Francisco J. Osuna-Prieto

Purpose: Succinate is a circulating metabolic intermediate and signaling metabolite associated with several physiological and immunometabolic processes. However, whether circulating succinate relates to resting cardiovascular physiology in humans remains poorly understood. Therefore, we examined the association between fasting plasma succinate concentrations and resting heart rate (HR) and heart rate variability (HRV) parameters in young sedentary adults. Methods: We analyzed 85 sedentary young adults (18–25 years; 56 women) from the ACTIBATE study cohort (NCT02365129). Plasma succinate was measured enzymatically under fasting conditions. Resting heart rate (HR) and heart rate variability (HRV), non-invasive markers of autonomic function, were measured in fasting, thermoneutral conditions using the Polar RS800CX system. Results: Higher fasting succinate concentrations showed a modest positive association with resting HR (β=0.213; R²=0.074; P = 0.046), independent of sex and BMI. In exploratory sex-stratified analyses, the association remained significant in men (β=0.379; R²=0.200; P = 0.034) but not in women (β=0.112; R² =–0.024; P = 0.417), although no significant Succinate × Sex interaction was detected. Participants with succinate levels above the cohort median showed a higher resting HR (+4 bpm; 95% CI: +0.1 to +8.3; P = 0.045) compared with those below the median, despite comparable body composition and cardiometabolic profiles (all P≥0.105). There was no association between levels of succinate and any HRV parameters (all P≥0.226). Conclusion: Elevated fasting plasma succinate is associated with higher resting HR in young sedentary adults. While causality cannot be inferred, these findings suggest that circulating succinate may represent a systemic metabolic marker associated with resting cardiovascular physiology in young adults. Longitudinal and mechanistic studies are warranted to clarify the physiological relevance and directionality of these associations.

Cold exposure activates brown adipose tissue (BAT), a therapeutic target to mitigate cardiometabolic diseases. Emerging evidence suggests that bile acids may influence BAT activity through metabolic and endocrine signaling pathways. Characterizing changes in circulating bile acids during cold exposure may uncover new pathways to improve metabolic health in humans. We analysed 56 young (21.7 ± 2.3 years old), sedentary adults (43 women, 77%) from the ACTIBATE cohort (NCT02365129) before the intervention in whom plasma samples were available for bile acid analyses. Eighteen plasma bile acid species were analyzed using liquid chromatography-tandem mass spectrometry before (i.e., baseline), 60, and 120 min during a personalized cooling protocol. BAT volume, activity, and radiodensity were assessed via ¹⁸ F-fluorodeoxyglucose positron emission tomography-computed tomography scan ( ¹⁸ F-FDG PET-CT) at the end of the cooling protocol. During the 2-hour cold exposure, plasma levels of total, secondary, and conjugated bile acids decreased by 24–30% (all P < 0.001). In normal-weight participants, most reductions remained significant after adjustment for PET-CT time, and glycolithocholic acid (GLCA) showed consistent positive associations with BAT volume and glucose uptake, as well as an inverse association with radiodensity (|r|≤0.41, adj. FDR ≤ 0.25; R ≤ 0.34, P ≤ 0.038 in adjusted regression models). In participants with overweight or obesity, most bile-acid changes lost statistical significance after adjustment for PET-CT time, although lithocholic acid and its sulfated derivative remained positively correlated with BAT radiodensity (|r|≤0.53; adj. FDR ≤ 0.25). Acute cold exposure is associated with changes in circulating bile acids in humans, with patterns differing by body-weight status. In normal-weight individuals, GLCA displayed consistent associations with BAT volume and glucose uptake, suggesting a possible link between bile acid and BAT activation. Further studies are needed to confirm these observations and to clarify the physiological relevance of bile acid signaling in human thermogenic adaptation.

Bile acids (BAs) play a key role in cholesterol metabolism and inflammation. Although altered circulating BA profiles have been reported in cardiometabolic disorders such as type 2 diabetes (T2D) and obesity, their relationship with coronary artery disease (CAD) remains poorly understood. We conducted a systematic review of human studies searching PubMed, Web of Science, and Scopus, assessing circulating BA concentrations in adults with angiographically confirmed CAD compared to non-CAD (NCAD) controls. Risk of bias was evaluated using the Newcastle–Ottawa Scale. From 2782 records, four observational studies met the inclusion criteria. All reported lower circulating BA concentrations in individuals with CAD compared to NCAD controls, with differences ranging from −5.4% to −52.8%. Two studies found a significant inverse association between BA levels and CAD. One study reported lower BA levels only in CAD in men, while another found the reduction more pronounced in individuals with T2D. However, all studies were observational, and most lacked adjustment for confounders such as sex and age. Current evidence suggests that lower circulating BA levels are linked to CAD and may be influenced by sex and T2D status. Further mechanistic and prospective studies are needed to clarify the relevance and directionality of this association.

