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.

The effects of a 20-week exercise program on blood-circulating biomarkers related to brain health in overweight or obese children: The ActiveBrains project.

BACKGROUND: Emerging research supports the idea that exercise positively affects neurodevelopment. However, the mechanisms linking exercise with brain health are largely unknown. We aimed to investigate the effect of exercise on (a) blood biomarkers selected based on previous evidence (brain-derived neurotrophic factor, ß-hydroxybutyrate (BHB), cathepsin B (CTSB), kynurenine, fibroblast growth factor 21 (FGF21), soluble vascular cell adhesion molecule-1 (sVCAM-1)); and (b) a panel of 92 neurology-related proteins (discovery analysis). We also investigated whether changes in these biomarkers mediate the effects of exercise on brain health (hippocampal structure and function, cognitive performance, and mental health). METHODS: We randomized 81 overweight/obese children (10.1 ± 1.1 years, 41% girls) into 2 groups: either 20 weeks of aerobic plus resistance exercise or control. Candidate biomarkers were assessed using enzyme-linked immunosorbent assay (ELISA) for kynurenine, FGF21, and CTSB; colorimetry for ß-hydroxybutyrate; and XMap for brain-derived neurotrophic factor and soluble vascular cell adhesion molecule-1. The 92 neurology-related proteins were analyzed by an antibody-based proteomic analysis. RESULTS: Our intervention had no significant effect on candidate biomarkers (all p > 0.05). In the discovery analysis, a reduction in circulating macrophage scavenger receptor type-I was observed (standardized differences between groups = -0.3, p = 0.001). This effect was validated using ELISA methods (standardized difference = -0.3, p = 0.01). None of the biomarkers mediated the effects of exercise on brain health. CONCLUSIONS: Our study does not support a chronic effect of exercise on candidate biomarkers. We observed that while chronic exercise reduced the levels of macrophage scavenger receptor type-I, it did not mediate the effects of exercise on brain health. Future studies should explore the implications of this novel biomarker for overall health.

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.

The Infrared Thermography Toolbox: An Open-access Semi-automated Segmentation Tool for Extracting Skin Temperatures in the Thoracic Region including Supraclavicular Brown Adipose Tissue.

Infrared thermography (IRT) is widely used to assess skin temperature in response to physiological changes. Yet, it remains challenging to standardize skin temperature measurements over repeated datasets. We developed an open-access semi-automated segmentation tool (the IRT-toolbox) for measuring skin temperatures in the thoracic area to estimate supraclavicular brown adipose tissue (scBAT) activity, and compared it to manual segmentations. The IRT-toolbox, designed in Python, consisted of image pre-alignment and non-rigid image registration. The toolbox was tested using datasets of 10 individuals (BMI = 22.1 ± 2.1 kg/m2, age = 22.0 ± 3.7 years) who underwent two cooling procedures, yielding four images per individual. Regions of interest (ROIs) were delineated by two raters in the scBAT and deltoid areas on baseline images. The toolbox enabled direct transfer of baseline ROIs to the registered follow-up images. For comparison, both raters also manually drew ROIs in all follow-up images. Spatial ROI overlap between methods and raters was determined using the Dice coefficient. Mean bias and 95% limits of agreement in mean skin temperature between methods and raters were assessed using Bland-Altman analyses. ROI delineation time was four times faster with the IRT-toolbox (01:04 min) than with manual delineations (04:12 min). In both anatomical areas, there was a large variability in ROI placement between methods. Yet, relatively small skin temperature differences were found between methods (scBAT: 0.10 °C, 95%LoA[-0.13 to 0.33 °C] and deltoid: 0.05 °C, 95%LoA[-0.46 to 0.55 °C]). The variability in skin temperature between raters was comparable between methods. The IRT-toolbox enables faster ROI delineations, while maintaining inter-user reliability compared to manual delineations. (Trial registration number (ClinicalTrials.gov): NCT04406922, [May 29, 2020]).

A larger brown fat volume and lower radiodensity are related to a greater cardiometabolic risk, especially in young men.

