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Omega-6 and omega-3 oxylipins may be surrogate markers of systemic inflammation, which is one of the triggers for the development of cardiometabolic disorders. In the current study, we investigated the relationship between plasma levels of omega-6 and omega-3 oxylipins with body composition and cardiometabolic risk factors in middle-aged adults. Seventy-two 72 middle-aged adults (39 women; 53.6±5.1 years old; 26.7±3.8 kg/m2) were included in this cross-sectional study. Plasma levels of omega-6 and omega-3 fatty acids and oxylipins were determined using targeted lipidomic. Body composition, dietary intake, and cardiometabolic risk factors were assessed with standard methods. The plasma levels of the omega-6 fatty acids and derived oxylipins, the hydroxyeicosatetraenoic acids (HETEs; arachidonic acid (AA)-derived oxylipins) and dihydroxy-eicosatrienoic acids (DiHETrEs; AA-derived oxylipins), were positively associated with glucose metabolism parameters (i.e., insulin levels and homeostatic model assessment of insulin resistance index (HOMA); all r≥0.21, P

Background: Mutations in genes encoding lipoprotein lipase (LPL) or its regulators can cause severe hypertriglyceridemia (HTG). Thus far, the effect of genetic HTG on the lipid profile has been mainly determined via conventional techniques. Objective: To show detailed differences in the (apo)lipoprotein profile of patients with genetic HTG by combining LC-MS and NMR techniques. Methods: Fasted serum from 7 patients with genetic HTG and 10 normolipidemic controls was used to measure the concentration of a spectrum of apolipoproteins by LC-MS, and to estimate the concentration and size of lipoprotein subclasses and class-specific lipid composition using NMR spectroscopy. Results: Patients with genetic HTG compared to normolipidemic controls had higher levels of apoB48 (fold change [FC] 11.3, P, P, P=0.007), apoC-III (FC 3.4, P, Pi.e., chylomicrons and very low-density lipoproteins [VLDL]; FC 3.0, Pi.e., chylomicrons, VLDL), explaining high levels of apoC-I, apoC-II, apoC-III and apoE, whereas small atherogenic LDL particles are absent. The presence of chylomicrons in patients with HTG weakens the accuracy of the NMR-based model as it was designed for normolipidemic fasted individuals.

Purpose: This study aimed to (1) evaluate the acute effects of different interrepetition rest full-squat protocols on countermovement jump (CMJ) height, velocity loss (VL), and skin temperature (Tsk) and (2) determine whether the VL, the changes in Tsk, or the individual strength level is associated with the change in CMJ height. Methods: Sixteen resistance-trained men randomly performed 3 squat protocols at maximal intended velocity with 60% of the 1-repetition maximum (sets × repetitions [interrepetition rest]): traditional (2 × 6 [0 s]), cluster 2 (2 × 6 [30 s every 2 repetitions]), and cluster 1 (1 × 12; [36 s every repetition]), plus a control session. CMJ height was assessed before and 2, 4, and 8 minutes after the protocols. Results: There was a significant main effect of protocol for the VL (F = 20.54, P F = 12.85, P cluster 2 > cluster 1). However, we found a comparable reduction of CMJ height after 8 minutes: traditional (−3.4% [4.2%]), cluster 2 (−5.3% [4.9%]), cluster 1 (−5.4% [2.9%]), and control (−4.2% [3.6%]). Overall, mean Tsk acutely decreased after all the protocols. Higher individual strength level (but not VL or the changes in Tsk) was associated with lower CMJ-height loss (P Conclusions: Although different interrepetition rest full-squat protocols may alter the loss in velocity and power, they result in a similar decrease in Tsk and CMJ height, which could be more influenced by individual strength level than VL or changes in Tsk.

Background The application of cold exposure has emerged as an approach to enhance whole-body lipid catabolism. The global effect of cold exposure on the lipidome in humans has been reported with mixed results depending on intensity and duration of cold. Methods This secondary study was based on data from a previous randomized cross-over trial (ClinicalTrials.gov ID: NCT03012113). We performed sequential lipidomic profiling in serum during 120 min cold exposure of human volunteers. Next, the intracellular lipolysis was blocked in mice (eighteen 10-week-old male wild-type mice C57BL/ 6J) using a small-molecule inhibitor of adipose triglyceride lipase (ATGL; Atglistatin), and mice were exposed to cold for a similar duration. The quantitative lipidomic profiling was assessed in-depth using the Lipidyzer platform. Findings In humans, cold exposure gradually increased circulating free fatty acids reaching a maximum at 60 min, and transiently decreased total triacylglycerols (TAGs) only at 30 min. A broad range of TAG species was initially decreased, in particular unsaturated and polyunsaturated TAG species with ≤5 double bonds, while after 120 min a significant increase was observed for polyunsaturated TAG species with ≥6 double bonds in humans. The mechanistic study in mice revealed that the cold-induced increase in polyunsaturated TAGs was largely prevented by blocking adipose triglyceride lipase. Interpretation We interpret these findings as that cold exposure feeds thermogenic tissues with TAG-derived fatty acids for combustion, resulting in a decrease of circulating TAG species, followed by increased hepatic production of polyunsaturated TAG species induced by liberation of free fatty acids stemming from adipose tissue., Netherlands CardioVascular Research Initiative: `the Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development Royal Netherlands Academy of Sciences' CVON201720 GENIUS-II, Fundacion Alfonso Martin Escudero, Maria Zambrano - Ministerio de Universidades y la Union Europea -NextGenerationEU RR_C_2021_04, Spanish Government FPU19/01609, European Foundation for the Study of Diabetes (EFSD), NWO XOmics project 184.034.019

