Borja Martinez-Tellez

BACKGROUND: Cardiorespiratory fitness (CRF) is a strong predictor of mortality and noncommunicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified 2 signatures of CRF (1 metabolomic and 1 proteomic) from UK Biobank participants who completed a risk-stratified submaximal cycle ergometer test, with CRF estimated from the heart rate response to incremental workload. METHODS: These signatures were validated in an independent sample of UK participants with data on metabolomics (n=354 222) and proteomics (n=29 961) to investigate prospective associations with all-cause mortality and noncommunicable diseases. Prospective associations were evaluated using Cox proportional hazards models adjusted for age, sex, ethnicity, socioeconomic status, lifestyle factors (including smoking, alcohol intake, diet, and body mass index), and relevant medical history. RESULTS: Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed 2 novel signatures of CRF (1 metabolomic and 1 proteomic) that robustly reflect CRF levels (R ² : 0.50–0.60). Over an average of 9 years of follow-up, we observed 27 659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic signature of CRF was strongly associated with a 39% to 54% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (90% in both), cardiovascular disease (42%–47%), and colorectal cancer (33%–39%). Additionally, the proteomic signature of CRF was associated with a 17% lower risk of all-cause mortality, and with a 22% to 39% lower risk of type 2 diabetes and cardiovascular disease. CONCLUSIONS: Together, these findings indicate that circulating metabolites and proteins are associated with CRF and with subsequent risk of mortality and noncommunicable diseases.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity-related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and ≥3 years, anthropometric, metabolic, mental health and quality-of-life outcomes, cardiovascular morbidity and mortality, remission of obesity-related complications, serious adverse events and all-cause mortality. Sixty-six RCTs (66 comparisons) were identified – orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2) – enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all-cause mortality. In dedicated complication-specific trials, semaglutide and tirzepatide showed benefit on heart-failure-related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight-loss efficacy, complication profile and safety.

Aims: Cold exposure activates brown adipose tissue (BAT) and promotes thermogenic and metabolic adaptations. While BAT activation has been linked to improved cardiometabolic health, how acute cold exposure reshapes the circulating lipidome in humans remains incompletely understood. Materials and Methods: We profiled 656 plasma lipid species across 14 subclasses in 58 young sedentary adults (72% women) before and during a 2‐h cold exposure using mass spectrometry‐based lipidomics and assessed their associations with BAT volume, activity and mean radiodensity. Results: Here, we demonstrate that acute cold exposure increased circulating membrane‐associated phospholipids while decreasing triacylglycerol (TG) and phosphatidylethanolamine (PE) species, indicating a redistribution of lipid classes towards structural and signalling lipids. These lipid alterations were structurally selective, with both phospholipids and TG showing the largest shifts among species with shorter and less unsaturated acyl chains. Notably, cold‐induced reductions in circulating TG species were negatively correlated with BAT mean radiodensity, linking systemic lipid remodelling to BAT activation. Conclusions: These findings define a distinct lipidomic signature of acute cold exposure in humans and suggest that even short‐term BAT activation is associated with coordinated remodelling of circulating lipid networks. This lipid remodelling may reflect enhanced BAT lipid utilisation and contribute to the cardiometabolic benefits associated with cold exposure. Future studies are warranted in more diverse populations, including older individuals and those with obesity or type 2 diabetes, in whom BAT activity and lipid metabolism differ substantially.

Brown adipose tissue (BAT) is increasingly recognized as a metabolically active tissue in humans, although its physiological relevance remains incompletely understood. In rodents, BAT is well characterized, with interscapular BAT (iBAT) representing the main thermogenic depot. In contrast, the existence and persistence of iBAT in adult humans have long been overlooked. In this review, we synthesize anatomical, histological, imaging, and molecular evidence supporting the presence of a potentially active iBAT depot within the dorsocervical subcutaneous adipose tissue in humans. Gene expression and histological studies have conclusively identified dorsocervical subcutaneous adipose tissue as iBAT in human neonates. In adults, the persistence of this depot has been suggested by early histological observations, although definitive molecular confirmation is still lacking. More recent data from HIV‐1‐infected individuals report increased expression of BAT‐related markers in the dorsocervical region; however, histological analyses have not consistently confirmed the presence of iBAT in this population. In parallel, two independent cold‐induced ¹⁸ F‐FDG‐PET/CT studies have reported elevated glucose uptake in this area, with a higher prevalence in women. Taken together, these findings suggest that a dorsocervical subcutaneous adipose depot with BAT‐like characteristics may persist into adulthood, particularly in women. Nevertheless, targeted biopsy studies combined with molecular and cellular analyses, together with advanced PET‐CT imaging using tracers capable of assessing thermogenic activity in vivo, are required to clarify whether this tissue represents classical BAT, a beige adipose depot, or a developmentally retained adipose niche. Defining the identity and function of this depot would advance current concepts of human adipose tissue heterogeneity.

