Maternal diets during pregnancy and lactation are critical determinants that regulate the metabolic homeostasis in offspring. Our previous research demonstrated that maternal genistein (GEN) intervention ameliorated the dysregulation of glucolipid metabolism induced by intrauterine overnutrition in adult offspring, accompanied by changes in the composition of gut microbiota; however, the underlying mechanisms remain unclear. Here, we used a maternal overnutrition model induced by excess energy intake before and throughout pregnancy and lactation, with maternal GEN administered during the same period. The female offspring were raised on a standard chow diet until sacrificed at 24 weeks. The mRNA levels of browning markers were quantified in inguinal subcutaneous adipose tissues, followed by methylation analysis via the MassArray method. Cecal contents were collected for untargeted metabolomic analysis and a target quantitative analysis of methionine cycle metabolites. Spearman correlation analyses were used to assess whether cecal metabolites are involved in the methylation of browning-related genes and influence their expression. The results showed that maternal GEN supplementation reversed the downregulation of browning markers caused by perinatal high-fat diets in adult female offspring, consistent with a reduction in their methylation levels. Subsequently, we also found that maternal GEN consumption altered cecal metabolite profiles in offspring, promoting the production of bile acids, potent regulators of glucolipid metabolism, and reducing metabolites involved in the methionine cycle, key methyl donors for the methylation process. Furthermore, the abundances of these metabolites were significantly correlated with the methylation and expression levels of browning markers. Overall, this discovery suggested that maternal GEN intake decreased the methylation level of browning markers and induced browning in white adipose tissue of offspring, which correlated with alterations in cecal metabolites. We provide a novel theoretical basis for GEN as a promising nutritional supplement to break the vicious cycle of maternal metabolic disturbances being transmitted to offspring.

A maternal high-fat diet (HFD) deteriorates the long-term metabolic health of offspring. Circadian rhythms are crucial for regulating metabolism. However, the impact of maternal HFD on the circadian clock in white adipose tissue (WAT) remains unexplored. This study aimed to identify transcriptional rhythmic alterations in inguinal WAT of adult male offspring induced by maternal HFD. To this end, female mice were fed an HFD and their male offspring were raised on a standard chow diet until 16 weeks of age. Transcriptome was performed and the data was analyzed using CircaCompare. The results showed that maternal HFD before and throughout pregnancy significantly altered the circadian rhythm of inguinal WAT while slightly modifying the WAT clock in adult male offspring. Specifically, maternal HFD contributed to gaining rhythmicity of Cry2, resulted in the elevated amplitude of Nr1d2, and led to increased midline estimating statistic of rhythm (MESOR) of Clock and Nr1d2. Furthermore, maternal HFD changed the rhythmic pattern of metabolic genes, such as Pparγ, Hacd2, and Acsl1, which are significantly enriched in metabolic regulation pathways. In conclusion, a maternal HFD before and throughout pregnancy altered the circadian rhythm of inguinal WAT in adult offspring. These alterations may play a significant role in disturbing metabolic homeostasis, potentially leading to metabolic dysfunction in adult male offspring.

The long-term prognosis of congenital hypothyroidism (CH) has become apparent since the introduction of newborn screening programs; however, the risk of obesity in patients with CH remains unclear. Early adiposity rebound (AR) is one of the predictors of obesity in adults. This study evaluated AR and the adolescent body mass index (BMI) in Japanese patients with CH. We longitudinally collected anthropometric measurements from 288 patients aged 1-10 yr and plotted their BMI curves to determine the age at onset of AR. We also evaluated the effects of thyroid function, presence of distal femoral epiphysis (DFE) ossification, and disease type on AR age and adolescent BMI. The mean AR ages were determined to be 5.5 ± 1.4 yr in boys and 5.9 ± 1.5 yr in girls. There were no significant differences in AR age or adolescent BMI according to thyroid-stimulating hormone or free T4 levels before treatment initiation or according to disease type. However, at the last visit, more than half of the boys without DFE ossification had higher BMI SD scores than those with DFE ossification. These findings raise the possibility that severe prolonged fetal hypothyroidism may have a lasting influence after birth despite early treatment initiation.

Poor intrauterine environments increase the prevalence of chronic metabolic diseases in offspring, whereas maternal exercise is an effective measure to break this vicious intergenerational cycle. Placenta is increasingly being studied to explore its role in maternal-fetal metabolic cross-talk. The association between placental miRNA and offspring development trajectories has been established, yet the specific role and mechanism thereof in maternal exercise-induced metabolic protection remain elusive. Here, C57BL/6 female mice were subjected to either a normal control or a high-fat diet (HFD), half of the HFD-fed dams were housed with voluntary wheel running for 3 weeks before and during gestation. At embryonic day 18.5, we sacrificed parturient mice and then conducted miRNA-seq, transcriptomic, and metabolomic profiling of the placenta. Our data revealed that maternal HFD resulted in significant alterations in both miRNA and gene expressions, as well as metabolic pathways of the placenta, whereas prenatal exercise negated these perturbations. The common differentially expressed transcripts among three groups were enriched in multiple critical pathways involving energy expenditure, signal transduction, and fetal development. Through integrated analysis of multiomics data, we speculated that maternal exercise reversed the suppression of miR-495-5p induced by HFD, thereby inhibiting miR-495-5p-targeted Snx7 and modulating kynurenic acid production. These datasets provided novel mechanistic insight into how maternal exercise positively affects the metabolic homeostasis of offspring. The discovered important miRNAs, mRNAs, and metabolites could be promising predictive and therapeutic targets for protecting offspring metabolic health.

Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations' metabolic health.

Maternal obesity has been related to offspring predisposition to cardiometabolic disease development throughout life. Thus, this study aimed to analyze the impact of maternal obesity on cardiac progenitor cells and cardiometabolic disease of adult offspring.

The litter size reduction experimental model was used to induce obesity in female Swiss mice. Small Litter Dam (SLD-F1) and Normal Litter Dam (NLD-F1) were crossed with healthy male mice, and their offspring were followed up until 90 days old when they were euthanized. Adult offspring of obese dams (SLD-F2) had increased body mass, Lee Index and fat deposits. Heart analysis demonstrated cardiac hypertrophy, fibrosis, oxidative stress, increased cardiac mast cell number, decreased cellular proliferation, increased proinflammatory cytokines, and mitochondrial dynamic impairment. These cardiometabolic modifications were accompanied by reduced c-kit+ and Sca-1+ cardiac progenitor cell (CPC) populations and impaired CPC differentiation into new cardiomyocytes.

In conclusion, Obese mother-offspring developed cardiometabolic changes in adulthood that negatively impacted the CPC niches and, consequently, the formation of new cardiomyocytes. This process seems to be an essential mechanism involved in the pathophysiology of the disease, impairing cardiac homeostasis.

To determine the basis for perinatal nutritional mismatch causing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus, we examined adult phenotype, hepatic transcriptome, and pancreatic β-islet function. In prenatal caloric-restricted rats with intrauterine growth restriction (IUGR) and postnatal exposure to high fat with fructose (HFhf) or high carbohydrate, we investigated male and female IUGR-HFhf and IUGR-high carbohydrate, vs HFhf and control offspring. Males more than females displayed adiposity, glucose intolerance, insulin resistance, hyperlipidemia, and hepatomegaly with hepatic steatosis. Male hepatic triglyceride synthesis, de novo lipogenesis genes increased, while female lipolysis, β-oxidation, fatty acid efflux, and FGF21 genes increased. IUGR-HFhf males demonstrated reduced β-islet insulin and humanin, and type 1 diabetes mellitus human amniotic fluid increased humanin. Humanin suppression disabled glucose stimulated insulin, ATP production, with apoptotic diminished β-islet viability. Humanin and FGF21 may reverse perinatal nutritional mismatched phenotype by restoring functional β islets and preventing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus.

Gestational diabetes mellitus (GDM) is linked to higher newborn weight and an increased risk of macrosomia. The newborn single-nucleotide polymorphism (SNP) of the ADIPOQ gene rs266729 is linked to a higher birth weight of the offspring of healthy pregnant women.

This study aims to evaluate the relationship between newborn ADIPOQ rs266729 polymorphism, cord blood adiponectin, maternal glycemic and lipid metabolism, and maternal adiponectin levels at 24 to 28 weeks of gestation (WG) and at birth and its impact on newborn weight in a cohort of GDM mothers.

This study involved 71 women diagnosed with GDM and 142 control pregnant women. The ADIPOQ (rs266729) gene polymorphisms were genotyped using TaqMan real-time PCR analysis. Maternal and cord blood adiponectin levels were measured using human total adiponectin ELISA kits. We performed a Pearson correlation analysis to identify significant correlations between maternal metabolic parameters and adiponectin levels at 24-28 WG and birth and the weight of newborns. A logistic regression analysis was also conducted to identify potential macrosomia predictors.

We found no significant differences in the distribution of the allele (C, G) (p = 0.82) and genotype (CC, CG, GG) (p = 0.46) of APIPOQ rs266729 among normoponderal and macrosomic newborns from the GDM mothers group. Maternal fasting glucose at 24-28 WG was higher in the GDM mothers who gave birth to macrosomic newborns (106 ± 17 vs. 93 ± 10 mg/dL, p < 0.0001). Adiponectin levels in the cord blood of newborns from mothers with GDM were lower than those in newborns from control mothers (p < 0.0001). In correlation analysis, we identified a weak positive correlation between the newborn weight of GDM mothers and cord blood adiponectin (r = 0.262), maternal fasting glucose level at 24-28 WG (r = 0.288), and maternal adiponectin level at birth (0.334). Multivariate logistic regression, after adjusting for confounders, revealed that maternal fasting glucose levels at 24-28 WG had an OR of 11.59, and cord blood adiponectin levels had an OR of 30.31 for macrosomia.

The preliminary findings of our pilot study suggest that in the gestational diabetes mellitus group, the ADIPOQ rs266729 polymorphism in newborns is not associated with a higher birth weight, maternal fasting glucose levels between 24 and 28 WG were a predictor for macrosomia, and cord blood adiponectin levels were lower than those from control mothers. Further large-scale studies are needed to confirm our findings.

Stressors associated with the ongoing ethnic tensions may be the drivers of more frequent night eating, and subsequently, a higher body mass index.

To examine the association of night eating with body mass index (BMI) and waist circumference among health sciences students in Northern Kosovo.