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.

Purpose: Brown adipose tissue (BAT) increases metabolic heat production in response to cold exposure. Body size and composition are involved in the human cold response, yet the influence of BAT herein have not fully been explored. Here, we aimed to study the association of the cold-induced shivering threshold time with body composition, BAT, the perception of shivering and skin temperature in young adults. Methods: 110 young healthy adults (81 females; age = 21.7 ± 2.1 years, BMI = 24.2 ± 4.3 kg/m2) underwent 2 h of individualized cooling, followed by the quantification of BAT using a18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography-computed tomography (PET-CT) scan. Body mass index (BMI), lean mass, fat mass and body surface area (BSA) were also measured. Shivering threshold time was defined as the time until shivering occurred using an individualized cooling protocol. Results: The shivering threshold time was on average 116.1 min for males and 125.8 min for females, and was positively associated to BMI (β = 3.106; R2 = 0.141; p = 0.001), lean mass (β = 2.295; R2 = 0.128; p = 0.001) and fat mass (β = 1.492; R2 = 0.121; p = 0.001) in females, but not in males (all p ≥ 0.409). The shivering threshold time was positively associated with BSA in males (p = 0.047) and females (p = 0.001), but it was not associated with BAT volume or [18F]FDG uptake nor with the perception of shivering and skin temperature perception in both sexes. Conclusion: The shivering threshold time is positively associated with whole-body adiposity and lean mass in females, but not in males. The shivering threshold time was positively associated with BSA, but no association was observed with BAT nor with the perception of shivering or skin temperature. Future research should consider the influence of body composition when applying cooling protocols among individuals with different phenotypical features., Spanish Government PI13/01393 PTA 12264-I, Retos de la Sociedad DEP 2016-79512-R, European Commission, Spanish Government FPU 13/03410, Fundacion Iberoamericana de Nutricion (FINUT), Redes Tematicas de Investigacion Cooperativa RETIC Red SAMID RD16/0022, AstraZeneca, University of Granada Plan Propio de Investigacion 2016 - Excellence actions: Unit of Excellence on Exercise and Health (UCEES), Plan Propio de Investigacion 2018: Programa ContratosPuente, Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades (ERDF) SOMM17/6107/UGR, Fundacion Carolina C.2016-574,961, Fundacion Alfonso Martin Escudero, Ministerio de Universidades y la Union Europea-NextGenerationEU RR_C_2021_04

This study aimed to investigate the effects of different exercise training programs on fasting plasma levels of oxylipins, endocannabinoids (eCBs), and eCBs-like molecules in middle-aged sedentary adults. A 12-week randomized controlled trial was conducted using a parallel group design. Sixty-five middle-aged adults (40–65 years old) were randomly assigned to: (a) no exercise (control group), (b) concurrent training based on international physical activity recommendations (PAR group), (c) high-intensity interval training (HIIT group), and (d) HIIT together with whole-body electromyostimulation (HIIT + EMS group). Plasma levels of oxylipins, eCBs, and eCBs-like molecules were determined in plasma samples before and after the intervention using targeted lipidomics. Body composition was assessed through dual-energy X-ray absorptiometry, and dietary intake through a food frequency questionnaire and three nonconsecutive 24-hr recalls. The physical activity recommendations, HIIT, and HIIT-EMS groups showed decreased plasma levels of omega-6 and omega-3-derived oxylipins, and eCBs and eCBs-like molecules after 12 weeks (all Δ ≤ −0.12; all p p > .05). However, after post hoc corrections, plasma levels of anandamide and oleoylethanolamide were increased in the physical activity recommendations group compared with the control group (anandamide: Δ = 0.05 vs. −0.09; oleoylethanolamide: Δ = −0.12 vs. 0.013, all p ≤ .049). In conclusion, this study reports that a 12-week exercise training intervention, independent of the modality applied, does not modify fasting plasma levels of omega-6 and omega-3 oxylipins, eCBs, and eCBs-like molecules in middle-aged sedentary adults.

