Obesity-related derangements of coagulation and fibrinolysis: a study of obesity-discordant monozygotic twin pairs

Coagulation and fibrinolytic activities are under strong genetic control. We studied the effects of acquired obesity, independent of genetic factors on coagulation and fibrinolysis activities in obesity-discordant healthy monozygotic (MZ) twin pairs. Fourteen obesity-discordant (BMI within-pair difference >3 kg/m(2)) and 10 concordant (BMI difference <2 kg/m(2)) MZ twin pairs were identified from the nationwide FinnTwin16 study. Body composition (dual-energy x-ray absorptiometry), abdominal fat distribution (magnetic resonance imaging), liver fat (magnetic resonance spectroscopy), high sensitivity C-reactive protein, insulin sensitivity (euglycemic hyperinsulinemic clamp), and a panel of different markers of blood coagulation and fibrinolysis in the fasting state were measured. Strong resemblance was observed in most coagulation factors within all twin pairs, with the intraclass correlations ranging from 0.73 to 0.97, P < 0.03. However, the activities of fibrinogen and FIX, FXI, and FXII, and plasminogen activator inhibitor-1 (PAI-1) activities were increased in the obese co-twins (P < 0.05) and strongly correlated with the measures of adiposity, inflammation, and insulin resistance (r = 0.32-0.73, P < 0.05) among the twin individuals. Intrapair differences in fibrinogen and PAI-1 correlated with those in BMI, adiposity, and fasting insulin levels (r = 0.40-0.58, P < 0.05) indicating the independent effect of obesity. Derangements of blood coagulation and fibrinolysis are present already in early adulthood in obese subjects. Acquired obesity, independent of genetic factors, increases the activities of fibrinogen and activities of FIX, FXI, FXII, and PAI-1. This study confirms the mechanisms of simultaneous activities of intrinsic coagulation factors and impaired fibrinolysis predisposing obese subjects to thrombosis.     

Genetic influences on growth traits of BMI: a longitudinal study of adult twins

Objective: To investigate the interplay between genetic factors influencing baseline level and changes in BMI in adulthood. Methods and Procedures: A longitudinal twin study of the cohort of Finnish twins (N = 10,556 twin individuals) aged 20–46 years at baseline was conducted and followed up 15 years. Data on weight and height were obtained from mailed surveys in 1975, 1981, and 1990. Results: Latent growth models revealed a substantial genetic influence on BMI level at baseline in males and females (heritability (h²) 80% (95% confidence interval 0.79–0.80) for males and h² = 82% (0.81, 0.84) for females) and a moderate‐to‐high influence on rate of change in BMI (h² = 58% (0.50, 0.69) for males and h² = 64% (0.58, 0.69) for females). Only very weak evidence for genetic pleiotropy was observed; the genetic correlation between baseline and rate of change in BMI was very modest (−0.070 (–0.13, −0.068) for males and 0.04 (0.00, 0.08) for females. Discussion: Our population‐based results provide a basis for identifying genetic variants for change in BMI, in particular weight gain. Furthermore, they demonstrate for the first time that such genetic variants for change in BMI are likely to be different from those affecting level of BMI.     

Genetic and Environmental Influences on the Tracking of Body Size from Birth to Early Adulthood

Objective: This study identified genetic and environmental influences on the tracking of body size from birth to 16 to 18.5 years of age. Research Methods and Procedures: Longitudinal information was collected from a nationally representative sample of Finnish twin adolescents (birth cohorts 1975 to 1979) and their parents through questionnaires mailed when the twins were ages 16 and 18.5 years old. The sample included 702 monozygotic, 724 same‐sex dizygotic, and 762 opposite‐sex dizygotic sets of twins. The measures used were length, weight, ponderal index (kilograms per cubic meters), and gestational age at birth, and height, weight, and body mass index (kilograms per square meters) at 16 to 18.5 years of age. The changes in genetic and environmental influences on body size from birth to early adulthood were analyzed by quantitative genetic modeling. Results: The twins who had a higher weight or ponderal index at birth were taller and heavier in early adulthood, whereas those who were longer at birth were taller, but not heavier, later in life. Adult height was affected more by the birth size than body mass index. In the genetic modeling analyses, the genetic factors accounting for the variation of body size became more apparent with age, and both genetic and environmental influences on stature had a sizable carry‐over effect from birth to late adolescence, whereas for relative weight, the influences were more age‐specific. Discussion: The genetic and environmental architecture of body size changes from birth to adulthood. Even in monozygotic twins who share their genetic background, the initially larger twin tended to remain larger, demonstrating the long‐lasting effects of fetal environment on final body size.     

The nature and reactivity of the ‘essential’ thiol in rabbit muscle creatine kinase III (EC 2.7.3.2)

Rabbit muscle creatine kinase III (EC 2.7.3.2) can be reacted with 2-chloromercuri-4-nitrophenol and this results in the incorporation of two moles of mercurial per mole of enzyme subunit in a biphasic reaction. The second-order rate constant for the slow reaction is 475 ± 42 M^?1 s^?1. S-Carboxamidomethyl-creatine kinase reacts with a single mole of mercurial per mole of subunit. The rate constant, 466 ± 57 M^?1 s^?1, is almost identical to that for the slow reaction of the native enzyme. The reaction between 3-carboxy-4-nitrophenylthio-creatine kinase and 2-chloromercuri-4-nitrophenol has a second-order rate constant of 449 ± 56 M^?1 s^?1. The results may be explained if the mercurial reacts very rapidly with that cysteine residue which reacts independently with iodoacetamide or 5,5′-dithiobis(2-nitrobenzoic acid). However, 2-chloromercuri-4-nitrophenol also reacts more slowly with a second cysteine residue. Definition of the essentiality of thiol groups in enzymes by reaction with labile ligands, here represented by organomercurials, clearly must be approached with caution.     

Competitive success of southern populations of Betula pendula and Sorbus aucuparia under simulated southern climate experiment in the subarctic

Global warming has been commonly accepted to facilitate species’ range shifts across latitudes. Cross‐latitudinal transplantations support this; many tree species can well adapt to new geographical areas. However, these studies fail to capture species’ adaptations to new light environment because the experiments were not designed to explicitly separate species’ responses to light and temperature. Here we tested reaction norms of tree seedlings in reciprocal transplantations 1,000 km apart from each other at two latitudes (60°N and 69°N). In contrast to past studies, we exposed our experimental plants to same temperature in both sites (temperature of 60°N growing site is recorded to adjust temperature of 69°N site in real time via Internet connection) while light environment (photoperiod, light quality) remained ambient. Shoot elongation and autumn coloration were studied in seedlings of two deciduous trees (Betula pendula and Sorbus aucuparia), which were expected to respond differently to day length. Sorbus as a member of Rosaceae family was assumed to be indifferent to photoperiod, while Betula responds strongly to day length. We hypothesized that (1) southern and northern populations of both species perform differently; (2) southern populations perform better in both sites; (3) autumn phenology of southern populations may delay in the northern site; (4) and Sorbus aucuparia is less dependent on light environment. According to the hypotheses, shoot elongation of northern population was inherently low in both species. An evolutionary consequence of this may be a competitive success of southern populations under warming climate. Southern population of B. pendula was delayed in autumn coloration, but not in growth cessation. Sorbus aucuparia was less responsive to light environment. The results suggest that light provides selection pressure in range shifts, but the response is species dependent.     

Cardiovascular disease,obesity, and type 2 diabetes in children born after assisted reproductive technology: A population-based cohort study