A cross-sectional study was carried out at the University of Prishtina in Kosovska Mitrovica from November 2018 to March 2019. Participants completed a socio-demographic questionnaire, the Night Eating Questionnaire (NEQ), the Beck's Anxiety Inventory (BAI) and the Perceived Stress Scale (PSS). Body weight, height, and waist circumference were measured by the research team.

The study sample consisted of 534 students. The night eating score was 14.4 ± 4.5 out of 52 (prevalence of night eating syndrome was 3.0%). Overall, the average BMI was 23.7 ± 4.5 kg/m2 (27.2% of students were overweight and 7.5% were obese). Moderate level of stress as measured by the PSS was observed 61.8% and high level of stress was recorded among 5.8%. Also, 9.2% students reported moderate BAI score and 6.0% students reported severe BAI score. After adjustment for socio-demographic characteristics, health behaviors, sleep, stress and anxiety levels, no association of night eating with BMI and waist circumference was observed.

These findings showed that there is an absence of the association between night eating, BMI and waist circumference among students who live in a post-conflict setting. There may be other factors that mediate the relationship between food intake at night and body mass index.

To review evidence supporting human umbilical cord mesenchymal stem cells (UC-MSC) as an innovative model system advancing obesity precision medicine.

Obesity prevalence is increasing rapidly and exposures during fetal development can impact individual susceptibility to obesity. UC-MSCs exhibit heterogeneous phenotypes associated with maternal exposures and predictive of child cardiometabolic outcomes. This recent evidence supports UC-MSCs as a precision model serving three purposes: (1) as a mechanistic tool to interrogate biological underpinnings of obesity in human studies, (2) as a sensitive index of early life causes and determinants of obesity, and (3) as a marker and transducer of susceptibility, highlighting populations most at risk for future obesity. Data from UC-MSCs emphasize nutrient sensing and lipid partitioning as phenotypes most relevant to neonatal and early childhood adiposity and implicate a role for these cell-autonomous features of mesodermal tissues in the biological underpinnings of obesity.

The nutritional environment during fetal and early postnatal life has a long-term impact on growth, development, and metabolic health of the offspring, a process termed "nutritional programming." Rodent models studying programming effects of nutritional interventions use either purified or grain-based rodent diets as background diets. However, the impact of these diets on phenotypic outcomes in these models has not been comprehensively investigated. We used a previously validated (C57BL/6J) mouse model to investigate the effects of infant milk formula (IMF) interventions on nutritional programming. Specifically, we investigated the effects of maternal diet type (i.e., grain-based vs purified) during early lactation and prior to the intervention on offspring growth, metabolic phenotype, and gut microbiota profile. Maternal exposure to purified diet led to an increased post-weaning growth velocity in the offspring and reduced adult diet-induced obesity. Further, maternal exposure to purified diet reduced the offspring gut microbiota diversity and modified its composition post-weaning. These data not only reinforce the notion that maternal nutrition significantly influences the programming of offspring vulnerability to an obesogenic diet in adulthood but emphasizes the importance of careful selection of standard background diet type when designing any preclinical study with (early life) nutritional interventions.

Metabolic diseases, including obesity, dyslipidemia, and type 2 diabetes, have become severe challenges worldwide. The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that an adverse intrauterine environment can increase the risk of metabolic disorders in offspring. Studies have demonstrated that maternal exercise is an effective intervention for improving the offspring metabolic health. However, the pathways through which exercise works are unclear. It has been reported that the gut microbiota mediates the effect of maternal exercise on offspring metabolism, and epigenetic modifications have also been proposed to be important molecular mechanisms. Microbial metabolites can influence epigenetics by providing substrates for DNA or histone modifications, binding to G-protein-coupled receptors to affect downstream pathways, or regulating the activity of epigenetic modifying enzymes. This review aims to summarize the intergenerational effect of maternal exercise and proposes that gut microbiota-metabolites-epigenetic regulation is an important mechanism by which maternal exercise improves offspring metabolism, which may yield novel targets for the early prevention and intervention of metabolic diseases.

Background/Objectives: Childhood obesity is a global health problem that affects at least 41 million children under the age of five. Increased BMI in children is associated with serious long-term health consequences, such as type 2 diabetes, cardiovascular disease, and psychological problems, including depression and low self-esteem. Although the etiology of obesity is complex, research suggests that the diet and lifestyle of pregnant women play a key role in shaping metabolic and epigenetic changes that can increase the risk of obesity in their children. Excessive gestational weight gain, unhealthy dietary patterns (including the Western diet), and pregnancy complications (such as gestational diabetes) are some of the modifiable factors that contribute to childhood obesity. The purpose of this narrative review is to summarize the most important and recent information on the impact of the diet and lifestyle of pregnant women on the risk of childhood obesity. Methods: This article is a narrative review that aims to summarize the available literature on the impact of pregnant women's diet and lifestyle on the risk of obesity in their offspring, with a focus on metabolic and epigenetic mechanisms. Results/Conclusions: Current evidence suggests that a pregnant woman's lifestyle and diet can significantly contribute to lowering the risk of obesity in their offspring. However, further high-quality research is needed to understand better the metabolic and epigenetic relationships concerning maternal factors that predispose offspring to obesity.

Obesity is currently an increasing public health burden due to its related metabolic and cardiovascular complications. In Western countries, a significant number of people are overweight or obese, and this trend is, unfortunately, becoming increasingly common even among the pediatric population. In this narrative review, we analyzed the role of nutrition during growth and its impact on the risk of developing metabolic syndrome and cardiovascular complications later in life. An impactful role in determining the phenotypic characteristics of the offspring is the parental diet carried out before conception. During intrauterine growth, the main risk factors are represented by an unbalanced maternal diet, excessive gestational weight gain, and impaired glycemic status. Breastfeeding, on the other hand, has many beneficial effects, but at the same time the quality of breast milk may be modified if maternal overweight or obesity subsists. Complementary feeding is likewise pivotal because an early introduction before 4 months of age and a high protein intake contribute to weight gain later. Knowledge of these mechanisms may allow early modification of risk factors by implementing targeted preventive strategies.

Our understanding of the origins of noncommunicable diseases has evolved over the years with greater consideration given to the lasting influence exposures and experiences during the preconceptional and prenatal periods can have. Research highlights the associations of parental exposures (e.g., diet, obesity, gestational diabetes, lipid profile, toxic exposures and microbiome) with the infant/fetal methylome and suggest associations with infant, child and/or adolescent chronic health outcomes. Thus, epigenetics and specifically cord blood DNA methylation may have utility as biomarkers for disease risk identification and stratification in pediatrics. However, for cord blood DNA methylation analyses to be leveraged as biomarkers of disease risk in pediatric clinical practice, the results must be replicable, validated and clinically meaningful. Challenges and opportunities to this prospect are herein discussed.

The last decade has seen remarkable progress in the characterization of methylation clocks that can serve as indicators of biological age in humans and many other mammalian species. While the biological processes of aging that underlie these clocks have remained unclear, several clues have pointed to a link to developmental mechanisms. These include the presence in the vicinity of clock CpG sites of genes that specify development, including those of the Hox (homeobox) and polycomb classes. Here we discuss how recent advances in programmatic theories of aging provide a framework within which methylation clocks can be understood as part of a developmental process of aging. This includes how such clocks evolve, how developmental mechanisms cause aging, and how they give rise to late-life disease. The combination of ideas from evolutionary biology, biogerontology and developmental biology open a path to a new discipline, that of developmental gerontology (devo-gero). Drawing on the properties of methylation clocks, we offer several new hypotheses that exemplify devo-gero thinking. We suggest that polycomb controls a trade-off between earlier developmental fidelity and later developmental plasticity. We also propose the existence of an evolutionarily-conserved developmental sequence spanning ontogenesis, adult development and aging, that both constrains and determines the evolution of aging.

The maternal-fetal interface is composed of the placenta, which is affiliated with the fetus, and the maternal decidua. During pregnancy, the placenta is mainly responsible for nutrient transport and immune tolerance maintenance, which plays a key role in fetal growth and development and pregnancy maintenance. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that exists in various cell types at the maternal-fetal interface and is involved in multiple cellular processes. Recent studies have highlighted the role of AhR in regulating various physiological processes, including glucose and lipid metabolism, as well as tryptophan metabolism and immune responses, within non-pregnant tissues. This review shifts focus towards understanding how AhR modulation impacts metabolism and immune regulation at the maternal-fetal interface. This may implicate the development of pregnancy-related complications and the potential target of the AhR pathway for therapeutic strategies against poor pregnancy outcomes.

Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9-20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.

Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.

Maternal obesity has long-term effects on offspring metabolic health. Among the potential mechanisms, prior research has indicated potential disruptions in circadian rhythms and gut microbiota in the offspring. To challenge this hypothesis, we implemented a maternal high fat diet regimen before and during pregnancy, followed by a standard diet after birth. Our findings confirm that maternal obesity impacts offspring birth weight and glucose and lipid metabolisms. However, we found minimal impact on circadian rhythms and microbiota that are predominantly driven by the feeding/fasting cycle. Notably, maternal obesity altered rhythmic liver gene expression, affecting mitochondrial function and inflammatory response without disrupting the hepatic circadian clock. These changes could be explained by a masculinization of liver gene expression similar to the changes observed in polycystic ovarian syndrome. Intriguingly, such alterations seem to provide the first-generation offspring with a degree of protection against obesity when exposed to a high fat diet.

Diabetes is more apparent in adulthood but may be dormant in childhood and originates during early fetal development. In fetal biometry, femur length (FL) is crucial for assessing fetal growth and development. This study aimed to assess potential associations between fetal femur growth and prediabetic biomarkers in Bangladeshi children.

A cohort study embedded in a population-based maternal food and micronutrient supplementation (MINIMat) trial was conducted in Matlab, Bangladesh. The children in the cohort were followed up until 15 years of age. In the original trial, pregnancy was confirmed by ultrasound before 13 gestational weeks (GWs). Afterward, ultrasound assessments were performed at 14, 19, and 30 GWs. FL was measured from one end to the other, capturing a complete femoral image. The FL was standardized by GW, and a z-score was calculated. FBG and HbA1c levels were determined in plasma and whole blood, and the triglyceride-glucose index, a biomarker of insulin resistance, was calculated as Ln [fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. Multivariable linear regression analysis using a generalized linear model was performed to estimate the effects of FL at 14, 19 and 30 GWs on prediabetic biomarkers at 9 and 15 years of age. Maternal micronutrient and food supplementation group, parity, child sex, and BMI at 9 years or 15 years were included as covariates.