Objective To synthesise the evidence on the effects of exercise interventions in children and adolescents during and beyond cancer treatment, and to evaluate the methodological quality and certainty of this evidence. Design Umbrella review of systematic reviews with meta-analyses. Data source PubMed, Web of Science, Scopus, SPORTDiscus and CINAHL were searched from inception to January 2026. Eligibility criteria for selecting studies Systematic reviews with meta-analysis of controlled trials (randomised or non-randomised) evaluating exercise interventions in children and adolescents (≤19 years) during and beyond cancer treatment. Reviews without quantitative synthesis, those including only observational studies, or interventions where the isolated effect of exercise could not be determined were excluded. Results 19 systematic reviews with meta-analyses, including 53 primary studies (n=2361 participants), were identified, yielding 80 effect estimates. Attending to the most comprehensive meta-analyses, exercise induced significant benefits on cardiorespiratory fitness (mean difference (MD) 6.92% (95% CI 1.01% to 12.82%)), cognitive function (standardised mean difference (SMD) 0.26 (95% CI 0.08 to 0.44)) and cognitive performance (SMD 0.41 (95% CI 0.17 to 0.65)), with moderate certainty of evidence. Exercise also induced significant benefits on muscle strength (SMD 0.81 (95% CI 0.05 to 1.57)), functional mobility (MD −1.17 s (95% CI −1.86 to −0.49)) and cancer-related fatigue (SMD −0.62 (95% CI −1.21 to −0.03)), although the certainty was low or very low. These effects were observed across meta-analyses focused exclusively on studies conducted during treatment (n=26), after treatment (n=3) or both (n=51). In contrast, no significant effects of exercise were observed for depression, bone mineral density, health-related quality of life, anthropometry or other clinical outcomes (such as mortality, relapse risk and withdrawal rates). Conclusion Exercise appears to be a beneficial intervention in childhood cancer for improving some physical, cognitive and psychosocial outcomes. However, more high-quality research is warranted to strengthen clinical recommendations and inform personalised exercise prescriptions, given that the certainty of evidence remains variable and overall low across outcomes. PROSPERO registration number CRD420251031412.

Background: Gut bacteria have been implicated in a wide range of health conditions, yet their potential role in preventing and treating muscle-wasting disorders remains largely unexplored. Objective: We aimed to investigate whether specific gut microbial species are associated with muscle strength and to explore underlying mechanisms linking the gut microbiota to muscle health. Design: We conducted metagenomic analyses in cohorts of younger and older adults extensively phenotyped for muscle strength. Associations were tested between bacterial taxa and performance measures. Causality was assessed by oral supplementation of candidate species in antibiotic-treated mice. Metabolomic profiling and muscle phenotyping were performed to elucidate mechanisms. Results: The relative abundance of Roseburia inulinivorans , but not other Roseburia species, was positively associated with multiple strength measures including handgrip, leg press and bench press in humans. Supplementation of R. inulinivorans in mice significantly enhanced forelimb grip strength, whereas other Roseburia species had no effect. Metabolomic analyses revealed that R. inulinivorans reduced amino acid concentrations in the caecum and plasma, while activating the purine and pentose phosphate pathway in muscle. These changes coincided with increased muscle fibre size and a shift from type I to type II fibres. Accordingly, we observed that the relative abundance of R. inulinivorans is lower in older adults compared with young adults. Conclusion: R. inulinivorans emerges as a species-specific modulator of muscle strength, linking gut microbiota to muscle metabolism and function. These findings support its potential as a probiotic candidate for nutraceutical interventions targeting age-related muscle-wasting diseases. Trial registration number: NCT02365129 .

