Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure. RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: ß = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

Endometrial whole metabolome profile at the receptive phase: influence of Mediterranean Diet and infertility.

Introduction: Several metabolite classes have been identified in human endometrium, including lipids, nucleotides, amino acids, organic acids, and sugars. The first studies suggest the importance of metabolites in endometrial functions, as imbalance in uterine metabolites has been associated with low implantation rate and endometriosis. Nevertheless, most of studies have put emphasis on specific metabolite classes, and we lack the knowledge of the whole metabolome composition in human uterus. Further, a healthy dietary pattern has been shown to potentially protect against different endometrial dysfunctions and is a potential modulator of metabolomic composition and, consequently, the intrauterine microenvironment. The Mediterranean Diet (MD), characterized by a high intake of fruits, vegetables, cereals, nuts, legumes, fish, and olive oil, and a low consumption of meat, dairy products, and processed foods, has been associated with a wide range of benefits for health. Indeed, the MD pattern has displayed a beneficial role in endometriosis management and fertility; however, the relationship between the MD and the endometrial metabolome is still unknown. In our study, we set out to analyze receptive-phase endometrial metabolome profiles among women with infertility and their associations with MD. Methods: The study included women with male factor infertility (n=8), unexplained infertility (n=10), recurrent implantation failure (n=14), and endometriosis (n=13). The endometrial metabolome was analyzed with ultrahigh-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS). The MD adherence of the participants was assessed using the 14-point MEDAS questionnaire of adherence to the MD. Results: We provide the whole metabolome profile of the endometrium, where 925 different metabolites were identified. Among these metabolites, lipids comprised the largest part, where polyunsaturated fatty acids (PUFAs) prevailed. Women with endometriosis and recurrent implantation failure were found to have lower levels of PUFAs compared to women with male factor and unexplained infertility (i.e., no clear endometrial alterations), identifying a metabolome profile associated with infertility diagnoses where altered endometrial functions are suspected. Moreover, MD adherence seemed to be associated with the endometrial metabolomic profile in a manner dependent on the health status of the uterus. Conclusion: The study findings provide insight into the molecular background of female infertility and lead to identification of potential molecular biomarkers and possibilities for modulating the endometrial microenvironment and, thereby, endometrial functions involved in embryo implantation and infertility.

Exercise-induced changes on exerkines that might influence brown adipose tissue metabolism in young sedentary adults.

ABSTRACTIn rodents, exercise alters the plasma concentration of exerkines that regulate white adipose tissue (WAT) browning or brown adipose tissue (BAT) metabolism. This study aims to analyse the acute and chronic effect of exercise on the circulating concentrations of 16 of these exerkines in humans. Ten young sedentary adults (6 female) performed a maximum walking effort test and a resistance exercise session. The plasma concentration of 16 exerkines was assessed before, and 3, 30, 60, and 120 min after exercise. Those exerkines modified by exercise were additionally measured in another 28 subjects (22 women). We also measured the plasma concentrations of the exerkines before and after a 24-week exercise programme (endurance + resistance; 3-groups: control, moderate-intensity and vigorous-intensity) in 110 subjects (75 women). Endurance exercise acutely increased the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, and follistatin-like protein 1 (3 min after exercise), and musclin and fibroblast growth factor 21 (30 and 60 min after exercise), decreasing the plasma concentration of leptin (30 min after exercise). Adiponectin, atrial natriuretic peptide (ANP), ß-aminoisobutyric acid, meteorin-like, follistatin, pro-ANP, irisin and myostatin were not modified or not detectable. The resistance exercise session increased the plasma concentration of lactate 3 min after exercise. Chronic exercise did not alter the plasma concentration of these exerkines. In sedentary young adults, acute endurance exercise releases to the bloodstream exerkines that regulate BAT metabolism and WAT browning. In contrast, neither a low-volume resistance exercise session nor a 24-week training programme modified plasma levels of these molecules.HighlightsAcute endurance exercise increases the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, follistatin-like protein 1, musclin, and fibroblast growth factor 21, and decrease the plasma concentration of leptin.The exercise-induced change in lactate plasma concentration is positively associated with brown adipose tissue volume, glucose uptake and radiodensity.Neither acute resistance exercise nor chronic exercise significantly alter the plasma concentration of these exerkines.Trial registration: ClinicalTrials.gov identifier: NCT02365129.

