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Equine recurrent uveitis (ERU) is a spontaneously occurring autoimmune disease and one of the leading causes of blindness in horses worldwide. Its similarities to autoimmune-mediated uveitis in humans make it a unique spontaneous animal model for this disease. Although many aspects of ERU pathogenesis have been elucidated, it remains not fully understood and requires further research. CD4+ T cells have been a particular focus of research. In a previous study, we showed metabolic alterations in CD4+ T cells from ERU cases, including an increased basal oxygen consumption rate (OCR) and elevated compensatory glycolysis. To further investigate the underlying reasons for and consequences of these metabolic changes, we quantified reactive oxygen species (ROS) production in CD4+ T cells from ERU cases and compared it to healthy controls, revealing significantly higher ROS production in ERU-affected horses. Additionally, we aimed to define mitochondrial fuel oxidation of glucose, glutamine, and long-chain fatty acids (LCFAs) and identified significant differences between CD4+ T cells from ERU cases and controls. CD4+ T cells from ERU cases showed a lower dependency on mitochondrial glucose oxidation and greater metabolic flexibility for the mitochondrial oxidation of glucose and LCFAs, indicating an enhanced ability to switch to alternative fuels when necessary. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic flexibility (MetF), defined as the ability to switch between fat and glucose oxidation, is increasingly recognised as a critical marker for assessing responses to dietary interventions. Previously, we showed that the consumption of multifibre bread improved insulin sensitivity and reduced low‐density lipoprotein cholesterol (LDLc) levels in overweight and obese individuals. As a secondary objective, we aimed to explore whether our intervention could also improve MetF. Methods: In this study, 39 subjects at cardiometabolic risk participated in a double‐blind, randomised, crossover trial lasting 8 weeks, repeated twice. During each phase, participants consumed either 150 g of standard bread daily or bread enriched with a mixture of seven dietary fibres. MetF response was assessed using a mixed‐meal tolerance test (MMTT), analysing changes in respiratory quotient (∆RQ) measured using indirect calorimetry. Results: Although there were no significant differences in ∆RQ changes induced by dietary fibre between the two diets, these changes were positively correlated with postprandial triglyceride excursion (∆TG) at baseline. Subgroup analysis of baseline fasting and postprandial plasma metabolites was conducted to characterise MetF responders. These responders exhibited higher baseline fasting LDLc levels and greater post‐MMTT ∆TG. Conclusion: In conclusion, although dietary fibres did not directly impact MetF in this study, our findings highlight potential determinants of MetF response, warranting further investigation in dedicated future interventions. Highlights: The term 'metabolic flexibility' (MetF) was initially used to describe the ability of helminths to generate energy through either aerobic respiration or anaerobic respiration, enabling them to adapt to environmental changes. This concept was later applied to human metabolism, emphasising the body's capacity to switch between different energy sources, such as carbohydrates and fats, based on energy requirements.MetF has been studied in the context of transitions between fasting and fed states, or in response to insulin stimulation. It refers to the body's ability to adapt its energy utilisation in response to changing metabolic demands.Research has shown that insulin resistance, often linked to type 2 diabetes and obesity, may be associated with reduced MetF, characterised by altered patterns of carbohydrate and fat oxidation. [ABSTRACT FROM AUTHOR]

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (THs), through their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, which leads to a reduction in energy expenditure as well as in lipid and glucose metabolism. The objective of this study was to evaluate whether the metabolic deregulations induced by hypothyroidism could be avoided through regulatory mechanisms involved in metabolic flexibility. To this end, the response to induced hypothyroidism was compared in males from two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and C57BL/6J mice, which are prone to DIO. The results show that propylthiouracil (PTU)-induced hypothyroidism led to metabolic deregulations, particularly a reduction in hepatic lipid synthesis in both strains. Furthermore, in contrast to the C57BL/6J mice, the WSB/EiJ mice were resistant to the metabolic dysregulations induced by hypothyroidism, mainly through enhanced lipid metabolism in their adipose tissue. Indeed, WSB/EiJ mice compensated for the decrease in hepatic lipid synthesis by mobilizing lipid reserves from white adipose tissue. Gene expression analysis revealed that hypothyroidism stimulated the hypothalamic orexigenic circuit in both strains, but there was unchanged melanocortin 4 receptor (Mc4r) and leptin receptor (LepR) expression in the hypothyroid WSB/EiJ mice strain, which reflects their adaptability to maintain their body weight, in contrast to C57BL/6J mice. Thus, this study showed that WSB/EiJ male mice displayed a resistance to the metabolic dysregulations induced by hypothyroidism through compensatory mechanisms. This highlights the importance of metabolic flexibility in the ability to adapt to disturbed circulating TH levels. [ABSTRACT FROM AUTHOR]

Purpose: This study examined metabolic flexibility with respect to fat metabolism during exercise in children who are lean (n=11; 10.9[0.9] y) and overweight/obese (OW/OB; n=9; 10.3[1.2] y). Method: Participants were grouped based on body mass index percentiles for age and sex. Groups were mixed in age and sex. Participants completed two 20-minute exercise bouts on a cycle ergometer, separated by a 10-minute rest. Bout 1 consisted of 10 minutes at 50% VO2peak and 10 minutes at 75% VO2peak. Bout 2 was 20 minutes at 50% VO2peak. Absolute fat oxidation rate (FOR), FOR relative to body mass, FOR relative to fat-free mass, and proportional fat use were measured at 10 minutes of bout 1 and 5, 10, 15, and 20 minutes of bout 2. Results: Absolute FOR was higher in the OW/OB group (range: 117.8 [55.1]–206.2 [48.3] mg·min−1) than in the lean group (81.1 [32.2]–152.2 [38.2] mg·min−1); however, there were no significant main effects for group or significant interactions for proportional fat use, FOR relative to body mass, or FOR relative to fat-free mass. Conclusion: Children in this age range who are overweight/obese do not display impaired metabolic flexibility with respect to fat metabolism during exercise. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance is a frequent precursor of typical obesity and metabolic syndrome complications. However, accurate diagnosis remains elusive because of its pathophysiological complexity and heterogeneity. Herein, we have explored the utility of insulin secretion dynamics in response to an oral glucose tolerance test as a surrogate marker to identify distinct metabotypes of disease severity. Methods: The study population consisted of children with obesity and insulin resistance, stratified according to the post-challenge insulin peak timing (i.e., early, middle, and late peak), from whom fasting and postprandial plasma and erythrocytes were collected for metabolomics analysis. Results: Children with late insulin peak manifested worse cardiometabolic health (i.e., higher blood pressure, glycemia, and HOMA-IR scores) than early responders. These subjects also showed more pronounced changes in metabolites mirroring failures in energy homeostasis, oxidative stress, metabolism of cholesterol and phospholipids, and adherence to unhealthy dietary habits. Furthermore, delayed insulin peak was associated with impaired metabolic flexibility, as reflected in compromised capacity to regulate mitochondrial energy pathways and the antioxidant defense in response to glucose overload. Conclusions: Altogether, these findings suggest that insulin resistance could encompass several phenotypic subtypes characterized by graded disturbances in distinctive metabolic derangements occurring in childhood obesity, which serve as severity predictive markers. [ABSTRACT FROM AUTHOR]

Aim: To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole‐body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission. Methods: 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non‐treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2peak). Muscle biopsies were obtained at rest and immediately post‐exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3‐hydroxyacyl‐CoA dehydrogenase (HAD) activity were assessed. Results: HT showed higher absolute mitochondrial respiratory capacity and post‐exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT. Conclusion: Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT. [ABSTRACT FROM AUTHOR]