A total of 1.2% (6/515) of the participants had impaired fasting glucose during preadolescence, which increased to 3.5% (15/433) during adolescence. At 9 years, 6.3% (32/508) of the participants had elevated HbA1c%, which increased to 28% (120/431) at 15 years. Additionally, the TyG index increased from 9.5% (49/515) (during preadolescence) to 13% (56/433) (during adolescence). A one standard deviation decrease in FL at 14 and 19 GWs was associated with increased FBG (β = - 0.44 [- 0.88, - 0.004], P = 0.048; β = - 0.59 [- 1.12, - 0.05], P = 0.031) and HbA1c (β = - 0.01; [- 0.03, -0.005], P = 0.007; β = - 0.01 [- 0.03, - 0.003], P = 0.018) levels at 15 years. FL was not associated with diabetic biomarkers at 9 years.

Mid-trimester impaired femur growth may be associated with elevated prediabetic biomarkers in Bangladeshi adolescents.

This study aimed to explore whether famine exposure during early life are associated with a high risk of Type 2 Diabetes Mellitus (T2DM) in adulthood and the role of socioeconomic status (SES) on this effect.

We conducted a secondary data analysis based on data from a cross-sectional survey, collected 3,355 participants born between January 1, 1941 and December 31, 1966. Participants were categorized into four groups based on their date of birth, unexposed (individuals born in 1963-1966), infant exposed (individuals born in 1959-1962), childhood exposed (individuals born in 1949-1958), and adolescent exposed (born in 1941-1948). The association of famine exposure with T2DM risk in adults and conducted separately in plain area and mountain area was assessed using logistics regression model.

22.35% of participants were diagnosed with T2DM, of which 43.47% were from the childhood famine-exposed group, representing the highest proportion among all subgroups (p < 0.001). Participants exposed to famine during childhood and adolescence from the lower SES mountain areas showed a significantly higher prevalence of T2DM in adulthood than those from the plain areas (p < 0.001). The adolescence stage exposed famine will increase the risk of T2DM in the mountain area (OR 2.46, 95% CI 1.61, 3.77).

No strong evidence demonstrates that exposure to famine during the early life stage increases the risk of developing T2DM in adulthood. However, populations with lower SES are likely to be exposed to more risk factors for T2DM.

The gut plays a crucial role in metabolism by regulating the passage of nutrients, water and microbial-derived substances to the portal circulation. Additionally, it produces incretins, such as glucose-insulinotropic releasing peptide (GIP) and glucagon-like derived peptide 1 (GLP1, encoded by gcg gene) in response to nutrient uptake. We aimed to investigate whether offspring from overweight rats develop anomalies in the barrier function and incretin transcription. We observed pro-inflammatory related changes along with a reduction in Claudin-3 levels resulting in increased gut-permeability in fetuses and offspring from overweight rats. Importantly, we found decreased gip mRNA levels in both fetuses and offspring from overweight rats. Differently, gcg mRNA levels were upregulated in fetuses, downregulated in female offspring and unchanged in male offspring from overweight rats. When cultured with high glucose, intestinal explants showed an increase in gip and gcg mRNA levels in control offspring. In contrast, offspring from overweight rats did not exhibit any response in gip mRNA levels. Additionally, while females showed no response, male offspring from overweight rats did exhibit an upregulation in gcg mRNA levels. Furthermore, female and male offspring from overweight rats showed sex-dependent anomalies when orally challenged with a glucose overload, returning to baseline glucose levels after 120 min. These results open new research questions about the role of the adverse maternal metabolic condition in the programming of impairments in glucose homeostasis, enteroendocrine function and gut barrier function in the offspring from overweight mothers and highlight the importance of a perinatal maternal healthy metabolism.

Epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNA molecules, play a critical role in gene expression and regulation in livestock species, influencing development, reproduction and disease resistance. DNA methylation patterns silence gene expression by blocking transcription factor binding, while histone modifications alter chromatin structure and affect DNA accessibility. Livestock-specific histone modifications contribute to gene expression and genome stability. Non-coding RNAs, including miRNAs, piRNAs, siRNAs, snoRNAs, lncRNAs and circRNAs, regulate gene expression post-transcriptionally. Transgenerational epigenetic inheritance occurs in livestock, with environmental factors impacting epigenetic modifications and phenotypic traits across generations. Epigenetic regulation revealed significant effect on gene expression profiling that can be exploited for various targeted traits like muscle hypertrophy, puberty onset, growth, metabolism, disease resistance and milk production in livestock and poultry breeds. Epigenetic regulation of imprinted genes affects cattle growth and metabolism while epigenetic modifications play a role in disease resistance and mastitis in dairy cattle, as well as milk protein gene regulation during lactation. Nutri-epigenomics research also reveals the influence of maternal nutrition on offspring's epigenetic regulation of metabolic homeostasis in cattle, sheep, goat and poultry. Integrating cyto-genomics approaches enhances understanding of epigenetic mechanisms in livestock breeding, providing insights into chromosomal structure, rearrangements and their impact on gene regulation and phenotypic traits. This review presents potential research areas to enhance production potential and deepen our understanding of epigenetic changes in livestock, offering opportunities for genetic improvement, reproductive management, disease control and milk production in diverse livestock species.

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.