Longitudinal associations between cardiovascular biomarkers and metabolic syndrome during puberty: the PUBMEP study.

Puberty has been described as a life stage of considerable metabolic risk specially for those with obesity. The low-grade systemic inflammatory status associated with obesity could be one of the connections with metabolic syndrome (MetS). Thus, we aimed to assess the relationship between inflammatory and cardiovascular biomarkers and the development of MetS during puberty. Seventy-five children from the PUBMEP study (33 females), aged 4-18 years, were included. Cardiovascular and inflammatory biomarkers were measured in the prepubertal and pubertal stage, including high-sensitivity C-reactive protein (CRP), leptin, tumor necrosis factor-alpha (TNFα), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP-1), total plasminogen activator inhibitor-1 (tPAI), resistin, adiponectin, myeloperoxidase (MPO), and soluble intercellular adhesion molecule-1 (sICAM-1). MetS was diagnosed at each measurement point. Mixed-effects and logistic regressions were performed. Those children with MetS in puberty presented higher prepubertal values of several cardiometabolic biomarkers in comparison to those without MetS (z-score body mass index (zBMI), waist circumference, insulin, HOMA-IR, leptin, and tPAI (p < 0.05)). For prepubertal children with obesity, the odds of developing MetS in puberty were significantly higher in those having high zBMI (OR = 4.27; CI: 1.39-22.59) or high concentrations of tPAI (OR = 1.19; CI: 1.06-1.43). CONCLUSION: Those with obesity with higher prepubertal tPAI plasma levels had 19% higher odds of having MetS at puberty highlighting the existence of association between MetS, obesity, and inflammation already in puberty. Thus, assessing cardiometabolic and inflammatory status in children with obesity already at prepuberty is key to avoiding future comorbidities. WHAT IS KNOWN: • Inflammation, metabolic syndrome, and obesity may have their onset in childhood. • Puberty is a life stage characterized for an increased cardiovascular risk. WHAT IS NEW: • Prepuberty state could be an early indicator of future cardiometabolic risk. • Children with obesity and high total plasminogen have higher odds of future metabolic syndrome.

Fitness Levels and Gender Are Related With the Response of Plasma Adipokines and Inflammatory Cytokines in Prepubertal Children.

Background and Aim: Changes in adipokines have been related with the development of metabolic syndrome, frequently associated with obesity, and other risk factors. Fitness seems to promote a healthy cardiovascular status and could be a protector factor, just from childhood. Therefore, the present study aimed to evaluate the relationship between fitness levels with plasma adipokines and inflammatory biomarkers in prepubertal children. Methods: One hundred and thirty-seven healthy normal-weight prepubertal children were recruited from local schools and divided after performing the fitness tests, into two groups according to fitness level-low cardiovascular fitness group (LF) and equal or higher cardiovascular fitness group (HF). Anthropometric variables, blood pressure (BP) and plasma insulin, and leptin, resistin, adiponectin, tumor necrosis factor-alpha, hepatic growth factor, interleukin (IL)-8, monocyte chemoattractant protein-1, nerve growth factor (NGF), and plasminogen activator inhibitor-1 (PAI-1) were measured fasting in both groups to be compared. Univariate analysis of variance, comparative analysis, binary logistic regression, stepwise linear regression, and principal component analysis were conducted to evaluate the association between fitness, BMI, gender, and the biochemical parameters. Results: Girls and boys with HF presented lower waist circumference Z-score, BMI Z-score, systolic BP (only boys) as well as lower levels of leptin and NGF compared with their respective LF group. Regarding the association between variables, fitness showed an inverse relationship with BMI Z-score, leptin, PAI-1, HOMA-IR, resistin, IL-8, and NGF. Conclusion: An adequate level of fitness seems to protect against risk factors related to low-grade inflammation and altered adipokines that are related to the onset of obesity just from the prepubertal stage.

Impact of Physical Activity Intensity Levels on the Cardiometabolic Risk Status of Children: The Genobox Study.