Metabolic flexibility (MetFlex) describes the ability to respond and adapt to changes in metabolic demand and substrate availability. The relationship between physical (in)activity and MetFlex is unclear. This study aimed to determine whether sedentary time, physical activity (PA), and cardiorespiratory fitness associate with MetFlex. Sedentary time, standing, and PA were measured with accelerometers for 4 weeks in 64 sedentary adults with metabolic syndrome [37 women, 27 men; 58.3 (SD 6.8) years]. Fitness (VO2max; mL·kg-1·min-1) was measured with graded maximal cycle ergometry. MetFlex was assessed with indirect calorimetry as the change in respiratory exchange ratio (βRER) from fasting to insulin stimulation with hyperinsulinemic-euglycemic clamp and from low-intensity to maximal exercise. Carbohydrate (CHOox) and fat oxidation (FATox) were calculated from respiratory gases. High sedentary time associated with higher fasting RER [β = 0.35 (95% confidence interval: 0.04, 0.67)], impaired insulin-stimulated MetFlex (ΔRER) [β=-0.41 (-0.72, -0.09)], and lower fasting FATox [β=-0.36 (-0.67, -0.04)]. Standing associated with lower fasting RER [β=-0.32 (-0.62, -0.02)]. Higher standing time and steps/day associated with higher fasting FATox [β = 0.31 (0.01, 0.61), and b = 0.26 (0.00, 0.53)]. Light-intensity and total PA associated with better insulin-stimulated MetFlex [β = 0.33 (0.05, 0.61)], and b = 0.33 (0.05, 0.60)]. Higher VO2max associated with higher CHOox during maximal exercise [β = 0.81 (0.62, 1.00)], as well as during insulin stimulation [β = 0.43 (0.13, 0.73)]. P values are less than 0.05 for all associations. Sedentary time and PA associate with MetFlex. Reducing sitting and increasing PA of even light intensity might aid in the prevention of metabolic diseases in risk populations through their potential effects on energy metabolism. [ABSTRACT FROM AUTHOR]

Age-associated declines in aerobic capacity promote the development of various metabolic diseases. In rats selectively bred for high/low intrinsic aerobic capacity, greater aerobic capacity reduces susceptibility to metabolic disease while increasing longevity. However, little remains known how intrinsic aerobic capacity protects against metabolic disease, particularly with aging. Here, we tested the effects of aging and intrinsic aerobic capacity on systemic energy expenditure, metabolic flexibility and mitochondrial protein synthesis rates using 24-month-old low-capacity (LCR) or high-capacity runner (HCR) rats. Rats were fed low-fat diet (LFD) or high-fat diet (HFD) for eight weeks, with energy expenditure (EE) and metabolic flexibility assessed utilizing indirect calorimetry during a 48 h fast/re-feeding metabolic challenge. Deuterium oxide (D2O) labeling was used to assess mitochondrial protein fraction synthesis rates (FSR) over a 7-day period. HCR rats possessed greater EE during the metabolic challenge. Interestingly, HFD induced changes in respiratory exchange ratio (RER) in male and female rats, while HCR female rat RER was largely unaffected by diet. In addition, analysis of protein FSR in skeletal muscle, brain, and liver mitochondria showed tissue-specific adaptations between HCR and LCR rats. While brain and liver protein FSR were altered by aerobic capacity and diet, these effects were less apparent in skeletal muscle. Overall, we provide evidence that greater aerobic capacity promotes elevated EE in an aged state, while also regulating metabolic flexibility in a sex-dependent manner. Modulation of mitochondrial protein FSR by aerobic capacity is tissue-specific with aging, likely due to differential energetic requirements by each tissue. [ABSTRACT FROM AUTHOR]

Introduction: Desulfovibrio vulgaris Hildenborough is a gram-negative anaerobic bacterium belonging to the sulfate-reducing bacteria that exhibits highly versatile metabolism. By switching from one energy mode to another depending on nutrients availability in the environments„ it plays a central role in shaping ecosystems. Despite intensive efforts to study D. vulgaris energy metabolism at the genomic, biochemical and ecological level, bioenergetics in this microorganism remain far from being fully understood. Alternatively, metabolic modeling is a powerful tool to understand bioenergetics. However, all the current models for D. vulgaris appeared to be not easily adaptable to various environmental conditions. Methods: To lift off these limitations, here we constructed a novel transparent and robust metabolic model to explain D. vulgaris bioenergetics by combining whole-cell proteomic analysis with modeling approaches (Flux Balance Analysis). Results: The iDvu71 model showed over 0.95 correlation with experimental data. Further simulations allowed a detailed description of D. vulgaris metabolism in various conditions of growth. Altogether, the simulations run in this study highlighted the sulfate-to-lactate consumption ratio as a pivotal factor in D. vulgaris energy metabolism. Discussion: In particular, the impact on the hydrogen/formate balance and biomass synthesis is discussed. Overall, this study provides a novel insight into D. vulgaris metabolic flexibility. [ABSTRACT FROM AUTHOR]

Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

People with spinal cord injury (SCI) tend to be more sedentary and increase fat accumulation, which could have a negative influence on metabolic flexibility. The aim of this study was to investigate the capacity to oxidize fat in a homogenous sample of men with thoracic SCI compared with healthy noninjured men during an arm cycling incremental test. Forty-one men, 21 with SCI and 20 noninjured controls, performed an incremental arm cycling test to determine peak fat oxidation (PFO) and the intensity of exercise that elicits PFO (Fatmax). PFO was expressed in absolute values (g/min) and relative to whole-body and upper-body lean mass ([mg·min-1].kg-1) through three different models (adjusting by cardiorespiratory fitness and fat mass). Gross mechanical efficiency was also calculated. PFO was higher in SCI than in noninjured men (0.27 + 0.07 vs. 0.17 + 0.07 g/min; 5.39 + 1.30 vs. 3.29 f 1.31 [mg·min-1]·kg-1 whole-body lean mass; 8.28 + 2.11 vs. 5.08 * 2.12 [mg·min-111·kg-1 upper-body lean mass). Fatmax was found at a significantly higher percentage of VOzpeak in men with SCI (33.6% + 8.2% vs. 23.696 * 6.4%). Differences persisted and even increased in the fully adjustment model and at any intensity. Men with SCI showed significantly higher gross mechanical efficiency at 35 and 65 W than the noninjured group. Men with SCI showed higher fat oxidation when compared with noninjured men at any intensity, even increased after full adjustment for lean mass, fat mass, and cardiorespiratory fitness. These findings suggest that SCI men could improve their metabolic flexibility and muscle mass for greater efficiency, not being affected by their fat accumulation. [ABSTRACT FROM AUTHOR]

We propose a novel method for assessing metabolic flexibility (MF) through indirect calorimetry. A total of twenty healthy volunteers (10 females; 10 males) aged 45–65 were categorized into a Low-Intensity activity group (LI, 0–1 session of 1 h per week) and a High-Intensity activity group (HI, 5–6 sessions of 2 h per week). Volunteers underwent a stepwise exercise test on a cycle ergometer, connected to a calorimeter, to examine respiratory gas exchange to evaluate peak fatty acid Oxidation (PFO) and peak carbohydrate oxidation (PCO). Circulating peroxisome proliferator-activated receptor α (PPARα) biomarkers, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio and N-oleoylethanolamine (OEA), and the endocannabinoid- 2-arachidonoylglycerol (2-AG), were evaluated. We developed two MF parameters: the MF index (MFI), calculated by the product of PFO normalized per kg of fat-free mass (FFM) and the percentage of VO2max at PFO, and the peak energy substrates' oxidation (PESO), computed by summing the kilocalories from the PFO and PCO, normalized per kg FFM. The MFI and PESO were significantly different between the HI and LI groups, showing strong correlations with the circulating bioactive substances. Higher DHA/EPA ratio (p ≤ 0.05) and OEA (p ≤ 0.01), but lower 2-AG levels (p ≤ 0.01) were found in the HI group. These new parameters successfully established a functional link between MF and the balance of PPARα/endocannabinoid systems. [ABSTRACT FROM AUTHOR]

