Metabolic Phenotype Research Articles

Development of a PBPK Model for Lamotrigine which Incorporates Metabolism by UGT2B10: Impact of UGT2B10 Poor Metabolizer Phenotype and Pregnancy.

An updated physiologically based pharmacokinetic (PBPK) model was developed for lamotrigine by incorporating a component of metabolism due to a UDP-glucuronyltransferase (UGT) 2B isozyme. This was assigned to UGT2B10 based on recent in vitro data in our laboratory demonstrating metabolism of lamotrigine by this isozyme (Tang et al. AAPS J 26:107, 2024). The PBPK model developed in this work was able to reasonably recapitulate the exposure of lamotrigine after single (IV and Oral) and multiple (Oral) doses. The predicted/observed maximal plasma concentration (Cmax) ratio ranged from 0.8 to 1.4 across all simulated studies and for 16 out of 18 simulated studies was between 0.8 and 1.25. Similarly, the predicted/observed area under the curve (AUC) ratio ranged from 0.6 to 1.44 across all simulated studies and for 18 out of 26 of the simulated studies the ratio was between 0.8 and 1.25. There was a slight tendency to overpredict the lamotrigine AUC on multiple dosing. The median predicted fraction metabolised (fm) by UGT2B10 in the model was 60%. With this fm value, the in vivo clinical DDI between lamotrigine and valproate was reasonably recapitulated considering only UGT2B10 inhibition (Predicted/Observed AUC ratios ranged from 0.65 - 1.2). Information on the prevalence of UGT2B10 poor metabolizer phenotypes and longitudinal changes in UGT1A4 and UGT2B10 expression during pregnancy were incorporated into the PBPK model and the plasma concentrations in subjects with different UGT2B10 phenotypes and in different trimesters of pregnancy were simulated. The simulated concentrations in pregnant subjects were in line with those reported during pregnancy.

Deletion of Arntl, a component of the molecular clock, in adipocytes leads to cellular hypertrophy by increasing insulin sensitivity via FGF21

Brain and muscle Arnt-like protein 1 (BMAL1), encoded by Aryl hydrocarbon receptor nuclear translocator like 1 (Arntl) gene, is a transcription factor that regulates the circadian rhythm of the expressions of several genes. The link between the loss of BMAL1 function in adipose tissue and obesity has been reported. Although these previous studies have suggested that dysregulation of lipolysis is a contributing factor, but the detailed mechanism has not been fully understood. This study aimed to elucidate the role of BMAL1 in adipocytes using adipocyte-specific Arntl deficient (AAKO) mice. Deletion of Arntl in adipocytes leads to increased cellular insulin sensitivity, which in turn, inhibited lipolysis in adipocytes and caused cellular hypertrophy. The expression levels of Fgf21 in adipose tissue were significantly elevated in AAKO mice compared to Arntlflox/flox mice. Double knockout of Arntl and Fgf21 in adipocytes abolished metabolic phenotypes such as decreased circulating non-esterified fatty acid levels, adipocyte hypertrophy, and increased insulin sensitivity in AAKO mice. These results indicated that BMAL1 regulates fat mobilization and insulin signaling in adipocytes via FGF21 during the stationary phase. This is the possible mechanism by which disruption of circadian rhythm induces obesity.

Research on genetic variant characteristics in ADME genes based on whole-exome sequencing in the Han Chinese population.