Childhood obesity has been related to metabolic syndrome and low-grade chronic inflammation. This study aimed to evaluate the impact of physical activity intensities and practice on inflammation, endothelial damage, and cardiometabolic risk factors in children. There were 513 participants, aged 6-14 years, recruited for the study. Physical activity was measured by accelerometry, and the children were classified into four groups according to quartiles of moderate to vigorous physical activity (MVPA) practice as very low active, low active, moderate active, and high active. Anthropometric measures, blood pressure, and plasma metabolic and proinflammatory parameters were analyzed. Very low active group presented a worse lipid profile and higher insulin, leptin, adiponectin, resistin, matrix metallopeptidase-9, and tissue plasminogen activator inhibitor-1, while lower levels of tumor necrosis factor-alpha, Type 1 macrophages, and interleukin 8 than high-active children. Regression analyses showed that a higher MVPA practice was associated with lower levels of triacylglycerols (ß: -0.118; p = .008), resistin (ß: -0.151; p = .005), tPAI (ß: -0.105; p = .046), and P-selectin (ß: -0.160; p = .006), independently of sex, age, and body mass index (BMI). In contrast, a higher BMI was associated with higher levels of insulin (ß: 0.370; p < .001), Homeostasis Model Assessment (ß: 0.352; p < .001), triacylglycerols (ß: 0.209; p < .001), leptin (ß: 0.654; p < .001), tumor necrosis factor-alpha (ß: 0.182; p < .001), Type 1macrophages (ß: 0.181; p < .001), and tissue plasminogen activator inhibitor (ß: 0.240; p < .001), independently of sex, age, and MVPA. A better anthropometric, metabolic, and inflammatory profile was detected in the most active children; however, these differences were partly due to BMI. These results suggest that a higher MVPA practice and a lower BMI in children may lead to a better cardiometabolic status.

Association of Diet, Physical Activity Guidelines and Cardiometabolic Risk Markers in Children.

The aim was to identify different dietary and physical activity (PA) patterns in 5- to 14-year-old children with a high prevalence of overweight and obesity using cluster analysis based on their adherence to the Spanish Society of Community Nutrition dietary guidelines and levels of PA, and to determine their associations with age, sex, body composition, and cardiometabolic risk markers. In 549 children, hierarchical cluster analysis was used to identify subgroups with similar adherence to dietary recommendations and level of PA. Three clusters were identified: Cluster 1, with the lowest level of vigorous PA and adherence to dietary recommendations; Cluster 2, with the lowest levels of moderate and vigorous PA and the highest adherence to dietary recommendations; and Cluster 3, with the highest level of PA, especially vigorous PA and a medium level adherence to dietary recommendations. Cluster 3 had lower total body fat and higher lean body mass percentages than Cluster 2. Cluster 2 had lower high-density lipoprotein cholesterol and higher low-density lipoprotein cholesterol levels than Cluster 1. The results from our study suggest that it is important to consider adherence to PA recommendations together with adherence to dietary guidelines to understand patterns of obesogenic habits in pediatric populations with high prevalence of overweight and obesity.

The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity.