Combat sports athletes seeking a competitive edge often engage in weight management practices to become larger than their opponents, which ultimately includes periods of gradual weight loss, rapid weight loss, and weight regain. This pattern of weight loss and regain is known as weight cycling and often includes periods of low energy availability, making combat sports athletes susceptible to metabolic dysfunction. This narrative review represents an effort to explore the metabolic perturbations associated with weight cycling and outline the short-, medium-, and long-term effects on metabolic flexibility, function, and health. The short-term effects of rapid weight loss, such as a reduced metabolic rate and alterations to insulin and leptin levels, may prelude the more pronounced metabolic disturbances that occur during weight regain, such as insulin resistance. Although definitive support is not currently available, this cycle of weight loss and regain and associated metabolic changes may contribute to metabolic syndrome or other metabolic dysfunctions over time. [ABSTRACT FROM AUTHOR]

This comprehensive review explores the critical role of fatty acid (FA) metabolism in cardiac diseases, particularly heart failure (HF), and the implications for therapeutic strategies. The heart's reliance on ATP, primarily sourced from mitochondrial oxidative metabolism, underscores the significance of metabolic flexibility, with fatty acid oxidation (FAO) being a dominant source. In HF, metabolic shifts occur with an altered FA uptake and FAO, impacting mitochondrial function and contributing to disease progression. Conditions like obesity and diabetes also lead to metabolic disturbances, resulting in cardiomyopathy marked by an over-reliance on FAO, mitochondrial dysfunction, and lipotoxicity. Therapeutic approaches targeting FA metabolism in cardiac diseases have evolved, focusing on inhibiting or stimulating FAO to optimize cardiac energetics. Strategies include using CPT1A inhibitors, using PPARα agonists, and enhancing mitochondrial biogenesis and function. However, the effectiveness varies, reflecting the complexity of metabolic remodeling in HF. Hence, treatment strategies should be individualized, considering that cardiac energy metabolism is intricate and tightly regulated. The therapeutic aim is to optimize overall metabolic function, recognizing the pivotal role of FAs and the need for further research to develop effective therapies, with promising new approaches targeting mitochondrial oxidative metabolism and FAO that improve cardiac function. [ABSTRACT FROM AUTHOR]

The influence of menstrual cycle phase and fitness status on metabolism during high-intensity interval exercise (HIIE) was assessed. Twenty-five females (24.4 (3.6) years) were categorized by normal menstrual cycle (n = 14) vs. oral contraceptive (OC) use (n = 11) and by aerobic fitness, high-fitness females (HFF; n = 13) vs. low-fitness females (LFF; n = 12). HIIE was four sets of four repetitions with a 3 min rest between intervals on a cycle ergometer at a power output halfway between the ventilatory threshold and V̇O2peak and performed during follicular (FOL: days 2–7 or inactive pills) and luteal phases (LUT: day ∼21 or 3rd week of active pills). Substrate oxidation was assessed via indirect calorimetry, blood lactate via finger stick, and recovery of skeletal muscle oxidative metabolism (mV̇O2) via continuous-wave near-infrared spectroscopy. HFF oxidized more fat (g·kg−1) during the full session (FOL: p = 0.050, LUT: p = 0.001), high intervals (FOL: p = 0.048, LUT: p = 0.001), low intervals (FOL: p = 0.032, LUT: p = 0.024), and LUT recovery (p = 0.033). Carbohydrate oxidation area under the curve was greater in HFF during FOL (FOL: p = 0.049, LUT: p = 0.124). Blood lactate was lower in LFF in FOL (p ≤ 0.05) but not in LUT. Metabolic flexibility (Δ fat oxidation g·kg−1·min−1) was greater in HFF than LFF during intervals 2–3 in FOL and 1–4 in LUT (p ≤ 0.05). Fitness status more positively influences exercise metabolic flexibility during HIIE than cycle phase or OC use. [ABSTRACT FROM AUTHOR]

High versus low aerobic capacity significantly impacts the risk for metabolic diseases. Rats selectively bred for high or low intrinsic aerobic capacity differently modify hepatic bile acid metabolism in response to high-fat diets (HFDs). Here we tested if a bile acid sequestrant would alter hepatic and whole body metabolism differently in rats with high and low aerobic capacity fed a 1-wk HFD. Male rats (8 mo of age) that were artificially selected to be high (HCR) and low-capacity runners (LCR) with divergent intrinsic aerobic capacities were transitioned from a low-fat diet (LFD, 10% fat) to an HFD (45% fat) with or without a bile acid sequestrant (BA-Seq, 2% cholestyramine resin) for 7 days while maintained in an indirect calorimetry system. HFD þ BA-Seq increased fecal excretion of lipids and bile acids and prevented weight and fat mass gain in both strains. Interestingly, HCR rats had increased adaptability to enhance fecal bile acid and lipid loss, resulting in more significant energy loss than their LCR counterpart. In addition, BA-Seq induced a greater expression of hepatic CYP7A1 gene expression, the rate-limiting enzyme of bile acid synthesis in HCR rats both on HFD and HFD þ BA-Seq diets. HCR displayed a more significant reduction of RQ in response to HFD than LCR, but HFD þ BA-Seq lowered RQ in both groups compared with HFD alone, demonstrating a pronounced impact on metabolic flexibility. In conclusion, BA-Seq provides uniform metabolic benefits for metabolic flexibility and adiposity, but rats with higher aerobic capacity display adaptability for hepatic bile acid metabolism. [ABSTRACT FROM AUTHOR]

Background: The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the-art proton nuclear magnetic resonance spectrometry (1H-NMRS) metabolomics profiling, that androgen excess in women induces a certain masculinization of postprandial metabolism that is modulated by obesity. Materials and methods: Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity. Patients were submitted to isocaloric separate glucose, lipid and protein oral challenges in alternate days and fasting and postprandial serum samples were submitted to 1H-NMRS metabolomics profiling for quantification of 36 low-molecular-weight polar metabolites. Results: The largest postprandial changes were observed after glucose and protein intake, with lipid ingestion inducing smaller differences. Changes after glucose intake consisted of a marked increase in carbohydrates and byproducts of glycolysis, and an overall decrease in byproducts of proteolysis, lipolysis and ketogenesis. After the protein load, most amino acids and derivatives increased markedly, in parallel to an increase in pyruvate and a decrease in 3-hydroxybutyric acid and glycerol. Obesity increased β- and d-glucose and pyruvate levels, with this effect being observed mostly after glucose ingestion in women with PCOS. Regardless of the type of macronutrient, men presented increased lysine and decreased 3-hydroxybutyric acid. In addition, non-obese men showed increased postprandial β-glucose and decreased pyroglutamic acid, compared with non-obese control women. We observed a common pattern of postprandial changes in branched-chain and aromatic amino acids, where men showed greater amino acids increases after protein intake than control women and patients with PCOS but only within the non-obese participants. Conversely, this increase was blunted in obese men but not in obese women, who even presented a larger increase in some amino acids compared with their non-obese counterparts. Interestingly, regardless of the type of macronutrient, only obese women with PCOS showed increased leucine, lysine, phenylalanine and tryptophan levels compared with non-obese patients. Conclusions: Serum 1H-NMRS metabolomics profiling indicated sexual dimorphism in the responses to oral macronutrient challenges, which were apparently driven by the central role of postprandial insulin effects with obesity, and to a lesser extent PCOS, exerting modifying roles derived from insulin resistance. Hence, obesity impaired metabolic flexibility in young adults, yet sex and sex hormones also influenced the regulation of postprandial metabolism. Plain English Summary: The polycystic ovary syndrome (PCOS) is a common endocrine disorder in women. PCOS is associated with diabetes, obesity and cardiometabolic disease. Mild excess of androgens (male hormones) characterize PCOS, and facilitate that body fat accumulates in the visceral abdominal area. Visceral fat promotes insulin resistance increasing the risk for diabetes and cardiometabolic disease, and further androgen excess. We here explored intermediate metabolism after the separate administration of either carbohydrates, fats or proteins, in young adult women with or without PCOS and in men, using state-of-the-art proton nuclear magnetic resonance metabolomics profiling. Results suggest that postprandial metabolomics profiles reflect mostly insulin actions, with changes derived from insulin resistance being more important with obesity but also being influenced by male sex and PCOS in women. Highlights: We studied postprandial metabolomics profiles after separate macronutrient challenges. Changes in these profiles derived from postprandial insulin effects and insulin resistance. These changes translate metabolic flexibility. Obesity impaired metabolic flexibility in young adults. Sex, sex hormones and PCOS also influenced postprandial metabolism. [ABSTRACT FROM AUTHOR]

