Male Offspring Of Control Dams Research Articles

High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring.

Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

212-LB: Gestational Exposure to Low-Dose Benzene Predisposes to Diabetes in Adulthood

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes, vaping, and evaporation of benzene-containing petrol processes. Epidemiological studies demonstrated the association with type 2 diabetes (T2D) and the development of insulin resistance (IR). Because maternal environmental stressors can greatly affect offspring health, we hypothesized that exposure to low concentrations of benzene during critical windows of development may contribute to the escalating prevalence of metabolic imbalance and diabetes in offspring. Specifically, we tested the hypothesis that prenatal exposure to benzene at concentrations relevant to cigarette smoking or vaping, would prime hypothalamic gliosis, resulting in exacerbated metabolic outcomes following exposure to a high-fat diet in adulthood. Pregnant C57BL/6JB dams were exposed to benzene at 50ppm or filtered air throughout gestation, and offspring metabolic phenotype was evaluated before and after high-fat-diet (HFD) feeding for 6 months. The male offspring of benzene-exposed dams exhibited exaggerated hyperglycemia on a chow diet compared to the male offspring of control dams, whereas female offspring did not differ according to prenatal treatment. No changes in body weight, body composition, or early postnatal hypothalamic glial activation were observed between groups. Regardless, adult male offspring of benzene-exposed dams exhibited severe impairment in the parameters of energy homeostasis (Vo2, VCO2, and heat production), suggesting the effect of metabolic reprogramming in whole-body metabolic regulation in adult offspring. In summary, prenatal benzene exposure at low dose programs offspring for increased susceptibility to diet induced metabolic changes in adulthood in a sexually dimorphic manner. Disclosure L. Koshko: None. L.K. Debarba: None. O. Didyuk: None. P.I. Fakhoury: None. M. Sadagurski: None. U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC.

Long-term effects of pro-opiomelanocortin methylation induced in food-restricted dams on metabolic phenotypes in male rat offspring.

ObjectiveMaternal malnutrition affects the growth and metabolic health of the offspring. Little is known about the long-term effect on metabolic indices of epigenetic changes in the brain caused by maternal diet. Thus, we explored the effect of maternal food restriction during pregnancy on metabolic profiles of the offspring, by evaluating the DNA methylation of hypothalamic appetite regulators at 3 weeks of age.MethodsSprague-Dawley rats were divided into 2 groups: a control group and a group with a 50% food-restricted (FR) diet during pregnancy. Methylation and expression of appetite regulator genes were measured in 3-week-old offspring using pyrosequencing, real-time polymerase chain reaction, and western blotting analyses. We analyzed the relationship between DNA methylation and metabolic profiles by Pearson's correlation analysis.ResultsThe expression of pro-opiomelanocortin (POMC) decreased, whereas DNA methylation significantly increased in male offspring of the FR dams, compared to the male offspring of control dams. Hypermethylation of POMC was positively correlated with the levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol in 3-week-old male offspring. In addition, there were significant positive correlations between hypermethylation of POMC and the levels of triglycerides, HDL-C, and leptin in 6-month-old male offspring.ConclusionOur findings suggest that maternal food restriction during pregnancy influences the expression of hypothalamic appetite regulators via epigenetic changes, leading to the development of metabolic disorders in the offspring.

Maternal Prenatal Folic Acid Supplementation Programs Offspring Lipid Metabolism by Aberrant DNA Methylation in Hepatic ATGL and Adipose LPL in Rats.

The effects of maternal prenatal folic acid supplementation (FAS) on offspring lipid metabolism in adulthood remains unclear, although prenatal FAS is compulsively suggested in many countries. Female Sprague-Dawley rats were fed with control (CON) or FAS diets before and during pregnancy. Male offspring of CON and FAS dams were further divided into two groups at seven weeks for CON and high-fat (HF) diet interventions for eight weeks in adulthood (n = 10). The interactive effects of maternal prenatal FAS and offspring HF in adulthood on lipid metabolism and DNA methylation of genes involved in lipids metabolism were assessed. The male offspring of FAS dams had elevated serum and liver triglyceride level when fed with HF compared to the male offspring of CON dams. The mRNA and protein expression levels of hepatic ATGL and adipose LPL were significantly decreased in offspring of FAS dams than in offspring of CON dams. Furthermore, maternal prenatal FAS resulted in elevated DNA methylation levels in the promoter and first exon region of hepatic ATGL and adipose LPL in offspring. Maternal FAS exacerbated the adverse effects of HF on lipid metabolism in offspring through inducing aberrant DNA methylation levels of hepatic ATGL and adipose LPL.

Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring

Epidemiological and animal studies suggest that the alteration of hormonal and metabolic environment during fetal and neonatal development can contribute to development of metabolic syndrome in adulthood. In this paper, we investigated the impact of maternal high-fat (HF) diet on hypothalamic leptin sensitivity and body weight gain of offspring. Adult Wistar female rats received a HF or a control normal-fat (C) diet for 6 wk before gestation until the end of the suckling period. After weaning, pups received either C or HF diet during 6 wk. Body weight gain and metabolic and endocrine parameters were measured in the eight groups of rats formed according to a postweaning diet, maternal diet, and gender. To evaluate hypothalamic leptin sensitivity in each group, STAT-3 phosphorylation was measured in response to leptin or saline intraperitoneal bolus. Pups exhibited similar body weights at birth, but at weaning, those born to HF dams weighed significantly less (-12%) than those born to C dams. When given the HF diet, males and females born to HF dams exhibited smaller body weight and feed efficiency than those born to C dams, suggesting increased energy expenditure programmed by the maternal HF diet. Thus, maternal HF feeding could be protective against adverse effects of the HF diet as observed in male offspring of control dams: overweight (+17%) with hyperleptinemia and hyperinsulinemia. Furthermore, offspring of HF dams fed either C or HF diet exhibited an alteration in hypothalamic leptin-dependent STAT-3 phosphorylation. We conclude that maternal high-fat diet programs a hypothalamic leptin resistance in offspring, which, however, fails to increase the body weight gain until adulthood.

The interaction between prenatal stress and neonatal handling on nociceptive response latencies in male and female rats

Neonatal handling produces physiological and behavioral changes that persist into adulthood. These effects are opposite to those resulting from prenatal stress (PS). We examined the interaction between PS and handling on nociception in adult male and female rats. Randomly selected pregnant rats were subjected to restraint stress on days 13–17 of gestation for 25 min each day, or left undisturbed. At birth, selected stressed/nonstressed litters were assigned to be handled. Handling consisted of 15 min of separation from the dam, once per day, from postnatal days 1–14. At 4 months of age, rats were placed on a 50°C hot plate, and their latencies to paw lick were recorded. Prenatal stress and handling interacted to affect latencies in male rats. Handled (H)/PS rats had significantly lower paw lick latencies than nonhandled (NH)/PS rats ( p < 0.05). However, handling had no effect on the male offspring of control dams. Handling elevated paw lick latencies in the female offspring of control dams, an effect that was most pronounced in diestrous vs. estrous rats. The NH/PS rats showed significantly elevated latencies compared to NH/NS rats ( p < 0.05). These results suggest that handling effects on nociception are most apparent in rats subjected to PS; in males at least, these effects would otherwise not be present.