BackgroundSome earlier studies have found indications of significant changes in cardiometabolic risk factors in children born after assisted reproductive technology (ART). Most of these studies are based on small cohorts with high risk of selection bias. In this study, we compared the risk of cardiovascular disease, obesity, and type 2 diabetes between singleton children born after ART and singleton children born after spontaneous conception (SC).Methods and findingsThis was a large population-based cohort study of individuals born in Norway, Sweden, Finland, and Denmark between 1984 and 2015. Data were obtained from national ART and medical birth registers and cross-linked with data from national patient registers and other population-based registers in the respective countries. In total, 122,429 children born after ART and 7,574,685 children born after SC were included. Mean (SD) maternal age was 33.9 (4.3) years for ART and 29.7 (5.2) for SC, 67.7% versus 41.8% were primiparous, and 45.2% versus 32.1% had more than 12 years of education. Preterm birth (<37 weeks 0 days) occurred in 7.9% of children born after ART and 4.8% in children born after SC, and 5.7% versus 3.3% had a low birth weight (<2,500 g). Mean (SD) follow-up time was 8.6 (6.2) years for children born after ART and 14.0 (8.6) years for children born after SC. In total, 135 (0.11%), 645 (0.65%), and 18 (0.01%) children born after ART were diagnosed with cardiovascular disease (ischemic heart disease, cardiomyopathy, heart failure, or cerebrovascular disease), obesity or type 2 diabetes, respectively. The corresponding values were 10,702 (0.14%), 30,308 (0.74%), and 2,919 (0.04%) for children born after SC. In the unadjusted analysis, children born after ART had a significantly higher risk of any cardiovascular disease (hazard ratio [HR] 1.24; 95% CI 1.04–1.48; p = 0.02), obesity (HR 1.13; 95% CI 1.05–1.23; p = 0.002), and type 2 diabetes (HR 1.71; 95% CI 1.08–2.73; p = 0.02). After adjustment, there was no significant difference between children born after ART and children born after SC for any cardiovascular disease (adjusted HR [aHR]1.02; 95% CI 0.86–1.22; p = 0.80) or type 2 diabetes (aHR 1.31; 95% CI 0.82–2.09; p = 0.25). For any cardiovascular disease, the 95% CI was reasonably narrow, excluding effects of a substantial magnitude, while the 95% CI for type 2 diabetes was wide, not excluding clinically meaningful effects. For obesity, there was a small but significant increased risk among children born after ART (aHR 1.14; 95% CI 1.06–1.23; p = 0.001). Important limitations of the study were the relatively short follow-up time, the limited number of events for some outcomes, and that the outcome obesity is often not considered as a disease and therefore not caught by registers, likely leading to an underestimation of obesity in both children born after ART and children born after SC.ConclusionsIn this study, we observed no difference in the risk of cardiovascular disease or type 2 diabetes between children born after ART and children born after SC. For obesity, there was a small but significant increased risk for children born after ART.Trial registration numberISRCTN11780826.

Emma Norrman and co-workers study the health of children born with and without assisted reproductive technology.     

Effect of orlistat on eating behavior among participants in a 3-year weight maintenance trial

Objective: To examine the effect of orlistat on dietary restraint, disinhibition, hunger, and binge eating and to understand the relation between changes in eating behavior and weight maintenance. Methods and Procedures: Subjects were 306 women and men (age: 19–45 years; BMI: 37.5 ± 4.1 kg/m²) included in the Scandinavian Multicenter study of Obese subjects with the Metabolic Syndrome, a 3‐year clinical trial of orlistat or placebo following an 8‐week very low energy diet (VLED). Outcomes were changes in weight and in the Three Factor Eating Questionnaire (TFEQ) and Binge Eating Scale (BES) between screening and 17 and 33 months after randomization. As reported previously, weight gain following VLED was lower in subjects treated with orlistat than with placebo. Results: Compared to screening results, dietary restraint was increased and disinhibition, hunger, and binge eating were decreased in both groups. These changes were similar in both groups with the exception of the hunger score at month 33 that was reduced more in the placebo than in the orlistat group (difference between groups ?1.1 (95% CI (?2.0, ?0.2)) P = 0.014). In multivariate analyses, scores for restraint, disinhibition and binge eating were associated with weight loss after adjustment for BMI, gender, age, and treatment (all P ≤ 0.002, model R ² = 0.12–0.17). Discussion: Orlistat did not affect eating behavior differently in any substantial way than the placebo did in this long‐term weight maintenance trial. The results indicate that increased restraint and decreased disinhibition and binge eating are important for sustained weight maintenance in obese subjects with the metabolic syndrome.     

Brain serotonin transporter binding of [123I]ADAM: within-subject variation between summer and winter data

The neurotransmitter serotonin (5-HT) controls several physiological functions, and a disturbance of the 5-HT system is implicated in many psychiatric conditions. Seasonal variation has been suggested in the 5-HT system. We investigated within-subject seasonal variation in brain serotonin transporter (SERT) binding with the SERT-ligand [(123)I]ADAM and single photon emission computed tomography (SPECT) in 12 healthy individuals. No systematic variation was found in the midbrain or thalamus areas between scans done in summer and winter. Our results suggest that factors other than season are more important in causing within-subject variation of brain SERT binding between summer and winter.     

