NAMPT reduction-induced NAD+ insufficiency contributes to the compromised oocyte quality from obese mice.

Maternal obesity is associated with multiple adverse reproductive outcomes, whereas the underlying molecular mechanisms are still not fully understood. Here, we found the reduced nicotinamide phosphoribosyl transferase (NAMPT) expression and lowered nicotinamide adenine dinucleotide (NAD+ ) content in oocytes from obese mice. Next, by performing morpholino knockdown assay and pharmacological inhibition, we revealed that NAMPT deficiency not only severely disrupts maturational progression and meiotic apparatus, but also induces the metabolic dysfunction in oocytes. Furthermore, overexpression analysis demonstrated that NAMPT insufficiency induced NAD+ loss contributes to the compromised developmental potential of oocytes and early embryos from obese mice. Importantly, in vitro supplement and in vivo administration of nicotinic acid (NA) was able to ameliorate the obesity-associated meiotic defects and oxidative stress in oocytes. Our results indicate a role of NAMPT in modulating oocyte meiosis and metabolism, and uncover the beneficial effects of NA treatment on oocyte quality from obese mice.

Pregnant Women Living with Obesity: A Cross-Sectional Observational Study of Dietary Quality and Pregnancy Outcomes.

Good maternal nutrition is key to optimal maternal and foetal health. A poor-quality diet is often associated with obesity, and the prevalence and severity of maternal obesity has increased significantly in recent years. This study observed dietary intakes in pregnant women living with obesity and assessed the quality of their diet. In total, 140 women with a singleton pregnancy, aged > 18 years and BMI ≥ 35 kg/m2, were recruited from antenatal clinics, weighed and completed food diaries at 16-, 28- and 36-weeks' gestation. Clinical data were recorded directly from the women's medical records. Nutrient intake was determined using 'MicrodietTM', then compared to Dietary Reference Values (DRVs). Energy intakes were comparable with DRVs, but intakes of sugar and saturated fatty acids were significantly higher. Intake of fibre and several key micronutrients (Iron, Iodine, Folate and Vitamin D) were significantly low. Several adverse obstetric outcomes were higher than the general obstetric population. Women with obesity, often considered 'over nourished', may have diets deficient in essential micronutrients, often associated with poor obstetric outcomes. To address the intergenerational transmission of poor health via poor diets warrants a multi-disciplinary approach focusing away from 'dieting' onto positive messages, emphasising key nutrients required for good maternal and foetal health.

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers.

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.

Drivers of food consumption among overweight mother-child dyads in Malawi.

To address the increase in overweight and obesity among mothers and children in sub-Saharan Africa, an understanding of the factors that drive their food consumption is needed. We hypothesized food consumption in Malawi is driven by a combination of factors, including season, food accessibility (area of residence, convenience of purchasing food, female autonomy), food affordability (household resources, food expenditures, household food insecurity), food desirability (taste preferences, body size preferences), demographics, and morbidity. Participants in Lilongwe and Kasungu Districts were enrolled across three types of mother-child dyads: either the mother (n = 120), child (n = 80), or both (n = 74) were overweight. Seven-day dietary intake was assessed using a quantitative food frequency questionnaire during the dry and rainy seasons. Drivers associated with intake of calories, macronutrients, and 11 food groups at p<0.1 in univariate models were entered into separate multivariate linear regression models for each dietary intake outcome. Mother-child dyads with an overweight child had a higher percent of calories from carbohydrates and lower percent of calories from fat compared to dyads with a normal weight child (both p<0.01). These mothers also had the highest intake of grains (p<0.01) and their children had the lowest intake of oil/fat (p = 0.01). Household food insecurity, maternal taste preferences, and maternal body size preferences were the most consistent predictors of food group consumption. Household food insecurity was associated with lower intake of grains, fruits, meat and eggs, oil/fat, and snacks. Maternal taste preferences predicted increased consumption of grains, legumes/nuts, vegetables, fish, and oil/fat. Maternal body size preferences for herself and her child were associated with consumption of grains, legumes/nuts, dairy, and sweets. Predictors of food consumption varied by season, across food groups, and for mothers and children. In conclusion, indicators of food affordability and desirability were the most common predictors of food consumption among overweight mother-child dyads in Malawi.

