Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood.

BACKGROUND: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. METHODS: In this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). FINDINGS: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. INTERPRETATION: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. FUNDING: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyv€askyl€a, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001), the Food and Health Bureau of Hong Kong SAR's Health and Medical Research Fund (HMRF grants 15162161 and 07181036) and the CUHK Direct Grants for Research (2016¢033 and 2018¢034), and a postdoctoral fellowship from K. Carole Ellison (to T.W.). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. This work was supported by European Union's Horizon 2020 research and innovation programme LongITools 874739.

Interactive effects of aging and aerobic capacity on energy metabolism-related metabolites of serum, skeletal muscle, and white adipose tissue.

Aerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial ß-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

Effects of exercise and dietary interventions on serum metabolites in men with insomnia symptoms: A 6-month randomized controlled trial.

Accumulating evidence show that exercise and diet interventions are associated with improved sleep quality. Studies investigating the effects of exercise and dieting on circulating metabolomics in people with sleep disorders, particularly insomnia, are scarce. This 6-month randomized study aimed to assess the effects of exercise and dietary interventions on serum metabolites in men with insomnia symptoms. Seventy-two Finnish men (age: 51.6 ±â€¯10.1 years) with chronic insomnia symptoms who were assigned to different intervention groups completed this study (exercise, n = 24; diet, n = 27; and control, n = 21). The Shapiro-Wilk W-test, Levene test, Spearman correlation analysis, and analysis of variance were used for data analysis. We found that exercise and diet intervention were associated with improved sleep quality and with a number of metabolites across different biochemical pathways. Although we could not show causality, our findings provide new insight into the biological mechanisms underlying the health effects of physical activity, diet, and sleep quality. Further investigation is needed to better understand the link among lifestyle, sleep quality, and metabolic health.

Branched-Chain and Aromatic Amino Acids Are Associated With Insulin Resistance During Pubertal Development in Girls.

PURPOSE: Cross-sectional studies in children show branched-chain and aromatic amino acids are associated with insulin resistance, but whether these associations persist from childhood to adulthood is not known. This study aimed to assess whether circulating amino acids associate with insulin resistance during pubertal development. METHODS: This was a 7.5-year longitudinal study from childhood to early adulthood. A total of 396 nondiabetic Finnish girls aged 11.2 ± .8 years at baseline participated in the study which was conducted at the Health Science Laboratory, University of Jyväskylä. Serum concentrations of glucose and insulin were determined by enzymatic photometric methods and amino acids by nuclear magnetic resonance spectroscopy. Insulin resistance was determined by the homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: All amino acids were positively associated with HOMA-IR both before and after menarche (p < .05 for all), except for histidine. Branched-chain amino acids and aromatic amino acids showed the strongest associations, the magnitude of correlation coefficients being similar before and after menarche (R2 = .064-.171). After adjusting for body mass index z-score and height, the associations between branched-chain amino acids and aromatic amino acids and HOMA-IR remained significant both before and after menarche. CONCLUSIONS: Branched-chain amino acids and aromatic amino acids associate with insulin resistance during pubertal development, independent of adiposity. Further studies are needed to determine whether changes in amino acid metabolism link pubertal hyperinsulinemia to accelerated physiological growth and/or heightened cardiometabolic risk later in life.

Differences in acoustic impedance of fresh and embedded human trabecular bone samples-Scanning acoustic microscopy and numerical evaluation.

Trabecular bone samples are traditionally embedded and polished for scanning acoustic microscopy (SAM). The effect of sample processing, including dehydration, on the acoustic impedance of bone is unknown. In this study, acoustic impedance of human trabecular bone samples (n = 8) was experimentally assessed before (fresh) and after embedding using SAM and two-dimensional (2-D) finite-difference time domain simulations. Fresh samples were polished with sandpapers of different grit (P1000, P2500, and P4000). Experimental results indicated that acoustic impedance of samples increased significantly after embedding [mean values 3.7 MRayl (fresh), 6.1 MRayl (embedded), p < 0.001]. After polishing with different papers, no significant changes in acoustic impedance were found, even though higher mean values were detected after polishing with finer (P2500 and P4000) papers. A linear correlation (r = 0.854, p < 0.05) was found between the acoustic impedance values of embedded and fresh bone samples polished using P2500 SiC paper. In numerical simulations dehydration increased the acoustic impedance of trabecular bone (38%), whereas changes in surface roughness of bone had a minor effect on the acoustic impedance (-1.56%/0.1 µm). Thereby, the numerical simulations corroborated the experimental findings. In conclusion, acoustic impedance measurement of fresh trabecular bone is possible and may provide realistic material values similar to those of living bone.

Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD. METHODS: Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H MRS). Serum samples were analyzed using a nuclear magnetic resonance (NMR) metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot. RESULTS: Increased branched-chain amino acid (BCAA), aromatic amino acid (AAA) and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all). Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all), whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all). CONCLUSIONS: Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis.

Gut-adipose tissue axis in hepatic fat accumulation in humans.

BACKGROUND & AIMS: Recent evidence suggests that in animals gut microbiota composition (GMC) affects the onset and progression of hepatic fat accumulation. The aim of this study was to investigate in humans whether subjects with high hepatic fat content (HHFC) differ in their GMC from those with low hepatic fat content (LHFC), and whether these differences are associated with body composition, biomarkers and abdominal adipose tissue inflammation. METHODS: Hepatic fat content (HFC) was measured using proton magnetic resonance spectroscopy ((1)H MRS). Fecal GMC was profiled by 16S rRNA fluorescence in situ hybridization and flow cytometry. Adipose tissue gene expression was analyzed using Affymetrix microarrays and quantitative PCR. RESULTS: The HHFC group had unfavorable GMC described by lower amount of Faecalibacterium prausnitzii (FPrau) (p<0.05) and relatively higher Enterobacteria than the LHFC group. Metabolically dysbiotic GMC associated with HOMA-IR and triglycerides (p<0.05 for both). Several inflammation-related adipose tissue genes were differentially expressed and correlated with HFC (p<0.05). In addition, the expression of certain genes correlated with GMC dysbiosis, i.e., low FPrau-to-Bacteroides ratio. CONCLUSIONS: HHFC subjects differ unfavorably in their GMC from LHFC subjects. Adipose tissue inflammation may be an important link between GMC, metabolic disturbances, and hepatic fat accumulation.