Extracellular vesicles from bone mesenchymal stem cells transport microRNA-206 into osteosarcoma cells and target NRSN2 to block the ERK1/2-Bcl-xL signaling pathway

Osteosarcoma (OS) is a kind of malignant tumor originating from mesenchymal tissues. Bone mesenchymal stem cells-derived extracellular vesicles (BMSCs-EVs) can play important roles in OS. This study investigated the mechanism of BMSCs-EVs on OS. BMSC surface antigens and adipogenic and osteogenic differentiation were detected by flow cytometry, and oil red O and alizarin red staining. EVs were isolated from BMSCs by differential centrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot (WB). miR-206 and neurensin-2 (NRSN2) levels in human osteoblast hFOB 1.19 or OS cells (143B, MG-63, Saos2, HOS) were detected by RT-qPCR. Human OS cells with lower miR-206 levels were selected and treated with BMSCs-EVs or pSUPER-NRSN2. The uptake of EVs by 143B cells, cell proliferation, apoptosis, invasion, and migration were detected by immunofluorescence, 5-ethynyl-2’-deoxyuridine (EdU) and colony formation assays, flow cytometry, scratch test, and transwell assays. The binding sites between miR-206 and NRSN2 were predicted by Starbase database and verified by dual-luciferase assay. The OS xenograft model was established and treated with BMSCs-EVs. Tumor growth rate and volume, cell proliferation, and p-ERK1/2, ERK1/2, and Bcl-xL levels were detected by vernier caliper, immunohistochemistry, and WB. BMSCs-EVs were successfully extracted. miR-206 was diminished and NRSN2 was promoted in OS cells. BMSCs-EVs inhibited proliferation, migration, and invasion, and promoted apoptosis of OS cells. BMSCs-EVs carried miR-206 into OS cells. Inhibition of miR-206 in EVs partially reversed the inhibitory effect of EVs on malignant behaviors of OS cells. miR-206 targeted NRSN2. Overexpression of NRSN2 reversed the inhibitory effect of EVs on OS cells. NRSN2 activated the ERK1/2-Bcl-xL pathway. BMSC-EVs inhibited OS growth in vivo. In summary, BMSC-EVs targeted NRSN2 and inhibited the ERK1/2-Bcl-xL pathway by carrying miR-206 into OS cells, thus inhibiting OS progression.Key words: Osteosarcoma, bone mesenchymal stem cells, extracellular vesicle, miR-206, NRSN2, ERK1/2- Bcl-xL     

Fatty acid esterification of lipoprotein-associated estrone in human plasma and follicular fluid

Estrogen fatty acid esters constitute a unique family of extremely hydrophobic hormonal derivatives which are exclusively transported in lipoprotein particles in plasma. In estradiol, the fatty acyl residues are conjugated at the 17beta-hydroxyl of the steroid D-ring, leaving the phenolic 3-hydroxyl group unsubstituted and, therefore, preserving antioxidative efficacy. The 17beta-fatty acid derivative of estradiol is proposedly an even more efficient antioxidant protecting LDL and HDL than the parent steroid. Previous studies have established that the enzyme lecithin:cholesterol acyltransferase which catalyzes the fatty acid esterification of 3beta-hydroxyl group of cholesterol, also catalyzes the formation of estrogen 17beta-esters. Estrone, the principal estrogen in the postmenopausal female, has a keto group at carbon-17 and has been thought unable to form fatty acid esters. However, we detected hydrophobic derivatives of estrone following incubations with human plasma and ovarian follicular fluid. These derivatives accumulated in HDL and LDL during incubation showing chemical characteristics similar to estrone-3-fatty acid esters. Liquid chromatographic-mass spectrometric analyses established the presence of unhydrolyzed estrone esters consisting of different fatty acid species, the major one being estrone-3-linoleate, in human HDL particles following incubation of estrone with plasma. These extremely hydrophobic estrone conjugates could, in theory, represent a storage form of this estrogen.