During the last decades, endocrine-disrupting chemicals (EDCs) have attracted the attention of the scientific community, as a result of a deepened understanding of their effects on human health. These compounds, which can reach populations through the food chain and a number of daily life products, are known to modify the activity of the endocrine system. Regarding vulnerable groups like pregnant mothers, the potential damage they can cause increases their importance, since it is the health of two lives that is at risk. EDCs can affect the gestation process, altering fetal development, and eventually inducing the appearance of many disorders in their childhood and/or adulthood. Because of this, several of these substances have been studied to clarify the influence of their prenatal exposure on the cognitive and psychomotor development of the newborn, together with the appearance of non-communicable diseases and other disorders. The most novel research on the subject has been gathered in this narrative review, with the aim of clarifying the current knowledge on the subject. EDCs have shown, through different studies involving both animal and human investigation, a detrimental effect on the development of children exposed to the during pregnancy, sometimes with sex-specific outcomes. However, some other studies have failed to find these associations, which highlights the need for deeper and more rigorous research, that will provide an even more solid foundation for the establishment of policies against the extended use of these chemicals.

Childhood obesity has become a global epidemic, with significant increases in prevalence over recent decades. While excessive calorie consumption and physical inactivity are known factors, emerging research highlights the role of endocrine-disrupting chemicals (EDCs), particularly obesogens, in obesity's pathogenesis. This review explores the historical context of the environmental obesogens hypothesis, their sources, mechanism of action, impact on prenatal and postnatal development, and epigenetics. Additionally, it discusses the long-term consequences of childhood obesity and proposes prevention strategies that will mitigate negative health effects. Obesogens were found to disrupt hormonal balance and metabolic processes through various mechanisms such as altering gene expression, hormonal interference, and inflammation. Especially significant was exposure during critical windows of development, which correlates with an increased risk of obesity in childhood or adolescence. Long-term effects of childhood obesity include chronic health conditions and psychosocial issues. A comprehensive approach is necessary to address childhood obesity encompassing genetic, environmental, and lifestyle factors. Prevention strategies should focus on reducing obesogen exposure, promoting healthy lifestyles, and implementing regulatory policies. Future research should investigate obesogens-diet interactions, microbiome impacts, and combined obesogens effects. Long-term human studies are also crucial for validating findings from animal models and allowing for informed decision-making to combat the obesity pandemic.

Several epidemiological, clinical and experimental studies in recent decades have shown the relationship between exposure to stressors during development and health outcomes later in life. The characterization of these susceptible phases, such as preconception, gestation, lactation and adolescence, and the understanding of factors that influence the risk of an adult individual for developing obesity, metabolic and cardiovascular diseases, is the focus of the DOHaD (Developmental Origins of Health and Disease) research line. In this sense, advancements in molecular biology techniques have contributed significantly to the understanding of the mechanisms underlying the observed phenotypes, their morphological and physiological alterations, having as a main driving factor the epigenetic modifications and their consequent modulation of gene expression. The present narrative review aimed to characterize the different susceptible phases of development and associated epigenetic modifications, and their implication in the development of non-communicable diseases. Additionally, we provide useful insights into interventions during development to counteract or prevent long-term programming for disease susceptibility.

The increasing prevalence of diabetes is of particular concern in women of childbearing age because of the short and long-term consequences of maternal diabetes for the health of the offspring, such as a greater risk of developing metabolic impairments and cognitive deficits. In addition, maternal diet during pregnancy and lactation might contribute to preventing or ameliorating adverse offspring outcomes. Recently, we described that access to snacks exacerbates glucose intolerance in mildly hyperglycemic pregnant dams. Therefore, we hypothesized that these offspring would show greater impairment in metabolic and behavioral outcomes across the lifespan. Neonatal STZ treatment was employed to induce maternal mild hyperglycemia in females. After mating, normo- and hyperglycemic dams were given access either to standard chow or standard show plus snacks. Male and female offspring were evaluated on postnatal days (PND) 30, 90, and 360. Offspring behavior was assessed in the marble burying task, the open-field test, the elevated-plus maze, and sucrose preference. Glucose tolerance and morphometric analyses were also carried out. Maternal hyperglycemia increased body weight and fat deposition only on PND 30, while retroperitoneal fat deposition was reduced in the offspring of snack-fed dams. However, maternal snack intake reduced offspring body weight and length on PND 90. Fasting glucose was increased in females born to hyperglycemic, snack-fed dams on PND 90. Glucose clearance was altered by both maternal conditions in male offspring on PND 30, however, this sex difference was reversed on PND 90, with maternal hyperglycemia impairing glucose clearance only in females. In addition, maternal hyperglycemia reduced anxiety-like behavior in female offspring on PND 30, especially in the offspring of snack-fed dams, while maternal snack intake reduced sucrose preference in both males and females in adulthood. These results suggest that the effects of maternal hyperglycemia during pregnancy and lactation on offspring outcomes were not exacerbated by snack intake. Although additive effects of the two maternal conditions were hypothesized, the absence of such effects could be related to the mild maternal hyperglycemia induced by STZ treatment even when combined with snack intake. While maternal hyperglycemia alone impaired some offspring outcomes, its association with snack intake did not aggravate those impairments but rather resulted in outcomes more similar to those of offspring born to normoglycemic dams. Finally, females were found to be more susceptible to both the effects of maternal hyperglycemia and snack intake on metabolism and behavior.