Objectives: Although cold exposure is commonly believed to be causally related to acute viral respiratory infections, its effect on the immune system is largely unexplored. In this study, we determined transcript levels of a large panel of immune genes in blood before and after cold exposure. We included both Dutch Europid and Dutch South Asian men to address whether the immune system is differently regulated in the metabolically vulnerable South Asian population. Methods: Fasted blood samples were obtained from nonobese Dutch Europid (n = 11; mean age 26 ± 3 y) and Dutch South Asian (n = 12; mean age 28 ± 3 y) men before and directly after short-term (∼2.5 h) mild cold exposure. Transcript levels of 144 immune genes were measured using a dual-color reverse transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) assay. Results: Cold exposure acutely upregulated mRNA levels of GNLY (+35%, P < 0.001) and PRF1 (+45%, P < 0.001), which encode cytotoxic proteins, and CCL4 (+8%, P < 0.01) and CCL5 (+5%, P < 0.05), both pro-inflammatory chemokines. At thermoneutrality, mRNA levels of four markers of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR)-family, involved in inflammasomes, were lower in Dutch South Asians compared to Dutch Europids, namely NLRP2 (−57%, P < 0.05), NLRP7 (−17%, P < 0.05), NLRP10 (−21%, P < 0.05), and NLRC4 (−23%, P < 0.05). Conclusions: Mild cold exposure acutely increases mRNA levels of genes involved in cytotoxicity of immune cells in blood. In addition, Dutch South Asians display lower circulating mRNA levels of inflammasome genes compared to Dutch Europids.

The role of lifestyle behaviors on neck adipose tissue (NAT), a fat depot that appears to be involved in the pathogenesis of different cardiometabolic diseases and in inflammatory status, is unknown. In this cross-sectional and exploratory study, the authors examined the relationship between sedentary time and physical activity (PA) with neck adiposity in young adults. A total of 134 subjects (69% women, 23 ± 2 years) were enrolled. The time spent in sedentary behavior and PA of different intensity were objectively measured for 7 consecutive days (24 hr/day), using a wrist (nondominant)-worn accelerometer. The NAT volume was assessed using computed tomography, and the compartmental (subcutaneous, intermuscular, and perivertebral) and total NAT volumes were determined at the level of vertebra C5. Anthropometric indicators and body composition (by dual-energy X-ray absorptiometry) were determined. The time spent in light physical activity and moderate physical activity (MPA) and the overall PA were inversely associated with the intermuscular NAT volume in men, as were the MPA and overall PA with total NAT volume (all ps ≤ .04). Sedentary time was directly related to the total NAT volume (p = .04). An opposite trend was observed in women, finding a direct relationship of MPA with the subcutaneous NAT; of light physical activity, MPA, and overall PA with the perivertebral NAT; and of light physical activity with total NAT volumes (all ps ≤ .05). The observed associations were weak, and after adjusting for multiplicity, the results became nonsignificant (p > .05). These findings suggest that the specific characteristics of PA (time and intensity) might have sex-dependent implications in the accumulation of NAT.

In 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), beta-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.

The study was supported by the Spanish Ministry of Economy and Competitiveness via Retos de la Sociedad (DEP2016-79512-R to J.R.R.) and European Regional Development Funds (ERDF), the Spanish Ministry of Education (FPU 16/02828), the University of Granada Plan Propio de Investigacion 2016-Excellence actions: Unit of Excellence on Exercise and Health (UCEES), the Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades (ERDF: ref. SOMM17/6107/UGR), The Netherlands CardioVascular Research Initiative "the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences" (CVON2017-20 GENIUS-2) to P.C.N.R., and the Chinese Scholarship Council (CSC; No. 201707060012 to X.D., No. 201607060017 to W.Y.). B.M.T. is supported by an individual postdoctoral grant from the Fundacion Alfonso Martin Escudero., Context: Bile acids (BA) are known for their role in intestinal lipid absorption and can also play a role as signaling molecules to control energy metabolism. Prior evidence suggests that alterations in circulating BA levels and in the pool of circulating BA are linked to an increased risk of obesity and a higher incidence of type 2 diabetes in middleaged adults. Objective: We aimed to investigate the association between plasma levels of BA with cardiometabolic risk factors in a cohort of well-phenotyped, relatively healthy young adults. Methods: Body composition, brown adipose tissue, serum classical cardiometabolic risk factors, and a set of 8 plasma BA (including glyco-conjugated forms) in 136 young adults (age 22.1 ± 2.2 years, 67% women) were measured. Results: Plasma levels of chenodeoxycholic acid (CDCA) and glycoursodeoxycholic acid (GUDCA) were higher in men than in women, although these differences disappeared after adjusting for body fat percentage. Furthermore, cholic acid (CA), CDCA, deoxycholic acid (DCA), and glycodeoxycholic acid (GDCA) levels were positively, yet weakly associated, with lean body mass (LBM) levels, while GDCA and glycolithocholic acid (GLCA) levels were negatively associated with 18F-fluorodeoxyglucose uptake by brown adipose tissue. Interestingly, glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), and GUDCA were positively associated with glucose and insulin serum levels, HOMA index, low-density lipoprotein cholesterol, tumor necrosis factor alpha, interleukin (IL)-2, and IL-8 levels, but negatively associated with high-density lipoprotein cholesterol, ApoA1, and adiponectin levels, yet these significant correlations partially disappeared after the inclusion of LBM as a confounder. Conclusion: Our findings indicate that plasma levels of BA might be sex dependent and are associated with cardiometabolic and inflammatory risk factors in young and relatively healthy adults., Spanish Ministry of Economy and Competitiveness via Retos de la Sociedad DEP2016-79512-R, European Commission Spanish Government FPU 16/02828, University of Granada Plan Propio de Investigacion 2016-Excellence actions: Unit of Excellence on Exercise and Health (UCEES), Consejeria de Conocimiento, Investigacion y Universidades (ERDF) SOMM17/6107/UGR, Netherlands CardioVascular Research Initiative "the Dutch Heart Foundation" CVON2017-20 GENIUS-2 Netherlands CardioVascular Research Initiative "Dutch Federation of University Medical Centers" CVON2017-20 GENIUS-2, Netherlands CardioVascular Research Initiative "Netherlands Organisation for Health Research and Development" CVON2017-20 GENIUS-2 Netherlands CardioVascular Research Initiative "Royal Netherlands Academy of Sciences" CVON2017-20 GENIUS-2, China Scholarship Council 201707060012 201607060017, Fundacion Alfonso Martin Escudero, Junta de Andalucia