The editorial discusses breakthroughs in tumor stem cell research, focusing on signaling pathways that regulate cancer stem cell (CSC) behavior and the role of cell fusion in tumor development and metastasis. It highlights the importance of understanding the interaction between cancer-associated fibroblasts (CAFs) and prostate cancer stem cells (PCSCs) in the tumor microenvironment. The research emphasizes the complexity of CSCs, their metabolic flexibility, and immune evasion mechanisms, posing challenges for targeted therapy. By targeting specific markers, disrupting metabolic pathways, and countering immune evasion, more effective treatments for cancer may be developed. [Extracted from the article]

The editorial discusses breakthroughs in tumor stem cell research, focusing on signaling pathways that regulate cancer stem cells (CSCs) and the role of cell fusion in tumor development and metastasis. It highlights the importance of understanding the interaction between cancer-associated fibroblasts (CAFs) and prostate cancer stem cells (PCSCs) in the tumor microenvironment. The research emphasizes the complexity of CSCs, their metabolic flexibility, and immune evasion mechanisms, posing challenges for targeted therapy. By targeting specific markers, disrupting metabolic pathways, and countering immune evasion, more effective treatments for cancer may be developed. [Extracted from the article]

This article discusses breakthroughs in tumor stem cell research, focusing on the signaling pathways and mechanisms that regulate cancer stem cells (CSCs). The article highlights the importance of understanding these pathways in order to develop targeted therapies for eliminating CSCs and treating cancer. It also explores the role of cell fusion in tumor development and metastasis, as well as the complex interaction between cancer-associated fibroblasts (CAFs) and prostate cancer stem cells (PCSCs) in the tumor microenvironment. The article concludes by emphasizing the need for further research and innovative perspectives to advance cancer therapy and improve patient outcomes. [Extracted from the article]

Summary: The greater duckweed (Spirodela polyrhiza 7498) exhibits trophic diversity (photoautotrophic, heterotrophic, photoheterotrophic, and mixotrophic growth) depending on the availability of exogenous organic carbon sources and light.Here, we show that the ability to transition between various trophic growth conditions is an advantageous trait, providing great phenotypic plasticity and metabolic flexibility in S. polyrhiza 7498.By comparing S. polyrhiza 7498 growth characteristics, metabolic acclimation, and cellular ultrastructure across these trophic modes, we show that mixotrophy decreases photosynthetic performance and relieves the CO2 limitation of photosynthesis by enhancing the CO2 supply through the active respiration pathway. Proteomic and metabolomic analyses corroborated that S. polyrhiza 7498 increases its intracellular CO2 and decreases reactive oxygen species under mixotrophic and heterotrophic conditions, which substantially suppressed the wasteful photorespiration and oxidative‐damage pathways. As a consequence, mixotrophy resulted in a higher biomass yield than the sum of photoautotrophy and heterotrophy.Our work provides a basis for using trophic transitions in S. polyrhiza 7498 for the enhanced accumulation of value‐added products. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the impact of 4 weeks, 16:8 time restricted eating (TRE) on markers of metabolic health and 10-km time trial (TT) performance in middle-age male cyclists. Subjects (n = 12; age, 40–60 years; V̇o2peak, 41.8 ± 5.6 ml·kg−1·min−1) consisting of individuals following a habitual Western diet completed a familiarization and 2 experimental trials [PRE] and [POST]. Following habitual Western diet without TRE, anthropometric measures were assessed, followed by completion of a graded exercise test and 10-km TT. Subjects then adhered to a 4-week TRE protocol where all calories had to be consumed within a self-selected 8-hour window and then returned for repeat testing. Although self-reported caloric intake did not statistically change PRE to POST, body mass (PRE, 83.2 ± 13.4 vs. POST, 80.7 ± 12.6 kg), fat mass (∼2.5 kg), and blood pressure (systolic, 8 mm Hg; diastolic, 4 mm Hg) were all significantly lower POST (all p < 0.05), with no changes in fat-free mass. Furthermore, fat oxidation significantly increased (PRE, 0.36 ± 0.03 vs. POST, 0.42 ± 0.03 g·min−1; p = 0.04) following the TRE intervention and 10-km TT performance improved by ∼2 minutes POST (PRE, 29.7 ± 7.3 vs. POST, 27.4 ± 5.5 minutes; p = 0.02). Overall, our data demonstrated that middle-age male cyclists adhering to a 4-week TRE protocol can improve their body composition profile and 10-km TT performance without detriments to fat-free mass. [ABSTRACT FROM AUTHOR]

Endurance exercise training and weight loss (WL) have been associated with changes in fat oxidation. However, there is limited evidence investigating the impact of sprint interval training (SIT)‐induced WL on fat oxidation in adults. To investigate the impact of SIT with or without WL on fat oxidation, 34 adults aged 19–60 years (males, n = 15) took part in 4‐week SIT. SIT consisted of 30‐s Wingates starting with two intervals and working up to four interspersed with 4 min of active recovery. Fat oxidation was estimated via indirect calorimetry using a metabolic cart during submaximal cycling. Following the intervention, participants were classified into a WL group (weight change >0 kg) or a non‐WL group (weight change ≤0 kg). No difference in resting fat oxidation (p = 0.642) and respiratory exchange ratio (RER) (p = 0.646) were observed between the groups. There was a significant interaction for the WL group with increased submaximal fat oxidation usage (p = 0.005) and decreased submaximal RER over the duration of the study (p = 0.017). When adjusted for baseline weight and sex, submaximal fat oxidation usage remained significant (p < 0.05), while RER did not (p = 0.081). The WL group had higher work volume, relative peak power, and mean power than the non‐WL group (p < 0.05). Short‐term SIT elicited significant improvements in submaximal RER and fat oxidation (FOx) in adults that lost weight, which may be explained by an increase in work volume throughout SIT training. [ABSTRACT FROM AUTHOR]

Non-communicable diseases (NCDs) have risen rapidly worldwide, sparking interest in causative agents and pathways. Patulin (PAT), a xenobiotic found in fruit products contaminated by molds, is postulated to be diabetogenic in animals, but little is known about these effects in humans. This study examined the effects of PAT on the insulin signaling pathway and the pyruvate dehydrogenase complex (PDH). HEK293 and HepG2 cells were exposed to normal (5 mM) or high (25 mM) glucose levels, insulin (1.7 nM) and PAT (0.2 μM; 2.0 μM) for 24 h. The qPCR determined gene expression of key enzymes involved in carbohydrate metabolism while Western blotting assessed the effects of PAT on the insulin signaling pathway and Pyruvate Dehydrogenase (PDH) axis. Under hyperglycemic conditions, PAT stimulated glucose production pathways, caused defects in the insulin signaling pathway and impaired PDH activity. These trends under hyperglycemic conditions remained consistent in the presence of insulin. These findings are of importance, given that PAT is ingested with fruit and fruit products. Results suggest PAT exposure may be an initiating event in insulin resistance, alluding to an etiological role in the pathogenesis of type 2 diabetes and disorders of metabolism. This highlights the importance of both diet and food quality in addressing the causes of NCDs. [ABSTRACT FROM AUTHOR]

The role of mitochondrial function in health and disease has become increasingly recognized, particularly in the last two decades. Mitochondrial dysfunction as well as disruptions of cellular bioenergetics have been shown to be ubiquitous in some of the most prevalent diseases in our society, such as type 2 diabetes, cardiovascular disease, metabolic syndrome, cancer, and Alzheimer's disease. However, the etiology and pathogenesis of mitochondrial dysfunction in multiple diseases have yet to be elucidated, making it one of the most significant medical challenges in our history. However, the rapid advances in our knowledge of cellular metabolism coupled with the novel understanding at the molecular and genetic levels show tremendous promise to one day elucidate the mysteries of this ancient organelle in order to treat it therapeutically when needed. Mitochondrial DNA mutations, infections, aging, and a lack of physical activity have been identified to be major players in mitochondrial dysfunction in multiple diseases. This review examines the complexities of mitochondrial function, whose ancient incorporation into eukaryotic cells for energy purposes was key for the survival and creation of new species. Among these complexities, the tightly intertwined bioenergetics derived from the combustion of alimentary substrates and oxygen are necessary for cellular homeostasis, including the production of reactive oxygen species. This review discusses different etiological mechanisms by which mitochondria could become dysregulated, determining the fate of multiple tissues and organs and being a protagonist in the pathogenesis of many non–communicable diseases. Finally, physical activity is a canonical evolutionary characteristic of humans that remains embedded in our genes. The normalization of a lack of physical activity in our modern society has led to the perception that exercise is an "intervention". However, physical activity remains the modus vivendi engrained in our genes and being sedentary has been the real intervention and collateral effect of modern societies. It is well known that a lack of physical activity leads to mitochondrial dysfunction and, hence, it probably becomes a major etiological factor of many non–communicable diseases affecting modern societies. Since physical activity remains the only stimulus we know that can improve and maintain mitochondrial function, a significant emphasis on exercise promotion should be imperative in order to prevent multiple diseases. Finally, in populations with chronic diseases where mitochondrial dysfunction is involved, an individualized exercise prescription should be crucial for the "metabolic rehabilitation" of many patients. From lessons learned from elite athletes (the perfect human machines), it is possible to translate and apply multiple concepts to the betterment of populations with chronic diseases. [ABSTRACT FROM AUTHOR]

The diagnostics of anaerobic glycolytic metabolism which play a subordinate role in elite rowing and parameters such as maximum lactate accumulation rate (νLa.max) have thus far not been associated with ergometer rowing performance. The aim of the study was to quantify the glycolytic energy metabolism (WGly) during a 2000 m ergometer rowing time trial (RTT) and νLa.max during a 10 s maximum ergometer rowing sprint test (RST) and to unravel associations between those variables and RTT performance. Combined post-exercise lactate measurements and oxygen uptake after RST and RTT were used to determine νLa.max and glycolytic energy contribution (WGly) in seven male and three female German U 23 national rowers (N = 10, 19.8 ± 0.9 years, 183.2 ± 7.0 cm height, 79.9 ± 13.3 kg body mass, 16.4 ± 5.1 % body fat). WGly during RTT ranged from 7 to 15.5% and νLa.max between 0.25 and 0.66 mmol∙L−1∙s−1. νLa.max correlated with WGly (p < 0.05, r = 0.74) and the mechanical power output (W) for the first 300 m (300first) during RTT (p < 0.05, r = 0.67). νLa.max further correlated with ∆300first−last (W) for the first and last 300 m (300last) during RTT (p < 0.01, r = 0.87) and also within the subgroup of male rowers. νLa.max displays a wide spectrum of individual differences in rowers. Due to this and its correlation to specific phases of RTT, it contributes to an individual energetic performance profile in rowing. Future studies must undermine the role of νLa.max for exercise performance and whether it serves as a marker that can be specifically targeted for a training-induced increase or decrease. [ABSTRACT FROM AUTHOR]

Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathological comorbidities, including altered whole‐body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with β2 receptor agonists (e.g. formoterol) improves metabolic and skeletal muscle function. We aimed first to examine if restricting physical activity following injury affects metabolic and skeletal muscle function, and second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age‐matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24 h evaluations of physical activity and whole‐body metabolism were conducted following VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity and untargeted metabolomics. Restricting activity chronically after VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate following VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force‐producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. Key points: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health.Modelling VML injury‐induced physical activity restriction altered whole‐body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity.The β2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole‐body metabolism while mitigating functional deficits resulting from injury.Understanding of chronic effects of the clinically available and FDA‐approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury. [ABSTRACT FROM AUTHOR]

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only. [ABSTRACT FROM AUTHOR]

Background: Resting skeletal muscle in insulin resistance prefers to oxidize carbohydrate rather than lipid, exhibiting metabolic inflexibility. Although this is established in resting muscle, complexities involved in directly measuring fuel oxidation using indirect calorimetry across a muscle bed have limited studies of this phenomenon in working skeletal muscle. During mild exercise and at rest, whole-body indirect calorimetry imperfectly estimates muscle fuel oxidation. We provide evidence that a method termed "ΔRER" can reasonably estimate fuel oxidation in skeletal muscle activated by exercise. Methods: Completely sedentary volunteers (n = 20, age 31 ± 2 years, V̇O2peak 24.4 ± 1.5 mL O2 per min/kg) underwent glucose clamps to determine insulin sensitivity and graded exercise consisting of three periods of mild steady-state cycle ergometry (15, 30, 45 watts, or 10%, 20%, and 30% of maximum power) with measurements of whole-body gas exchange. ΔRER, the RER in working muscle, was calculated as (V̇CO2exercise –V̇CO2rest)/(V̇O2exercise – V̇O2rest), from which the fraction of fuel accounted for by lipid was estimated. Results: Lactate levels were low and stable during steady-state exercise. Muscle biopsies were used to estimate mitochondrial content. The rise of V̇O2 at onset of exercise followed a monoexponential function, with a time constant of 51 ± 7 sec, typical of skeletal muscle; the average O2 cost of work was about 12 mL O2/watt/min, representing a mechanical efficiency of about 24%. At work rates of 30 or 45 watts, active muscle relied predominantly on carbohydrate, independent of insulin sensitivity within this group of very sedentary volunteers. Conclusions: The fraction of muscle fuel oxidation from fat was predicted by power output (P < 0.001) and citrate synthase activity (P < 0.05), indicating that low mitochondrial content may be the main driver of fuel choice in sedentary people, independent of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: Type 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The RabGTPase-activating protein TBC1D4 represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling glucose transporter GLUT4 translocation. A human loss-of-function mutation in TBC1D4 is associated with impaired glycemic control and elevated T2DM risk. The study's aim was to investigate TBC1D4 function in cardiac substrate metabolism and adaptation to MI. Methods: Cardiac glucose metabolism of male Tbc1d4-deficient (D4KO) and wild type (WT) mice was characterized using in vivo [18F]-FDG PET imaging after glucose injection and ex vivo basal/insulin-stimulated [3H]-2-deoxyglucose uptake in left ventricular (LV) papillary muscle. Mice were subjected to cardiac ischemia/reperfusion (I/R). Heart structure and function were analyzed until 3 weeks post-MI using echocardiography, morphometric and ultrastructural analysis of heart sections, complemented by whole heart transcriptome and protein measurements. Results: Tbc1d4-knockout abolished insulin-stimulated glucose uptake in ex vivo LV papillary muscle and in vivo cardiac glucose uptake after glucose injection, accompanied by a marked reduction of GLUT4. Basal cardiac glucose uptake and GLUT1 abundance were not changed compared to WT controls. D4KO mice showed mild impairments in glycemia but normal cardiac function. However, after I/R D4KO mice showed progressively increased LV endsystolic volume and substantially increased infarction area compared to WT controls. Cardiac transcriptome analysis revealed upregulation of the unfolded protein response via ATF4/eIF2α in D4KO mice at baseline. Transmission electron microscopy revealed largely increased extracellular matrix (ECM) area, in line with decreased cardiac expression of matrix metalloproteinases of D4KO mice. Conclusions: TBC1D4 is essential for insulin-stimulated cardiac glucose uptake and metabolic flexibility. Tbc1d4-deficiency results in elevated cardiac endoplasmic reticulum (ER)-stress response, increased deposition of ECM and aggravated cardiac damage following MI. Hence, impaired TBC1D4 signaling contributes to poor outcome after MI. [ABSTRACT FROM AUTHOR]

Non-communicable diseases (NCD) are the slow-motion disasters with imminent global health care burden. The current dietary management for NCD is dominated by the calorie balance model. Apart from the quantitative balance of calorie, healthy bioenergetics requires temporal eating and fasting rhythms, and the subsequent switching for different metabolic fuels. We herein term these three bioenergetic attributes, i.e., caloric balance, diurnal eating-fasting rhythm, and metabolic flexibility, as the metabolic tempo. These three attributes are intertwined with each other; alteration of one attribute affects one or more other attributes. Lifestyle-induced disrupted metabolic tempo presents a high flux of mixed carbon substrates to mitochondria, with the resulting congestion and indecisiveness of metabolic switches. Such indecisiveness impairs metabolic flexibility, promotes anabolism, and accumulates the energy storage pools. The triggers from hypoxic inducible factor expression could further promote the metabolic gridlock and adipocyte maladaptation. The maladaptive adipocytes lead to ectopic fat deposition, increased circulating lipid levels, insulin resistance, and chronic systemic inflammation. These continuum set stages for clinical NCDs. We propose that the restoration of all tempo attributes through the combined diet-, time-, and calorie-restricted interventions could be the preferred strategy for NCD management. [ABSTRACT FROM AUTHOR]

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as "brain fog", fatigue and clotting problems. Explanations for "long COVID" include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can "tip" the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer's metabolism needs to be "tipped" back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response. [ABSTRACT FROM AUTHOR]

Mitochondrial plasticity including mitochondrial dynamics, metabolic flexibility, and mitochondrial quality control, impact tumor cells' progression and determine immune cells' fate. Complement C1q binding protein (C1QBP) plays an indispensable role through regulating mitochondrial morphology, metabolism, and autophagy. C1QBP promotes mitochondrial plasticity to impact tumor metastasis and their therapeutic response. At the same time, C1QBP is involved in regulating immune cells' maturation, differentiation, and effector function through the enhancement of mitochondrial function. In this regard, manipulation of C1QBP has been shown to adjust the competitive balance between tumor cells and immune cells. In the course of evolution, mitochondrial plasticity has endowed numerous advantages against the relentless microenvironment of tumors. In this current review, we summarize the current knowledge of the mechanism of C1QBP regulation of cancer and immunity. We explain this process in vision of potentially new anticancer therapies. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are essential for maintaining energy homeostasis as part of the adaptive stress response. Most work to date has characterized the metabolic role of GCs via the activation of the glucocorticoid receptor (nr3c1; GR), which is activated under high GC conditions. However, GCs also bind to the mineralocorticoid receptor (nr3c2; MR), a high-affinity corticosteroid receptor active under basal GC conditions. Despite the expression of MR in skeletal muscles, almost nothing is known about its physiological role. Here we tested the hypothesis that the MR promotes anabolic processes during resting cortisol levels and curtails the catabolic actions of the GR during high (stressed) levels of cortisol. To determine the effect of MR, a zebrafish line with a ubiquitous MR knockout (MRca402/ca402) was utilized. The GR was activated in the same group by chronically treating fish with exogenous cortisol. In the muscle, MR primarily promoted nutrient storage, and restricted energy substrate mobilization under resting conditions, whereas GR activation resulted in increased nutrient utilization. Interestingly, MR loss improved GR-driven metabolic flexibility, suggesting that the activation state of these receptors is a key determinant of skeletal muscle ability to switch fuel sources. To determine if the anabolism-promoting nature of MR was due to an interaction with insulin, fish were co-injected with insulin and the fluorescent glucose analogue 2-NBDG. A loss of MR abolished insulin-stimulated glucose uptake in the skeletal muscle. Taken together, we postulate that MR acts as a key modulator of glucose metabolism in the musculature during basal and stress conditions. [ABSTRACT FROM AUTHOR]

The present work aimed to examine the association between physical activity (PA) and sedentary behaviour with maximal fat oxidation (MFO) in young individuals. A total of 77 active adults (30 women; 22.8 ± 4.5 years) were included in this cross-sectional study in which PA and sedentary behaviour were measured using accelerometers for 7 consecutive days. PA was classified into different intensities (i.e. light, moderate, vigorous, and moderate-to-vigorous) and sedentary behaviour into sedentary time (i.e. time, number of bouts, and length of bouts) and sedentary breaks (i.e. time, number of breaks, and length of breaks). MFO was determined using a graded cycloergometer test through indirect calorimetry and relativized to lean mass (MFOLM) and lean leg mass (MFOLL). Positive associations were found for light and vigorous PA in relation with MFO, MFOLM and MFOLL, independently of cofounders (P ≤ 0.01). Moreover, a negative association was found between MFO and MFOLM and the length of sedentary bouts which was accentuated after adjusting by cardiorespiratory fitness (P ≤ 0.05). These results suggest that light and vigorous PA and sedentary behaviour are related to MFO during exercise. Despite this, further interventional studies are needed to clarify if increments of light and vigorous PA could enhance MFO in different populations. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects and mechanism of hyperinsulinemia on the metabolic switch to β-hydroxybutyrate (BHB) absorption and utilization under a starvation or hypoxic environment in proximal tubular epithelial cells. Methods: A high-fat diet-induced hyperinsulinemia model in ZDF rats was used to test the expression of key enzymes/proteins of ketone body metabolism in the kidney. Notably, 12-week-old renal tubule SMCT1 specific knockout mice (SMCT1 flox/floxCre+) and control mice (SMCT1 flox/floxCre-) were used to confirm the roles of SMCT1 in kidney protection under starvation. The changes of key enzymes/proteins of energy metabolism, mitochondrial function, and albumin endocytosis in HK2 cells under low glucose/hypoxic environments with or without 50 ng/mL insulin were studied. Silent information regulation 2 homolog 3 (SIRT3) was overexpressed to evaluate the effect of hyperinsulinemia on the metabolic switch to BHB absorption and utilization through the SIRT3/SMCT1 pathway in HK2 cells. Results: In ZDF rats, the expression of HMGCS2 increased, the SMCT1 expression decreased, while SCOT remained unchanged. In renal tubule SMCT1 gene-specific knockout mice, starvation for 48 h induced an increase in the levels of urine retinol-binding protein, N-acetyl-β-glucosaminidase, and transferrin, which reflected tubular damages. In HK2 cells under an environment of starvation and hypoxia, the levels of key enzymes related to fatty acid oxidation and ketone body metabolism were increased, whereas glucose glycolysis did not change. The addition of 2 mmol/l BHB improved ATP production, mitochondrial biosynthesis, and endocytic albumin function, while cell apoptosis was reduced in HK2 cells. The addition of 50 ng/ml insulin resulted in the decreased expression of SMCT1 along with an impaired mitochondrial function, decreased ATP production, and increased apoptosis. The overexpression of SIRT3 or SMCT1 reversed these alterations induced by a high level of insulin both in low-glucose and hypoxic environments. Conclusions: The increased absorption and utilization of BHB is part of the metabolic flexibility of renal tubular epithelial cells under starvation and hypoxic environments, which exhibits a protective effect on renal tubular epithelial cells by improving the mitochondrial function and cell survival. Moreover, hyperinsulinemia inhibits the absorption of BHB through the inhibition of the SIRT3/SMCT1 pathway. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF), the most common sustained arrhythmia, is closely intertwined with metabolic abnormalities. Recently, a metabolic paradox in AF pathogenesis has been suggested: under different forms of pathogenesis, the metabolic balance shifts either towards (e.g., obesity and diabetes) or away from (e.g., aging, heart failure, and hypertension) fatty acid oxidation, yet they all increase the risk of AF. This has raised the urgent need for a general consensus regarding the metabolic changes that predispose patients to AF. "Metabolic flexibility" aptly describes switches between substrates (fatty acids, glucose, amino acids, and ketones) in response to various energy stresses depending on availability and requirements. AF, characterized by irregular high-frequency excitation and the contraction of the atria, is an energy challenge and triggers a metabolic switch from preferential fatty acid utilization to glucose metabolism to increase the efficiency of ATP produced in relation to oxygen consumed. Therefore, the heart needs metabolic flexibility. In this review, we will briefly discuss (1) the current understanding of cardiac metabolic flexibility with an emphasis on the specificity of atrial metabolic characteristics; (2) metabolic heterogeneity among AF pathogenesis and metabolic inflexibility as a common pathological basis for AF; and (3) the substrate-metabolism mechanism underlying metabolic inflexibility in AF pathogenesis. [ABSTRACT FROM AUTHOR]