Obesity rates are increasing almost everywhere in the world, although the pace and timing for this increase differ when populations from developed and developing countries are compared. The sharp and more recent increase in obesity rates in many Latin American countries is an example of that and results from regional characteristics that emerge from interactions between multiple factors. Aware of the complexity of enumerating these factors, we highlight eight main determinants (the physical environment, food exposure, economic and political interest, social inequity, limited access to scientific knowledge, culture, contextual behaviour and genetics) and discuss how they impact obesity rates in Latin American countries. We propose that initiatives aimed at understanding obesity and hampering obesity growth in Latin America should involve multidisciplinary, global approaches that consider these determinants to build more effective public policy and strategies, accounting for regional differences and disease complexity at the individual and systemic levels.

Overconsumption of energy-rich foods that disrupt caloric balance is a fundamental cause of overweight, obesity and diabetes. Dysglycemia and the resulting cardiovascular disease cause substantial morbidity and mortality worldwide, as well as high societal cost. The prevalence of obesity in childhood and adolescence is increasing, leading to younger diabetes diagnosis, and higher severity of microvascular and macrovascular complications. An important goal is to identify early life conditions that increase future metabolic risk, toward the goal of preventing diabetes and cardiovascular disease. An ample body of evidence implicates prenatal and postnatal childhood growth trajectories in the programming of adult metabolic disease. Human epidemiological data show that accelerated childhood growth increases risk of type 2 diabetes in adulthood. Type 2 diabetes results from the combination of insulin resistance and pancreatic β-cell failure, but specific mechanisms by which accelerated postnatal growth impact one or both of these processes remain uncertain. This review explores the metabolic impact of overnutrition during postnatal life in humans and in rodent models, with specific attention to the connection between accelerated childhood growth and future adiposity, insulin resistance, β-cell mass and β-cell dysfunction. With improved knowledge in this area, we might one day be able to modulate nutrition and growth in the critical postnatal window to maximize lifelong metabolic health.

To develop a visual prediction model for gestational diabetes (GD) in pregnant women and to establish an effective and practical tool for clinical application.

To establish a prediction model, the modelling set included 1756 women enrolled in the Zunyi birth cohort, the internal validation set included 1234 enrolled women, and pregnant women in the Wuhan cohort were included in the external validation set. We established a demographic-lifestyle factor model (DLFM) and a demographic-lifestyle-environmental pollution factor model (DLEFM) based on whether the women were exposed to environmental pollutants. The least absolute shrinkage and selection lasso-logistic regression analyses were used to identify the independent predictors of GD and construct a nomogram for predicting its occurrence.

The DLEFM regression analysis showed that a family history of diabetes (odd ratio [OR] 2.28; 95% confidence interval [CI] 1.05-4.71), a history of GD in pregnant women (OR 4.22; 95% CI 1.89-9.41), being overweight or obese before pregnancy (OR 1.71; 95% CI 1.27-2.29), a history of hypertension (OR 2.61; 95% CI 1.41-4.72), sedentary time (h/day) (OR 1.16; 95% CI 1.08-1.24), monobenzyl phthalate (OR 1.95; 95% CI 1.45-2.67) and Q4 mono-ethyl phthalate concentration (OR 1.85; 95% CI 1.26-2.73) were independent predictors. The area under the receiver operating curves for the internal validation of the DLEFM and the DLFM constructed using these seven factors was 0.827 and 0.783, respectively. The calibration curve of the DLEFM was close to the diagonal line. The DLEFM was thus the more optimal model, and the one which we chose.

A nomogram based on preconception factors was constructed to predict the occurrence of GD in the second and third trimesters. It provided an effective tool for the early prediction and timely management of GD.

Maternal smoking during pregnancy (MSDP) is associated with lower birth weight, childhood obesity, and elevated blood pressure (BP) in offspring. We aimed to examine whether birth weight and body mass index (BMI) mediate the effect of MSDP on BP in children. The study included 14,713 children aged 8 to 15 years from the National Health and Nutrition Examination Surveys from 1999 to 2018. General third-variable models were used to examine the mediating effects of birth weight and BMI on the association of MSDP with BP. A total of 1928 (13.1%) children were exposed to MSDP. MSDP was associated with reduced birth weight (p < 0.001), increased BMI (p < 0.001), and elevated systolic BP (p = 0.005). MSDP was not associated with systolic BP after adjustment for birth weight and BMI z-score (p = 0.875), with 95.0% of the effect of MSDP on BP mediated by birth weight (39.1%) and BMI (55.9%). In conclusion, lower birth weight and increased obesity measures mediate the adverse effects of MSDP on BP in children. These findings provide novel mechanistic insight into the adverse effect of MSDP on BP in children and have implications for preventing hypertension in later life.

Food and nutrition-related factors, including foods and nutrients consumed, dietary patterns, use of dietary supplements, adiposity, and exposure to food-related environmental contaminants, have the potential to impact semen quality and male and female fertility; obstetric, fetal, and birth outcomes; and the health of future generations, but gaps in evidence remain. On 9 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and the school's Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships between food, nutrition, and fertility. Topics addressed included male fertility, female fertility and gestation, and intergenerational effects. This meeting report summarizes the presentations and deliberations from the meeting. Regarding male fertility, a positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility. In females, body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders, a leading cause of female infertility. Females with obesity have worse fertility treatment, pregnancy-related, and birth outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes. Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

The population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50-80 years old Inter99 participants.