Objective: To examine the effects of 24-week moderate (MOD-EX) and vigorous-intensity concurrent training (VIG-EX) on bone parameters and plasma levels of osteoglycin and sclerostin and their interplay with body composition and cardiometabolic risk factors in young, sedentary men and women. Design: Secondary study from the ACTIBATE randomized controlled trial (ClinicalTrials.gov ID: NCT02365129). Methods: This study was performed at the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada. Bone parameters were measured by dual-energy X-ray absorptiometry, and osteoglycin and sclerostin levels, by enzyme-linked immunosorbent assay. Results: 145 young sedentary adults were assigned to a control (CON, n = 54), a MOD-EX (n = 48), or a VIG-EX (n = 43). 106 participants were included in the per-protocol analyses (CON, n = 42; MOD-EX, n = 33; and VIG-EX, n = 31). After 24 weeks of concurrent training, we observed no differences in changes in bone parameters (all P time × group ≥ .300), osteoglycin (P time × group = .250), and sclerostin levels (P time × group = .489). Moreover, we found no correlations between osteoglycin and sclerostin levels with body composition (all P ≥ .639) and cardiometabolic risk factors (all P ≥ .119). Conclusion: 24 weeks of concurrent training did not alter bone parameters, and plasma levels of osteoglycin and sclerostin in young, sedentary adults. Moreover, osteoglycin and sclerostin are not related with bone parameters and cardiometabolic risk factors in this population. These findings suggest that longer concurrent training interventions may be needed to enhance bone parameters in young, sedentary adults.

Summary: Objective: Children with overweight/obesity (OW/OB) exhibit poor cardiometabolic health, yet mechanisms influencing brain health remain unclear. We examined the differences in neurological‐related circulating proteins in plasma among children with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) and the association with metabolic syndrome markers.Methods: In this cross‐sectional study, we included 84 Caucasian children (39% girls), aged 10.1 ± 1.1 years, from the ActiveBrains project (NCT02295072). A ninety‐two‐protein targeted approach using Olink's® technology was used.Results: We identified distinct concentrations of CD38, LAIR2, MANF and NRP2 proteins in MHO compared with MUO. Moreover, individual metabolic syndrome (MS) markers were linked to nine proteins (CD38, CPM, EDA2R, IL12, JAMB, KYNU, LAYN, MSR1 and SMOC2) in children with OW/OB. These proteins play crucial roles in diverse biological processes (e.g., angiogenesis, cholesterol transport, nicotinamide adenine dinucleotide (NAD+) catalysis and maintenance of blood–brain barrier) related to brain health.Conclusion: Our proteomics study suggests that cardiometabolic health (represented by MHO/MUO or individual MS markers) is associated with the concentration in plasma of several proteins involved in brain health. Larger‐scale studies are needed to contrast/confirm these findings, with CD38 standing out as a particularly noteworthy and robust discovery.

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/m(2)). BAT volume, F-18-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 (Delta 2h = 0.58 +/- 0.98 ng/mL; p = 0.007), GDF15 (Delta 2h = 19.63 +/- 46.2 pg/mL; p = 0.013), FGF21 (Delta 2h = 33.72 +/- 55.13 pg/mL; p = 0.003), and IL6 (Delta 1h = 1.98 +/- 3.56 pg/mL; p = 0.048) and reduced BMP8b (Delta 2h = -37.12 +/- 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Delta 2h: beta = 0.456; R-2 = 0.307; p = 0.001), but not with F-18-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 intra-assessment resting metabolic rate variability is related to cardiometabolic health, as suggested by previous literature. We studied whether that variability (expressed as coefficient of variation [CV; %]) for oxygen consumption (VO₂), carbon dioxide production (VCO₂), respiratory exchange ratio (RER), and resting energy expenditure (REE) is similar between men and women, and if is similarly associated with cardiometabolic risk factors. Gas exchange in 72 middle-aged adults was measured by indirect calorimetry. Anthropometrics and body composition, cardiorespiratory fitness, circulating cardiometabolic risk factors, and heart rhythm parameters were also determined. Men and women presented similar intra-assessment resting metabolic rate variability (all p > 0.05). Notably, in men, CV for RER was positively associated with BMI and adiposity (both standardized β = 0.35, Ps ≤ 0.048), while CVs for VO₂, VCO₂, and REE were negatively associated (standardized β ranged from −0.37 to −0.46, all p ≤ 0.036) with cardiometabolic risk factors. In women, CVs for VCO₂ and REE were negatively associated with adiposity (both standardized β = −0.36, Ps ≤ 0.041) and cardiometabolic risk Z-score (standardized β = −0.40 and −0.38, respectively, Ps ≤ 0.05). In conclusion, intra-assessment resting metabolic rate variability could be considered an indicator of cardiometabolic health in middle-aged adults.

Capsinoids may exert ergogenic effects on resistance exercises. However, the acute effects of capsinoids on neuromuscular performance in humans are unknown. Here, we aimed to investigate the acute effects of dihydrocapsiate on lower- and upper-body neuromuscular performance parameters in resistance-trained individuals. 25 young adults (n = 6 women; age = 26 +/- 3 years; body mass index = 24.3 +/- 2.8 kg/m2) with >= 1-year resistance training experience were included in this triple-blind (participants, intervention researchers, and data analysts were blinded), placebo-controlled, crossover study. Lower- and upper-body ballistic strength (countermovement jump [CMJ] height and bench press throw [BPT] peak velocity), maximum dynamic strength (estimated 1 repetition maximum in squat and bench press [BP]), and strength-endurance (mean set velocity [squat] and number of repetitions to failure [bench press]) were assessed in 2 independent sessions (>= 7 days separation). Participants ingested 12 mg of dihydrocapsiate or placebo 30 min before each trial. We found no significant differences between dihydrocapsiate and placebo conditions in ballistic strength, (CMJ height 33.20 +/- 8.07 vs 33.32 +/- 7.85 cm; BPT peak velocity 2.82 +/- 0.77 vs 2.82 +/- 0.74 m/s) maximal dynamic strength (estimated squat 1RM: 123.76 +/- 40.63 vs 122.66 +/- 40.97 kg; estimated BP 1RM: 99.47 +/- 43.09 vs 99.60 +/- 43.34 kg), and strength-endurance (squat mean set velocity 0.66 +/- 0.07 vs 0.66 +/- 0.05 m/s; number BP repetitions to failure 13.00 +/- 3.56 vs 13.00 +/- 4.78) (all P >= 0.703). We conclude that dihydrocapsiate does not acutely improve neuromuscular performance in trained young adults. Capsinoids - non-pungent analogs of capsaicin - have been recently proposed as potential ergogenic compounds in humans.However, the effects of a single dose of capsinoids on neuromuscular performance parameters in humans remains unknown.12 mg of dihydrocapsiate does not improve neuromuscular performance in resistance-trained young adults.Dihydrocapsiate should not be recommended as an ergogenic aid to acutely increase neuromuscular performance.

Circulating bile acids (BA) are signaling molecules that control glucose and lipid metabolism. However, the effects of acute exercise on plasma levels of BA in humans remain poorly understood. Here, we evaluate the effects of a bout of maximal endurance exercise (EE) and resistance exercise (RE) on plasma levels of BA in young, sedentary adults. Concentration of eight plasma BA was measured by liquid chromatography--tandem mass spectrometry before and 3, 30, 60, and 120 min after each exercise bout. Cardiorespiratory fitness (CRF) was assessed in 14 young adults (21.8 +/- 2.5 yo, 12 women); muscle strength was assessed in 17 young adults (22.4 +/- 2.5 yo, 11 women). EE transiently decreased plasma levels of total, primary, and secondary BA at 3 and 30 min after exercise. RE exerted a prolonged reduction in plasma levels of secondary BA (p < 0.001) that lasted until 120 min. Primary BA levels of cholic acid (CA) and chenodeoxycholic acid (CDCA) were different across individuals with low/high CRF levels after EE (p = 0.044); CA levels were different across individuals with low/high handgrip strength levels. High CRF individuals presented higher levels of CA and CDCA 120 min after exercise vs baseline (+77% and +65%) vs the low CRF group (-5% and -39%). High handgrip strength levels individuals presented higher levels of CA 120 min after exercise versus baseline (+63%) versus the low handgrip strength group (+6%). The study findings indicate that an individual's level of physical fitness can influence how circulating BA respond to both endurance and resistance exercise. Additionally, the study suggests that changes in plasma BA levels after exercising could be related to the control of glucose homeostasis in humans.

Background: Gut bacteria play a crucial role in the metabolism of bile acids (BA). Whether an association exists between the fecal microbiota composition and circulating BA levels in humans is poorly understood. Here, we investigated the relationship between fecal microbiota diversity and composition with plasma levels of BA in young adults. Methods: Fecal microbiota diversity/composition was analyzed with 16S rRNA sequencing in 80 young adults (74% women; 21.9 ± 2.2 years old). Plasma levels of BA were measured using liquid chromatography-tandem mass spectrometry. PERMANOVA and Spearman correlation analyses were used to investigate the association between fecal microbiota parameters and plasma levels of BA. Results: Fecal microbiota beta (P = 0.025) and alpha diversity indexes of evenness (rho = 0.237, P = 0.033), Shannon (rho = 0.313, P = 0.004), and inverse Simpson (rho = 0.283, P = 0.010) were positively associated with plasma levels of the secondary BA glycolithocholic acid (GLCA). The relative abundance of genera belonging to the Firmicutes and Bacteroidetes phyla was positively correlated with plasma levels of GLCA (all rho ≥ 0.225, P ≤ 0.049). However, the relative abundance of species from Firmicutes and Bacteroidetes phyla were negatively correlated with plasma levels of primary and secondary BA (all rho ≤ − 0.220, P ≤ 0.045), except for the relative abundance of Bacteroides vulgatus, Alistipes onderdonkii, and Bacteroides xylanisolvens species (Bacteroidetes phylum) that were positively correlated with the plasma levels of GLCA. Conclusions: The relative abundance of specific fecal bacteria species is associated with plasma levels of BA in young adults. However, further investigations are required to validate whether the composition of the gut microbiota can regulate the plasma concentrations of BA in humans.