Cancer cachexia is one of the leading causes of mortality for late-stage cancer patients. One of its key characteristics is abnormal metabolism and loss of metabolic flexibility, i.e., loss of ability to switch between use of fats and carbohydrates as needed. Here, it is hypothesized that late-stage systemic cancer creates a chronic resource drain on the body that may result in the same metabolic adaptations that occur during intense endurance exercise, activating some of the same mechanisms of nutrient consumption that are supposed to be transient during strenuous physical activity. This hypothesis is evaluated by creating a mathematical model that characterizes the relationships between increased exercise intensity and carbohydrate and fat oxidation. The model is parametrized using published data on these characteristics for a group of professional athletes, moderately active individuals, and individuals with metabolic syndrome. Transitions between different zones of relative nutrient consumption as a function of increased effort are captured through explicitly modeling ventilatory thresholds, particularly VT1 and VT2, where fat is primarily used below VT1, both carbohydrates and fats are used between VT1 and VT2, and where carbohydrates become the primary source of fuel above VT2. A simulation is conducted of projected patterns of nutrient consumption when simulated "effort" remains between VT1 and VT2, or above VT2, and it is proposed that it is the scenario when the simulated effort is maintained primarily above VT2 that most closely resembles metabolic patterns characteristic of cachexia. A discussion of a broader framework for understanding cachectic metabolism using insights from exercise physiology, including potential intervention strategies, concludes this paper. [ABSTRACT FROM AUTHOR]

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). Methods: Patients receiving LT for non‐alcoholic steatohepatitis (NASH) (n = 35) and non‐NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole‐body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). Results: The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post‐prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p <.001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI‐PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat‐free muscle volume and directly with visceral adipose tissue. Conclusion: Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non‐alcoholic fatty liver disease after LT. [ABSTRACT FROM AUTHOR]

The present work examines the relationships between maximal fat oxidation during a graded exercise test (MFO), the intensity of exercise that elicits MFO (Fatmax), and traditional cardiometabolic risk factors in healthy, sedentary adults. A total of 119 (81 women) young, sedentary adults (22.1 ± 2.2 years old), and 71 (37 women) middle-aged, sedentary adults (53.4 ± 4.9 years old) participated in the current study. Systolic and diastolic blood pressures were determined following standard procedures. Plasma glucose, insulin, total cholesterol, high-density lipoprotein cholesterol and triglycerides were determined in a fasted state and the homeostatic model assessment of insulin resistance index and low-density lipoprotein cholesterol levels subsequently calculated. A sex and age group-specific cardiometabolic risk Z-score was also calculated for each subject based on waist circumference, systolic and diastolic blood pressure, plasma glucose, high-density lipoprotein cholesterol and triglycerides. MFO and Fatmax were determined using a walking graded exercise test using indirect calorimetry. No clear association was seen of MFO and Fatmax with any cardiometabolic risk factor (all P≥0.05), except for a weak, inverse association between Fatmax and the fatty liver index (P=0.027). Similarly, neither MFO nor Fatmax was apparently associated with the cardiometabolic risk Z-score (all P≥0.05). The current findings suggest an uncertain association of MFO and Fatmax during a graded exercise test with the cardiometabolic profile of healthy, sedentary adults. The study of the physiological mechanisms that trigger the onset of metabolic disorders has received considerable attention in recent years, with changes in MFO and Fatmax being highlighted as a potential key factor. This work shows that MFO and Fatmax during a graded exercise test are not associated with the cardiometabolic profile in sedentary, healthy adults. Further studies are needed to elucidate which other physiological disorders are related to cardiometabolic risk. [ABSTRACT FROM AUTHOR]

African Americans (AA) are disproportionately burdened by metabolic diseases. While largely unexplored between Caucasian (C) and AA, differences in mitochondrial bioenergetics may provide crucial insight to mechanisms for increased susceptibility to metabolic diseases. AA display lower total energy expenditure and resting metabolic rate compared to C, but paradoxically have a higher amount of skeletal muscle mass, suggestive of inherent energetic efficiency differences between these races. Such adaptations would increase the chances of overnutrition in AA; however, these disparities would not explain the racial difference in insulin resistance (IR) in healthy subjects. Hallmarks associated with insulin resistance (IR), such as reduced mitochondrial oxidative capacity and metabolic inflexibility are present even in healthy AA without a metabolic disease. These adaptations might be influential of mitochondrial "substrate preference" and could play a role in disproportionate IR rates among races. A higher glycolytic flux and provision of shuttles transferring electrons from cytosol to mitochondrial matrix could be a contributing factor in development of IR via heightened reactive oxygen species (ROS) production. This review highlights the above concepts and provides suggestions for future studies that could help delineate molecular premises behind potential impairments in insulin signaling and metabolic disease susceptibility in AA. [ABSTRACT FROM AUTHOR]

Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal. [Display omitted] • Time-resolved metabolomic responses to six physiological challenges in healthy individuals • Subject-level response profiles for >2,600 metabolites measured in blood, urine, or breath • Three showcases of data usage for exploring human metabolism under challenge conditions • Interactive querying and visualization of response profiles and statistics at humet.org Weinisch et al. introduce the HuMet Repository (https://humet.org), a web-based resource for exploring dynamic metabolic responses of healthy subjects to six physiological stimuli, including prolonged fasting, oral glucose/lipid loads, and exercise. The repository enables searching, analyzing, and visualizing time-resolved metabolomics data comprising 2,656 metabolites in human blood, urine, or breath. [ABSTRACT FROM AUTHOR]

Cells have metabolic flexibility that allows them to adapt to changes in substrate availability. Two highly relevant metabolites are glucose and fatty acids (FA), and hence, glycolysis and fatty acid oxidation (FAO) are key metabolic pathways leading to energy production. Both pathways affect each other, and in the absence of one substrate, metabolic flexibility allows cells to maintain sufficient energy production. Here, we show that glucose starvation or sustained pyruvate dehydrogenase (PDH) activation by dichloroacetate (DCA) induce large genetic remodeling to propel FAO. The extracellular signal-regulated kinase 5 (ERK5) is a key effector of this multistep metabolic remodeling. First, there is an increase in the lipid transport by expression of low-density lipoprotein receptor-related proteins (LRP), e.g., CD36, LRP1 and others. Second, an increase in the expression of members of the acyl-CoA synthetase long-chain (ACSL) family activates FA. Finally, the expression of the enzymes that catalyze the initial step in each cycle of FAO, i.e., the acyl-CoA dehydrogenases (ACADs), is induced. All of these pathways lead to enhanced cellular FAO. In summary, we show here that different families of enzymes, which are essential to perform FAO, are regulated by the signaling pathway, i.e., MEK5/ERK5, which transduces changes from the environment to genetic adaptations. [ABSTRACT FROM AUTHOR]

Background: There is a growing interest among the research community and clinical practitioners to investigate cardiopulmonary exercise test (CPET) procedures and protocols utilized in supine cycling. Materials and Methods: The current study investigated the effects of posture on indicators of exercise intensity including gas exchange threshold (GET), respiratory compensation point (RCP), and the rate of peak oxygen uptake (V̇O2 peak), as well as the role of V̇O2 mean response time (MRT) in determining exercise intensity domains in nineteen healthy men (age: 22 ± 3 years). Two moderate-intensity step-transitions from 20 to 100 Watt (W) were completed, followed by a maximal CPET. After completing the ramp test, participants performed a constant-load at 90% of their attained peak power output (PPO). Results: No differences were observed in the V̇O² MRT between the two positions, although the phase II-time constant (τV̇O2p) was 7 s slower in supine position compared to upright (p = 0.001). The rate of O² uptake in the supine position at GET and RCP were lower compared to the upright position (208 ± 200 mL·min−1 (p = 0.007) and 265 ± 235 mL·min−1 (p = 0.012) respectively). Besides, V̇O2 peak was significantly decreased (by 6%, p = 0.002) during supine position. These findings were confirmed by the wide limits of agreement between the measures of V̇O2 in different postures (V̇O2 peak: −341 to 859; constant-load test: −528 to 783; GET: −375 to 789; RCP: −520 to 1021 all in mL·min−1). Conclusion: Since an accurate identification of an appropriate power output (PO) from a single-visit CPET remains a matter of debate, especially for supine cycling, we propose that moderate-intensity step-transitions preceding a ramp CPET could be a viable addition to ensure appropriate exercise-intensity domain determination, in particular upon GET-based prescription. [ABSTRACT FROM AUTHOR]

Maximum and minimum metabolic rates in birds are flexible traits and such flexibility can be advantageous in variable climates. The climatic variability hypothesis (CVH) posits that more variable climates should result in greater metabolic flexibility for geographically distinct populations. Whether the CVH applies to sympatric species occupying microclimates differing in variability is unknown. Microclimates of open habitats are likely more variable than those of sheltered habitats. If the CVH extends to microclimates, we expect birds from open habitats to show greater flexibility than those from sheltered habitats. To test this extension of the CVH, we compared seasonal variation in microclimates and metabolic rates for sympatric horned larks Eremophila alpestris , which occupy open habitats, and house sparrows Passer domesticus , which occupy sheltered habitats. We measured operative temperature (T e, an integrative measure of the thermal environment), summit metabolic rate (M sum, maximal cold-induced metabolic rate), and basal metabolic rate (BMR, minimal maintenance metabolic rate) in summer and winter. For both winter and summer, daily minimum T e was similar between open and sheltered habitats but maximum T e was higher for open habitats. Winter microclimates, however, were colder for open than for sheltered habitats after accounting for convective differences. Both species increased M sum in winter, but seasonal M sum flexibility was greater for larks (43%) than for sparrows (31%). Winter increases in BMR were 92.5% and 11% for larks and sparrows, respectively, with only the former attaining statistical significance. Moreover, species * season interactions in general linear models for whole-organism metabolic rates were significant for BMR and showed a similar, although not significant, pattern for M sum, with greater seasonal metabolic flexibility in horned larks than in house sparrows. These results suggest that extending the CVH to sympatric bird species occupying different microclimates may be valid. [ABSTRACT FROM AUTHOR]

Commensal fungus-Candida albicans turn pathogenic during the compromised immunity of the host, causing infections ranging from superficial mucosal to dreadful systemic ones. C. albicans has evolved various adaptive measures which collectively contribute towards its enhanced virulence. Among fitness attributes, metabolic flexibility and vigorous stress response are essential for its pathogenicity and virulence. Metabolic flexibility provides a means for nutrient assimilation and growth in diverse host microenvironments and reduces the vulnerability of the pathogen to various antifungals besides evading host immune response(s). Inside the host micro-environments, C. albicans efficiently utilizes the multiple fermentable and non-fermentable carbon sources to sustain and proliferate in glucose deficit conditions. The utilization of alternative carbon sources further highlights the importance of understanding these pathways as the attractive and potential therapeutic target. A thorough understanding of metabolic flexibility and adaptation to environmental stresses is warranted to decipher in-depth insights into virulence and molecular mechanisms of fungal pathogenicity. In this review, we have attempted to provide a detailed and recent understanding of some key aspects of fungal biology. Particular focus will be placed on processes like nutrient assimilation and utilization, metabolic adaptability, virulence factors, and host immune response in C. albicans leading to its enhanced pathogenicity. [ABSTRACT FROM AUTHOR]

Summary: C4 photosynthesis involves a series of biochemical and anatomical traits that significantly improve plant productivity under conditions that reduce the efficiency of C3 photosynthesis. We explore how evolution of the three classical biochemical types of C4 photosynthesis (NADP‐ME, NAD‐ME and PCK types) has affected the functions and properties of mitochondria. Mitochondria in C4 NAD‐ME and PCK types play a direct role in decarboxylation of metabolites for C4 photosynthesis. Mitochondria in C4 PCK type also provide ATP for C4 metabolism, although this role for ATP provision is not seen in NAD‐ME type. Such involvement has increased mitochondrial abundance/size and associated enzymatic capacity, led to changes in mitochondrial location and ultrastructure, and altered the role of mitochondria in cellular carbon metabolism in the NAD‐ME and PCK types. By contrast, these changes in mitochondrial properties are absent in the C4 NADP‐ME type and C3 leaves, where mitochondria play no direct role in photosynthesis. From an eco‐physiological perspective, rates of leaf respiration in darkness vary considerably among C4 species but does not differ systematically among the three C4 types. This review outlines further mitochondrial research in key areas central to the engineering of the C4 pathway into C3 plants and to the understanding of variation in rates of C4 dark respiration. [ABSTRACT FROM AUTHOR]

We investigated whether substituting the final half within 60-min bouts of exercise with passive warm or cold water immersion would provide similar or greater benefits for cardiometabolic health. Thirty healthy participants were randomized to two of three short-term training interventions in a partial crossover (12 sessions over 14–16 days, 4 week washout): (i) EXS: 60 min cycling 70% maximum heart rate (HRmax), (ii) WWI: 30 min cycling then 30 min warm water (38–40°C) immersion, and/or (iii) CWI: 30 min cycling then 30 min cold water (10–12°C) immersion. Before and after, participants completed a 20 min cycle work trial, V. O2max test, and an Oral Glucose Tolerance Test during which indirect calorimetry was used to measure substrate oxidation and metabolic flexibility (slope of fasting to post-prandial carbohydrate oxidation). Data from twenty two participants (25 ± 5 year, BMI 23 ± 3 kg/m2, Female = 11) were analyzed using a fixed-effects linear mixed model. V. O2max increased more in EXS (interaction p = 0.004) than CWI (95% CI: 1.1, 5.3 mL/kg/min, Cohen's d = 1.35), but not WWI (CI: −0.4, 3.9 mL/kg/min, d = 0.72). Work trial distance and power increased 383 ± 223 m and 20 ± 6 W, respectively, without differences between interventions (interaction both p > 0.68). WWI lowered post-prandial glucose ∼9% (CI −1.9, −0.5 mmol/L; d = 0.63), with no difference between interventions (interaction p = 0.469). Substituting the second half of exercise with WWI provides similar cardiometabolic health benefits to time matched exercise, however, substituting with CWI does not. [ABSTRACT FROM AUTHOR]