Genetic variants in absorption, distribution, metabolism, and excretion (ADME) genes affect drug efficacy and side effects. Whole-exome sequencing (WES) effectively identifies these variants. Findings from Western populations may not apply to the Han Chinese population due to ethnic differences. This study aimed to investigate genetic variants, metabolic phenotypes, and drug impacts related to ADME genes in the Han Chinese population using WES data. ADME genes and drug profiles were sourced from multiple databases. WES data were collected from 357 samples at Third Xiangya Hospital and 5,000 samples from the "HuaBiao Project." After WES, fastp was used for quality control; BWA, samtools, and the Picard software were used for comparison, sequencing, and de-duplication; GATK was used for base quality score recalibration; and variant quality score recalibration was carried out after detecting the variants, and the variants were annotated using ANNOVAR. ADME genes and drug profiles were obtained through PharmGKB and other databases, and then all variants in the exonic regions of ADME genes were extracted. The distributional characteristics of these variants, ethnic differences, and metabolic phenotype distribution of important ADME genes, such as CYP2B6, were analyzed. Prediction of deleterious variants of ADME gene employed the ADME gene variant prediction framework, and western blotting and enzyme assays were used to validate the impact of harmful variants. We integrated 604 ADME genes and 972 drugs. There were 33,925 single nucleotide polymorphisms (SNPs) and 484 insertion-deletions (InDels) in 5,357 Han Chinese WES samples; 88.9 % were rare. Of the SNPs, 60.9 % are new functional mutations in enzyme and transporter genes; InDels also affected these genes. We discovered Chinese-specific variants in key ADME genes and ethnic-specific metabolic phenotypes that could affect drug use. Finally, we screened 3,657 potentially harmful mutations; 45.6 % are novel. Western blotting and enzyme activity assays confirmed several harmful mutations significantly reduced CYP2C19 gene expression and function (P < 0.01).

Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.

Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.

Role of CYP2D6 polymorphisms in tramadol metabolism in a context of co-medications and overweight.

Very few quantitative data exist on tramadol metabolites, which hampers our understanding of their role in efficacy and safety of tramadol. We aimed to provide quantitative data on tramadol and its 5 main metabolites in a patient cohort and to determine whether metabolite ratios can be predictive of a CYP2D6 metabolism phenotype. We also aimed to investigate the influence of co-medications and patient profile (BMI, glycemia, lipid levels) on tramadol metabolite ratios. Overall, 37 patient samples from the CONSTANCES cohort contained tramadol and its 5 metabolites. Mean concentrations found tramadol at 343.2±223.2μg/L, M1 at 62.4±41.4μg/L, M2 at 210.0±272.3, M3 at 1.76±3.0μg/L, M4 at 1.8±2.8μg/L and M5 at 31.8±28.4μg/L. The most frequent CYP2D6 phenotype was extensive metabolizers (51.3%), followed by intermediate metabolizers (24.3%) and poor metabolizers (10.8%). CYP2D6-inhibiting co-medications impacted tramadol metabolism independently of CYP2D6 metabolism phenotype. Lipid parameters and glycemia were significantly associated with changes in tramadol metabolic ratios. Metabolic ratios are not sufficient to determine the CYP2D6 metabolic phenotype in patients. CYP2D6 inhibitors and obesity/NAFLD/diabetes impact tramadol metabolism. These factors are likely to impact the analgesic efficacy and safety profile of tramadol, justifying the need for further studies in this area.

SF1-specific deletion of the energy sensor AMPKγ2 induces obesity.

AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy expenditure, peripheral glucose and lipid metabolism. However, most research on hypothalamic AMPK has concentrated on the catalytic subunits AMPKα1 and AMPKα2, with little focus on the regulatory subunits. To fill this gap of knowledge, we investigated the effects of selectively deleting the regulatory isoform AMPKγ2, which is a primary "energy sensor", in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH). Complete metabolic phenotyping and molecular analyses in brown adipose tissue (BAT), white adipose tissue (WAT) and liver were carried out. Our findings reveal that, in contrast to the obesity-protective effect of the genetic deletion of AMPKα subunits, the loss of AMPKγ2 in SF1 neurons leads to a sex-independent and feeding-independent obesity-prone phenotype due to decreased thermogenesis in brown adipose tissue (BAT) and reduced browning of WAT, resulting in lower energy expenditure. Additionally, SF1-Cre AMPKγ2 mice exhibit hepatic lipid accumulation, but surprisingly maintain normal glucose homeostasis. Overall, these results highlight the distinct roles of AMPK subunits within the hypothalamus.

Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.

Colorectal cancer (CRC) represents a prototypical example of a cancer type for which inter- and intra-tumor heterogeneities remain major challenges for the clinical management of patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity and phenotypic plasticity and sustain disease progression. In particular, acidosis is a common hallmark of solid tumors, including CRC, and it is known to induce aggressive cancer cell phenotypes. In this study, we report that long-term adaptation to acidic pH conditions is associated with common metabolic alterations, including a glycolysis-to-respiration switch and a higher reliance on the activity of phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition of PHGDH activity or mitochondrial respiration induces greater growth-inhibitory effects in acidosis-exposed CRC cells in 2D and 3D culture conditions, and in patient-derived CRC organoids. These data pave the way for drugs targeting the acidic tumor compartment as a "one-size-fits-all" therapeutic approach to delay CRC progression.

Senescent myoblasts exhibit an altered exometabolome that is linked to senescence-associated secretory phenotype signaling.

Cellular senescence has been implicated in the aging-related dysfunction of satellite cells, the resident muscle stem cell population primarily responsible for the repair of muscle fibers. Despite being in a state of permanent cell cycle arrest, these cells remain metabolically active and release an abundance of factors that can have detrimental effects on the cellular microenvironment. This phenomenon is known as the senescence-associated secretory phenotype (SASP), and its metabolic profile is poorly characterized in senescent muscle. In the present investigation, we examined the intracellular and extracellular metabolome of C2C12 myoblasts using a bleomycin (BLEO)-mediated model of DNA damage-induced senescence. We also evaluated the relationship between the senescent metabolic phenotype and SASP signaling through molecular and network-based analyses. Senescent myoblasts exhibited a significantly altered extracellular metabolome (i.e., exometabolome), including increased secretion of several aging-associated metabolites. Four of these metabolites-trimethylamine-N-oxide (TMAO), xanthine, choline, and oleic acid-were selected for individual dose-response experiments to determine whether they could drive the senescence phenotype. Although most of the tested metabolites did not independently alter senescence markers, oleic acid treatment of healthy myoblasts significantly upregulated the SASP genes Ccl2, Cxcl12, and Il33 (p < 0.05). A gene-metabolite interaction network further revealed that oleic acid was one of the most interconnected metabolites to key senescence-associated genes. Notably, oleic acid interacted with several prominent SASP genes, suggesting a potential epigenetic effect between this monounsaturated fatty acid and SASP regulation. In summary, the exometabolome, particularly oleic acid, is implicated in SASP signaling within senescent myoblasts.NEW & NOTEWORTHY Cellular senescence and its accompanying secretory phenotype [i.e., the senescence-associated secretory phenotype (SASP)] have been linked to the aging-associated dysfunction of skeletal muscle, yet little is known about this phenomenon in satellite cells. We report that senescent myoblasts experience a significantly altered extracellular metabolome primarily characterized by the substantial release of nonesterified fatty acids. Targeted evaluation of several extracellular senescence-associated metabolites reveals a potential epigenetic role for long-chain fatty acids, particularly oleic acid, in regulating SASP-related gene expression.

Metabolic Profiles of Critical Care Patients to Confirm Sepsis and Further Understand the Metabolic Phenotype of Sepsis.

Sepsis remains a major concern in health care globally. Despite decades of research, incidence is on the rise, and mortality remains high. Costs are staggering. Additionally, the outdated sepsis bundle established based on SIRS, remains the standard by which providers are held accountable. It is now accepted that organ dysfunction in sepsis is secondary to cellular metabolic dysregulation. Technology for metabolic monitoring should be explored for improved, early recognition of sepsis. We sought to investigate the underlying metabolic profile of patients with sepsis, to determine the value of continuous metabolic monitoring technology. The investigators partnered with industry, to trial noninvasive monitoring of the cellular metabolite carbon dioxide, under a prospective, observational design. During the 6-month trial, the investigators collected data from the electronic medical record of patients using the technology, to determine the specific metabolic differences between patients with and without sepsis. The investigators found serum carbon dioxide (paCO2) was significantly lower in patients with sepsis, and, low paCO2 had a significant inverse relationship to serum lactate. This finding supports the notion that paCO2 is low in sepsis secondary to metabolic dysregulation and not hyperventilation, which had historically explained low paCO2 under the SIRS model. Metabolic monitoring is available, easy to apply and manage, and contributes valuable information in the detection of sepsis. Further research should be done to understand trends in serum CO2 and its relationship to the development of sepsis. This study also provides important further support for the emerging understanding of the dysregulated host response in sepsis.

Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster.

The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we examine the possibility that the Drosophila ortholog of Hypoxia inducible factor 1α (Hif1α) is also required to activate the larval glycolytic program. CRISPR/Cas9 was used to generate new loss-of-function alleles in the Drosophila gene similar (sima), which encodes the sole fly ortholog of Hif1α. The resulting mutant strains were analyzed using a combination of metabolomics and RNAseq for defects in carbohydrate metabolism. Our studies reveal that sima mutants fail to activate aerobic glycolysis and die during larval development with metabolic phenotypes that mimic those displayed by dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein. These findings demonstrate that Sima/HIF1α is required during embryogenesis to coordinately up-regulate carbohydrate metabolism in preparation for larval growth. Notably, our study also reveals that the Sima-dependent gene expression profile shares considerable overlap with that observed in dERR mutant, suggesting that Sima/HIF1α and dERR cooperatively regulate embryonic and larval glycolytic gene expression.

Heart-derived factors and organ cross-talk in settings of health and disease: new knowledge and clinical opportunities for multimorbidity.

Cardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross-talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross-talk. Early evidence for the secretion of cardiac-specific factors facilitating organ cross-talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum-Golgi pathway. More recently, studies in cardiomyocyte-specific genetic mouse models have revealed cardiac-initiated organ cross-talk. Cardiomyocyte-specific modulation of microRNAs (miR-208a and miR-23-27-24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G-protein-coupled receptor kinase 2 (GRK2), mutant α-myosin heavy-chain (αMHC), ubiquitin-like modifier-activating enzyme (ATG7), oestrogen receptor alpha (ERα) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non-classical mechanisms including the release of extracellular vesicles. Cross-talk between the heart and the brain has also been described (e.g. via miR-1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease.

Model-Informed Recommendation of Mavacamten Posology for Chinese Adults With Obstructive Hypertrophic Cardiomyopathy.

Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure-response (E-R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER-CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E-R models, and the observed VLVOTg and LVEF from EXPLORER-CN were successfully simulated. Next, five echocardiography-guided titration regimens (plus the EXPLORER-CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down-titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up-titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.

Hyper-energy metabolism of oxidative phosphorylation and enhanced glycolysis contributes to radioresistance in glioma cells

The concept of dual-state hyper-energy metabolism characterized by elevated glycolysis and OxPhos has gained considerable attention during tumor growth and metastasis in different malignancies. However, it is largely unknown how such metabolic phenotypes influence the radiation response in aggressive cancers. Therefore, the present study aimed to investigate the impact of hyper-energy metabolism (increased glycolysis and OxPhos) on the radiation response of a human glioma cell line. Modulation of the mitochondrial electron transport chain was carried out using a 2,4-dinitrophenol (DNP). Metabolic characterization was carried out by assessing glucose uptake, lactate production, mitochondrial mass, membrane potential, and ATP production. The radiation response was examined by cell growth, clonogenic survival, and cell death assays. Macromolecular oxidation was assessed by DNA damage, lipid peroxidation, and protein carbonylation assay. Hypermetabolic OPM-BMG cells exhibited a significant increase in glycolysis and OxPhos following irradiation as compared to the parental BMG-1 cells. Enhanced radioresistance of OPM-BMG cells was evidenced by the increase in α/β ratio (9.58) and D1 dose (4.18 Gy) as compared to 4.36 and 2.19 Gy in BMG-1 cells respectively. Moreover, OPM-BMG cells were found to exhibit increased resistance against radiation-induced cell death, and macromolecular oxidation as compared to BMG-1 cells. Inhibition of glycolysis and mitochondrial complex-II significantly enhanced the radiosensitivity of OPM-BMG cells compared to BMG-1 cells. Our results demonstrate that the hyper-energy metabolism of increased glycolysis and OxPhos confer radioresistance. Consequently targeting glycolysis and OxPhos in combination with radiation may overcome therapeutic resistance in aggressive cancers like glioma.