Objectives Neck adipose tissue (NAT) volume increases with general adiposity, with fat accumulating in different neck tissue compartments. In patients with certain malignant/benign tumours, the accumulation of NAT, and certain NAT distributions, have been associated with cardiometabolic risk (CMR). However, it is unknown whether the same relationships exist in healthy people, and whether NAT accumulation and distribution are related to the inflammatory status. Methods In this cross-sectional study, 139 young healthy adults (68% women) underwent a computed tomography scan to quantify the volume of compartmental (i.e., subcutaneous, intermuscular and perivertebral) and total NAT at the height of vertebra C5. Anthropometric indicators were measured, and body composition determined using dual energy X-ray absorptiometry. Information on CMR factors (i.e., blood glycaemic and lipid markers, blood pressure and physical fitness) was also gathered, and a CMR score calculated. Several plasma cytokines and serum components of the innate immune system were measured to determine the inflammatory status. Results Compartmental and total NAT volumes were directly related to body mass index (BMI), and lean, fat, and visceral adipose tissue (VAT) masses (all, P

Supported by the Spanish Ministry of Economy and Competitiveness via Fondo de Investigación Sanitaria del Instituto de Salud Carlos III grant PI13/01393 (to JRR), Retos de la Sociedad grant DEP2016-79512-R (to JRR), and European Regional Development Funds (ERDF); Spanish Ministry of Education grant FPU13/04365 (to GS-D); the Fundación Iberoamericana de Nutrición (to JRR); Redes Temáticas de Investigación Cooperativa grant Red SAMID RD16/0022 (to AG); the AstraZeneca HealthCare Foundation; the University of Granada Plan Propio de Investigación 2016—Excellence actions:Unit of Excellence on Exercise and Health (to JRR)—and Plan Propio de Investigación 2018—Programa Contratos-Puente (to GS-D); and Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidadesgrant SOMM17/6107/UGR (to JRR) via the ERDF., Background: Several studies have explored the role of human brown adipose tissue (BAT) in energy expenditure. However, the link between BAT and appetite regulation needs to be more rigorously examined. Objective: We aimed to investigate the associations of BAT volume and 18F-fluordeoxyglucose (18F-FDG) uptake after a personalized cold exposure with energy intake and appetite-related sensations in young healthy humans. Methods: A total of 102 young adults (65 women; age: 22.08 ± 2.17 y; BMI: 25.05 ± 4.93 kg/m 2) took part in this cross-sectional study. BAT volume, BAT 18F-FDG uptake, and skeletal muscle 18FFDG uptake were assessed by means of static 18F-FDG positronemission tomography and computed tomography scans after a 2-h personalized exposure to cold. Energy intake was estimated via an objectively measured ad libitum meal and three nonconsecutive 24-h dietary recalls. Appetite-related sensations (i.e., hunger and fullness) were recorded by visual analog scales before and after a standardized breakfast (energy content = 50% of basal metabolic rate) and the ad libitum meal. Body composition was assessed by a whole-body DXA scan. Results: BAT volume and 18F-FDG uptake were not associated with quantified ad libitum energy intake (all P > 0.088), nor with habitual energy intake estimated from the 24-h dietary recalls (all P > 0.683). Lean mass was positively associated with both the energy intake from the ad libitum meal (β: 17.612, R2 = 0.213; P < 0.001) and the habitual energy intake (β: 16.052, R2 = 0.123; P = 0.001). Neither the interaction BAT volume × time elapsed after meal consumption nor that of BAT 18F-FDG uptake × time elapsed after meal consumption had any significant influence on appetite-related sensations after breakfast or after meal consumption (all P > 0.3). Conclusions: Neither BAT volume, nor BAT 18F-FDG uptake after cold stimulation, are related to appetite regulation in young adults. These results suggest BAT plays no important role in the regulation of energy intake in humans. This trial was registered at clinicaltrials.gov as NCT02365129., Fondo de Investigación Sanitaria del Instituto de Salud Carlos III grant PI13/01393 (to JRR), Retos de la Sociedad grant DEP2016-79512-R (to JRR), Redes Temáticas de Investigación Cooperativa grant Red SAMID RD16/0022 (to AG), Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidadesgrant SOMM17/6107/UGR (to JRR) via the ERDF.

