Associations between anxiety, body mass index, and sex hormones in women

Background: Several studies have shown a positive association between anxiety and obesity, particularly in women. We aimed to study whether sex hormone alterations related to obesity might play a role in this association. Patients and methods: Data for this study were obtained from a population-based cohort study (the LIFE-Adult-Study). A total of 3,124 adult women (970 premenopausal and 2,154 postmenopausal) were included into the analyses. The anxiety symptomatology was assessed using the GAD-7 questionnaire (cut-off ≥ 10 points). Sex hormones were measured from fasting serum samples. Results: We did not find significant differences in anxiety prevalence in premenopausal obese women compared with normal-weight controls (4.8% vs. 5.5%). Both obesity and anxiety symptomatology were separately associated with the same sex hormone alteration in premenopausal women: higher total testosterone level (0.97 ± 0.50 in obese vs. 0.86 ± 0.49 nmol/L in normal-weight women, p = 0.026 and 1.04 ± 0.59 in women with vs. 0.88 ± 0.49 nmol/L in women without anxiety symptomatology, p = 0.023). However, women with anxiety symptomatology had non-significantly higher estradiol levels than women without anxiety symptomatology (548.0 ± 507.6 vs. 426.2 ± 474.0 pmol/L), whereas obesity was associated with lower estradiol levels compared with those in normal-weight group (332.7 ± 386.5 vs. 470.8 ± 616.0 pmol/L). Women with anxiety symptomatology had also significantly higher testosterone and estradiol composition (p = 0.006). No associations of sex hormone levels and BMI with anxiety symptomatology in postmenopausal women were found. Conclusions: Although both obesity and anxiety symptomatology were separately associated with higher testosterone level, there was an opposite impact of anxiety and obesity on estradiol levels in premenopausal women. We did not find an evidence that the sex hormone alterations related to obesity are playing a significant role in anxiety symptomatology in premenopausal women. This could be the explanation why we did not find an association between obesity and anxiety. In postmenopausal women, other mechanisms seem to work than in the premenopausal group

Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial

18openInternationalBothObjective To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss. Design For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided). The green-MED group further consumed green tea (3–4 cups/day) and Mankai (a Wolffia globosa aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided). IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS). Results Participants (age=51 years; 88% men; body mass index=31.3 kg/m2; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS. Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups. Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (−38.9% proportionally), as compared with MED (−19.6% proportionally; p=0.035 weight loss adjusted) and HDG (−12.2% proportionally; p<0.001). After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of Naringenin and 2-5-dihydroxybenzoic-acid in green-MED. Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p<0.05 for all). Conclusion The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half.openYaskolka Meir, Anat; Rinott, Ehud; Tsaban, Gal; Zelicha, Hila; Kaplan, Alon; Rosen, Philip; Shelef, Ilan; Youngster, Ilan; Shalev, Aryeh; Blüher, Matthias; Ceglarek, Uta; Stumvoll, Michael; Tuohy, Kieran; Diotallevi, Camilla; Vrhovsek, Urska; Hu, Frank; Stampfer, Meir; Shai, IrisYaskolka Meir, A.; Rinott, E.; Tsaban, G.; Zelicha, H.; Kaplan, A.; Rosen, P.; Shelef, I.; Youngster, I.; Shalev, A.; Blüher, M.; Ceglarek, U.; Stumvoll, M.; Tuohy, K.; Diotallevi, C.; Vrhovsek, U.; Hu, F.; Stampfer, M.; Shai, I

The metabolomic-gut-clinical axis of Mankai plant-derived dietary polyphenols

24openInternationalBothBackground: Polyphenols are secondary metabolites produced by plants to defend themselves from environmental stressors. We explored the effect of Wolffia globosa ‘Mankai’, a novel cultivated strain of a polyphenol-rich aquatic plant, on the metabolomic-gut clinical axis in vitro, in-vivo and in a clinical trial. Methods: We used mass-spectrometry-based metabolomics methods from three laboratories to detect Mankai phenolic metabolites and examined predicted functional pathways in a Mankai artificial-gut bioreactor. Plasma and urine polyphenols were assessed among the 294 DIRECT-PLUS 18-month trial participants, comparing the effect of a polyphenol-rich green-Mediterranean diet (+1240 mg/polyphenols/day, provided by Mankai, green tea and walnuts) to a walnuts-enriched (+440 mg/polyphenols/day) Mediterranean diet and a healthy controlled diet. Results: Approximately 200 different phenolic compounds were specifically detected in the Mankai plant. The Mankai-supplemented bioreactor artificial gut displayed a significantly higher relative-abundance of 16S-rRNA bacterial gene sequences encoding for enzymes involved in phenolic compound degradation. In humans, several Mankai-related plasma and urine polyphenols were differentially elevated in the green Mediterranean group compared with the other groups (p < 0.05) after six and 18 months of intervention (e.g., urine hydroxy-phenyl-acetic-acid and urolithin-A; plasma Naringenin and 2,5-diOH-benzoic-acid). Specific polyphenols, such as urolithin-A and 4-ethylphenol, were directly involved with clinical weight-related changes. Conclusions: The Mankai new plant is rich in various unique potent polyphenols, potentially affecting the metabolomic-gut-clinical axisopenYaskolka Meir, A.; Tuohy, K.; von Bergen, M.; Krajmalnik-Brown, R.; Heinig, U.; Zelicha, H.; Tsaban, G.; Rinott. E.; Kaplan, A.; Aharoni, A.; Zeibich, L.; Chang, D.; Dirks, B.; Diotallevi, C.; Arapitsas, P.; Vrhovsek, U.; Ceglarek, U.; Haange, S.; Rolle-Kampczyk, U.; Engelmann, B.; Lapidot, M.; Colt, M.; Sun, Q.; Shai, I.Yaskolka Meir, A.; Tuohy, K.; von Bergen, M.; Krajmalnik-Brown, R.; Heinig, U.; Zelicha, H.; Tsaban, G.; Rinot, T.E.; Kaplan, A.; Aharoni, A.; Zeibich, L.; Chang, D.; Dirks, B.; Diotallevi, C.; Arapitsas, P.; Vrhovsek, U.; Ceglarek, U.; Haange, S.; Rolle-Kampczyk, U.; Engelmann, B.; Lapidot, M.; Colt, M.; Sun, Q.; Shai, I