Maternal High-Fat-High-Carbohydrate Diet-Induced Obesity Is Associated with Increased Appetite in Peripubertal Male but Not Female C57Bl/6J Mice.

Diet-induced maternal obesity might play a critical role in altering hypothalamic development, predisposing the offspring to obesity and metabolic disease later in life. The objective of this study was to describe both phenotypic and molecular sex differences in peripubertal offspring energy homeostasis, using a mouse model of maternal obesity induced by a high-fat-high-carbohydrate (HFHC) diet. We report that males, not females, exposed to a maternal HFHC diet had increased energy intake. Males exposed to a maternal HFHC diet had a 15% increased meal size and a 46% increased frequency, compared to the control (CON) males, without a change in energy expenditure. CON and HFHC offspring did not differ in body weight, composition, or plasma metabolic profile. HFHC diet caused decreased hypothalamic glucocorticoid expression, which was further decreased in males compared to females. Maternal weight, maternal caloric intake, and male offspring meal frequency were inversely correlated with offspring hypothalamic insulin receptor (IR) expression. There was a significant interaction between maternal-diet exposure and sex in hypothalamic IR. Based on our preclinical data, we suggest that interventions focusing on normalizing maternal nutrition might be considered to attenuate nutritional influences on obesity programming and curb the continuing rise in obesity rates.

Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia.

Vitamin B12 (B12) is a micronutrient essential for one-carbon (1C) metabolism. B12 deficiency disturbs the 1C cycle and alters DNA methylation which is vital for most metabolic processes. Studies show that B12 deficiency may be associated with obesity, insulin resistance and gestational diabetes; and with obesity in child-bearing women. We therefore hypothesised that the associations between B12 deficiency, BMI and the metabolic risk could be mediated through altered 1C metabolites in early pregnancy. We explored these associations in two different early pregnancy cohorts in the UK (cohort 1; n = 244 and cohort 2; n = 60) with anthropometric data at 10-12 weeks and plasma/serum sampling at 16-18 weeks. B12, folate, total homocysteine (tHcy), methionine, MMA, metabolites of 1C metabolism (SAM, SAH) and anthropometry were measured. B12 deficiency (< 150 pmol/l) in early pregnancy was 23% in cohort 1 and 18% in cohort 2. Regression analysis after adjusting for likely confounders showed that B12 was independently and negatively associated with BMI (Cohort 1: ß = - 0.260, 95% CI (- 0.440, - 0.079), p = 0.005, Cohort 2: (ß = - 0.220, 95% CI (- 0.424, - 0.016), p = 0.036) and positively with HDL cholesterol (HDL-C) (ß = 0.442, 95% CI (0.011,0.873), p = 0.045). We found that methionine (ß = - 0.656, 95% CI (- 0.900, - 0.412), p < 0.0001) and SAH (ß = 0.371, 95% CI (0.071, 0.672), p = 0.017) were independently associated with triglycerides. Low B12 status and alteration in metabolites in 1C metabolism are common in UK women in early pregnancy and are independently associated with maternal obesity and dyslipidaemia. Therefore, we suggest B12 monitoring in women during peri-conceptional period and future studies on the pathophysiological relationship between changes in 1C metabolites and its association with maternal and fetal outcomes on larger cohorts. This in turn may offer potential to reduce the metabolic risk in pregnant women and their offspring.

Multigenerational maternal obesity increases the incidence of HCC in offspring via miR-27a-3p.

