Metabolic Changes Research Articles

Transcriptional control of a metabolic switch regulating cellular methylation reactions is part of a common response to stress in divergent bee species.

Recent global declines in bee health have elevated the need for a more complete understanding of the cellular stress mechanisms employed by diverse bee species. We recently uncovered the biomarker lethal (2) essential for life (l(2)efl) genes as part of a shared transcriptional program in response to a number of cell stressors in the western honey bee (Apis mellifera). Here we describe another shared stress responsive gene, Glycine N-methyl transferase (Gnmt), which is known as a key metabolic switch controlling cellular methylation reactions. We observed Gnmt induction by both abiotic and biotic stressors. We also found increased levels of the GNMT reaction product sarcosine in the midgut after stress linking metabolic changes with the observed changes in gene regulation. Prior to this study, Gnmt upregulation has not previously been associated with cellular stress responses in other organisms. To determine whether this novel stress-responsive gene would behave similarly in other bee species, we first characterized the cellular response to ER stress in lab-reared adults of the solitary alfalfa leafcutting bee (Megachile rotundata) and compared with age-matched honey bees. The novel stress gene Gnmt was induced in addition to a number of canonical gene targets induced in both bee species upon UPR activation, suggesting that stress-induced regulation of cellular methylation reactions is a common feature of bees. Therefore, this study suggests that honey bee can serve as an important model for bee biology more broadly, although studies on diverse bee species will be required to fully understand global declines in bee populations.

Millifluidic magnetophoresis-based chip for age-specific fractionation: evaluating the impact of age on metabolomics and gene expression in yeast.

A novel millifluidic process introduces age-based fractionation of S. pastorianus var. carlsbergensis yeast culture through magnetophoresis. Saccharomyces yeast is a model organism for aging research used in various industries. Traditional age-based cell separation methods were labor-intensive, but techniques like magnetic labeling have eased the process by being non-invasive and scalable. Our approach introduces an age-specific fractionation using a 3D-printed millfluidic chip in a two-step process, ensuring efficient cell deflection in the magnetic field and counteracting magnetic induced convection. Among various channel designs, the pinch-shaped channel proved most effective for age differentiation based on magnetically labeled bud scar numbers. Metabolomic analyses revealed changes in certain amino acids and increased NAD+ levels, suggesting metabolic shifts in aging cells. Gene expression studies further underlined these age-related metabolic changes. This innovative platform offers a high-throughput, non-invasive method for age-specific yeast cell fractionation, with potential applications in industries ranging from food and beverages to pharmaceuticals.

Characterizing poorly controlled type 2 diabetes using 1H-NMR metabolomics

IntroductionThe prevalence of type 2 diabetes has surged to epidemic proportions and despite treatment administration/adherence, some individuals experience poorly controlled diabetes. While existing literature explores metabolic changes in type 2 diabetes, understanding metabolic derangement in poorly controlled cases remains limited.ObjectiveThis investigation aimed to characterize the urine metabolome of poorly controlled type 2 diabetes in a South African cohort.MethodUsing an untargeted proton nuclear magnetic resonance metabolomics approach, urine samples from 15 poorly controlled type 2 diabetes patients and 25 healthy controls were analyzed and statistically compared to identify differentiating metabolites.ResultsThe poorly controlled type 2 diabetes patients were characterized by elevated concentrations of various metabolites associated with changes to the macro-fuel pathways (including carbohydrate metabolism, ketogenesis, proteolysis, and the tricarboxylic acid cycle), autophagy and/or apoptosis, an uncontrolled diet, and kidney and liver damage.ConclusionThese results indicate that inhibited cellular glucose uptake in poorly controlled type 2 diabetes significantly affects energy-producing pathways, leading to apoptosis and/or autophagy, ultimately contributing to kidney and mild liver damage. The study also suggests poor dietary compliance as a cause of the patient’s uncontrolled glycemic state. Collectively these findings offer a first-time comprehensive overview of urine metabolic changes in poorly controlled type 2 diabetes and its association with secondary diseases, offering potential insights for more targeted treatment strategies to prevent disease progression, treatment efficacy, and diet/treatment compliance.

Metabolic changes enhance necroptosis of type 2 diabetes mellitus mice infected with Mycobacterium tuberculosis.