This work was supported by the Fundacion Alfonso Martin Escudero (to B.M.T), by the Dutch Heart Foundation (2017T016 to S.K.), by the Dutch Society for Diabetes Research (NVDO; Prof. dr. J. Terpstra Award to S.K.), the Dutch Diabetes Foundation (2015.81.1808 to M.R.B.) and the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE and CVON2017 GENIUS-2 to P.C.N.R.), 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% ± 10% vs +30% ± 7%; P = 0.05) but did not differ between morning and evening in females (+37% ± 9% vs +30% ± 10%; P = 0.42). Only in males, supraclavicular skin temperature upon cold increased more in morning than evening (+0.2 ± 0.1 °C vs −0.2 ± 0.2 °C; P = 0.05). In males, circulating free fatty acid (FFA) levels were increased after morning cold exposure, but not evening (+90% ± 18% vs +9% ± 8%; P < 0.001). In females, circulating FFA (+94% ± 21% vs +20% ± 5%; P = 0.006), but also triglycerides (+42% ± 5% vs +29% ± 4%, P = 0.01) and cholesterol levels (+17% ± 2% vs 11% ± 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., Fundacion Alfonso Martin Escudero, Netherlands Heart Foundation 2017T016 CVON2014-02 ENERGISE CVON2017 GENIUS-2, Dutch Society for Diabetes Research (NVDO), Dutch Diabetes Foundation 2015.81.1808, Netherlands Cardiovascular Research Initiative

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.

Background: Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for infammatory and metabolic disorders in middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown. Methods: Cross-sectional study in 100 (65% women) individuals aged 18–25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory ftness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample. Results: Individuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+42.5%), tri‑ glycerides (+63.9%), C-reactive protein (+124.2%), diastolic blood pressure (+5.5%), and pro-infammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity. Conclusions: Plasma succinate levels are linked to a specifc pro-infammatory omega-6 signature pattern and higher VAT levels, and seem to refect the cardiovascular status of young adults., Spanish Ministry of Economy and Competitiveness via Retos de la Sociedad (DEP2016-79512-R to JRR and RTI2018-093919-B to SFV), European Regional Development Funds (ERDF), Spanish Ministry of Education (FPU16/02828, FPU16/05159, FPU17/01523 and FPU19/01609), University of Granada Plan Propio de Investigación 2016-Excellence actions–Unit of Excellence on Exercise and Health (UCEES), Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades (ERDF: ref. SOMM17/6107/UGR), The Spanish Ministry of Science and Innovation (PI20/00095 to VCM and PI20/00338 to JV) co-fnanced by the European Regional Development Fund (ERDF), Ramón y Cajal program (RYC2019026490-I) from the Spanish Ministry of Science and Innovation, co-fnanced by the ERDF, y Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona (HR20-00051 to S.F.-V.), The Netherlands CardioVascular Research Initiative: ‘the Dutch Heart Foundation, Dutch Federation of University Medical Centers, The Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences’ (CVON2017-20 GENIUS-2) to PCNR, Chinese Scholarship Council (CSC, No. 201707060012) to XD, Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria, co-fnanced by the ERDF, Fundación Alfonso Martin Escudero

The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (− 8.4%, P = 0.032 vs 15.7%, P P vs 19.1%, P P = 0.024) after adjusting for study design but not BAT volume (β: 0.39, 95% CI [− 0.01–0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism.

Activation of brown adipose tissue (BAT) and promotion of white adipose tissue (WAT) browning is considered a potential tool to combat obesity and cardiometabolic disorders. The use of plant-based dietary components has become one of the most used strategies for activating BAT and promoting WAT browning in rodents. The main reason is because plant-based dietary components are usually recognized as safe when the dose is properly adjusted, and they can easily be administrated by being added to the diet or dissolved in water. The present systematic review aimed to study the effects of plant-based dietary components on activation of BAT and promotion of WAT browning in rodents. A systematic search of PubMed and Scopus (from 1978 to 2019) identified eligible studies. Studies assessing the effects of plant-based dietary components added to diet and/or water on uncoupling protein 1 (UCP1) expression in BAT and/or WAT were included. Studies that used dietary components of animal origin, did not specify the effects on UCP1, or were conducted in other species different from mice or rats were excluded. Of 3919 studies identified in the initial screening, 146 studies were finally included in the review. We found that tea extract catechins, resveratrol, capsaicin and capsinoids, cacao extract flavanols, and quercetin were the most studied components. Scientific evidence suggests that some of these dietary components activate BAT and promote WAT browning via activation of the AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) pathways. These findings reveal that there is strong scientific evidence supporting the use of plant-based dietary components to activate BAT and promote WAT browning in rodents and thus to potentially combat obesity and cardiometabolic disorders.

