The development of cardiometabolic (CM) diseases is associated with chronic low-grade inflammation, partly linked to alterations of the gut microbiota (GM) and reduced intestinal integrity. The SINFONI project investigates a multifunctional (MF) nutritional strategy's impact combining different bioactive compounds on inflammation, GM modulation and CM profile. In this randomized crossover-controlled study, 30 subjects at CM-risk consumed MF cereal-products, enriched with polyphenols, fibers, slowly-digestible starch, omega-3 fatty acids or Control cereal-products (without bioactive compounds) for 2 months. Metabolic endotoxemia (lipopolysaccharide (LPS), lipopolysaccharide-binding protein over soluble cluster of differentiation-14 (LBP/sCD14), systemic inflammation and cardiovascular risk markers, intestinal inflammation, CM profile and response to a one-week fructose supplementation, were assessed at fasting and post mixed-meal. GM composition and metabolomic analysis were conducted. Mixed linear models were employed, integrating time (pre/post), treatment (MF/control), and sequence/period. Compared to control, MF intervention reduced intestinal inflammation (fecal calprotectin, p = 0.007) and endotoxemia (fasting LPS, p < 0.05), without alteration of systemic inflammation. MF decreased serum branched-chain amino acids compared to control (p < 0.05) and increased B.ovatus, B.uniformis, A.butyriciproducens and unclassified Christensenellaceae.CAG-74 (p < 0.05). CM markers were unchanged. A 2-month dietary intervention combining multiple bioactive compounds improved intestinal inflammation and induced GM modulation. Such strategy appears as an effective strategy to target low-grade inflammation through multi-target approach.

The pancreatic islets of Langerhans are central to fine-tuning metabolism to ensure metabolic homeostasis during the transition between fasting and feeding. Insulin and glucagon, the principal hormones generated and secreted by islets, exert powerful control in various metabolic tissues to drive nutrient uptake, storage and metabolism. Their canonical actions on glycaemia have positioned these hormones in opposition, however, their metabolic actions extend beyond controlling blood levels of glucose. Indeed, these islet hormones are just as influential in regulating lipid and amino acid metabolism and it is becoming clear that many of these actions involve an interplay between insulin and glucagon, which is contrary to the dogmatic view that these hormones are antagonistic in nature. Finally, we postulate that examining the effects of islet hormones on the metabolism of individual metabolites is overly simplistic. Here, we discuss the actions of each islet hormone alone and in combination with the others in regulating glucose and amino acid metabolism and explore how these signalling networks are closely linked and strongly influence one another.

To identify metabolic signatures of insulin action/secretion in Indigenous Americans (IAs) and their association with diabetes.

We defined circulating metabolomic signatures of insulin action/secretion in 446 IAs, including glucose disposal rate during low-dose insulin clamp (Mlow) and endogenous glucose production (EGP) during insulin infusion (suppression of hepatic glucose production). We then determined associations of these metabolic scores with glucose tolerance (in a separate set of ∼700 IAs) and diabetes/metabolic risk in ∼2,000 individuals (from Coronary Artery Risk Development in Young Adults [CARDIA] study). We used tissue-specific gene-metabolite mapping to pinpoint genetic pathways of type 2 diabetes (T2D) implicated by metabolomic signatures.

In young IAs (mean age 29 years; mean BMI 34.9 kg/m2) without diabetes, phenotype-metabolome associations across multiple insulin action phenotypes were linked to mechanisms of fatty acid and amino acid metabolism and inflammation (among others). Metabolite-based scores of insulin action were strongly related to incident diabetes in our discovery IA population (Mlow; 49 metabolites; standardized hazard ratio [HR] 0.49; 95% CI 0.35-0.69; P < 0.0001) and also associated with measures of insulin resistance in a distinct IA population (|ρ| ∼0.3-0.5 correlation) and in the CARDIA group (median age 33 years). At ∼20 years of follow-up in CARDIA, we observed a strong BMI- and glucose-independent association of the metabolite profile of Mlow (HR 0.65; 95% CI 0.56-0.74; P < 0.0001) and EGP suppression (HR 0.66; 95% CI 0.57-0.76; P < 0.0001) with incident diabetes, directionally opposed to BMI and glucose. Genes implicated by the metabolomic signatures were strongly linked to T2D.

Metabolic signatures of clamp-determined insulin action are strongly associated with incident diabetes, suggesting causal-functional pathways of T2D.

An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.

Insulin dysregulation (ID) is a common metabolic disorder in horses, characterized by hyperinsulinemia and/or peripheral insulin resistance. The critical role of hyperinsulinemia in endocrinopathic laminitis has driven research into the insulinotropic effects of dietary nutrients and the reciprocal impact of ID on nutrient metabolism. The relationship between ID and carbohydrate metabolism has been extensively studied; however, the effects of ID on protein metabolism in horses remain largely unexplored. This review begins with an overview of the importance of insulin in the regulation of muscle protein synthesis and degradation and then examines the current understanding of the interplay between ID and protein and carbohydrate metabolism in horses. Horses with ID exhibit altered resting plasma amino acid concentrations and shifts in postprandial amino acid dynamics. Recent work illustrated that ID horses had higher levels of plasma amino acids following a protein meal and delayed postprandial clearance from the blood compared to non-ID horses. The postprandial muscle synthetic response does not seem to be diminished in ID horses, but alterations in key cellular signaling molecules have been reported. ID horses display a pronounced hyperinsulinemic response following the consumption of feeds providing a range of protein, non-structural carbohydrate, starch and water-soluble carbohydrate intakes. Recent studies have shown that ID horses have an increased postprandial incretin response, contributing to the observed hyperinsulinemia. To minimize the postprandial insulin response, thresholds for carbohydrate consumption have recently been proposed. Similar thresholds should be established for protein to aid in the refinement of nutritional strategies to manage ID horses.