BACKGROUND & AIMS: Obesity is an independent risk factor for malignancies, including hepatocellular carcinoma (HCC). However, it remains unknown whether maternal obesity affects the incidence of HCC in offspring. Thus, we aimed to investigate this association and its underlying mechanisms. METHODS: Diethylnitrosamine (DEN) was used to induce HCC in a high-fat diet (HFD)-induced multigenerational obesity model. RNA-sequencing was performed to identify the genes and microRNAs (miRNAs) that were altered over generations. The role of the miR-27a-3p-Acsl1/Aldh2 axis in HCC was evaluated in cell lines and HCC-bearing nude mice, and its intergenerational impact was studied in pregnant mice and their offspring. RESULTS: Under HFD stress, maternal obesity caused susceptibility of offspring to DEN-induced HCC, and such susceptibility was cumulative over generations. We identified that Acsl1 and Aldh2, direct targets of miR-27a-3p, were gradually changed over generations. Under hyperlipidemic conditions, downregulation of Acsl1 and Aldh2 increased cell proliferation (in vitro) or tumor growth (in vivo) in synergy. Intratumor injection of an miR-27a-3p agomir exacerbated tumor growth by downregulating Acsl1 and Aldh2; while intratumor injection of an miR-27a-3p antagomir had the opposite effect. Moreover, serum miR-27a-3p levels gradually increased in the HFD-fed maternal lineage over generations. Injecting pregnant mice with an miR-27a-3p agomir not only upregulated hepatic miR-27a-3p and downregulated Acsl1/Aldh2 in offspring (fetus, young and adult stages), but also exacerbated HCC development in DEN-treated offspring. In human HCC, upregulated miR-27a-3p and downregulated Acsl1/Aldh2 were negatively correlated with survival on TCGA analysis; while, hepatic miR-27a-3p was negatively correlated with Acsl1/Aldh2 expression in tumor/non-tumor tissues from fatty/non-fatty livers. CONCLUSIONS: Maternal obesity plays a role in regulating cumulative susceptibility to HCC development in offspring over multiple generations through the miR-27a-3p-Acsl1/Aldh2 axis. LAY SUMMARY: It is not currently known how maternal obesity affects the incidence of liver cancer in offspring. In this study, we identified a microRNA (miR-27a-3p) that was upregulated in obese mothers and could be passed on to their offspring. This microRNA enhanced the risk of liver cancer in offspring by regulating 2 genes (Acsl1 and Aldh2). This mechanism could be a future therapeutic target.

Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring.

Exposure to certain environmental factors during the early stages of development was found to affect health in adulthood. Among other environmental factors, oxidative stress has been suggested to be involved in fetal programming, leading to elevated risk for metabolic disorders, including type 2 diabetes; however, the possibility that antioxidant consumption during early life may affect the development of diabetes has scarcely been studied. The aim of this study was to investigate the effects of N-acetyl-l-cysteine (NAC) given during pregnancy and lactation on the susceptibility of offspring to develop glucose intolerance at adulthood. C57bl6/J mice were given NAC during pregnancy and lactation. High fat diet (HFD) was given to offspring at an age of 6 weeks for an additional 9 weeks, till the end of the study. Isolated islets of NAC-treated offspring (6 weeks old, before HFD feeding) had an increased efficacy of glucose-stimulated insulin secretion and a higher resistance to oxidative damage. Following HFD feeding, glucose tolerance and insulin sensitivity of NAC-treated offspring were improved. In addition, islet diameter was lower in male offspring of NAC-treated mice compared to their HFD-fed littermates. NAC consumption during early life improves glucose tolerance in adulthood in mice.

Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis.

Obesity during pregnancy is a known health risk for mother and child. Since obesity is associated with increased inflammatory markers, our objectives were to determine interleukin-6 (IL-6) levels in obese mice and to examine the effect of IL-6 on placental endothelial cells. Placentas, blood, and adipose tissue of C57BL/6N mice, kept on high fat diet before and during pregnancy, were harvested at E15.5. Serum IL-6 levels were determined and endothelial cell markers and IL-6 expression were measured by qRT-PCR and western blot. Immunostaining was used to determine surface and length densities of fetal capillary profiles and placental endothelial cell homeostasis. Human placental vein endothelial cells were cultured and subjected to proliferation, apoptosis, senescence, and tube formation assays after stimulation with hyperIL-6. Placental endothelial cell markers were downregulated and the percentage of senescent endothelial cells was higher in the placental exchange zone of obese dams and placental vascularization was strongly reduced. Additionally, maternal IL-6 serum levels and IL-6 protein levels in adipose tissue were increased. Stimulation with hyperIL-6 provoked a dose dependent increase of senescence in cultured endothelial cells without any effects on proliferation or apoptosis. Diet-induced maternal obesity led to an IUGR phenotype accompanied by increased maternal IL-6 serum levels. In the placenta of obese dams, this may result in a disturbed endothelial cell homeostasis and impaired fetal vasculature. Cell culture experiments confirmed that IL-6 is capable of inducing endothelial cell senescence.

Timing of Gestational Weight Gain and Adverse Perinatal Outcomes in Overweight and Obese Women.