Osteoarthritis associated with metabolic syndrome: epidemiology, pathogenesis, treatment

Metabolic syndrome (MS) is a complex of metabolic disorders, including insulin resistance, abdominal obesity, diabetes mellitus, hyperuricemia and arterial hypertension. According to the World Health Organization, the number of people with obesity worldwide is steadily increasing, taking on the characteristics of a “pandemic”. Against this backdrop, diseases pathogenetically linked to MS, such as osteoarthritis (OA), are gaining particular significance. Modern biochemical and molecular-genetic research has provided new data on the etiology and pathogenesis of OA, allowing the identification of phenotypes of the condition. One such phenotype is OA associated with MS, or metabolic OA. The development of this form of the disease is influenced by numerous factors, including hypersecretion of pro-inflammatory adipokines, transformation of synovial macrophages, direct effects of free fatty acids, biomechanical overload of joints, and others. Treatment of metabolic OA, in addition to standard approaches outlined in numerous clinical guidelines, has its own specific features. Particular emphasis is placed on weight reduction through lifestyle modification, strengthening of musculo-tendinous complexes, and concomitant therapy for metabolic disorders. These measures have demonstrated significant therapeutic effects, including pain reduction, decreased inflammation, and slowing of disease progression. One of the modern comprehensive remedies with phytonutritional components is Revocca capsules (“BIOTECHNOS”, Russia). Their composition in daily dosage includes phytosterols (calculated as β-sitosterol) at 100 mg, unsaponifiable compounds from avocado and soybean oils (in a 1:2 ratio) at 300 mg, rosehip extract at 300 mg, resveratrol at 70 mg, and zinc (as zinc citrate) at 12 mg. Given the increasing number of patients with the metabolic phenotype of OA, comprehensive hypolipidemic and anti-inflammatory therapy provided by multi-component drugs is becoming increasingly significant.

A Fast-Pass, Desorption Electrospray Ionization Mass Spectrometry Strategy for Untargeted Metabolic Phenotyping.

Desorption electrospray ionization mass spectrometry imaging (DESI-MSI) provides direct analytical readouts of small molecules that can be used to characterize the metabolic phenotypes of genetically engineered bacteria. In an effort to accelerate the time frame associated with the screening of mutant libraries, we have developed a high-throughput DESI-MSI analytical workflow implementing a single raster line-scan strategy that facilitates the collection of location-resolved molecular information from engineered strains on a subminute time scale. Evaluation of this "Fast-Pass" DESI-MSI phenotyping workflow on analytical standards demonstrated the capability of acquiring full metabolic profiling information with a throughput of ∼40 s per sample. This Fast-Pass strategy was implemented in the analysis of genetically edited Escherichia coli strains that have been engineered to produce various free-fatty acids (FFAs) for applications relevant to biofuels. Due to the untargeted nature of DESI-MSI, the investigation of these strains yielded molecular information for both global metabolites and targeted detection of accumulated bioproducts, allowing simultaneous readouts of strain-specific chemical profiles and comparative measurements of FFA production levels.

Tumor Metabolism as a Factor Affecting Diversity in Cancer Cachexia.