The Inter99 cohort comprises individuals aged 30-60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbidities.

The study was approved by the Medical Ethics Committee, Capital Region, Denmark (H-20076231) and by the Danish Data Protection Agency through the Capital Region of Denmark's registration system (P-2020-1074). Informed consent will be obtained before examinations. Findings will be disseminated in peer-reviewed journals, at conferences and via presentations to stakeholders, including patients and public health policymakers.

NCT05166447.

Antenatal maternal depression is associated with poor pregnancy outcomes and long-term effects on the offspring. Previous studies have identified links between antenatal depression and placental DNA methylation and between placental epigenetic aging and poor pregnancy outcomes, such as preterm labor and preeclampsia. The relationship between antenatal depression and poor pregnancy outcomes may be partly mediated via placental aging.

This study aimed to investigate whether antenatal depressive symptoms are associated with placental epigenetic age acceleration, an epigenetic aging clock measure derived from the difference between methylation age and gestational age at delivery.

The study included 301 women who provided placenta samples at delivery as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies - Singletons that recruited participants from diverse race and ethnic groups at 12 US clinical sites (2009-2013). Women underwent depression screening using the Edinburgh Postnatal Depression Scale up to 6 times across the 3 trimesters of pregnancy. Depressive symptoms status was determined for each pregnancy trimester using an Edinburgh Postnatal Depression Scale score, in which a score of ≥10 was defined as having depressive symptoms and a score of <10 was defined as not having depressive symptoms. Placental DNA methylation was profiled from placenta samples. Placental epigenetic age was estimated using a methylation-based age estimator (placental "epigenetic clock") that has previously been found to have high placental gestational age prediction accuracy for uncomplicated term pregnancies. Placental age acceleration was defined to be the residual upon regressing the estimated epigenetic age on gestational age at delivery. Associations between an Edinburgh Postnatal Depression Scale score of ≥10 and an Edinburgh Postnatal Depression Scale score of <10 in the first, second, and third trimesters of pregnancy (ie, depressive symptoms vs none in each trimester) and placental age acceleration were tested using multivariable linear regression adjusting for maternal age, parity, race and ethnicity, and employment.

There were 31 (10.3%), 48 (16%), and 49 (16.4%) women with depressive symptoms (ie, Edinburgh Postnatal Depression Scale score of ≥10) in the first, second, and third trimesters of pregnancy, respectively. Of these women, 21 (7.2%) had sustained first- and second-trimester depressive symptoms, 19 (7%) had sustained second- and third-trimester depressive symptoms, and 12 (4.8%) had sustained depressive symptoms throughout pregnancy. Women with depressive symptoms in the second trimester of pregnancy had 0.41 weeks higher placental age acceleration than women without depressive symptoms during the second trimester of pregnancy (β=0.21 weeks [95% confidence interval, -0.17 to 0.58; P=.28] during the first trimester of pregnancy; β=0.41 weeks [95% confidence interval, 0.10-0.71; P=.009] during the second trimester of pregnancy; β=0.17 weeks [95% confidence interval, -0.14 to 0.47; P=.29] during the third trimester of pregnancy). Sustained first- and second-trimester depressive symptoms were associated with 0.72 weeks higher placental age acceleration (95% confidence interval, 0.29-1.15; P=.001) than no depressive symptom in the 2 trimesters. The association between second-trimester depressive symptoms and higher placental epigenetic age acceleration strengthened in the analysis of pregnancies with male fetuses (β=0.53 weeks; 95% confidence interval, 0.06-1.08; P=.03) but was not significant in pregnancies with female fetuses.

Antenatal depressive symptoms during the second trimester of pregnancy were associated with an average of 0.41 weeks of increased placental age acceleration. Accelerated placental aging may play an important role in the underlying mechanism linking antenatal depression to pregnancy complications related to placental dysfunction.

Metabolic bariatric surgery (MBS) helps reduce comorbidities, such as hypertension and gestational diabetes, and is more effective than diet management for women with obesity-related health issues. Vitamin B12, vitamin D, and iron play important roles in ensuring the health of a neonate. However, pregnancies occurring after MBS may face complications related to micronutrient deficiencies, particularly of vitamins B12 and D and iron. This study aimed to investigate the vitamin B12, vitamin D, ferritin, and iron status of pregnant women who underwent MBS compared with women without MBS history. The study included 217 pregnant women (105 with a history of MBS and 112 without a history of MBS) who visited a major maternity hospital in Abu Dhabi, United Arab Emirates (UAE) between July 2021 and November 2022. The maternal vitamin B12, vitamin D, iron, and ferritin levels were measured twice, initially during the first or second trimester and subsequently during the third trimester. The iron was measured once during the pregnancy. Vitamin B12 deficiency was higher among pregnant women with MBS history compared to non-bariatric pregnant women (24.4% vs. 3.9%, p < 0.001). Women with a history of MBS had a higher prevalence of vitamin D deficiency (62.3% vs. 37.7%, p < 0.002). Linear regression analysis indicated that vitamin B12 levels decreased by 55 pg/mL in women with a history of MBS and by 4.6 pg/mL with a unit increase in body mass index (kg/m2). Furthermore, vitamin D levels in women with a history of MBS decreased by 4.9 ng/mL during pregnancy. Metabolic bariatric surgery is associated with vitamin B12, vitamin D, and iron deficiencies during pregnancy.