-time PCR. Antioxidant gene expression (CAT, GPX1, GSS) decreased, the pro-autophagic ULK1 gene increased and the chaperone-mediated autophagy regulator PHLPP1 decreased in OB GDM(-) vs. NW. On the other hand, PHLPP1 expression increased in OB GDM(+) vs. OB GDM(-). When analyzing results in relation to fetal sex, we found sexual dimorphism for both antioxidant and CMA-related gene expressions. These preliminary results can pave the way for further analyses aimed at elucidating the placental autophagy role in metabolic pregnancy disorders and its potential targetability for the treatment of diabetes outcomes.

Phenotypic and Epigenetic Adaptations of Cord Blood CD4+ T Cells to Maternal Obesity.

Pregravid obesity has been shown to disrupt the development of the offspring's immune system and increase susceptibility to infection. While the mechanisms underlying the impact of maternal obesity on fetal myeloid cells are emerging, the consequences for T cells remain poorly defined. In this study, we collected umbilical cord blood samples from infants born to lean mothers and mothers with obesity and profiled CD4 T cells using flow cytometry and single cell RNA sequencing at resting and following ex vivo polyclonal stimulation. We report that maternal obesity is associated with higher frequencies of memory CD4 T cells suggestive of in vivo activation. Moreover, single cell RNA sequencing revealed expansion of an activated subset of memory T cells with maternal obesity. However, ex vivo stimulation of purified CD4 T cells resulted in poor cytokine responses, suggesting functional defects. These phenotypic and functional aberrations correlated with methylation and chromatin accessibility changes in loci associated with lymphocyte activation and T cell receptor signaling, suggesting a possible link between maternal obesogenic environment and fetal immune reprogramming. These observations offer a potential explanation for the increased susceptibility to microbial infection in babies born to mothers with obesity.

Reducing intergenerational obesity and diabetes risk.

To address the intergenerational transmission of obesity and diabetes, strategies promoting the health of women of reproductive age appear to be urgently needed. In this narrative review, we summarise what has been learned from many prenatal clinical trials, discuss the emerging evidence from preconception clinical trials and highlight persistent gaps and critical future directions. Most trials tested prenatal interventions that resulted in a limited gestational weight gain of ~1 kg and reduced gestational diabetes by 20-30%. These interventions also reduced macrosomia by 20-40% but had little-to-no impact on other offspring outcomes at birth or beyond. Far fewer trials tested preconception interventions, with almost all designed to improve conception or live-birth rates in overweight or obese women with infertility rather than reduce intergenerational risks in diverse populations. Preconception trials have successfully reduced weight by 3-9 kg and improved markers of glucose homeostasis and insulin resistance by the end of the intervention but whether effects were sustained to conception is unclear. Very few studies have reported offspring outcomes at birth and beyond, with no evidence thus far of beneficial effects on offspring obesity or diabetes risks. Further efforts to develop effective and scalable strategies to reduce risk of obesity and diabetes before conception should be prioritised, especially for diverse and under-resourced populations at disparately high risk of obesity and diabetes. Future clinical trials should include interventions with high potential for dissemination, diverse populations, thorough maternal phenotyping from enrolment through to conception and pregnancy, and rigorous assessment of offspring obesity and diabetes risks from birth onwards, including into the third generation.

Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark.

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.

Parental SIRT1 Overexpression Attenuate Metabolic Disorders Due to Maternal High-Fat Feeding.

Maternal obesity can contribute to the development of obesity and related metabolic disorders in progeny. Sirtuin (SIRT)1, an essential regulator of metabolism and stress responses, has recently emerged as an important modifying factor of developmental programming. In this study, to elucidate the effects of parental SIRT1 overexpression on offspring mechanism, four experimental groups were included: (1) Chow-fed wild-type (WT)-dam × Chow-fed WT-sire; (2) High-fat diet (HFD)-fed WT-dam × Chow-fed WT-sire; (3) HFD-fed hemizygous SIRT1-transgenic (Tg)-dam × Chow-fed WT-sire; and (4) HFD-fed WT dam × Chow-fed Tg-sire. Our results indicate that Tg breeders had lower body weight and fat mass compared to WT counterparts and gave birth to WT offspring with reductions in body weight, adiposity and hyperlipidaemia compared to those born of WT parents. Maternal SIRT1 overexpression also reversed glucose intolerance, and normalised abnormal fat morphology and the expression of dysregulated lipid metabolism markers, including SIRT1. Despite having persistent hepatic steatosis, offspring born to Tg parents showed an improved balance of hepatic glucose/lipid metabolic markers, as well as reduced levels of inflammatory markers and TGF-ß/Smad3 fibrotic signalling. Collectively, the data suggest that parental SIRT1 overexpression can ameliorate adverse metabolic programming effects by maternal obesity.