Cancer cachexia is a multifaceted metabolic syndrome characterized by muscle wasting, fat redistribution, and metabolic dysregulation, commonly associated with advanced cancer but sometimes also evident in early-stage disease. More subtle body composition changes have also been reported in association with cancer, including sarcopenia, myosteatosis, and increased fat radiodensity. Emerging evidence reveals that body composition changes including sarcopenia, myosteatosis, and increased fat radiodensity, arise from distinct biological mechanisms and significantly impact survival outcomes. Importantly, these features often occur independently, with their combined presence exacerbating poor prognoses. Tumor plays a pivotal role in driving these host changes, either by acting as a metabolic parasite or by releasing mediators that disrupt normal tissue function. This review explores the diversity of tumor metabolism. It highlights the potential for tumor-specific metabolic phenotypes to influence systemic effects, including fat redistribution and sarcopenia. Addressing this tumorhost metabolic interplay requires personalized approaches that disrupt tumor metabolism while preserving host health. Promising strategies include targeted pharmacologic interventions and anti-cachexia agents like GDF-15 inhibitors. Nutritional modifications such as ketogenic diets and omega-3 fatty acid supplementation also merit further investigation. In addition to preserving muscle, these therapies will need to be evaluated for their capability to improve survival and quality of life. This review underscores the need for further research into tumor-driven metabolic effects on the host and the development of integrative treatment strategies to address the interconnected challenges of cancer progression and cachexia.

Glo1 reduction in mice results in age- and sex-dependent metabolic dysfunction.

Advanced glycation end products (AGEs) have been implicated as an important mediator of metabolic disorders including obesity, insulin resistance, and coronary artery disease. Glyoxalase 1 (Glo1) is a critical enzyme in the clearance of toxic dicarbonyl such as methylglyoxal, precursors of AGEs. The role of AGE-independent mechanisms that underly Glo1-induced metabolic disorders have yet to be elucidated. We performed a longitudinal study of female and male Glo1 heterozygous knockdown ( Glo1 +/- ) mice with ∼50% gene expression and screened metabolic phenotypes such as body weight, adiposity, glycemic control and plasma lipids. We also evaluated atherosclerotic burden, AGE levels, and gene expression profiles across cardiometabolic tissues (liver, adipose, muscle, kidney and aorta) to identify pathway perturbations and potential regulatory genes of Glo1 actions. Partial loss of Glo1 resulted in obesity, hyperglycemia, dyslipidemia, and alterations in lipid metabolism in metabolic tissues in an age- and sex-dependent manner. Glo1 +/- females displayed altered glycemic control and increased plasma triglycerides, which aligned with significant perturbations in genes involved in adipogenesis, PPARg, insulin signaling, and fatty acid metabolism pathways in liver and adipose tissues. Conversely, Glo1 +/- males developed increased skeletal muscle mass and visceral adipose depots along with changes in lipid metabolism pathways. For both cohorts, most phenotypes manifested after 14 weeks of age. Evaluation of methylglyoxal-derived AGEs demonstrated changes in only male skeletal muscle but not in female tissues, which cannot explain the broad metabolic changes observed in Glo1 +/- mice. Transcriptional profiles suggest that altered glucose and lipid metabolism may be partially explained by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Moreover, transcription factor (TF) analysis of the tissue-specific gene expression data identified TFs involved in cardiometabolic diseases such as Hnf4a (all tissues) and Arntl (aorta, liver, and kidney) which are female-biased regulators and whose targets are altered in response to Glo1 +/- . Our results indicate that Glo1 reduction perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without significant changes in AGEs across metabolic tissues. Rather, tissue-specific gene expression analysis suggests that key transcription factors such as Hfn4a and Arntl as well as metabolite changes from alternative methylglyoxal detoxification such as pyruvate, likely contribute to metabolic dysregulation in Glo1 +/- mice.