The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential "off-target" effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Bckdk-/- animals. As expected, BT2 failed to activate BCAA oxidation in these animals. Surprisingly, however, BT2 strongly reduced plasma tryptophan levels and promoted catabolism of tryptophan to kynurenine in both control and Bckdk-/- mice. Mechanistic studies revealed that none of the principal tryptophan catabolic or kynurenine-producing/consuming enzymes (TDO, IDO1, IDO2, or KATs) were required for BT2-mediated lowering of plasma tryptophan. Instead, using equilibrium dialysis assays and mice lacking albumin, we show that BT2 avidly binds plasma albumin and displaces tryptophan, releasing it for catabolism. These data confirm that BT2 activates BCAA oxidation via inhibition of BCKDK but also reveal a robust off-target effect on tryptophan metabolism via displacement from serum albumin. The data highlight a potential confounding effect for pharmaceutical compounds that compete for binding with albumin-bound tryptophan.

With the growing body of research on gut microbiota in recent years, various potential associations between gut microbiota and health or disease have been identified. However, the role of gut microbiota in Erectile dysfunction (ED) remains poorly understood. This study aimed to compare the changes in gut microbiota and metabolic pathways between ED males and healthy control group, contributing to the exploration of ED pathogenesis.

Fecal samples were collected from 19 ED patients and 15 healthy controls (aged from 18 to 60 years), with erectile function assessed using the 5-item version of the International Index of Erectile Function (IIEF-5). Macro-genomic sequencing was performed on the NovaSeq PE 150 platform to characterize the gut microbiota distribution among the groups.

No significant differences in alpha diversity of the gut microbiota were observed between the ED and control groups. Additionally, Principal component analysis (PCA) analysis revealed no notable changes in microbiota composition between the two groups. A comparison of the abundance of key species showed that, in the ED group, species such as Ruminococcus gnavus, Thomasclavelia ramosa, Clostridium sp. AF32-12BH, Clostridium nexile, and Eubacterium siraeum were more abundant, while the abundance of Bacteroides intestinalis was decreased compared to the control group. Furthermore, pathways related to nucleotide and lipid metabolism were found to be highly expressed in the ED group.

This pilot study found a decrease in the abundance of Bacteroides intestinalis and an increase in the abundance of Ruminococcus gnavus in the ED sample. These microbiota changes may contribute to ED by promoting atherosclerosis and inhibiting the degradation of branched-chain amino acids. In the future, it may be possible to achieve better outcomes for ED patients by precisely regulating the gut microbiota.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Although MASLD has been widely studied in persons with Type 2 diabetes (T2D), far less in known about the pathogenesis and severity of MASLD in Type 1 diabetes (T1D).

Determine metabolic perturbations associated with MASLD in persons with T1D.

We conducted a cross-sectional study of 30 participants with T1D. Based on the results of a FibroScan, participants were stratified as cases (MASLD) or controls. Metabolomic analyses were performed on plasma obtained from all participants after an overnight (after midnight) fast.

17 of 30 participants were classified as cases (MASLD) and 13 as controls. Cases had higher BMI (p=<0.001) and were taking higher daily insulin doses than controls (p=0.003). Metabolomic analyses revealed that those with MASLD had elevated levels of gluconeogenic substrates pyruvate (p=0.001) and lactate (p=0.043), gluconeogenic amino acids alanine (p<0.001) and glutamate (p=0.004), phenylalanine (p=0.003), and anthranilic acid (p=0.015). Lipidomics revealed, elevated ceramides (P=0.02), diacylglycerols (p=0.0009) and triacylglycerols (P=0.0004) in MASLD group. In those with MASLD, the acylcarnitines, isovalerylcarnitine (CAR.5.0) (P=0.002) and L-Palmitoylcarnitine (CAR.16.0) (P=0.048), were elevated. Pathway analyses using MetaboAnalyst 5.0 Software revealed that, pathways including phenylalanine and tyrosine metabolism, tryptophan metabolism, glucose-alanine cycle, glutamate metabolism, and glutathione metabolism were significantly enriched in those with MASLD.

Participants with T1D and MASLD manifest features of insulin resistance and metabolite perturbations suggesting enhanced gluconeogenesis, dysfunctional fat synthesis, and perturbed TCA cycle activity.

Liver transplant (LT) recipients are at high risk of cardiometabolic disease and mortality. However, routinely employed clinical risk tools have sub-optimal diagnostic performance due to transplant related biological changes. Metabolic vulnerability index (MVX) is a serum-based composite biomarker comprised of nutritional risk [metabolic malnutrition index or MMX] and chronic inflammation [inflammatory vulnerability index or IVX]. MVX is a predictor of cardiovascular risk and all-cause mortality in the general population, however, the effect of LT on MVX is unknown.

To better quantify MVX after transplantation, LT recipients (n = 181) prospectively enrolled in a natural history study were matched with non transplant controls from the MESA study of healthy individuals. All controls were matched 1:1 regarding age and gender. Additionally, lean controls were identified as those with BMI < 25 kg/m2 and BMI-matched controls who were propensity matched for BMI.

Compared to matched controls, LT recipients had significantly higher MVX (56.9 ± 10.1 vs. 45.8 ± 9.4 vs. 44.8 ± 9.3, p < 0.001), IVX [53.1 ± 12 vs. 39.3 ± 11.2 vs. 40.2 ± 10.9, p < 0.001), and MMX (58.7 ± 8.2 vs. 55.4 ± 6.5 vs. 53.1 ± 6.0, p < 0.001). No significant differences were noted in MVX in LT recipients who developed metabolic dysfunction associated steatotic liver disease (MASLD) after LT. In a multivariate analysis, MVX scores were positively associated with female gender, diabetes, serum AST and BMI, and negatively with dyslipidemia.

LT is associated with a significant increase in MVX and its components, suggesting a heightened risk in LT recipients that is above that of the non-LT population. Future well designed prospective studies are required to calibrate MVX to clinical outcomes in LT patients.

Glycine acts in an autocrine positive feedback loop in human β cells through its ionotropic receptors (GlyRs). In type 2 diabetes (T2D), islet GlyR activity is impaired by unknown mechanisms. We sought to investigate if the GlyR dysfunction in T2D is replicated by hyperglycemia per se, and to further characterize its action in β cells and islets.