Objectives: Brown adipose tissue (BAT) is important in the maintenance of cardiometabolic health in rodents. Recent reports appear to suggest the same in humans, although if this is true remains elusive partly because of the methodological bias that affected previous research. This cross-sectional work reports the relationships of cold-induced BAT volume, activity (peak standardized uptake, SUVpeak), and mean radiodensity (an inverse proxy of the triacylglycerols content) with the cardiometabolic and inflammatory profile of 131 young adults, and how these relationships are influenced by sex and body weight. Design: This is a cross-sectional study. Methods: Subjects underwent personalized cold exposure for 2 h to activate BAT, followed by static 18F-fluorodeoxyglucose PET-CT scanning to determine BAT variables. Information on cardiometabolic risk (CMR) and inflammatory markers was gathered, and a CMR score and fatty liver index (FLI) were calculated. Results: In men, BAT volume was positively related to homocysteine and liver damage markers concentrations (independently of BMI and seasonality) and the FLI (all P ≤ 0.05). In men, BAT mean radiodensity was negatively related to the glucose and insulin concentrations, alanine aminotransferase activity, insulin resistance, total cholesterol/HDL-C, LDL-C/HDL-C, the CMR score, and the FLI (all P ≤ 0.02). In women, it was only negatively related to the FLI (P < 0.001). These associations were driven by the results for the overweight and obese subjects. No relationship was seen between BAT and inflammatory markers (P > 0.05). Conclusions: A larger BAT volume and a lower BAT mean radiodensity are related to a higher CMR, especially in young men, which may support that BAT acts as a compensatory organ in states of metabolic disruption.

No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial.

Exercise modulates both brown adipose tissue (BAT) metabolism and white adipose tissue (WAT) browning in murine models. Whether this is true in humans, however, has remained unknown. An unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129) was therefore conducted to study the effects of a 24-week supervised exercise intervention, combining endurance and resistance training, on BAT volume and activity (primary outcome). The study was carried out in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada (Spain). One hundred and forty-five young sedentary adults were assigned to either (i) a control group (no exercise, n = 54), (ii) a moderate intensity exercise group (MOD-EX, n = 48), or (iii) a vigorous intensity exercise group (VIG-EX n = 43) by unrestricted randomization. No relevant adverse events were recorded. 97 participants (34 men, 63 women) were included in the final analysis (Control; n = 35, MOD-EX; n = 31, and VIG-EX; n = 31). We observed no changes in BAT volume (Δ Control: -22.2 ± 52.6 ml; Δ MOD-EX: -15.5 ± 62.1 ml, Δ VIG-EX: -6.8 ± 66.4 ml; P = 0.771) or 18F-fluorodeoxyglucose uptake (SUVpeak Δ Control: -2.6 ± 3.1 ml; Δ MOD-EX: -1.2 ± 4.8, Δ VIG-EX: -2.2 ± 5.1; p = 0.476) in either the control or the exercise groups. Thus, we did not find any evidence of an exercise-induced change on BAT volume or activity in young sedentary adults.

Cold-Induced Thermogenesis Shows a Diurnal Variation That Unfolds Differently in Males and Females.

CONTEXT: Cold exposure mobilizes lipids to feed thermogenic processes in organs, including brown adipose tissue (BAT). In rodents, BAT metabolic activity exhibits a diurnal rhythm, which is highest at the start of the wakeful period. OBJECTIVE: We investigated whether cold-induced thermogenesis displays diurnal variation in humans and differs between the sexes. METHODS: This randomized crossover study included 24 young and lean male (n = 12) and female (n = 12) participants who underwent 2.5-hour personalized cooling using water-perfused mattresses in the morning (7:45 am) and evening (7:45 pm), with 1 day in between. We measured energy expenditure (EE) and supraclavicular skin temperature in response to cold exposure. RESULTS: In males, cold-induced EE was higher in the morning than in the evening (+54% ±â€…10% vs +30% ±â€…7%; P = 0.05) but did not differ between morning and evening in females (+37% ±â€…9% vs +30% ±â€…10%; P = 0.42). Only in males, supraclavicular skin temperature upon cold increased more in morning than evening (+0.2 ±â€…0.1 °C vs -0.2 ±â€…0.2 °C; P = 0.05). In males, circulating free fatty acid (FFA) levels were increased after morning cold exposure, but not evening (+90% ±â€…18% vs +9% ±â€…8%; P < 0.001). In females, circulating FFA (+94% ±â€…21% vs +20% ±â€…5%; P = 0.006), but also triglycerides (+42% ±â€…5% vs +29% ±â€…4%, P = 0.01) and cholesterol levels (+17% ±â€…2% vs 11% ±â€…2%; P = 0.05) were more increased after cold exposure in morning than in evening. CONCLUSION: Cold-induced thermogenesis is higher in morning than evening in males; however, lipid metabolism is more modulated in the morning than the evening in females.

Thyroid function is not associated with brown adipose tissue volume and 18F-fluorodeoxyglucose uptake in young euthyroid adults.