This study was funded by the Spanish Ministry of Economy and Competitiveness via the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI13/01393) and PTA 12264-I, and by Retos de la Sociedad (DEP2016-79512-R) and European Regional Development Fund, the Spanish Ministry of Education (FPU 13/03410, FPU 15/04059), the Fundacion Iberoamericana de Nutricion (FINUT), the Redes Tematicas de Investigaci on Cooperativa RETIC network (Red SAMID RD16/0022), the AstraZeneca HealthCare Foundation, The University of Granada's Plan Propio de Investigacion 2016 -Excellence actions: Unit of Excellence on Exercise and Health (UCEES), the Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades (ERDF, SOMM17/6107/UGR), and the Fundacion Alfonso Martin Escudero. This study is part of a PhD thesis conducted within the framework of the Biomedicine Doctoral Studies Programme of the University of Granada, Spain., Background: Harnessing cold-induced thermogenesis (CIT) and brown adipose tissue (BAT) activity has been proposed as a means of counteracting a positive energy balance, and thus of combating obesity and its related comorbidities. However, it has remained unclear whether CIT and BAT activity show diurnal variation in humans - knowledge that might allow treatments based on these factors to be timeoptimized. Methods: A randomized crossover experiment was designed to examine whether CIT shows morning/ evening variation in young, healthy adults (n ¼ 14, 5 women). On the first experimental day, subjects' shivering thresholds were determined following a cooling protocol. After z96 h had elapsed, the subjects then returned on two further days (approx. 48 h apart) at 08:00 h or 18:00 in random order. On both the latter days, the resting energy expenditure (REE) was measured before the subjects underwent personalized cold exposure (i.e., according to their shivering threshold). CIT was then assessed for 60 min by indirect calorimetry. In an independent cross-sectional study (n ¼ 133, 88 women), subjects came to the laboratory between 8:00 and 18:00 h and their BAT 18F-fluordeoxyglucose (18F-FDG) uptake was assessed after personalized cold stimulation. Results: Both the REE and CIT were similar in the morning and evening (all P > 0.05). Indeed, 60 min of personalized-mild cold exposure in the morning or evening elicited a similar change in energy expenditure (16.8 ± 12.8 vs. 15.7 ± 15.1% increase above REE, P ¼ 0.72). BAT 18F-FDG uptake was also similar in the morning, evening and afternoon (all P > 0.05). Conclusion: CIT does not appear to show morning/evening variation in young healthy adults, with the current study design and methodology. BAT 18F-FDG uptake appears not to change across the day either, although experiments with a within-subject study design are needed to confirm these findings., Spanish Ministry of Economy and Competitiveness via the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III PI13/01393 PTA 12264-I, Retos de la Sociedad DEP2016-79512-R, European Commission, Spanish Government FPU 13/03410 FPU 15/04059, Fundacion Iberoamericana de Nutricion (FINUT), Redes Tematicas de Investigaci on Cooperativa RETIC network Red SAMID RD16/0022, AstraZeneca, University of Granada's Plan Propio de Investigacion, Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades (ERDF) SOMM17/6107/UGR, Fundacion Alfonso Martin Escudero

Human brown adipose tissue (BAT) volume has been consistently claimed as inversely associated with whole-body adiposity. However, recent advances in the assessment of human BAT suggest that previously reported associations may have been biased. The present cross-sectional study investigates the association of BAT volume, mean radiodensity, and 18F-fluordeoxyglucose (18F-FDG) uptake (assessed via a static positron emission tomography-computerized tomography (PET-CT) scan after a 2-hour personalized cold exposure) with whole-body adiposity (measured by dual-energy X-ray absorptiometry) in 126 young adults (42 men/84 women; 25±5 kg/m2). BAT volume, but not 18F-FDG uptake, was positively associated with body mass index (BMI), fat mass, and visceral adipose tissue mass in men, but not in women. These associations were independent of the date when the PET-CT was performed, insulin sensitivity and body surface area. BAT mean radiodensity, an inverse proxy of BAT fat content, was negatively associated was with BMI, waist circumference, fat mass and visceral adipose tissue mas in men and with percentage fat mass in women. These results refute the widely held belief that human BAT volume is reduced in obese persons, at least in young adults, and suggest that it might even be the opposite in young men.

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.