GlyR-mediated currents were measured using whole-cell patch-clamp in human β cells from donors with or without T2D, or after high glucose (15 mM) culture. We also correlated glycine-induced current amplitude with transcript expression levels through patch-seq. The expression of the GlyR α1, α3, and β subunit mRNA splice variants was compared between islets from donors with and without T2D, and after high glucose culture. Insulin secretion from human islets was measured in the presence or absence of the GlyR antagonist strychnine.

Although gene expression of GlyRs was decreased in T2D islets, and β cell GlyR-mediated currents were smaller, we found no evidence for a shift in GlyR subunit splicing. Glycine-induced currents are also reduced after 48 h culture of islets from donors without diabetes in high glucose, where we also find the reduction of the α1 subunit expression, but an increase in the α3 subunit. We discovered that glycine-evoked currents are highly heterogeneous amongst β cells, inversely correlate with donor HbA1c, and are significantly correlated to the expression of 92 different transcripts and gene regulatory networks (GRNs) that include CREB3(+), RREB1(+) and ZNF697(+). Finally, glucose-stimulated insulin secretion is decreased in the presence of the GlyR antagonist strychnine.

We demonstrate that glucose can modulate GlyR expression, and that the current decrease in T2D is likely due to the receptor gene expression downregulation, and not a change in transcript splicing. Moreover, we define a previously unknown set of genes and regulons that are correlated to GlyR-mediated currents and could be involved in GlyR downregulation in T2D. Among those we validate the negative impact of EIF4EBP1 expression on GlyR activity.

This review assessed the role of Branched-Chain Amino Acid Transaminase (BCAT) enzymes in human metabolism, and their involvement in the catabolism of branched-chain amino acids (BCAAs) and exploring the association between Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) through insulin resistance.

The analysis involves a comprehensive literature review of recent research findings related to BCAT enzymes, BCAA metabolism, T2DM, and AD. Relevant studies and articles were identified through systematic searches in databases such as PubMed, ScienceDirect, and other scholarly resources. Inclusion criteria encompassed research articles, reviews, and studies published in peer-reviewed journals, with a focus on human metabolism, BCAT enzymes, and the interplay between BCAA metabolism, T2DM, and AD.

The association between T2DM and AD suggests a potential metabolic link, particularly through dysregulated BCAA metabolism leading to insulin resistance. The impact of impaired insulin signaling is implicated in brain function and the accumulation of amyloid plaques facilitated by BCAT.

The identified link between BCAT, BCAA metabolism, T2DM, and AD suggests that disruptions in BCAT levels could serve as valuable indicators for early detection of insulin resistance and cognitive impairment as observed in Type 3 Diabetes which may present a promising therapeutic target.

Cardiometabolic diseases-including Type 2 diabetes and obesity-remain leading causes of global mortality. Recent advancements in metabolomics have facilitated the identification of metabolites that are integral to the development of insulin resistance, a characteristic feature of cardiometabolic disease. Key metabolites, such as branched-chain amino acids (BCAAs), ceramides, glycine, and glutamine, have emerged as valuable biomarkers for early diagnosis, risk stratification, and potential therapeutic targets. Elevated BCAAs and ceramides are strongly associated with insulin resistance and Type 2 diabetes, whereas glycine exhibits an inverse relationship with insulin resistance, making it a promising therapeutic target. Metabolites involved in energy stress, including ketone bodies, lactate, and nicotinamide adenine dinucleotide (NAD⁺), regulate insulin sensitivity and metabolic health, with ketogenic diets and NAD⁺ precursor supplementation showing potential benefits. Additionally, the novel biomarker N-lactoyl-phenylalanine further underscores the complexity of metabolic regulation and its therapeutic potential. This review underscores the potential of metabolite-based diagnostics and precision medicine, which could enhance efforts in the prevention, diagnosis, and treatment of cardiometabolic diseases, ultimately improving patient outcomes and quality of life.

Knee osteoarthritis (OA) is a common degenerative joint disease affecting global health. Its increasing prevalence, particularly among aging populations, remains a leading cause of disability. Besides conventional pharmacological and surgical treatments, dietary interventions are promising strategies to alleviate OA symptoms and progression. Unfortunately, scientific evidence does not support many commonly used, misleading ideas about nutrition in knee OA. Recent data highlight the detrimental effects of high-carbohydrate and high-fat diets, particularly those rich in refined sugars and saturated fats, which exacerbate systemic inflammation and contribute to cartilage degradation. Conversely, diets rich in omega-3 fatty acids, polyphenols, and dietary fiber have shown anti-inflammatory and chondroprotective properties. A Mediterranean diet rich in these nutrients effectively prevents the development of OA and its comorbidities, including obesity and cardiovascular disease. The role of supplements, such as glucosamine, chondroitin, and vitamin D, is questioned due to the lack of evidence supporting their efficacy in treating knee OA. Despite dietary recommendations published annually, there is still a need to debunk many myths that are not confirmed by current evidence. The significant research gaps require more extensive, controlled studies to establish evidence-based dietary recommendations (particularly carbohydrates, dietary fiber, and antioxidant intake). This comprehensive review provides insight into the various indications for the impact of nutrition on knee OA, focusing on key nutrients such as carbohydrates, fats, proteins, antioxidants, and selected micronutrients, providing the clinician with ready-to-implement nutritional modifications. Such an analysis may help clinicians and patients incorporate dietary strategies into treating knee OA, emphasizing the need for personalized, sustainable approaches.

Diabetic foot infections (DFIs) contribute to the global disability burden. Beta-lactams are the most commonly used antibiotics for treating DFIs. However, the use of antibiotics may lead to disruption of the healthy balance of the gut microbiota, causing dysbiosis.

Patients with infected diabetic foot ulcers (iDFUs) were treated with two kinds of beta-lactams (amoxicillin/clavulanic acid or ceftazidime) according to microbial sensitivity of causative agents via bolus or continuous administration modes. Changes in the gut microbiome of patients were analyzed. Diabetic patients without iDFUs were used as a control group. 16 S ribosomal RNA gene amplicon sequencing was performed on stool samples collected from participants.