OBJECTIVE: To evaluate whether inadequate or excessive gestational weight gain before the third trimester is associated with adverse pregnancy outcomes, and to evaluate the association of weight gain in the third trimester with fetal growth. METHODS: This was a retrospective cohort study of all eligible overweight and obese women with singleton pregnancies delivered at an academic institution between 2012 and 2014. Our primary exposure was inadequate or excess gestational weight gain during the first and second trimesters. Outcomes included small- (SGA) or large- (LGA) for-gestational-age birth weight as well adverse maternal outcomes and composite neonatal morbidity. Multivariable logistic regression was used to assess the relationship between weight gain and perinatal outcomes, and stratified analyses evaluated the relationship between third trimester weight gain and birth weight category. RESULTS: Of the 5,814 women, 1,280 (22%) had adequate, 1,428 (24.6%) had inadequate, and 3,106 (53.4%) had excessive weight gain in the first and second trimesters. Women with inadequate early gestational weight gain were more likely to deliver an SGA neonate (adjusted odds ratio [aOR] 1.59, 95% CI 1.23-2.06) and less likely to deliver an LGA neonate (aOR 0.73, 95% CI 0.54-0.98), whereas those with excessive early gestational weight gain were less likely to deliver an SGA neonate (aOR 0.66, 95% CI 0.52-0.85) and more likely to deliver an LGA neonate (aOR 1.66, 95% CI 1.32-2.1). Higher weight gain in the third trimester was associated with increased risk for LGA birth weight, but third trimester weight gain was not related to SGA birth weight. CONCLUSION: Early gestational weight gain is associated with birth weight category. Modifying weight gain in the third trimester may limit the risk for LGA birth weight, but higher weight gain in late gestation does not alter the association between inadequate early weight gain and the risk for SGA.

Socio-economic indicators, dietary patterns, and physical activity as determinants of maternal obesity in middle-income countries: Evidences from a cohort study in Mexico.

Maternal obesity is one of the main public health problems at a world level. It is a multifactorial disease with multiple causes, and few studies exist on its dietary patterns, physical activity and social determinants. This work aims to identify determinants of maternal obesity in a middle income country. Research is based on a prospective cohort design. Data were collected using questionnaires applied to pregnant women. Three dietary patterns were identified, and only half of the women carry out physical activity. The regression analysis showed an association between overweight/obesity and the following variables: age 25 to 29 years old (3.8; CI 1.6-9.0), 30 to 34 years old (3.7; CI 1.2-11.6); health problems during pregnancy (2.1; CI 1.0-4.1); socio-economic income (1.73; CI 1.54-2.05); hypertension (2.7; CI 1.4-4.5); mild food insecurity (1.9; CI 1.0-3.8); moderate insecurity (3.7; CI 0.92-15.4); refined food dietary pattern (.76; CI.61-.95). The risk of increasing BMI during pregnancy mainly depends on socioeconomic and demographic variables such as age, educational level, income, food insecurity, and dietary pattern. This study's results could be used as evidences for the revision, planning, and adjustment of interventions for the prevention and management of maternal obesity, as a part of the national strategies against overweight and obesity.

Multiple deprivation and other risk factors for maternal obesity in Portsmouth, UK.

BACKGROUND: Maternal obesity is known to be associated with a range of adverse outcomes, both for the mothers and their children. It may be more prevalent in areas with higher deprivation as measured by the Index of Multiple Deprivation (IMD), but this has not been demonstrated consistently. This study focused primarily on the relationship between maternal obesity and deprivation in a setting where areas of significant deprivation are surrounded by the overall affluent South East England. METHODS: The study used the records of 3830 women who delivered under the care of a Portsmouth hospital from 1 April 2013 to 31 March 2014. Logistic regression was used to analyse the association between national IMD quintiles and maternal obesity, accounting for the potential confounders of age, ethnic origin, smoking status and parity. RESULTS: Following adjustment, women in the most deprived IMD quintile were 1.60 (95% CI: 1.13, 2.26) times more likely to be obese compared to those in the least deprived quintile. Maternal obesity was also found to be associated with ethnicity and parity, but not with age or smoking status. CONCLUSIONS: Maternal obesity increased with increasing deprivation. IMD may be a useful group-level indicator when planning interventions aimed at tackling maternal obesity.