BACKGROUND: S100A4 is a metastasis-associated protein also reported as a promising marker for dysfunctional white adipose tissue (WAT) and insulin resistance (IR) in adult and adolescent populations. OBJECTIVE: We aimed to evaluate the association between the protein S100A4 and obesity and IR in children and during pubertal development. DESIGN AND METHODS: The study design consisted of three cross-sectional populations of 249, 11 and 19 prepubertal children respectively (named study population 1, 2 and 3), and a longitudinal population of 53 girls undergoing sexual maturation (study population 4). All subjects were classified into experimental groups according to their sex, obesity and IR status. All study populations counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as S100A4 plasma levels measured. The study population 1 was intended as the discovery population in which to elucidate the relationship between Obesity-IR and S100A4 plasma levels in prepubertal children. The cross-sectional populations 2 and 3 further counted on WAT gene expression data for investigating the molecular basis of this association. Instead, the longitudinal study population 4 presented blood whole-genome DNA methylation data at each temporal record, allowing deepening into the Obesity-IR-S1004 relationship during puberty as well as deciphering plausible epigenetic mechanisms altering S100A4 plasma levels. RESULTS: S100A4 plasma levels were strongly associated with several metabolic and anthropometric outcomes, namely IR, in prepubertal non-diabetic obese children. We also found highly significant positive associations during the course of puberty between the increase in S100A4 levels and the increase in HOMA-IR (P = 0.0003, FDR = 0.005) and insulin levels (P = 0.0003, FDR = 0.005). Methylation in two-enhancer related CpG sites of the S100A4 region (cg07245635 and cg10447638) was associated with IR biomarkers at the prepubertal stage and with longitudinal changes in these measurements. We further reported an association between visceral WAT (vWAT) S100A4 expression and HOMA-IR, insulin levels and BMI Z-Score, but not with circulating S100A4. CONCLUSIONS: We report for the first time the association of S100A4 with IR and WAT dysfunction in prepubertal populations as well as how the change in plasma S100A4 levels accompanies longitudinal trajectories of IR in children during pubertal development. Moreover, we propose epigenetic changes in two methylation sites and an altered S100A4 vWAT expression as plausible molecular mechanisms underlying this disturbance in obesity.

Inflammatory markers and bone mass in children with overweight/obesity: the role of muscular fitness.

OBJECTIVES: To examine which inflammatory markers are associated with bone mass and whether this association varies according to muscular fitness in children with overweight/obesity. METHODS: Plasma interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), epidermal growth factor, vascular endothelial growth factor A (VEGF), and C-reactive protein were analyzed in 55 children aged 8-11 years. A muscular fitness score was computed. Bone mineral content (BMC) of the total body-less head (TBLH) and lumbar spine (LS) were assessed using dual-energy x-ray absorptiometry. RESULTS: IL-6 (ß = -0.136) and VEGF (ß = -0.099) were associated with TBLH BMC, while TNF-α (ß = -0.345) and IL-1ß (ß = 0.212) were associated with LS BMC (P < 0.05). The interaction effect of muscular fitness showed a trend in the association of VEGF with TBLH BMC (P = 0.122) and TNF-α with LS BMC (P = 0.057). Stratified analyses by muscular fitness levels showed an inverse association of VEGF with TBLH BMC (ß = -0.152) and TNF-α with LS BMC (ß = -0.491) in the low-fitness group, while no association was found in the high-fitness group. CONCLUSION: IL-6, VEGF, TNF-α, and IL-1ß are significantly associated with bone mass. Higher muscular fitness may attenuate the adverse effect of high VEGF and TNF-α on bone mass.

Sedentarism, Physical Activity, Steps, and Neurotrophic Factors in Obese Children.

PURPOSE: This study aimed to examine the associations of sedentary time, physical activity (PA) and step-related behaviors with neurotrophic growth factors. METHODS: A total of 97 children with overweight/obesity age 8 to 11 yr participated in this study. Sedentary time, PA, and steps were measured by GT3X+ accelerometers in hip and nondominant wrist. Estimates of light, moderate, vigorous, and moderate-to-vigorous PA (MVPA) were obtained. Steps per daytime, peak 60-, 30-, and 1-min cadence were computed. The time accumulated (min·d) in different cadence bands of steps was also computed from hip accelerometer. Plasma levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin growth factor-1 (IGF-1) were determined by the XMap technology (Luminex IS 100/200 system, Luminex Corporation, Austin, TX). RESULTS: Light PA, moderate PA, MVPA, and the peak 60-min cadence were positively related with BDNF concentrations (all P < 0.05), and only light PA to VEGF (P = 0.048). No association was observed for IGF-1 (P > 0.05). The associations of light PA with BDNF and VEGF disappeared (all P > 0.05) after performing analyses with nondominant wrist-placement data. However, moderate PA and MVPA remained significantly associated with BDNF (both P < 0.05). The time accumulated in cadence bands of 40 to 59 steps per day and 60 to 79 steps per day (i.e., walking at slow pace) was positively associated with plasma BDNF (all P < 0.05). CONCLUSIONS: In conclusion, PA is positively related to plasma BDNF, whereas no relationship was observed for VEGF or IGF-1. Higher amounts of time spent in slow walking cadence bands could increment BDNF levels. Exercise-based randomized controlled trials in children with overweight/obesity should be carried out to better understand the influence of PA behaviors on the neurotrophic factors.

Inflammatory biomarkers and brain health indicators in children with overweight and obesity: The ActiveBrains project.

INTRODUCTION: Chronic inflammation plays an important role on the pathogenesis of several cardiovascular and metabolic diseases, as well as on brain function and behaviour. The aim of the present study was to examine the associations between inflammatory biomarkers and a wide range of brain health indicators (i.e., academic performance, executive function, behavioural and emotional functioning, and brain volume) in children with overweight/obesity. METHODS: A total of 107 children (10.0 ±â€¯1.1 years, 41% girls) from the ActiveBrains project were included in the analysis. Five inflammatory biomarkers were analysed in plasma: white blood cell (WBC) count, interleukin-6 (IL-6), interleukin-1ß, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP). Academic performance was assessed by Woodcock-Muñoz Tests of Achievement. Executive function was assessed through the Design Fluency Test for cognitive flexibility, the Stroop test for cognitive inhibition, and the Delayed Non-Match-to-Sample task for working memory. Behavioural and emotional functioning was evaluated through the Behavior Assessment System for Children (BASC) questionnaire. Total and regional brain volume was assessed by magnetic resonance imaging. RESULTS: IL-6 was inversely associated with adaptive skills (ß = -0.228; p = 0.030), while TNF-α was related to mathematics (ß = -0.198; p = 0.034). In addition, CRP was positively associated with externalizing (ß = 0.246; p = 0.046) and internalizing problems (ß = 0.234; p = 0.039), as well as the behavioural symptoms index (ß = 0.236; p = 0.047). However, these significant associations disappeared after multiple comparisons correction. Inflammatory biomarkers were not associated with executive function and total brain volumes. Regarding regional brain analyses, WBC was positively associated with gray matter volume in the left middle temporal gyrus (ß = 0.387; p < 0.001, k = 44), and CRP was positively associated with gray matter volume in the right superior temporal gyrus (ß = 0.439; p < 0.001, k = 29). Additionally, when adjusting by total brain volume, CRP was positively associated with gray matter volume in the right supplementary motor cortex (ß = 0.453; p < 0.001, k = 51). Moreover, both, IL-6 (ß = 0.366; p < 0.001, k = 81) and TNF-α (ß = 0.368; p < 0.001, k = 62) were positively associated with white matter volume around the right inferior frontal gyrus pars opercularis, while CRP was inversely associated with white matter volume around the left superior frontal gyrus (ß = -0.482; p < 0.001, k = 82). After adjusting by total brain volume, CRP was also inversely associated with white matter volume in 3 additional clusters (ß ranging from -0.473 to -0.404; p < 0.001, k = 87). CONCLUSIONS: Inflammation was slightly associated with brain health (i.e., academic performance, behavioural and emotional functioning and regional brain volume) in children with overweight or obesity. Further larger longitudinal and interventional studies are warranted to elucidate the short-term and long-term effect of systemic low-grade inflammation on children's brain health.

Evidence of high 18 F-fluorodeoxyglucose uptake in the subcutaneous adipose tissue of the dorsocervical area in young adults.

NEW FINDINGS: What is the central question of this study? In some studies, biopsies have been performed of the subcutaneous adipose tissue in the abdomen, and they failed to find browning markers. Is the abdomen the right place to take biopsies? What is the main finding and its importance? For first time, we observed that the glucose uptake in the dorsocervical subcutaneous adipose tissue is higher in comparison to other areas of subcutaneous adipose tissue. ABSTRACT: Neonates have subcutaneous brown adipose tissue (BAT) in the dorsocervical area, and it is thought that these depots gradually disappear with age. Here, we determined that young adults have high 18 F-flurodeoxyglucose (18 F-FDG) uptake in the subcutaneous adipose tissue (SAT) of the dorsocervical area. A total of 133 young adults (age 22 ± 2 years; body mass index 25 ± 5 kg m2 ) were included in the study. We performed a shivering threshold test for every participant. Later, we performed 2 h of personalized cold exposure, immediately before a positron emission tomography/computed tomography scan. We showed that 23 of 133 participants had 18 F-FDG uptake in the dorsocervical area that achieved the criteria to be considered BAT, mainly in women (96%, n = 22 of 23). In the whole sample, the glucose uptake in the SAT of the dorsocervical area was positively correlated with BAT volume and activity located in the supraclavicular area. We showed that the 18 F-FDG uptake of the SAT of the dorsocervical area in humans is different from that of other SAT areas. Future studies are warranted to confirm the brown signature of this tissue.

Fatty acid status and antioxidant defense system in mothers and their newborns after salmon intake during late pregnancy.

OBJECTIVE: The aim of the present study was to assess the maternal and newborn status of erythrocyte fatty acids and the antioxidant defense system after the intake of two portions of salmon per week during late pregnancy. METHODS: Pregnant women (N = 123) were randomly assigned to continue their habitual diet, which was low in oily fish (control group, n = 61) or to consume two 150-g salmon portions per week (salmon group, n = 62) beginning at 20 wk of gestation and lasting until delivery. Fatty acids, selenium, and glutathione concentrations and antioxidant defense enzyme activities were measured in maternal erythrocytes at 20, 34, and 38 wk of pregnancy, and in cord erythrocytes collected at birth. Plasma concentrations of antioxidant molecules were measured. RESULTS: Compared with the control group, consuming salmon had little effect on erythrocyte fatty acids in either mothers or newborns. Components of the antioxidant defense system did not differ between groups. Glutathione peroxidase activity and the concentrations of tocopherols, retinol, and coenzyme Q10 were significantly lower in cord blood compared with maternal blood at week 38 in both groups. CONCLUSION: Maternal and newborn erythrocyte fatty acids are not strongly affected by the intake of two portions of salmon per week during the second half of pregnancy, although erythrocyte docosahexaenoic acid might be increased in newborns. Maternal and newborn antioxidant defense systems are not impaired by intake of salmon from 20 wk gestation.

A serum metabolomics-driven approach predicts orange juice consumption and its impact on oxidative stress and inflammation in subjects from the BIONAOS study.

SCOPE: To identify biomarkers of orange juice (OJ) consumption containing different doses of polyphenols and to determine its impact on oxidative stress and inflammation using an untargeted metabolomics analysis. METHODS AND RESULTS: Thirty subjects aged 22-63 years from the BIONAOS study consumed a normal-polyphenol OJ (NPJ) or a high-polyphenol OJ (HPJ) (299 or 745 mg/L, respectively) for 12 weeks in a randomized, parallel, double-blind study. UHPLC-MS, univariate and multivariate statistical analysis and ROC curves were used to design biomarkers of consumption in serum. We propose betonicine, stachydrine, methyl glucopyranoside (alpha+beta), dihydroferulic acid and galactonate as a new metabolic signature to distinguish the intake of OJ with a different polyphenol content. Changes in metabolites related to OJ, oxidative stress and inflammation were observed. After HPJ consumption, the serum levels of hydroxyoctadecadienoic acid (9-HODE+13-HODE) and dihydroxyoctadecanoic acid (12,13-DiHOME and 9,10-DiHOME) decreased, whereas levels of 12-hydroxyeicosatetraenoic acid (12-HETE) increased. 5-HETE increased after the NPJ intervention exclusively. CONCLUSION: We designed a new panel of biomarkers to differentiate the intake of OJs containing different doses of polyphenols. On the other hand, the consumption of an OJ with a high content of flavanones improved oxidative stress and inflammatory biomarkers.

Role of Exercise in the Activation of Brown Adipose Tissue.

BACKGROUND: The energy-burning capacity of brown adipose tissue (BAT) makes it an attractive target for use in anti-obesity therapies. Moreover, due to its ability to oxidize glucose and lipids, BAT activation has been considered a potential therapy to combat type 2 diabetes and atherogenesis. SUMMARY: BAT is mainly regulated by the sympathetic nervous system (SNS); yet, recent findings have shown a group of novel activators that act independently of the stimulation of the SNS such as cardiac natriuretic peptides, irisin, interleukin-6, ß-aminoisobutyric acid and fibroblast growth factor 21 that could influence BAT metabolism. Several strategies are being examined to activate and recruit BAT with no side effects. In this review, we postulate that exercise might activate and recruit human BAT through the activation of SNS, heart and skeletal muscle. KEY MESSAGES: Epidemiological and well-designed exercise-based randomized controlled studies are needed to clarify if exercise is able to activate BAT in humans.

A Systematic Review of the Efficacy of Bioactive Compounds in Cardiovascular Disease: Phenolic Compounds.

The prevalence of cardiovascular diseases (CVD) is rising and is the prime cause of death in all developed countries. Bioactive compounds (BAC) can have a role in CVD prevention and treatment. The aim of this work was to examine the scientific evidence supporting phenolic BAC efficacy in CVD prevention and treatment by a systematic review. Databases utilized were Medline, LILACS and EMBASE, and all randomized controlled trials (RCTs) with prospective, parallel or crossover designs in humans in which the effects of BAC were compared with that of placebo/control were included. Vascular homeostasis, blood pressure, endothelial function, oxidative stress and inflammatory biomarkers were considered as primary outcomes. Cohort, ecological or case-control studies were not included. We selected 72 articles and verified their quality based on the Scottish Intercollegiate Guidelines Network, establishing diverse quality levels of scientific evidence according to two features: the design and bias risk of a study. Moreover, a grade of recommendation was included, depending on evidence strength of antecedents. Evidence shows that certain polyphenols, such as flavonols can be helpful in decreasing CVD risk factors. However, further rigorous evidence is necessary to support the BAC effect on CVD prevention and treatment.

Normal or High Polyphenol Concentration in Orange Juice Affects Antioxidant Activity, Blood Pressure, and Body Weight in Obese or Overweight Adults.

BACKGROUND: The consumption of orange juice may lead to reduced oxidative stress and may enhance the antioxidant defense system. OBJECTIVE: The aim was to evaluate the effects of the intake of orange juice containing either normal (NPJ) or high (HPJ) concentrations of polyphenols (299 and 745 mg/d, respectively) on the antioxidant defense system, oxidative stress biomarkers, and clinical signs of metabolic syndrome in 100 nonsmoking subjects who were either overweight or obese. METHODS: A randomized, double-blind crossover study was conducted over two 12-wk periods with a 7-wk washout period. The effects on enzymatic and nonenzymatic blood antioxidant defense systems, urinary and plasma oxidative stress biomarkers, and clinical signs of metabolic syndrome were evaluated before and after an intervention with both of the orange juices. Paired t tests and linear mixed-effects models were used to evaluate the effects of juice, time, and interactions. RESULTS: The intake of either NPJ or HPJ led to a decrease in urinary 8-hydroxy-2'-deoxyguanosine (NPJ: 935 ± 134 to 298 ± 19 ng/mg creatinine; HPJ: 749 ± 84 to 285 ± 17 ng/mg creatinine), 8-iso-prostaglandin F2α (NPJ: 437 ± 68 to 156 ± 14 ng/mg creatinine; HPJ: 347 ± 43 to 154 ± 13 ng/mg creatinine), erythrocyte catalase, and glutathione reductase activities. A decrease was also observed in body mass index, waist circumference, and leptin (all P < 0.05). The NPJ intervention decreased systolic and diastolic blood pressures (systolic blood pressure: 128 ± 1 to 124 ± 2 mm Hg; diastolic blood pressure: 79 ± 1 to 76 ± 1 mm Hg), whereas the HPJ intervention increased erythrocyte superoxide dismutase (SOD) activity (17.7 ± 1.5 to 23.1 ± 1.7 U/mg hemoglobin). CONCLUSIONS: Our results show that the consumption of either NPJ or HPJ protected against DNA damage and lipid peroxidation, modified several antioxidant enzymes, and reduced body weight in overweight or obese nonsmoking adults. Only blood pressure and SOD activity were influenced differently by the different flavanone supplementations. This trial was registered at clinicaltrials.gov as NCT01290250.

Genome-wide expression in visceral adipose tissue from obese prepubertal children.

Characterization of the genes expressed in adipose tissue (AT) is key to understanding the pathogenesis of obesity and to developing treatments for this condition. Our objective was to compare the gene expression in visceral AT (VAT) between obese and normal-weight prepubertal children. A total of fifteen obese and sixteen normal-weight children undergoing abdominal elective surgery were selected. RNA was extracted from VAT biopsies. Microarray experiments were independently performed for each sample (six obese and five normal-weight samples). Validation by quantitative PCR (qPCR) was performed on an additional 10 obese and 10 normal-weight VAT samples. Of 1276 differentially expressed genes (p < 0.05), 245 were more than two-fold higher in obese children than in normal-weight children. As validated by qPCR, expression was upregulated in genes involved in lipid and amino acid metabolism (CES1, NPRR3 and BHMT2), oxidative stress and extracellular matrix regulation (TNMD and NQO1), adipogenesis (CRYAB and AFF1) and inflammation (ANXA1); by contrast, only CALCRL gene expression was confirmed to be downregulated. In conclusion, this study in prepubertal children demonstrates the up- and down-regulation of genes that encode molecules that were previously proposed to influence the pathogenesis of adulthood obesity, as well as previously unreported dysregulated genes that may be candidate genes in the aetiology of obesity.

A Continuous Metabolic Syndrome Score Is Associated with Specific Biomarkers of Inflammation and CVD Risk in Prepubertal Children.

BACKGROUND/AIMS: We aimed to evaluate the use of a continuous metabolic syndrome (MetS) score and to assess the associations of this score with risk biomarkers of inflammation, endothelial damage and cardiovascular disease (CVD) in prepubertal children. METHODS: A total of 677 prepubertal children (295 obese, 146 overweight, and 236 normal-weight) were recruited. MetS traits, markers of inflammation, endothelial damage and CVD risk were measured, and a continuous MetS score was calculated, consisting of the sum/5 of the standardised scores of the MetS components. RESULTS: The continuous MetS score was significantly associated with active plasminogen activator inhibitor-1 (r = 0.406, p < 0.001), adiponectin (r = -0.212, p < 0.001), resistin (r = 0.263, p < 0.001), C-reactive protein (r = 0.254, p < 0.001), tumour necrosis factor alpha (r = 0.120, p = 0.003), myeloperoxidase (r = 0.188, p < 0.001) and sE-selectin (r = 0.278, p < 0.001). Children in the normal-weight, overweight and obese groups with MetS totalled 0 (0%), 1 (0.7%) and 24 (8.7%), respectively, whereas the at-risk children identified using the continuous MetS score in each group totalled 2 (0.85%), 17 (11.6%) and 167 (56.6%), respectively. CONCLUSIONS: The association of the continuous MetS score with specific risk biomarkers of inflammation, endothelial damage and CVD supports its use in the early identification of children at increased risk of metabolic dysfunction.

Influence of variants in the NPY gene on obesity and metabolic syndrome features in Spanish children.

Variants in the neuropeptide Y (NPY) gene have been associated with obesity and its traits. The objective of the present study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the NPY gene with obesity, metabolic syndrome features, and inflammatory and cardiovascular disease (CVD) risk biomarkers in Spanish children. We recruited 292 obese children and 242 normal-body mass index (BMI) children. Height, weight, BMI, waist circumference, clinical and metabolic markers, adipokines, and inflammatory (PCR, IL-6, IL-8 and TNF-α) and CVD risk biomarkers (MPO, MMP-9, sE-selectin, sVCAM, sICAM, and PAI-1) were analyzed. Seven SNPs in the NPY gene were genotyped. The results of our study indicate that anthropometric measurements, clinical and metabolic markers, adipokines (leptin and resistin), and inflammatory and CVD risk biomarkers were generally elevated in the obese group. The exceptions to this finding included cholesterol, HDL-c, and adiponectin, which were lower in the obese group, and glucose, LDL-c, and MMP-9, which did not differ between the groups. Both rs16147 and rs16131 were associated with the risk of obesity, and the latter was also associated with insulin resistance, triacylglycerols, leptin, and HDL-c. Thus, we confirm the association of rs16147 with obesity, and we demonstrate for the first time the association of rs16131 with obesity and its possible impact on the early onset of metabolic syndrome features, mainly triacylglycerols, in children.