Alpha diversity and beta diversity of gut microbiota of treated patients did not show significant differences between bolus and continuous modes. However, significant differences were observed between gut microbiota diversity of treated patients and control group. PCoA plots showed individualized responses of the patient's gut microbiota to antibiotics at different times using both administration forms associated with the pre-treatment state of microbiota composition. Enterococcus, Sellimonas, and Lachnoclostridium were the common bacterial markers differentially abundant in the gut microbiota of antibiotic-treated patients with iDFUs while Roseburia, Dorea, and Monoglobus were mainly abundant in the gut microbiota of patients without iDFUs. Predicted pathways like "Transporters", "ABC transporters" and "Phosphotranspherase system (PTS)" were upregulated in the gut microbiome of patients treated with bolus regime which may lead to increased intestinal barrier permeability.

The present study reported alterations in gut microbiota composition and functionality and provided the bacterial markers as well as potential metabolic signatures associated with each administration mode in patients with iDFUs, which may be used as a reference set for future studies of the effect of antibiotics administration on the gut microbiome of patients with iDFUs. This study shed light on the importance of understanding the effect of antibiotic administration form on gut microbiome in patients with iDFUs.

The DFIATIM Clinical Trial (Full title: "Rationalisation of ATB therapy in diabetic foot infection and its impact on the intestinal microbiota") is submitted to the European Union Clinical Trials Database under the EudraCT Number: 2019-001997-27. The date of registration is July 17th, 2020.

Insulin resistance in obesity and type 2 diabetes is associated with elevated plasma branched-chain amino acid (BCAA) levels. Here, we examined whether the ability of insulin to clear plasma BCAAs and any influence of acute exercise or exercise training on this response are intact in obesity and type 2 diabetes.

In four case-control studies of participants with type 2 diabetes matched to glucose-tolerant individuals with obesity and lean individuals, who underwent hyperinsulinaemic-euglycaemic clamps, we examined the effect of insulin on plasma BCAAs (studies I-IV), with or without prior acute exercise (60 min, 70%V ˙ O 2max ) (study II), and before and after 10 weeks of endurance exercise training (study III) or 8 weeks of high-intensity interval training (study IV).

Insulin sensitivity was reduced in individuals with type 2 diabetes compared with individuals with obesity (study I-IV) and lean individuals (studies I and IV), and in individuals with obesity vs lean individuals (study I) (all p<0.05). Exercise training (studies III and IV) increased insulin sensitivity in all groups (all p<0.01). Plasma BCAAs were elevated in individuals with type 2 diabetes compared with individuals with obesity (studies I, III and IV) and lean individuals (studies I and IV) (all p<0.05). The ability of insulin to reduce plasma BCAAs was significantly attenuated in participants with type 2 diabetes compared with both lean individuals (studies I and IV) and individuals with obesity (studies I, II and IV) (all p<0.05). Acute exercise slightly reduced plasma BCAAs in both individuals with type 2 diabetes and individuals with obesity but did not potentiate insulin's ability to reduce plasma BCAAs (study II). Exercise training had no impact on fasting BCAAs and did not affect insulin's ability to reduce plasma BCAAs in any group (studies III and IV) or rescue the attenuated insulin suppression of plasma BCAAs in participants with type 2 diabetes.

Our results demonstrate that insulin's ability to suppress plasma BCAAs is impaired in type 2 diabetes but is intact in individuals with obesity. Although acute exercise reduces fasting BCAA levels, neither acute exercise nor exercise training affects insulin's ability to suppress plasma BCAAs in glucose-tolerant individuals with or without obesity or in individuals with type 2 diabetes.

Milk protein contains high concentrations of branched-chain amino acids (BCAA) that play a critical role in anabolism and are implicated in the onset of obesity and chronic disease. Characterizing BCAA catabolism in the postprandial phase could elucidate the impact of protein intake on obesity risk established in the "early protein hypothesis."

To examine the acute effects of protein content of young child formulas as test meals on BCAA catabolism, observing postprandial plasma concentrations of BCAA in relation to their degradation products.

The TOMI Add-On Study is a randomized, double-blind crossover study in which 27 healthy adults consumed 2 isocaloric young child formulas with alternating higher (HP) and lower (LP) protein and fat content as test meals during separate interventions, while 9 blood samples were obtained over 5 hours. BCAA, branched-chain α-keto acids (BCKA), and acylcarnitines were analyzed using a fully targeted HPLC-ESI-MS/MS approach.

Mean concentrations of BCAA, BCKA, and acylcarnitines were significantly higher after HP than LP over the 5 postprandial hours, except for the BCKA α-ketoisovalerate (KIVA). The latter metabolite showed higher postprandial concentrations after LP. With increasing mean concentrations of BCAA, concentrations of corresponding BCKA, acylcarnitines, and urea increased until a breakpoint was reached, after which concentrations of degradation products decreased (for all metabolites except valine and KIVA and Carn C4:0-iso).

BCAA catabolism is markedly influenced by protein content of the test meal. We present novel evidence for the apparent saturation of the BCAA degradation pathway in the acute postprandial phase up to 5 hours after consumption.