Brown adipose tissue (BAT) activity is influenced by the outdoor temperature variation. However, people spend most of their time indoors, especially in colder regions and during cold seasons. Therefore, outdoor temperature is probably not an accurate tool to quantify the exposure of the participants before BAT quantification. We studied the association of wrist and personal environmental temperatures with cold-induced BAT and skeletal muscle [18F]fluorodeoxyglucose ([18F]FDG) uptake in adults. A total of 74 participants wore two iButtons during 7 days to measure wrist temperature (WT) and personal level of environmental temperature (Personal-ET). Thereafter, we performed a 2-h personalized cooling protocol before performing an [18F]FDG-PET/CT scan. WT was negatively associated with BAT volume ( R2 = 0.122; P = 0.002) and BAT activity [standardized uptake value (SUV)peak, R2 = 0.083; P = 0.012]. Moreover, Personal-ET was negatively associated with BAT volume ( R2 = 0.164; P < 0.001), BAT activity (SUVmean and SUVpeak, all R2 ≥ 0.167; P < 0.001), and skeletal muscle activity (SUVpeak, R2 = 0.122; P = 0.002). Interestingly, the time exposed to a certain Personal-ET (16–20°C) positively correlated only with [18F]FDG uptake by BAT (volume and activity; all P ≤ 0.05), whereas the time exposed to 12–15°C positively correlated only with measures of [18F]FDG uptake by skeletal muscle activity (all P ≤ 0.05). This study shows that WT and Personal-ET are associated with [18F]FDG uptake by BAT and skeletal muscle activity in adults within certain temperature thresholds. Moreover, our results suggest that [18F]FDG uptake by human BAT or skeletal muscle can be activated or inhibited in different ranges of ambient temperatures exposures. Results should be taken with caution because the observed associations were relatively weak.

Human brown adipose tissue (BAT) volume has been consistently claimed as inversely associated with whole-body adiposity. However, recent advances in the assessment of human BAT suggest that previously reported associations may have been biased. The present cross-sectional study investigates the association of BAT volume, mean radiodensity, and 18F-fluordeoxyglucose (18F-FDG) uptake (assessed via a static positron emission tomography-computerized tomography (PET-CT) scan after a 2-hour personalized cold exposure) with whole-body adiposity (measured by dual-energy X-ray absorptiometry) in 126 young adults (42 men / 84 women; 25±5 kg/m2). BAT volume, but not 18F-FDG uptake, was positively associated with body mass index (BMI), fat mass, and visceral adipose tissue mass in men, but not in women. These associations were independent of the date when the PET-CT was performed, insulin sensitivity and body surface area. BAT mean radiodensity, an inverse proxy of BAT fat content, was negatively associated was with BMI, waist circumference, fat mass and visceral adipose tissue mas in men and with percentage fat mass in women. These results refute the widely held belief that human BAT volume is reduced in obese persons, at least in young adults, and suggest that it might even be the opposite in young men.

Objective: To study the association between usual dietary factors (dietary energy density, nutrient intake, food group consumption, and dietary pattern) and brown adipose tissue (BAT) volume/F-18-fluorodeoxyglucose (F-18-FDG) uptake after personalized cold exposure in young healthy adults.Methods: A total of 122 young adults (n = 82 women; 22.0 +/- 2.1 years old; 24.8 +/- 4.8 kg/m(2)) took part in this cross-sectional study. Dietary factors were measured via a food frequency questionnaire and three non-consecutive 24 h recalls. Dietary energy density (foods and caloric beverages included) and macronutrient intakes were subsequently estimated using EvaIFINUT (R) software, food group consumption was estimated from the food frequency questionnaire, and different dietary patterns and quality indices were determined according to the reference methods. BAT volume, BAT F-18-FDG uptake, and skeletal muscle F-18-FDG uptake were assessed by static F-18-FDG positron-emission tomography and computed tomography (PET-CT) scans after a 2 h personalized exposure to cold.Results: A direct association was detected between dietary energy density and BAT Standardized Uptake Value (SUV)mean (beta = 0.215; R-2 = 0.044; P = 0.022), and between ethanol consumption and BAT volume (beta = 0.215; R-2 = 0.044; P = 0.022). The a priori Mediterranean dietary pattern was inversely associated with BAT SUVmean and SUVpeak (beta = -0.273; R-2 = 0.075; P = 0.003 and beta = -0.255; R-2 = 0.066; P = 0.005 respectively). In addition, the diet quality index for a Mediterranean diet and a pro-inflammatory dietary pattern (as determined via the dietary inflammatory index) were directly associated with BAT SUVmean and SUVpeak (SUVmean: beta = 0.238; R-2 = 0.053; P = 0.013 and beta = 0.256; R-2 = 0.052; P = 0.012 respectively; SUVpeak: beta = 0.278; R-2 = 0.073; P = 0.003 and beta = 0.248; R-2 = 0.049; P = 0.016 respectively). After controlling for multiplicity and possible confounders (sex, the evaluation wave and BMI), all the detected associations persisted.Conclusion: Dietary factors are slightly associated with BAT volume and/or F-18-FDG uptake after a personalized cold exposure in young adults. Our results provide an overall picture of the potential relationships between dietary factors and BAT-related variables in humans. (C) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