PURPOSE: Thyroid hormones (THs) are important mediators of brown adipose tissue (BAT) differentiation. However, the association of TH concentrations with human BAT is unclear. The present work examines the associations between circulating thyroid-stimulating hormone (TSH) and THs concentrations (i.e. free triiodothyronine, FT3, and free thyroxine, FT4), under thermoneutral (22-23°C) and cold-induced conditions, and BAT volume, 18F-fluorodeoxyglucose (18F-FDG) uptake and mean radiodensity. METHODS: A total of 106 young healthy, euthyroid adults (34 men/72 women; 22.0 ± 2.1 years old; 24.9 ± 4.6 kg/m2) participated in this cross-sectional study. BAT volume, 18F-FDG uptake and mean radiodensity were assessed after 2 h of personalized (i.e. contemplating each individual's shivering threshold) cold exposure via positron emission tomography/computed tomography (PET/CT) static scanning. TSH and THs levels were determined before (thermoneutral) and 1 h after the cold exposure. RESULTS: Cold exposure increased circulating FT4 (P = 0.038) and reduced TSH levels (P ≤ 0.001). Conversely, the FT3 serum concentration was not modified by cold exposure (P = 0.435). No associations were found between the TSH and THs thermoneutral (all P > 0.111) or cold-induced levels (all P > 0.067) and BAT volume, 18F-FDG uptake and mean radiodensity. These findings were independent of sex and BMI. CONCLUSIONS: Thyroid function is modulated by cold exposure, yet it is not associated with BAT volume or glucose metabolism assessed after 2 h of cold exposure in young healthy, euthyroid adults.

Omics Approaches in Adipose Tissue and Skeletal Muscle Addressing the Role of Extracellular Matrix in Obesity and Metabolic Dysfunction.

Extracellular matrix (ECM) remodeling plays important roles in both white adipose tissue (WAT) and the skeletal muscle (SM) metabolism. Excessive adipocyte hypertrophy causes fibrosis, inflammation, and metabolic dysfunction in adipose tissue, as well as impaired adipogenesis. Similarly, disturbed ECM remodeling in SM has metabolic consequences such as decreased insulin sensitivity. Most of described ECM molecular alterations have been associated with DNA sequence variation, alterations in gene expression patterns, and epigenetic modifications. Among others, the most important epigenetic mechanism by which cells are able to modulate their gene expression is DNA methylation. Epigenome-Wide Association Studies (EWAS) have become a powerful approach to identify DNA methylation variation associated with biological traits in humans. Likewise, Genome-Wide Association Studies (GWAS) and gene expression microarrays have allowed the study of whole-genome genetics and transcriptomics patterns in obesity and metabolic diseases. The aim of this review is to explore the molecular basis of ECM in WAT and SM remodeling in obesity and the consequences of metabolic complications. For that purpose, we reviewed scientific literature including all omics approaches reporting genetic, epigenetic, and transcriptomic (GWAS, EWAS, and RNA-seq or cDNA arrays) ECM-related alterations in WAT and SM as associated with metabolic dysfunction and obesity.

Endocrine Mechanisms Connecting Exercise to Brown Adipose Tissue Metabolism: a Human Perspective.

PURPOSE OF REVIEW: To summarize the state-of-the-art regarding the exercise-regulated endocrine signals that might modulate brown adipose tissue (BAT) activity and/or white adipose tissue (WAT) browning, or through which BAT communicates with other tissues, in humans. RECENT FINDINGS: Exercise induces WAT browning in rodents by means of a variety of physiological mechanism. However, whether exercise induces WAT browning in humans is still unknown. Nonetheless, a number of protein hormones and metabolites, whose signaling can influence thermogenic adipocyte's metabolism, are secreted during and/or after exercise in humans from a variety of tissues and organs, such as the skeletal muscle, the adipose tissue, the liver, the adrenal glands, or the cardiac muscle. Overall, it seems plausible to hypothesize that, in humans, exercise secretes an endocrine cocktail that is likely to induce WAT browning, as it does in rodents. However, even if exercise elicits a pro-browning endocrine response, this might result in a negligible effect if blood flow is restricted in thermogenic adipocyte-rich areas during exercise, which is still to be determined. Future studies are needed to fully characterize the exercise-induced secretion (i.e., to determine the effect of the different exercise frequency, intensity, type, time, and volume) of endocrine signaling molecules that might modulate BAT activity and/or WAT browning or through which BAT communicates with other tissues, during exercise. The exercise effect on BAT metabolism and/or WAT browning could be one of the still unknown mechanisms by which exercise exerts beneficial health effects, and it might be pharmacologically mimicked.

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.

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases.

The extracellular matrix (ECM) is a network of different proteins and proteoglycans that controls differentiation, migration, repair, survival, and development, and it seems that its remodeling is required for healthy adipose tissue expansion. Obesity drives an excessive lipid accumulation in adipocytes, which provokes immune cells infiltration, fibrosis (an excess of deposition of ECM components such as collagens, elastin, and fibronectin) and inflammation, considered a consequence of local hypoxia, and ultimately insulin resistance. To understand the mechanism of this process is a challenge to treat the metabolic diseases. This review is focused at identifying the putative role of ECM in adipose tissue, describing its structure and components, its main tissue receptors, and how it is affected in obesity, and subsequently the importance of an appropriate ECM remodeling in adipose tissue expansion to prevent metabolic diseases.