Testosterone imbalance may link depression and increased body weight in premenopausal women

Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance

Serum galectin-9 and decorin in relation to brain aging and the green-mediterranean diet: A secondary analysis of the DIRECT PLUS randomized trial

Background and AimsWe explored whether changes in serum proteomic profiles differed between participants with distinct brain aging trajectories, and whether these changes were influenced by dietary intervention.MethodsIn this secondary analysis of the 18-month DIRECT PLUS trial, 294 participants were randomized to one of three arms: 1) Healthy dietary guidelines (HDG); 2) Mediterranean (MED) diet (+440mg/day polyphenols from walnuts); or 3) low red/processed meat green-MED diet (+1240mg/day polyphenols from walnuts, Mankai plant, and green-tea). We measured 87 serum proteins (Olink-CVDII). We used Magnetic-Resonance-Imaging (MRI)-assessed 3D-T1-weighted brain scans for brain age calculation (by convolutional neural network) to identify protein markers reflecting the brain age gap (BAG; deviation of MRI-assessed brain age from chronological age).ResultsAt baseline, lower weight, waist circumference, diastolic blood pressure, and HbA1c parameters were associated with a younger brain age than expected. Specifically, higher levels of two proteins, Galectin-9 (Gal-9) and Decorin (DCN), were associated with accelerated brain aging (larger BAG). A proteomics principal-component-analysis (PCA) revealed a difference in PC1 between the two time-points for participants with accelerated brain aging. Between baseline and 18 months, Gal-9 significantly decreased among individuals who completed the intervention with attenuated brain aging, while DCN significantly increased among those who completed the trial with accelerated brain aging. A significant interaction was observed between the green-MED diet and proteomics PCA, resulting in a beneficial change compared to the HDG. Participants in the green-MED diet significantly decreased Gal-9 compared to the HDG diet and from baseline.ConclusionsHigher serum levels of Gal-9 and DCN may indicate an acceleration of brain aging and could be reduced by a green-MED/high-polyphenol (green tea and Mankai) and low-red/processed meat diet

The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: The Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS)

Background: The effect of diet on age-related brain atrophy is largely unproven. Objectives: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy. Methods: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols). Results: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P Conclusions: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186

Serum Peptidome Profiling Revealed Platelet Factor 4 as a Potential Discriminating Peptide Associated With Pancreatic Cancer

Purpose: Mass spectrometry-based serum peptidome profiling is a promising tool to identify novel disease-associated biomarkers, but is limited by preanalytical factors and the intricacies of complex data processing. Therefore, we investigated whether standardized sample protocols and new bioinformatic tools combined with external data validation improve the validity of peptidome profiling for the discovery of pancreatic cancer associated serum markers. Experimental Design: For discovery study, two sets of sera from patients with pancreatic cancer (n=40) and healthy controls (n=40) were obtained from two different clinical centers. For external data validation, we collected an independent set of samples from patients (n=20) and healthy controls (n=20). Magnetic beads (MB) with different surface functionalities were used for peptidome fractionation followed by MALDI-TOF MS. Data evaluation was carried out comparing two different bioinformatic strategies. Following proteome database search the matching candidate peptide was verified by MALDI-TOF MS after specific antibody-based immunoaffinity chromatography and independently confirmed by an ELISA assay. Results: Two significant peaks (m/z 3884; 5959) achieved a sensitivity of 86.3% and specificity of 97.6% for the discrimination of patients and healthy controls in the external validation set. Adding peak m/z 3884 to conventional clinical tumor markers (CA 19-9 and CEA) improved sensitivity and specificity as shown by ROC analysis (AUROCcombined=1.00). Mass spectrometry based m/z 3884 peak identification and following immunological quantitation revealed platelet factor 4 as the corresponding peptide. Conclusions: MALDI-TOF MS based serum peptidome profiling allowed the discovery and validation of platelet factor 4 as a new discriminating marker in pancreatic cancer

The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial

Background Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). Methods In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. Results Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: − 2.7%, green-MED: − 3.9%) and waist circumference (MED: − 4.7%, green-MED: − 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: − 4.2%, MED: − 6.0%, green-MED: − 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models). Conclusions A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression

Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genomewide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD