Mediating processes underlying the associations between maternal obesity and the likelihood of cesarean birth.

BACKGROUND: Pregnant women with obesity are more likely to experience cesarean birth compared to women without obesity. Yet, little is known about the underlying mechanisms. The objective of this study was therefore to evaluate how mediators contribute to the association between obesity and prelabor/intrapartum cesarean birth. METHODS: We retrospectively analyzed Swiss cohort data from 394,812 singleton, cephalic deliveries between 2005 and 2020. Obesity (BMI ≥ 30 kg/m2 ) was defined as the exposure and prelabor or intrapartum cesarean birth as the outcomes. Hypothesized mediators included gestational comorbidities, large-for-gestational-age infant, pregnancy duration >410/7 weeks, slower labor progress, labor induction, and history of cesarean birth. We performed path analyses using generalized structural equation modeling and assessed mediation by a counterfactual approach. RESULTS: Women with obesity had a cesarean birth rate of 39.36% vs. 24.12% in women without obesity. The path models mainly showed positive direct and indirect associations between obesity and cesarean birth. In the total sample, the mediation models explained up to 39.47% (95% CI 36.92-42.02) of the association between obesity and cesarean birth, and up to 57.13% (95% CI 54.10-60.16) when including history of cesarean birth as mediator in multiparous women. Slower labor progress and history of cesarean birth were found to be the most clinically significant mediators. CONCLUSIONS: This study provides empirical insights into how obesity may increase cesarean birth rates through mediating processes. Particularly allowing for a slower labor progress in women with obesity might reduce cesarean birth rates and prevent subsequent repeat cesarean births in multiparous women.

Effect of the IADPSG screening strategy for gestational diabetes on perinatal outcomes in Switzerland.

AIMS: To evaluate the impact adoption of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria on prevalence of gestational diabetes mellitus (GDM) and risks of perinatal outcomes. METHODS: Retrospectively, 155,103 women screened with selective two step criteria in Switzerland in period 1 (2005-2010) were compared to 170,427 women screened with IADPSG criteria in period 2 (2012-2017). GDM prevalence over time was established and multivariable regression used to assess variation in risks for GDM related events and perinatal outcomes. RESULTS: GDM prevalence increased steadily over both study periods from 1.8% to 9.0%. A risk reduction of GDM-related events was shown only for women with one or two risk factors for GDM present (relative risk (95% confidence interval)): (0.93 (0.90,0.97), 0.90 (0.83,0.96)). The comparison of perinatal outcomes between the two study periods revealed a significant lower risk for newborns large for gestational age (LGA) (0.93 (0.91-0.95)), pre-term delivery (0.94 (0.92-0.97)) and neonatal hypoglycemia (0.83 (0.77-0.90)) in period 2. CONCLUSION: The introduction of the IADPSG criteria for the screening of GDM increased prevalence by threefold with no substantial improvements in GDM related events for women without risk factors but reduced the risks for LGA, neonatal hypoglycemia and preterm birth.

11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches.

The inhibition of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which catalyzes the conversion of inactive 11-ketoglucocorticoids to active 11beta-hydroxyglucocorticoids, emerged as promising strategy to treat symptoms of the metabolic syndrome, including obesity and type 2 diabetes. In this study the leaves of the anti-diabetic medicinal plant loquat (Eriobotrya japonica) were phytochemically investigated following hints from a pharmacophore-based virtual screening and a bioactivity-guided approach. Determination of the 11beta-HSD1 and 11beta-HSD2 inhibitory activities in cell lysates revealed triterpenes from the ursane type as selective, low micro-molar inhibitors of 11beta-HSD1, that is, corosolic acid (1), 3-epicorosolic acid methyl ester (4), 2-alpha hydroxy-3-oxo urs-12-en-28-oic acid (6), tormentic acid methyl ester (8), and ursolic acid (9). Importantly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11beta-HSD1-inhibiting 11-keto-ursolic acid (17) and 3-acetyl-11-keto-ursolic acid (18) a structure-activity relationship was deduced for this group of pentacyclic triterpenes. The mechanism of action elucidated in the present work together with the previously determined pharmacological activities provides these natural products with an astonishing multi-targeted anti-diabetic profile.

Adverse perinatal outcomes for obese women are influenced by the presence of comorbid diabetes and hypertensive disorders.

Maternal obesity often occurs together with comorbid diabetes and hypertensive disorders. All three conditions are independently associated with negative perinatal outcomes. Our objective was to determine the risk and burden of adverse perinatal outcome that could be attributed to maternal obesity in combination with a comorbid status. We analyzed data from 324'664 singleton deliveries in Switzerland between 2005 and 2016. For the association of maternal obesity in the presence or absence of comorbidities with various perinatal outcomes, we estimated adjusted relative risk (RR) using multivariable regression modeling and determined the multivariable-adjusted attributable fraction of the population (AFp). Obesity was a main predictor for macrosomia, fracture of the clavicle, failure to progress in labor and prolonged labor. By stratifying women based on comorbidities, we identified significantly increased risk for preterm birth and early neonatal death only for women diagnosed with a comorbidity. However, various other outcomes were independently associated with either obesity or comorbidities. The AFp showed greatest reduction in comorbidities (15.4/15.0/13.2%), in macrosomia (6.3%) and in shoulder dystocia (4.8%) if all women were to become non-obese. We suggest that comorbidities such as diabetes and hypertensive disorders should be considered when relating maternal obesity to adverse perinatal outcomes.