Dense stroma activates the TGF-β1/FBW7 axis to induce metabolic subtype switching in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease. Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes. The impact of transforming growth factor β (TGF-β)-1/F-box and WD repeat domain-containing 7 (FBW7) on the switch of the metabolic subtype was further validated in vitro and in vivo. Finally, cell growth was performed to identify the TGF-β1/FBW7 ratio as a molecular marker for gemcitabine resistance. PDAC was stratified into the glycolytic subtype and lipogenic subtype. Furthermore, pancreatic cancer-associated fibroblasts-derived TGF-β1 and tumor cell-derived FBW7 were demonstrated to co-determine the metabolic phenotypes in PDAC. A high TGF-β1/FBW7 ratio always represented the glycolytic PDAC with dense stroma. This subtype of PDAC exhibited mesenchymal features and was predictive of unfavorable prognoses, despite being more sensitive than the lipogenic subtype to combination treatment with gemcitabine and an inhibitor of TGF-β receptor I (TGF-βR1). The TGF-β1/FBW7 ratio could be regarded as a molecular marker of metabolic phenotypes in PDAC and may contribute to the development of effective therapeutic strategies to improve the survival of PDAC patients.

DOP030 Mucosal deficiency of mitochondria-driven humoral immunity is linked to Crohn’s Disease

Abstract Background Secretory IgA (sIgA) is critical for the maintenance of the mucosal barrier function, preventing bacterial translocation and reducing the risk of chronic inflammation. Several decades of research have revealed a dysregulation of the B-cell compartment in inflammatory bowel disease (IBD) of yet unknown origin1,2. While increased serum levels of (auto)antibodies against S. cerevisiae or the intestinal M-cell expressed FimH receptor glycoprotein 2 (GP2) are observed in patients with Crohn’s disease (CD)3, some studies indicated an impaired generation of intestinal immunoglobulin-secreting plasma cells (PCs)4. To unravel the role of mucosal humoral immunity in CD pathogenesis, we aimed to provide an in-depth characterisation of colonic PC differentiation in patients with CD. Methods In-depth phenotyping of patients with CD in remission and non-IBD controls (hospitalised normals) was performed using multi-omics analyses (spatial single-cell proteomics, proteomics, metabolomics, and transcriptomics) of plasma or colon biopsy samples. Colonic switched memory B cells (sMBCs) were sorted from lamina propria mononuclear cells (LPMNCs) by magnetic-activated cell sorting and ex vivo differentiated into PCs. The impact of mitochondrial function on colonic PC maturation was studied in mitochondrial respiratory chain complex V-deficient ATP8 mutant mice and mice that underwent nutritional intervention. Results Despite a hyperactive colonic B-cell compartment, patients with CD displayed significantly diminished mucosal dimeric IgA (dIgA) and fecal IgA compared to non-IBD controls. Polymeric immunoglobulin receptor (PIGR) expression did not differ, excluding a defective epithelial transcytosis of dIgA. Spatial single-cell proteomics uncovered that colonic plasmablasts and immature CD19+CD45+ PCs were increased at the expense of the fully mature CD19-CD45- phenotype. Consistently, PCs generated ex vivo from CD-derived sMBCs revealed impaired capacity to differentiate into IgA-secreting PCs. Metabolic phenotyping indicated a colonic mitochondrial dysfunction in patients with CD that was also reflected in colonic PCs by increased expression of the cell-surface NADase CD38 in concert with decreased expression of mitochondrially encoded transcripts. Of note, splenic PCs isolated from ATP8 mutant mice displayed a hyperproliferative and low-differentiated phenotype, while colonic IgA-secreting PCs were reduced. Conversely, feeding mice an isocaloric glucose-free, high-protein diet, which promotes mitochondrial activity, increased colonic IgA levels. Conclusion In summary, this study links mitochondrial dysfunction to impaired PC differentiation in patients with CD, resulting in reduced levels of sIgA and thereby compromised mucosal barrier integrity.

Examining the Impact of Diet-and-Exercise-Induced Weight Loss on Drug Metabolism and Gastric Emptying in Patients with Obesity.

Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P <.05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.