Placental function in maternal obesity.

Maternal obesity is associated with pregnancy complications and increases the risk for the infant to develop obesity, diabetes and cardiovascular disease later in life. However, the mechanisms linking the maternal obesogenic environment to adverse short- and long-term outcomes remain poorly understood. As compared with pregnant women with normal BMI, women entering pregnancy obese have more pronounced insulin resistance, higher circulating plasma insulin, leptin, IGF-1, lipids and possibly proinflammatory cytokines and lower plasma adiponectin. Importantly, the changes in maternal levels of nutrients, growth factors and hormones in maternal obesity modulate placental function. For example, high insulin, leptin, IGF-1 and low adiponectin in obese pregnant women activate mTOR signaling in the placenta, promoting protein synthesis, mitochondrial function and nutrient transport. These changes are believed to increase fetal nutrient supply and contribute to fetal overgrowth and/or adiposity in offspring, which increases the risk to develop disease later in life. However, the majority of obese women give birth to normal weight infants and these pregnancies are also associated with activation of inflammatory signaling pathways, oxidative stress, decreased oxidative phosphorylation and lipid accumulation in the placenta. Recent bioinformatics approaches have expanded our understanding of how maternal obesity affects the placenta; however, the link between changes in placental function and adverse outcomes in obese women giving birth to normal sized infants is unclear. Interventions that specifically target placental function, such as activation of placental adiponectin receptors, may prevent the transmission of metabolic disease from obese women to the next generation.

Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring.

Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.

Influência da adiposidade durante a gestação de éguas da raça Crioula sobre o acúmulo de gordura em seus potros / Influence of adiposity during pregnancy of Crioulo mares on the fat accumulation in their foals

Este trabalho investigou a influência da adiposidade em éguas Crioulas gestantes sobre o peso e o acúmulo de gordura de seus potros do nascimento aos quatro meses de vida. Foram avaliadas 28 éguas Crioulas no terço final de gestação, divididas em dois grupos (normais e obesas) quanto ao peso, à circunferência de pescoço, à altura da crista do pescoço e à gordura subcutânea na base da cauda, bem como quanto à relação dessas medidas com as de seus potros, do parto aos 120 dias de idade. Os filhos de éguas obesas apresentaram maior deposição de gordura na base da cauda, no segundo mês (P<0,05), e na crista do pescoço (P=0,0022), no quarto mês de idade. Houve correlação positiva da altura da crista do pescoço da égua com o peso dos potros ao nascer (P=0,01; r= 0,54) e do peso corporal das éguas com gordura na base da cauda dos potros ao nascimento (P=0,03; r=0,49), além de forte associação entre gordura na base da cauda das éguas obesas com essa medida nos seus potros aos quatro meses (P=0,01; r=0,71). Essa diferença entre os grupos de potros quanto à adiposidade sugere que filhos de éguas obesas são mais propensos a acumular mais gordura já nos primeiros meses de vida.(AU)

This work investigated the influence of adiposity on pregnant Crioulo mares on the weight and fat deposition of their foals from birth to four months of life. Twenty-eight Crioulo mares were evaluated during the final third of gestation, divided into two groups (normal and obese) regarding weight, neck circumference, neck crest height and fat at the tail base, and the relation of these measurements with those of their foals from birth to 120 days old. The obese mares presented higher fat deposition at the tail base in the 2nd month (P< 0.05) and crest of the neck (P= 0.0022) in the 4th month of age. There was positive correlation between height of mare's neck crest and foal weight at birth (P= 0.01, r= 0.54) and body weight of mares between the fat at tail base of foals at birth (P= 0.03, r= 0.49), as well as strong association between fat at the tail base in obese mares with this measurement in their foals at 4 months (P= 0.01, r= 0.71). This difference of adiposity between groups suggests that obese mare's offspring are more likely to accumulate more fat in the first months of life.(AU)