Sex distribution of offspring-parents obesity: Angel's hypothesis revisited

This study, which is based on two cross sectional surveys' data, aims to establish any effect of parental obesity sex distribution of offspring and to replicate the results that led to the hypothesis that obesity may be associated with sex-linked recessive lethal gene. A representative sample of 4,064 couples living in Renfrew/Paisley, Scotland was surveyed 1972-1976. A total of 2,338 offspring from 1,477 of the couples screened in 1972-1976, living in Paisley, were surveyed in 1996. In this study, males represented 47.7% among the total offspring of the couples screened in 1972-1976. In the first survey there was a higher male proportion of offspring (53%, p < 0.05) from parents who were both obese, yet this was not significant after adjustment for age of parents. Also, there were no other significant differences in sex distribution of offspring according to body mass index, age, or social class of parents. The conditions of the original 1949 study of Angel (1949) (which proposed a sex-linked lethal recessive gene) were simulated by selecting couples with at least one obese daughter. In this subset, (n = 409), obesity in fathers and mothers was associated with 26% of offspring being male compared with 19% of offspring from a non-obese father and obese mother. Finally we conclude that families with an obese father have a higher proportion of male offspring. These results do not support the long-established hypotheses of a sex-linked recessive lethal gene in the etiology of obesity

Familial Associations of Adiposity: Findings from a Cross-Sectional Study of 12,181 Parental-Offspring Trios from Belarus

It is suggested that maternal adiposity has a stronger association with offspring adiposity than does paternal adiposity. Furthermore, a recent small study reported gender assortment in parental-offspring adiposity associations. We aimed to examine these associations in one of the largest studies to date using data from a low-middle income country that has recently undergone a major political and economic transition.In a cross-sectional study of 12,181 parental-offspring trios from Belarus (mean age (SD) of mothers 31.7 (4.9), fathers 34.1 (5.1) and children 6.6 (0.3) at time of assessment), we found positive graded associations of mother's and father's BMI with offspring adiposity. There was no evidence that these associations differed between mothers and fathers. For example, the odds ratio of offspring overweight or obesity (based on BMI) comparing obese and overweight mothers to normal weight mothers was 2.03 (95%CI 1.77, 2.31) in fully adjusted models; the equivalent result for father's overweight/obesity was 1.81 (1.58, 2.07). Equivalent results for offspring being in the top 10% waist circumference were 1.91 (1.67, 2.18) comparing obese/overweight to normal weight mothers and 1.72 (1.53, 1.95) comparing obese/overweight to normal weight fathers. Similarly, results for offspring being in the top 10% of percent fat mass were 1.58 (1.36, 1.84) and 1.76 (1.49, 2.07), for mother's and father's obese/overweight exposures respectively. There was no strong or consistent evidence of gender assortment--i.e. associations of maternal adiposity exposures with offspring outcomes were similar in magnitude for their daughters compared to equivalent associations in their sons and paternal associations were also similar in sons and daughters.These findings suggest that genetic and/or shared familial environment explain family clustering of adiposity. Interventions aimed at changing overall family lifestyle are likely to be important for population level obesity prevention

Circulating Docosahexaenoic Acid Associates with Insulin-Dependent Skeletal Muscle and Whole Body Glucose Uptake in OlderWomen Born from Normal Weight Mothers

Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. The circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: Thirty-seven elderly women were separated into elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using proton nuclear magnetic resonance (1H-NMR) and insulin-dependent tissue-specific glucose uptake in skeletal muscle was assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the docosahexaenoic acid percentage of the total long-chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (p = 0.015). DHA/FA associated significantly with skeletal muscle glucose uptake (GU) (p = 0.031) and the metabolizable glucose value derived from hyperinsulinemic-euglycemic clamp technique (M-value) in the OLM group only (p = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and this association is significantly weakened in the offspring of obese mothers.Peer reviewe

Effect of maternal obesity and preconceptional weight loss on male and female offspring metabolism and olfactory performance in mice

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. According to the “developmental origins of health and disease” (DOHaD) concept, maternal obesity predisposes the offspring to non-communicable diseases in adulthood. While a preconceptional weight loss (WL) is recommended for obese women, its benefits on the offspring have been poorly addressed. We evaluated whether preconceptional WL was able to reverse the adverse effects of maternal obesity in a mouse model, exhibiting a modification of foetal growth and of the expression of genes encoding epigenetic modifiers in liver and placenta. We tracked metabolic and olfactory behavioural trajectories of offspring born to control, obese or WL mothers. After weaning, the offspring were either put on a control diet (CD) or a high-fat (HFD). After only few weeks of HFD, the offspring developed obesity, metabolic alterations and olfactory impairments, independently of maternal context. However, male offspring born to obese mother gained even more weight under HFD than their counterparts born to lean mothers. Preconceptional WL normalized the offspring metabolic phenotypes but had unexpected effects on olfactory performance: a reduction in olfactory sensitivity, along with a lack of fasting-induced, olfactory-based motivation. Our results confirm the benefits of maternal preconceptional WL for male offspring metabolic health but highlight some possible adverse outcomes on olfactory-based behaviours

Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE)