Breast cancer (BC) remains the most prevalent malignancy among women worldwide. While genetic predisposition and reproductive history are key contributors to its development, modifiable risk factors are also important, particularly those linked to lifestyle behaviors, often influencing the endogenous metabolome. Over the past decade, mass spectrometry-based metabolomics has enabled agnostic investigations into correlations between the metabolome and BC risk. Here we review recent results from prospective nested case-control studies, which have led to the identification of significantly different metabolites between women who subsequently developed BC and those who did not. As replication of these findings remains limited, we emphasize the need for robust quantitative validation studies, cancer subtype-specific analyses in diverse populations, and expanded chemical space coverage of analytical assays.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women of reproductive age that encompasses a multitude of signs and symptoms, including hyperandrogenism, polycystic ovarian morphology, ovulatory dysfunction, and insulin resistance. The study aims to explore the role of aromatic amino acid (AAA) disorders in the syndrome. A systematic search on the databases Scopus, PubMed, and Google Scholar until 20 July 2024 over the past 5 years regarding metabolomic studies on PCOS patients' blood and the status of AAAs resulted in 12 related papers. Our review showed that AAA metabolic pathways are dysregulated, and their levels in the blood serum and plasma of PCOS patients in most studies are elevated due to inflammation and oxidative stress which, assisted by gut dysbiosis, give rise to insulin resistance that develops into PCOS. AAA abnormalities can also directly induce the defining symptoms of the syndrome through diminished neurotransmitter availability and impaired signaling. According to our review, AAA perturbations are detected in every stage of PCOS pathophysiology, making them valuable biomarkers for early diagnosis and management of the syndrome. Further investigation of the biological function, role, and impact of AAAs, probably alongside other metabolites, including BCAAs, could lead to the discovery of new tools for preventing and managing PCOS symptoms.

Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication associated with adverse short-term and long-term health outcomes for both mother and child. This study aimed to investigate the association between plasma amino acid concentrations and the incidence of GDM from 2019 to 2021.

Plasma levels of 37 amino acids were precisely measured using triple quadrupole mass spectrometry. The principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models identified metabolic differences between GDM and non-GDM groups. Conditional logistic regression, generalized linear model, and quantile g-computation were employed to assess the associations between individual or combined amino acids and GDM risk/blood glucose levels. The discriminatory power of various factors associated with the risk of GDM was evaluated using the area under the receiver operating characteristic curve (AUC-ROC).

A total of 969 pregnant women were included in this case-control study. OPLS-DA model identified 16 biomarkers that differentiated the GDM and non-GDM groups. After adjusting for potential covariates and correcting for multiple testing, conditional logistic regression analysis revealed that certain key amino acids, such as valine and isoleucine, were positively associated with the incidence of GDM, while glycine and serine were negatively associated with GDM risk (OR = 0.753-1.671, Pfdr = <0.001-0.001). Generalized linear model analysis showed that specific amino acids, including alpha-aminoadipic acid and arginine, were positively associated with blood glucose levels, while glycine and serine were negatively associated (β = -0.211-0.365, Pfdr = <0.001-0.045). Additionally, mixtures of the identified amino acids were significantly associated with an increased risk of GDM (P < 0.001). The combination of selected amino acids showed the highest ability to identify GDM in comparison with traditional risk factors and specific amino acids (AUC-ROC = 0.761, 95 % CI: 0.729-0.792). The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified two metabolic pathways related to GDM risk: "Glycine, Serine, and Threonine Metabolism" and "Arginine biosynthesis".

The overall amino acid profile, rather than disturbances in specific amino acids, may serve as a more important prevention or therapeutic target for GDM.

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and, either directly or indirectly, overall body health, encompassing metabolic and cardiovascular well-being. Given the heightened metabolic activity of the brain, there exists a considerable demand for nutrients in comparison to other organs. Among these, the branched-chain amino acids, comprising leucine, isoleucine, and valine, display distinctive significance, from their contribution to protein structure to their involvement in overall metabolism, especially in cerebral processes. Among the first amino acids that are released into circulation post-food intake, branched-chain amino acids assume a pivotal role in the regulation of protein synthesis, modulating insulin secretion and the amino acid sensing pathway of target of rapamycin. Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors, competing for a shared transporter. Beyond their involvement in protein synthesis, these amino acids contribute to the metabolic cycles of γ-aminobutyric acid and glutamate, as well as energy metabolism. Notably, they impact GABAergic neurons and the excitation/inhibition balance. The rhythmicity of branched-chain amino acids in plasma concentrations, observed over a 24-hour cycle and conserved in rodent models, is under circadian clock control. The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood. Disturbed sleep, obesity, diabetes, and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics. The mechanisms driving these effects are currently the focal point of ongoing research efforts, since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies. In this context, the Drosophila model, though underutilized, holds promise in shedding new light on these mechanisms. Initial findings indicate its potential to introduce novel concepts, particularly in elucidating the intricate connections between the circadian clock, sleep/wake, and metabolism. Consequently, the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle. They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health, paving the way for potential therapeutic interventions.

Patients with diabetes are at an increased risk for developing diabetic cardiomyopathy and other cardiovascular complications. Alterations in cardiac energy metabolism in patients with diabetes, including an increase in mitochondrial fatty acid oxidation and a decrease in glucose oxidation, are important contributing factors to this increase in cardiovascular disease. A switch from glucose oxidation to fatty acid oxidation not only decreases cardiac efficiency due to increased oxygen consumption but it can also increase reactive oxygen species production, increase lipotoxicity, and redirect glucose into other metabolic pathways that, combined, can lead to heart dysfunction. Currently, there is a lack of therapeutics available to treat diabetes-induced heart failure that specifically target cardiac energy metabolism. However, it is becoming apparent that part of the benefit of existing agents such as GLP-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors may be related to their effects on cardiac energy metabolism. In addition, direct approaches aimed at inhibiting cardiac fatty acid oxidation or increasing glucose oxidation hold future promise as potential therapeutic approaches to treat diabetes-induced cardiovascular disease.

CVDs is a leading cause of morbidity, mortality, and healthcare expenditure worldwide. Identifying individuals at risk or in the incipient stages of disease is instrumental in enabling timely interventions, preventive measures, and tailored treatment regimens. The landscape of CVDs is complicated by their heterogeneity, encompassing a spectrum of conditions such as coronary artery disease, heart failure, arrhythmias, and valvular disorders. In recent years, the integration of biomarkers into cardiovascular medicine has emerged as a paradigm-shifting approach with the potential to revolutionize early detection and risk stratification. By synthesizing a multitude of studies, we aim to provide a comprehensive resource that illuminates the transformative potential of biomarkers in ushering in a new era of precision cardiovascular medicine.

To identify the biomarkers for the detection and diagnosis of CVDs.

This review examines key studies from 2015 to the present that investigate the impact of cardiac biomarkers on cardiovascular outcomes. Data were gathered from PubMed, Cochrane Library, and Embase to ensure a comprehensive analysis. The review focuses on various cardiac biomarkers, assessing their levels and changes in relation to cardiovascular health, with special emphasis on advanced biomarkers such as proteomic and metabolomic markers in cardiovascular disease (CVD) diagnosis. Peer-reviewed studies published in English that evaluated the diagnostic, prognostic, or therapeutic role of cardiac biomarkers were included, with priority given to clinical trials, cohort studies, systematic reviews, and meta-analyses providing quantitative biomarker data. Studies unrelated to cardiac biomarkers, case reports, editorials, conference abstracts, and those with small sample sizes or insufficient methodological rigor were excluded. The review also accounts for potential confounding factors and research limitations, ensuring a balanced assessment of the literature. By synthesizing data from academic papers, clinical reports, and research articles, this study provides a comprehensive evaluation of the evolving role of cardiac biomarkers in CVD diagnosis and risk stratification.

Biomarkers play a pivotal role in cardiovascular disease risk prediction, diagnosis, and treatment by providing dynamic biological insights. High-sensitivity cardiac troponins (hs-cTn) enhance myocardial injury detection, while circulating microRNAs (miR-208, miR-499) serve as early indicators of myocardial infarction and heart failure. Lipoprotein(a) [Lp(a)] predicts long-term cardiovascular risk, and inflammatory biomarkers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are linked to adverse outcomes. Multi-biomarker panels, such as hs-cTn with B-type natriuretic peptide (BNP), improve heart failure prognosis, while metabolomic profiling enables precision medicine. Additionally, biomarkers like BNP and NT-proBNP facilitate real-time therapeutic monitoring. These findings underscore the critical role of biomarkers in refining risk stratification, improving diagnostic accuracy, and enabling personalized treatment strategies in cardiovascular medicine.

The advancement of cardiovascular biomarkers has significantly enhanced early detection, risk stratification, and personalized treatment. Emerging biomarkers, including genetic variants, metabolomics, microRNAs, and imaging-based markers, provide deeper insights into disease mechanisms. Integrating multi-omic approaches with artificial intelligence may further refine predictive accuracy and therapeutic decision-making. However, clinical translation requires rigorous validation through large-scale, multicenter studies to ensure reliability and applicability across diverse populations. Standardization, cost-effectiveness assessments, and the development of biomarker panels are essential for clinical adoption. Future research should focus on bridging discovery and implementation, advancing precision medicine to improve cardiovascular outcomes.

The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes. Inhibiting haem biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, owing to a haem-associated metabolon that channels BCAA-derived carbons into haem biosynthesis. Haem synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels than wild-type cells. Although exogenous haem supplementation can restore intracellular haem levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted haem synthesis. Finally, disruption of haem biosynthesis in BAT impairs thermogenic response and, in female but not male mice, hinders the cold-induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose haem biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.

Studies using metabolomics to study bariatric surgery have shown that amino acids are one of the most changed groups of metabolites after the intervention. However, the surgery-related variation in individual amino acids, as well as the long-term impact and the differences between the types of surgeries, have been poorly studied. The aim of this study was to investigate the changes in circulating amino acids after three types of bariatric surgery up to 36 months after the intervention.

We studied 63 participants diagnosed with T2D at baseline, who received either a sleeve gastrectomy, a Roux-en-Y gastric bypass or a biliopancreatic diversion with duodenal switch. We measured the concentrations of 16 circulating amino acids in fasting plasma before the surgery as well as after 4, 12, 24 and 36 months via liquid chromatography coupled with mass spectrometry (LC-MS/MS).

Eleven circulating amino acids were significantly modified by bariatric surgery. Glutamate, leucine and isoleucine showed the greatest decrease. Most of the changes in circulating amino acids occurred within 1 year of the operations. Only one measured plasmatic amino acid (threonine) had a significantly different change pattern according to surgery types. In repeated-measure correlations, changes in circulating amino acids were significantly associated with changes in adiposity and metabolic markers.

Bariatric surgery changes the levels of most circulating amino acids, and the effect occurs in the short term without major differences between surgery types. The mechanisms explaining these changes are not elucidated but likely include modifications in amino acid metabolism.

Amino acids are fundamental in several metabolic processes, and their levels can reflect metabolism impairments that contribute to obesity and related diseases. Our objective was to identify a urinary amino acid fingerprint in obese and overweight children in prepuberty and to correlate this profile with cardiometabolic alterations.

The study included 110 children, boys and girls aged 9-10 years, they were classified according to their BMI-for-age (Body Mass Index for age) into three groups: normal weight (NW) (n = 45), overweight (OW) (n = 21), and obese (OB) (n = 44). The 12-h urine samples were analyzed by LC-MS/MS to quantify 47 amino acids using the Amino Acids Analysis Kit (Zivak®, Turkey), values were corrected by creatinine concentration. Anthropometric measurements, cardiovascular parameters, and biochemical profiles were assessed following standard protocols.

When compared to NW, anthropometric measures, systolic and diastolic blood pressure, and serum uric acid levels were progressively elevated in the OW and OB groups. The OB group was characterized by elevated alpha-aminoadipic acid, asparagine, cystathionine, 1-methyl-histidine, serine, tryptophan, phenylalanine, and tyrosine. In contrast, the OW group presented the most expressive levels of glutamine, alpha-diaminopimelic, and sarcosine.

Our findings indicate that obese and overweight children exhibit a particular urinary amino acid fingerprint which is similar to that reported in studies with plasma. The altered amino acids, particularly tyrosine, are frequently associated with impairments in glucose homeostasis, insulin resistance, and diabetes mellitus type 2. Potential mechanisms for increasing the levels of these amino acids in excess of weight may include enhanced protein degradation and impaired oxidative metabolism.

Valine is an essential amino acid that participates in various physiological and metabolic activities. The objective of the present study was to investigate the influence of different valine levels in the diet on the reproductive performance of adult male Japanese quails. Forty male quail chicks (14-24 week old) were employed in a completely randomized design with 5 treatments (0.65, 0.75, 0.85, 0.95, and 1.05 % valine in the diet), 4 replicates and 2 birds in each replicate over a period of 35 days following a 14-day adaptation period. Semen was collected weekly, and its characteristics were analyzed. The birds were then ethically slaughtered, and histological analyses were performed on testicular samples. Results showed that the different valine levels had no significant effect on testicle volume, length and relative weight, although testicle diameter tended to decrease with increasing valine level in the diet in a linear and quadratic manner (p < 0.05). The total motility and progressive motility of sperm decreased with an increase in dietary valine (p < 0.05). Abnormal sperm morphology increased with increasing valine level in the diet and the difference between treatments was significant. Different valine levels in the diet significantly affected the height of seminiferous tubule epithelia, diameter and number of tubules as well as the tubular differentiation index of the testis; but the spermatogenic index was not affected by the treatments. The findings of the study indicate that when valine levels in the diet exceed 0.75 %, there is an adverse impact on testicular volume and diameter, as well as the qualitative properties of sperm in adult quails. It is advisable to pursue additional research in this area.

Breakthroughs in metabolomics technology have revealed the direct regulatory role of metabolites in physiology and disease. Recent data have highlighted the bioactive metabolites involved in the etiology and prevention and treatment of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Numerous studies reveal that endogenous metabolites biosynthesized by host organisms or gut microflora regulate metabolic responses and disorders. Lipids, amino acids, and bile acids, as endogenous metabolic modulators, regulate energy metabolism, insulin sensitivity, and immune response through multiple pathways, such as insulin signaling cascade, chemical modifications, and metabolite-macromolecule interactions. Furthermore, the gut microbial metabolites short-chain fatty acids, as signaling regulators have a variety of beneficial impacts in regulating energy metabolic homeostasis. In this review, we will summarize information about the roles of bioactive metabolites in the pathogenesis of many metabolic diseases. Furthermore, we discuss the potential value of metabolites in the promising preventive and therapeutic perspectives of human metabolic diseases.

Systemic insulin resistance plays an important role in the pathogenesis of type 2 diabetes and its complications. Although impaired branched-chain amino acid (BCAA) metabolism has been reported to be involved in the development of diabetes, the relationship between cardiac BCAA metabolism and the pathogenesis of diabetic cardiomyopathy (DbCM) remains unclear.

The aim of this study was to investigate BCAA metabolism in insulin-resistant hearts by using a novel mouse model of DbCM.

The cardiac phenotypes of adipocyte-specific 3'-phosphoinositide-dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice were assessed by histological analysis and echocardiography. The metabolic characteristics and cardiac gene expression were determined by mass spectrometry or RNA sequencing, respectively. Cardiac protein expression was evaluated by Western blot analysis.

A-PDK1KO mouse hearts exhibited hypertrophy with prominent insulin resistance, consistent with cardiac phenotypes and metabolic disturbances previously reported as DbCM characteristics. RNA sequencing revealed the activation of BCAA uptake in diabetic hearts. In addition, the key enzymes involved in cardiac BCAA catabolism were downregulated at the protein level in A-PDK1KO mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine caused cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1).

A-PDK1KO mice closely mimic the cardiac phenotypes and metabolic alterations observed in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and to the development of novel therapies for this disease.

Infections caused by the Gram-negative bacterium Helicobacter pylori (H. pylori) can lead to gastritis, gastric or duodenal ulcers, and even gastric cancer in humans. Investigating quantitative changes in soluble biomarkers associated with H. pylori infection offers a promising method for monitoring the progression of the infection, inflammatory response and potentially systemic consequences. This study aimed to identify, using an experimental model of H. pylori infection in guinea pigs, the specific metabolomic biomarkers in the serum of H. pylori-infected (32) versus uninfected (32) animals. The H. pylori status was confirmed through histological, molecular, and serological examinations. Metabolomic profiling was conducted using UPLC-QTOF/MS methods. The metabolomic biomarkers significantly associated with H. pylori infection were selected based on volcano plots and traditional univariate receiver operating characteristics (ROC). This study identified 12 unique metabolites significantly differentiating H. pylori-infected guinea pigs from uninfected ones. In summary, the metabolomic profiling of serum samples, in combination with ROC characteristics of the data, enhances the monitoring of H. pylori infection and related inflammatory responses in guinea pigs experimentally infected with these bacteria, with potential applications in humans for prediction the infection course and its systemic effects.

Gestational diabetes mellitus (GDM) is the most common pregnancy complication, significantly affecting maternal and neonatal health. Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by metabolic abnormalities, which notably elevates the risk of developing GDM during pregnancy.

In this study, we utilized ultra-high-performance liquid chromatography for untargeted metabolomics analysis of serum samples from 137 pregnant women in the early-to-mid-pregnancy. The cohort consisted of 137 participants, including 70 in the PCOS group (36 who developed GDM in mid-to-late pregnancy and 34 who did not) and 67 in the non-PCOS group (37 who developed GDM and 30 who remained GDM-free). The aim was to investigate metabolic profile differences between PCOS and non-PCOS patients and to construct early GDM prediction models separately for the PCOS and non-PCOS groups.

Our findings revealed significant differences in the metabolic profiles of PCOS patients, which may help elucidate the higher risk of GDM in the PCOS population. Moreover, tailored early GDM prediction models for the PCOS group demonstrated high predictive performance, providing strong support for early diagnosis and intervention in clinical practice.

Untargeted metabolomics analysis revealed distinct metabolic patterns between PCOS patients and non-PCOS patients, particularly in pathways related to GDM. Based on these findings, we successfully constructed GDM prediction models for both PCOS and non-PCOS groups, offering a promising tool for clinical management and early intervention in high-risk populations.

Gestational diabetes mellitus (GDM) represents a major public health concern due to adverse maternal postpartum and long-term outcomes. Current strategies to manage GDM fail to reduce the maternal risk to develop later impaired glucose tolerance (IGT) and type 2 diabetes (T2D). In a rodent model of diet-induced GDM without obesity, we explored the perinatal metabolic adaptations in dams with gestational IGT followed by either persistent or resolved postpartum IGT. Female Sprague-Dawley rats were fed a high-fat high-sucrose (HFHS) or a chow [control group (CTL)] diet, 1 wk before mating and throughout gestation (G). Following parturition, HFHS dams were randomized to two subgroups: one switched to a chow diet and the other one maintained on an HFHS diet throughout lactation (L). Oral glucose tolerance tests (OGTTs) were performed, and plasma metabolome-lipidome were characterized at G12 and L12. We found that 1) in GDM-pregnant dams, IGT was associated with incomplete fatty acid oxidation (FAO), enhanced gluconeogenesis, altered insulin signaling, and oxidative stress; 2) improved glucose tolerance postpartum seemed to restore complete FAO along with elevation of nervonic acid-containing sphingomyelins, assumed to impart β-cell protection; and 3) persistence of IGT after delivery was associated with metabolites known to predict the early onset of insulin and leptin resistance, with maintained liver dysfunction. Our findings shed light on the impact of postpartum IGT evolution on maternal metabolic outcome after an episode of GDM. They suggest innovative strategies, implemented shortly after delivery and targeted on these biomarkers, should be explored to curb or delay the transition from GDM to T2D in these mothers.NEW & NOTEWORTHY Specific metabolomic/lipidomic features are associated with GDM postpartum outcomes. GDM-pregnant dams exhibit partial fatty acid oxidation and boosted gluconeogenesis. Resolution of postpartum IGT relies on nervonic acid-sphingomyelin, a β-cell protector. Postpartum IGT persistence suggests muscle insulin resistance and liver dysfunction.

Plasma 1H-NMR metabolomic measures have yielded significant insight into the pathophysiology of cardiometabolic disease, but their inter-related nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated 1H-NMR metabolomic profiles with coronary artery disease (CAD) and ischemic stroke (IS). Principal component (PC) analysis was performed on 168 1H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve uncorrelated PCs, which were used in Cox-proportional hazard models. For each outcome, two-sample Mendelian randomization analyses were then conducted based on three nonoverlapping databases, followed by a meta-analysis. The first six PCs collectively explaining 88% of the total variance were identified. For CAD, results from Cox and Mendelian randomization analyses were generally directionally consistent. The pooled odds ratios (95% CI) for CAD per one-SD increase in genetically influenced PC1 and PC3 (both characterized by distinct apolipoprotein B [ApoB]-associated lipoprotein profiles) were 1.04 (1.03, 1.05) and 0.94 (0.93, 0.96), respectively. Besides, the pooled odds ratio (95% CI) for CAD per one-SD increase in genetically influenced PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 (1.03, 1.07). For IS, increases of PC3 and PC5 (characterized by increased amino acids) were associated with a lower risk and a higher risk, respectively. This study confirms associations of ApoB-associated lipoprotein profiles with CAD and IS, and highlights the possible existence of an ApoB-independent lipoprotein profile, characterized by a distinctive HDL subparticle distribution, driving CAD.

Dietary protein and essential amino acid (EAA) restriction promote favorable metabolic reprogramming, although the extent to which shared or EAA-specific mechanisms facilitate diet-associated phenotypes remains unclear. Here, we compared the physiological and molecular effects of dietary methionine, leucine, or isoleucine depletion (Met-D, Leu-D, and Ile-D) in C57BL/6J mice. Each diet elicited responses not phenocopied by mTORC1 inhibition, including reduced fat mass and hepatic amino acid catabolism. Ile-D yielded additional distinct responses, highlighted by histone H2A/H4 hypoacetylation and maintained hepatic acetyl-CoA levels despite downregulated FA β-oxidation. Multi-Omics Factor Analysis of 14,139 data points objectively affirmed Ile-D phenotypes are distinct from Met-D or Leu-D and identified several metabolic and chromatin features as primary discriminators. Metabolic and epigenetic responses to Ile-D were recapitulated in vitro , suggesting underlying mechanisms represent fundamental cellular properties. Together, these results demonstrate EAAs can stimulate unique phenotypes and highlight distinct molecular mechanisms by which EAAs may inform metabolic health.

Childhood obesity continues to be a critical public health concern with far-reaching implications for well-being.

This study aimed to investigate the association between metabolites in plasma and feces and indicators including body mass index (BMI), BMI for age Z score (BMIZ), and body fat distribution among children aged 6 to 9 years in China.

This cross-sectional study enrolled 424 healthy children, including 186 girls and 238 boys. Dual-energy X-ray absorptiometry was used to determine the body fat content and regional fat distribution. Plasma and fecal metabolites were analyzed using targeted metabolomic technologies.

A total of 200 plasma metabolites and 212 fecal metabolites were accurately quantified via ultra-performance liquid chromatography coupled with tandem mass spectrometry. By using orthogonal projections to latent structures discriminant analysis and random forest model, we discovered that 9 plasma metabolites and 11 fecal metabolites were associated with different weight statuses. After adjusting for potential covariates and false discovery rate correction, multiple linear regression analyses revealed that plasma metabolites (fumaric acid, glycine, l-glutamine, methylmalonic acid, and succinic acid) and fecal metabolites (protocatechuic acid) were negatively associated (β -1.373 to -.016, pFDR < 0.001-0.031; β -1.008 to -.071, pFDR 0.005-0.033), while plasma metabolites (isovaleric acid, isovalerylcarnitine, l-glutamic acid, and pyroglutamic acid) and fecal metabolites (3-aminoisobutanoic acid, butyric acid, N-acetylneuraminic acid, octanoylcarnitine, oleoylcarnitine, palmitoylcarnitine, stearoylcarnitine, taurochenodesoxycholic acid, and taurodeoxycholic acid) exhibited positive associations with BMI, BMIZ, and body fat distribution (β .023-2.396, pFDR < 0.001; β .014-1.736, pFDR < 0.001-0.049).

Plasma and fecal metabolites such as glutamine may serve as potential therapeutic targets for the development of obesity.