Purpose : Lactate has historically been mischaracterized as a metabolic byproduct associated with fatigue. The lactate shuttle paradigm describes its role in substrate exchange between glycolytic and oxidative tissues. Recent evidence has highlighted lactate as a key regulator of systemic energy metabolism and cellular signaling. While endogenous lactate production and clearance mechanisms during exercise are well established, the potential of exogenous lactate as an ergogenic fuel remains largely unexplored. Here, we aim to (1) synthesize current knowledge and discuss the mechanistic pathways through which exogenous lactate supplementation may enhance endurance performance in humans and (2) critically appraise the current limitations of high-dose exogenous lactate administration and outline novel formulation strategies, adapted from established sports nutrition practices, that warrant future investigation. Conclusion : Exogenous lactate supplementation holds promise as a novel fueling strategy to enhance endurance performance. However, human trials to date have failed to demonstrate performance benefits, potentially due to the low doses and bolus administration strategies employed. Future research should therefore focus on developing formulations capable of safely delivering physiologically relevant doses and evaluating their efficacy in well-controlled human studies.

Background: Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified two signatures of CRF (one metabolomic and one proteomic) from UK Biobank participants who completed a risk-stratified submaximal cycle ergometer test, with CRF estimated from the heart rate response to incremental workload. Methods: These signatures were validated in an independent sample of UK participants with data on metabolomics (n=354,222) and proteomics (n=29,961) to investigate prospective associations with all-cause mortality and non-communicable diseases. Prospective associations were evaluated using Cox proportional hazards models adjusted for age, sex, ethnicity, socioeconomic status, lifestyle factors (including smoking, alcohol intake, diet, and BMI), and relevant medical history. Results: Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed two novel signatures of CRF (one metabolomic and one proteomic) that robustly reflect CRF levels (R ² : 0.50-0.60). Over an average of 9 years of follow-up, we observed 27,659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic signature of CRF was strongly associated with a 39–54% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (90% in both), cardiovascular disease (42–47%), and colorectal cancer (33–39%). Additionally, the proteomic signature of CRF was associated with a 17% lower risk of all-cause mortality, and with a 22–39% lower risk of type 2 diabetes and cardiovascular disease. Conclusion: Together, these findings indicate that circulating metabolites and proteins are associated with CRF and with subsequent risk of mortality and non-communicable diseases.

Brown adipose tissue (BAT) is a metabolically highly active tissue that dissipates energy stored within its intracellular triglyceride droplets as heat. Others have previously utilized MRI to show that the fat fraction of human supraclavicular BAT (scBAT) decreases upon cold exposure, compared with baseline (i.e., pre‐cooling). However, comparisons to a control group that was not exposed to cold are largely lacking. We recently developed a non‐invasive dynamic MRI protocol that allows for quantifying scBAT fat fraction changes over time. Here, we aimed to study the effect of cold exposure versus thermoneutrality on fat fraction changes in human scBAT. Ten young (mean age: 21.5 ± 0.7 years), lean (mean BMI: 21.7 ± 0.5 kg/m ² ), 12 h‐fasted volunteers (9 females; 1 male) underwent up to 70 consecutive MRI scans each on two separate study visits in a cross‐over design. Participants were exposed to a temperature of 32°C for 10 scans (i.e., ±16 min), which was then either lowered to 18°C (i.e., cold exposure) or was maintained at 32°C (i.e., thermoneutrality). Dynamic fat fraction changes were quantified, and self‐reported thermal perception scores were monitored. The fat fraction in scBAT decreased over time upon cold exposure ( r = −.222, p < .001). Interestingly however, we also observed a decrease in scBAT fat fraction over time upon thermoneutrality ( r = −.212, p < .001). No difference was observed between the two temperature conditions ( p = .55), while self‐reported thermal perception scores were consistently higher (i.e., colder) upon cold exposure. In the trapezius muscle and the humerus bone as control tissues, the fat fraction was unaffected in both temperature conditions. The fat fraction in subcutaneous white adipose tissue (sWAT) however, also decreased over time upon cold exposure ( r = −.270, p < .001) and during thermoneutrality ( r = −.190, p < .001), again with no difference ( p = .92) between the two temperature conditions. In conclusion, our results show that in 12 h‐fasted, healthy individuals cold exposure and thermoneutrality similarly reduce the fat fraction within scBAT and sWAT. While we interpret that the cold exposure was sufficient to induce thermogenesis, we suggest that an increased lipolytic activity within adipocytes, as a consequence of fasting, may be the primary cause of the decreased fat fraction in both sWAT and scBAT in our study. The current study highlights the potential influence of fasting on the fat fraction in scBAT and stresses the importance of inclusion of a thermoneutral control group in studies investigating the BAT‐modulating effect of cold exposure.