The study was funded by the Spanish Ministry of Economy and Competitiveness via the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI13/01393 and CB16/10/00239) and PTA 12264-I, Retos de la Sociedad (DEP2016-79512-R), and European Regional Development Funds (ERDF). Other funders included the Spanish Ministry of Education (FPU 16/05159, 15/04059 and 19/02326), the Fundacion Iberoamericana de Nutricion (FINUT), the Redes Tematicas De Investigacion Cooperativa RETIC (Red SAMID RD16/0022), the AstraZeneca Health Care Foundation, the University of Granada Plan Propio de Investigacion 2016 (Excellence actions: Unit of Excellence on Exercise, Nutrition and Health [UCEENS]), and by the Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades (ERDF, SOMM17/6107/UGR). AMT was supported by Seneca Foundation through grant 19899/GERM/15 and the Ministry of Science Innovation and Universities RTI2018-093528-B-I0, as well as DJP (MINECO; RYC-2014-16938). BMT was supported by an individual postdoctoral grant from the Fundacion Alfonso Martin Escudero. We thank Dr. Matt Smith of Embr Labs Inc. for configuring the Embr Wave (R) devices used in this experiment., Where people live and work together it is not always possible to modify the ambient temperature; ways must therefore be found that allow individuals to feel thermally comfortable in such settings. The Embr Wave (R) is a wrist-worn device marketed as a 'personal thermostat' that can apply a local cooling stimulus to the skin. The aim of the present study was to determine the effect of an intermittent mild cold stimulus of 25 degrees C for 15-20 s every 5 min over 3.5 days under free-living conditions on 1) skin temperature, 2) perception of skin temperature, 3) sleep quality and 4) resting energy expenditure (REE) in young, healthy adults. Ten subjects wore the device for 3.5 consecutive days. This intervention reduced distal skin temperature after correcting for personal ambient temperature (P < 0.05), but did not affect the subjects' the perception of skin temperature, sleep quality or REE (all P >= 0.051). Thus, this intermittent mild cold regime can reduce distal skin temperature, and wearing it under free-living conditions for 3.5 days does not seem to impair the perception of skin temperature and sleep quality or modify REE., Spanish Ministry of Economy and Competitiveness via the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III PI13/01393 CB16/10/00239, PTA 12264-I, Retos de la Sociedad DEP2016-79512-R, European Commission, Spanish Government 16/05159 15/04059 19/02326, Fundacion Iberoamericana de Nutricion (FINUT), Redes Tematicas De Investigacion Cooperativa RETIC (Red SAMID) RD16/0022, AstraZeneca, University of Granada Plan Propio de Investigacion, Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades (ERDF) SOMM17/6107/UGR, Fundacion Seneca 19899/GERM/15, Ministry of Science Innovation and Universities RTI2018-093528-B-I0, MINECO RYC-2014-16938, Fundacion Alfonso Martin Escudero

Aim: To compare the effects of cold exposure and the β3-adrenergic receptor agonist mirabegron on plasma lipids, energy expenditure and brown adipose tissue (BAT) activity in South Asians versus Europids. Materials and Methods: Ten lean Dutch South Asian (aged 18-30 years; body mass index [BMI] 18-25 kg/m2 ) and 10 age- and BMI-matched Europid men participated in a randomized, double-blinded, cross-over study consisting of three interventions: short-term (~ 2 hours) cold exposure, mirabegron (200 mg one dose p.o.) and placebo. Before and after each intervention, we performed lipidomic analysis in serum, assessed resting energy expenditure (REE) and skin temperature, and measured BAT fat fraction by magnetic resonance imaging. Results: In both ethnicities, cold exposure increased the levels of several serum lipid species, whereas mirabegron only increased free fatty acids. Cold exposure increased lipid oxidation in both ethnicities, while mirabegron increased lipid oxidation in Europids only. Cold exposure and mirabegron enhanced supraclavicular skin temperature in both ethnicities. Cold exposure decreased BAT fat fraction in both ethnicities. After the combination of data from both ethnicities, mirabegron decreased BAT fat fraction compared with placebo. Conclusions: In South Asians and Europids, cold exposure and mirabegron induced beneficial metabolic effects. When combining both ethnicities, cold exposure and mirabegron increased REE and lipid oxidation, coinciding with a higher supraclavicular skin temperature and lower BAT fat fraction., Diabetes Research Foundation Fellowship 2015.81.1808, Netherlands CardioVascular Research Initiative: 'the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences' CVON2014-02 ENERGISE CVON2017-20 GENIUS-II, European Union (EU) 602485, European Research Council (NOMA-MRI) PCNR is an Established Investigator of the Netherlands Heart Foundation 2009T038