Knockdown of diacylglycerol kinase delta inhibits adipocyte differentiation and alters lipid synthesis.

OBJECTIVE: Decreased expression of diacylglycerol kinase delta (DGKδ) has been linked to insulin resistance in humans and mice and it is abundantly expressed in adipose tissue. Therefore, its role in adipogenesis was examined. DESIGN AND METHODS: 3T3-L1 pre-adipocytes were generated in which DGKδ expression had been knocked down and the effect of this on adipogenesis was determined. Lipidomic analyses were performed to determine levels of the DGKδ product phosphatidic acid (PA), its substrate diacylglycerol (DAG) and triglyceride (TG). RESULTS: Inhibiting DGKδ expression prevents adipogenesis. DGKδ knockdown in differentiating adipocytes blunted the increase in total levels of PA and DAG but did not affect the early rise in TG levels. DAG or PA species acting as TG precursors were only modestly reduced by DGKδ knockdown which significantly impaired the accumulation of DAG or PA species implicated in intracellular signaling. The DAG activated kinase PKCδ was also stimulated in DGKδ knockdown cells, despite no increase in detectable species of DAG. CONCLUSIONS: DGKδ is a novel regulator of adipogenesis and phosphorylates a quantitatively small pool of signaling DAG important for differentiation and indirectly affects overall levels of signaling DAG and PA species distinct from those acting as precursors for TG synthesis.

The human lipodystrophy protein seipin is an ER membrane adaptor for the adipogenic PA phosphatase lipin 1.

Disruption of the gene BSCL2 causes a severe, generalised lipodystrophy, demonstrating the critical role of its protein product, seipin, in human adipose tissue development. Seipin is essential for adipocyte differentiation, whilst the study of seipin in non-adipose cells has suggested a role in lipid droplet formation. However, its precise molecular function remains poorly understood. Here we demonstrate that seipin can inducibly bind lipin 1, a phosphatidic acid (PA) phosphatase important for lipid synthesis and adipogenesis. Knockdown of seipin during early adipogenesis decreases the association of lipin 1 with membranes and increases the accumulation of its substrate PA. Conversely, PA levels are reduced in differentiating cells by overexpression of wild-type seipin but not by expression of a mutated seipin that is unable to bind lipin 1. Together our data identify lipin as the first example of a seipin-interacting protein and reveals a novel molecular function for seipin in developing adipocytes.

Retinoic acid reduces glucocorticoid sensitivity in C2C12 myotubes by decreasing 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor activities.

Vitamin A is a nutrient with remarkable effects on adipose tissue and skeletal muscles, and plays a role in controlling energy balance. Retinoic acid (RA), the carboxylic form of vitamin A, has been associated with improved glucose tolerance and insulin sensitivity. In contrast, elevated glucocorticoids have been implicated in the development of insulin resistance and impaired glucose tolerance. Here, we investigated whether RA might counteract glucocorticoid effects in skeletal muscle cells by lowering 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1)-dependent local glucocorticoid activation and/or activation of glucocorticoid receptor (GR). We found a dose-dependent down-regulation of 11beta-HSD1 mRNA expression and activity upon incubation of fully differentiated mouse C2C12 myotubes with RA. In addition, RA inhibited GR transactivation by an 11beta-HSD1-independent mechanism. The presence of RA during myogenesis did not prevent myotube formation but resulted in relatively glucocorticoid-resistant myotubes, exhibiting very low 11beta-HSD1 expression and GR activity. The use of selective retinoic acid receptor (RAR) and retinoid X receptor ligands provided evidence that these effects were mediated through RARgamma. Importantly, short hairpin RNA against RARgamma abolished the effect of RA on 11beta-HSD1 and GR. In conclusion, we provide evidence for an important role of RA in the control of glucocorticoid activity during myogenesis and in myotubes. Disturbances of the nutrient and hormonal regulation of glucocorticoid action in skeletal muscles might be relevant for metabolic diseases.

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 by plant extracts used as traditional antidiabetic medicines.

Elevated glucocorticoids are a key risk factor for metabolic diseases, and the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) represents a promising therapeutic target. We measured the potential of six traditional antidiabetic medicinal plants extracts to inhibit 11beta-HSD1 activity and glucocorticoid receptor (GR) activation in transfected HEK-293 cells. Leave extracts of Eriobotrya japonica preferentially inhibited 11beta-HSD1 over 11beta-HSD2. Extracts of roasted but not native coffee beans preferentially inhibited 11beta-HSD1 over 11beta-HSD2, emphasizing the importance of sample preparation. Thus, natural compounds inhibiting 11beta-HSD1 may contribute to the antidiabetic effect of the investigated plant extracts.