Abstract Background: Maternal overweight, obesity, and gestational diabetes (GD) have been negatively associated with offspring development. Further knowledge regarding metabolic and nutritional alterations in these mother and their offspring are warranted. Methods: In an observational cohort study we included 331 pregnant women from Granada, Spain. The mothers were categorized into four groups according to BMI and their GD status; overweight (n:56), obese (n:64), GD (n:79), and healthy normal weight controls (n:132). We assessed maternal growth and nutritional biomarkers at 24 weeks (n = 269), 34 weeks (n = 310) and at delivery (n = 310) and the perinatal characteristics including cord blood biomarkers. Results: Obese and GD mothers had significantly lower weight gain during pregnancy and infant birth weight, waist circumference, and placental weight were higher in the obese group, including a significantly increased prevalence of macrosomia. Except for differences in markers of glucose metabolism (glucose, HbA1c, insulin and uric acid) we found at some measures that overweight and/or obese mothers had lower levels of transferrin saturation, hemoglobin, Vitamin B12 and folate and higher levels of C-reactive protein, erythrocyte sedimentation rate, ferritin, and cortisol. GD mothers had similar differences in hemoglobin and C-reactive protein but higher levels of folate. The latter was seen also in cord blood. Conclusions: We identified several metabolic alterations in overweight, obese and GD mothers compared to controls. Together with the observed differences in infant anthropometrics, these may be important biomarkers in future research regarding the programming of health and disease in children. Trial registration: The trial was registered at clinicaltrials.gov, identifier (NCT01634464). Keywords: Pregnancy, Maternal overweight, Maternal obesity, Gestational diabetes, Offspring, Fetal nutrition, Early programming, Vitamin B12, Folate, Iron status, Glucose metabolis

Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring : follow-up of 1 323 275 person years

Peer reviewedPublisher PD

Maternal Obesity and the Early Origins of Childhood Obesity: Weighing Up the Benefits and Costs of Maternal Weight Loss in the Periconceptional Period for the Offspring

There is a need to understand the separate or interdependent contributions of maternal prepregnancy BMI, gestational weight gain, glycaemic control, and macronutrient intake on the metabolic outcomes for the offspring. Experimental studies highlight that there may be separate influences of maternal obesity during the periconceptional period and late gestation on the adiposity of the offspring. While a period of dietary restriction in obese mothers may ablate the programming of obesity, it is associated with an activation of the stress axis in the offspring. Thus, maternal obesity may result in epigenetic changes which predict the need for efficient fat storage in postnatal life, while maternal weight loss may lead to epigenetic changes which predict later adversity. Thus, development of dietary interventions for obese mothers during the periconceptional period requires a greater evidence base which allows the effective weighing up of the metabolic benefits and costs for the offspring

Maternal obesity predisposes offspring towards the development of chronic kidney disease

Obesity together with insulin resistance promotes multiple metabolic abnormalities and is strongly associated with increased risk of chronic disease including type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD). The incidence of obesity is rising and affects all different stages of the lifespan. Importantly, obesity in women of reproductive has potential ramifications for offspring health. Maternal obesity is known to influence offspring development of obesity, T2D and CVD. In contrast, the relationship between maternal obesity and CKD has been less clearly defined. This thesis aims to determine whether maternal obesity increases offspring risk of CKD. Rodent models of maternal obesity were employed by feeding dams a high fat diet (HFD) for 6 weeks prior to mating, during gestation and lactation. At Day 20, there was evidence of renal inflammation and oxidative stress in the kidneys of rat offspring and the nuclear hormone receptor Farnesoid X receptor (FXR) was pathogenically implicated. At postnatal Week 9, the kidneys of rat offspring of obese mothers demonstrated increased markers of inflammation, oxidative stress and fibrosis, exacerbated by HFD-feeding in the offspring. The glucose-like peptide-1 (GLP-1) analogue, Exendin-4, ameliorated the negative renal effects of maternal. GLP-1 analogues may be useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring. Consistent with the metabolic effects observed in the rat, mouse offspring of obese mothers at postnatal Week 32 had increased fat deposition, insulin resistance and impaired glucose tolerance and renal pathology. Furthermore, postnatal feeding of HFD in offspring augmented these effects. Offspring of obese mothers were more prone to renal damage when an additional insult, such as streptozotocin-induced diabetes, was imposed. However, offspring obesity induced by HFD was the strongest predictor of weight gain, glucose intolerance, albuminuria and renal damage, which appeared to overpower the effect of maternal obesity. This thesis suggests that developmental programming resulting from in utero exposure to maternal obesity predisposes offspring towards CKD. Foetal exposure to maternal obesity should be considered as a significant risk factor for CKD

Mitochondrial damage accumulation in oocytes – a potential link between maternal obesity and increased cardiometabolic disease risk in offspring.

The developmental origins of health and disease (DoHAD) hypothesis suggests that negative maternal lifestyle choices, such as obesity, affect the health of her offspring. Clinical and laboratory studies support this hypothesis – offspring born to obese mothers are at increased risk for health conditions including cardiometabolic syndrome and congenital abnormalities. Maternal obesity damages the oocytes, contributing to the increased disease risk by transmitting damaged organelles and epigenetic modifications to the offspring. Mitochondria, the most abundant organelle in the oocyte, are damaged in oocytes from obese females. However, we do not understand if mitochondrial damage in oocytes is reversible nor why offspring are at increased risk for cardiometabolic syndrome like cardiomyopathy. Here we show that in mice fed a high fat/high sugar (HF/HS diet), improving female health with moderate, voluntary exercise does not reverse oocyte damage. We also tested if oocytes could activate mitophagy to repair obesity induced mitochondrial damage. Finally, we show that female offspring from obese mothers have mitochondrial damage in the heart that persists into adulthood. This damage causes dilated cardiomyopathy that worsens with age. These results provide an explanation for the persistence of damaged mitochondria in the oocytes of obese females. Additionally, they suggest that maternal obesity promotes the development of heart failure in offspring by inducing mitochondrial damage in the heart. Together, this data suggests mitochondrial damage caused by maternal obesity is non-reversible and contributes to cardiometabolic syndrome. The research provides potential mechanisms that support the DoHAD hypothesis and open new questions about how the changes to offspring health occur

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene