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Sex-specific effects of maternal weight loss on offspring cardiometabolic outcomes in the obese preeclamptic-like mouse model, BPH/5.

ABSTRACT: AbstractPreeclampsia (PE) is a hypertensive disorder that impacts 2-8% of pregnant women worldwide. It is characterized by new onset hypertension during the second half of gestation and is a leading cause of maternal and fetal morbidity/mortality. Maternal obesity increases the risk of PE and is a key predictor of childhood obesity and potentially offspring cardiometabolic complications in a sex-dependent manner. The influence of the maternal obesogenic environment, with superimposed PE, on offspring development into adulthood is unknown. Obese BPH/5 mice spontaneously exhibit late-gestational hypertension, fetal demise and growth restriction, and excessive gestational weight gain. BPH/5 females have improved pregnancy outcomes when maternal weight loss via pair-feeding is imposed beginning at conception. We hypothesized that phenotypic differences between female and male BPH/5 offspring can be influenced by pair feeding BPH/5 dams during pregnancy. BPH/5 pair-fed dams have improved litter sizes and increased fetal body weights. BPH/5 offspring born to ad libitum dams have similar sex ratios, body weights, and fecal microbiome as well as increased blood pressure that is reduced in the dam pair-fed offspring. Both BPH/5 male and female offspring born to pair-fed dams have a reduction in adiposity and an altered gut microbiome, while only female offspring born to pair-fed dams have decreased circulating leptin and white adipose tissue inflammatory cytokines. These sexually dimorphic results suggest that reduction in the maternal obesogenic environment in early pregnancy may play a greater role in female BPH/5 sex-dependent cardiometabolic outcomes than males. Reprograming females may mitigate the transgenerational progression of cardiometabolic disease.

SUBMITTER: Beckers KF

PROVIDER: S-EPMC9446412 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Sex-specific effects of maternal weight loss on offspring cardiometabolic outcomes in the obese preeclamptic-like mouse model, BPH/5.

Beckers Kalie F KF Schulz Christopher J CJ Flanagan Juliet P JP Adams Daniella M DM Gomes Viviane C L VCL Liu Chin-Chi CC Childers Gary W GW Sones Jenny L JL

Physiological reports 20220901 17

AbstractPreeclampsia (PE) is a hypertensive disorder that impacts 2-8% of pregnant women worldwide. It is characterized by new onset hypertension during the second half of gestation and is a leading cause of maternal and fetal morbidity/mortality. Maternal obesity increases the risk of PE and is a key predictor of childhood obesity and potentially offspring cardiometabolic complications in a sex-dependent manner. The influence of the maternal obesogenic environment, with superimposed PE, on offs ...[more]

PMID: 36065848

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Project description:Preeclampsia (PE) is a devastating hypertensive disorder of pregnancy closely linked to obesity. Long-term adverse outcomes may occur in offspring from preeclamptic pregnancies. Accordingly, sex-specific changes in pubertal development have been described in children from preeclamptic women, but the underlying mechanisms remain vastly unexplored. Features of PE are spontaneously recapitulated by the blood pressure high subline 5 (BPH/5) mouse model, including obesity and dyslipidemia in females before and throughout pregnancy, superimposed hypertension from late gestation to parturition and fetal growth restriction. A sexually dimorphic cardiometabolic phenotype has been described in BPH/5 offspring: while females are hyperphagic, hyperleptinemic, and overweight, with increased reproductive white adipose tissue (rWAT), males have similar food intake, serum leptin concentration, body weight and rWAT mass as controls. Herein, pubertal development and adiposity were further investigated in BPH/5 progeny. Precocious onset of puberty occurs in BPH/5 females, but not in male offspring. When reaching adulthood, the obese BPH/5 females display hypoestrogenism and hyperandrogenism. Kisspeptins, a family of peptides closely linked to reproduction and metabolism, have been previously shown to induce lipolysis and inhibit adipogenesis. Interestingly, expression of kisspeptins (Kiss1) and their cognate receptor (Kiss1r) in the adipose tissue seem to be modulated by the sex steroid hormone milieu. To further understand the metabolic-reproductive crosstalk in the BPH/5 offspring, Kiss1/Kiss1r expression in male and female rWAT were investigated. Downregulation of Kiss1/Kiss1r occurs in BPH/5 females when compared to males. Interestingly, dietary weight loss attenuated circulating testosterone concentration and rWAT Kiss1 downregulation in BPH/5 females. Altogether, the studies demonstrate reproductive abnormalities in offspring gestated in a PE-like uterus, which appear to be closely associated to the sexually dimorphic metabolic phenotype of the BPH/5 mouse model.

Project description:BackgroundLittle is known about the effect of intentional weight loss and subsequent weight regain on cardiometabolic risk factors in older adults. The objective of this study was to determine how cardiometabolic risk factors change in the year following significant intentional weight loss in postmenopausal women, and if observed changes were affected by weight and fat regain.MethodsEighty, overweight and obese, older women (age = 58.8±5.1 years) were followed through a 5-month weight loss intervention and a subsequent 12-month nonintervention period. Body weight/composition and cardiometabolic risk factors (blood pressure; total, high-density lipoprotein, and low-density lipoprotein cholesterol; triglycerides; fasting glucose and insulin; and Homeostatic Model Assessment of Insulin Resistance) were analyzed at baseline, immediately postintervention, and 6- and 12-months postintervention.ResultsAverage weight loss during the 5-month intervention was 11.4±4.1kg and 31.4% of lost weight was regained during the 12-month follow-up. On average, all risk factor variables were significantly improved with weight loss but regressed toward baseline values during the year subsequent to weight loss. Increases in total cholesterol, triglycerides, glucose, insulin, and Homeostatic Model Assessment of Insulin Resistance during the postintervention follow-up were significantly (p < .05) associated with weight and fat mass regain. Among women who regained weight, model-adjusted total cholesterol (205.8±4.0 vs 199.7±2.9mg/dL), low-density lipoprotein cholesterol (128.4±3.4 vs 122.7±2.4mg/dL), insulin (12.6±0.7 vs 11.4±0.7mg/dL), and Homeostatic Model Assessment of Insulin Resistance (55.8±3.5 vs 50.9±3.7mg/dL) were higher at follow-up compared with baseline.ConclusionsFor postmenopausal women, even partial weight regain following intentional weight loss is associated with increased cardiometabolic risk. Conversely, maintenance of or continued weight loss is associated with sustained improvement in the cardiometabolic profile.

Project description:Aims/hypothesisMetformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months.MethodsC57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay).ResultsAt 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring.Conclusions/interpretationMaternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.

Project description:BackgroundObesity in women of reproductive age has deleterious effects on reproductive and offspring health. In this study, we aimed to evaluate the association between the magnitude of periconceptional body-mass index (BMI) change and maternal and neonatal outcomes in obese infertile women who participated in the LIFEstyle study. The LIFEstyle study was a randomized controlled trial, evaluating if a six-month lifestyle intervention program prior to infertility treatment in obese infertile women improved birth rates, compared to prompt infertility treatment.Methods and findingsThis is an exploratory post hoc analysis of the LIFEstyle study. We recorded periconceptional BMI change in women with an ongoing pregnancy, pooling data of all women, regardless of randomization arm. Periconceptional BMI change was calculated using weight at randomization and the periconceptional weight (measured in kilograms 12 weeks before or after conception and expressed as BMI change in units BMI (kg/m2)). Subsequently, women were categorized into quartiles according to the magnitude of their periconceptional change in BMI. The odds of maternal and neonatal outcomes were calculated using logistic regression analysis, comparing women in each of the first three weight change quartiles separately, and combined, to women in the fourth quartile. The fourth quartile was chosen as reference group, since these women had the least weight loss. We adjusted for periconceptional BMI, nulliparity and smoking status. In addition, we performed a subgroup analysis for singleton pregnancies. In the LIFEstyle study, 321 obese infertile women achieved an ongoing pregnancy which was conceived within 24 months after randomization. Periconceptional BMI change was available in 244 of these women (76%). Median BMI at randomization was 35.9 kg/m2. Women in the first quartile (Q1) had a periconceptional BMI change of <-2.1 kg/m2, women in the second quartile (Q2) -2.1 to -0.9 kg/m2, women in the third quartile (Q3) -0.9 to 0.1 kg/m2 and women in the fourth quartile (Q4) gained ≥0.1 kg/m2. There were no significant differences between women in the quartiles regarding rates of excessive gestational weight gain (in term pregnancies), gestational diabetes, preterm birth, induction of labor, spontaneous vaginal birth and Caesarean section. Compared to women in Q4, the adjusted odds ratios, aOR, and 95% confidence interval for a hypertensive complication were; 0.55 (0.22-1.42) for women in Q1, 0.30 (0.12-0.78) for women in Q2, 0.39 (0.16-0.96) for women in Q3 and 0.39 (0.19-0.82) for women in Q1 to Q3 combined. In the subgroup analysis, investigating singleton pregnancies only, the statistically significant decreased rate of a hypertensive complication remained in women in Q2 (aOR 0.27, 95% CI 0.10-0.72) and Q3 (aOR 0.39, 95%CI 0.16-0.98) and when comparing women in Q1 to Q3 together to women in Q4 (aOR 0.38, 95%CI 0.18-0.80). Furthermore, there was a significantly decreased aOR (95%CI) of preterm birth in women in Q2 (0.24, 0.06-0.98) and when combining women in Q1 to Q3 (0.37, 0.14-0.97) compared to women in Q4.ConclusionsThese results suggest that a periconceptional decrease in BMI in obese infertile women could lead to a decrease of the rates of hypertensive pregnancy complications and preterm birth. The results are limited by the exploratory nature of the analyses and further evidence is necessary to provide more definitive conclusions.

Dataset Information

Sex-specific effects of maternal weight loss on offspring cardiometabolic outcomes in the obese preeclamptic-like mouse model, BPH/5.

Publications

Sex-specific effects of maternal weight loss on offspring cardiometabolic outcomes in the obese preeclamptic-like mouse model, BPH/5.

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