Previously, we found that Mycobacterium tuberculosis (Mtb) infection in type 2 diabetes mellitus (T2DM) mice enhances inflammatory cytokine production which drives pathological immune responses and mortality. In the current study, using a T2DM Mtb infection mice model, we determined the mechanisms that make T2DM mice alveolar macrophages (AMs) more inflammatory upon Mtb infection. Among various cell death pathways, necroptosis is a major pathway involved in inflammatory cytokine production by T2DM mice AMs. Anti-TNFR1 antibody treatment of Mtb-infected AMs from T2DM mice significantly reduced expression of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) (necroptosis markers) and IL-6 production. Metabolic profile comparison of Mtb-infected AMs from T2DM mice and Mtb-infected AMs of nondiabetic control mice indicated that 2-ketohexanoic acid and deoxyadenosine monophosphate were significantly abundant, and acetylcholine and pyridoxine (Vitamin B6) were significantly less abundant in T2DM mice AMs infected with Mtb. 2-Ketohexanoic acid enhanced expression of TNFR1, RIPK3, MLKL and inflammatory cytokine production in the lungs of Mtb-infected nondiabetic mice. In contrast, pyridoxine inhibited RIPK3, MLKL and enhanced expression of Caspase 3 (apoptosis marker) in the lungs of Mtb-infected T2DM mice. Our findings demonstrate that metabolic changes in Mtb-infected T2DM mice enhance TNFR1-mediated necroptosis of AMs, which leads to excess inflammation and lung pathology.

Evaluation of metabolic changes in clinic attendees with therapeutic carbohydrate restriction

Background: Obesity and related metabolic health disorders are major clinical problems that have become increasingly prevalent worldwide.Aim: This before-after study examined the impact of therapeutic carbohydrate restriction (TCR) in managing metabolic health and promoting weight loss in a clinical setting using indirect calorimetry (IC).Setting: Data were collected from medical records obtained from a specialised allied health clinic focusing on metabolic health.Methods: The study analysed retrospective data from 202 overweight or obese participants (77% female, mean age 47.3) who received TCR as part of a behavioural modification programme involving multiple visits where their lifestyle, body composition and respiratory quotient (RQ), a key indicator of fat oxidation were recorded.Results: The study found that TCR improved fat oxidation in 84% of participants at short term visit (around 2 weeks), with an average weight loss of 1.8 kg. At medium term visit (around 12 weeks), 82% of participants maintained an increase in fat oxidation rate, with an average weight loss of 3.9 kg. In addition, among those with recorded body composition and waist circumference, 71% of weight lost was from fat, with an average reduction of 4.9 cm in waist measurements.Conclusion: This real-world study suggests that personalised TCR guided by IC can be an effective strategy for improving metabolic flexibility to help manage excess weight and related co-morbidities in a free-living population. Further research is needed to examine the long-term effects of TCR using this approach.Contribution: The utilisation of IC allows for the examination of individual shifts and improvements in metabolism among patients undergoing TCR.

Epithelial-mesenchymal transition-related signaling pathways in gastric Cancer cells distinctively respond to long-term experimental ketosis.

The interrelationship between cellular metabolism and the epithelial-to-mesenchymal transition (EMT) process has made it an interesting topic to investigate the adjuvant effect of therapeutic diets in the treatment of cancers. However, the findings are controversial. In this study, the effects of glucose limitation along and with the addition of beta-hydroxybutyrate (bHB) were examined on the expression of specific genes and proteins of EMT, Wnt, Hedgehog, and Hippo signaling pathways, and also on cellular behavior of gastric cancer stem-like (MKN-45) and non-stem-like (KATO III) cells. The expression levels of chosen genes and proteins studied in cancer cells gradually adopted a low-glucose condition of one-fourth, along and with the addition of bHB, and compared to the unconditioned control cells. The long-term switching of the metabolic fuels successfully altered the expression profiles and behaviors of both gastric cancer cells. However, the results for some changes were the opposite. Glucose limitation along and with the addition of bHB reduced the CD44+ population in MKN-45 cells. In KATO III cells, glucose restriction increased the CD44+ population. Glucose deprivation alleviated EMT-related signaling pathways in MKN-45 cells but stimulated EMT in KATO III cells. Interestingly, bHB enrichment reduced the beneficial effect of glucose starvation in MKN-45 cells, but also alleviated the adverse effects of glucose restriction in KATO III cells. The findings of this research clearly showed that some controversial results in clinical trials for ketogenic diet in cancer patients stemmed from the different signaling responses of various cells to the metabolic changes in a heterogeneous cancer mass.

Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells.

MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I-related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.

Fluorine-18 fluorodeoxyglucose uptake change in liver, mediastinal blood pool, and lymphoid cell-rich organs during programmed cell death-1 immunotherapy in lymphoma.

The aim of this study was to evaluate metabolism change in reference organs (liver and mediastinum) and lymphoid cell-rich organs (spleen and bone marrow) during programmed cell death-1 immunotherapy in relapsed or refractory lymphoma patients. A total of 66 patients with baseline and serial monitoring fluorodeoxyglucose (FDG) PET/computed tomography scans were retrospectively enrolled. Mean standardized uptake value (SUV) and maximum SUV of evaluated organs were obtained by two reviewers, and their association with tumor burden and clinical response were evaluated. Immune-related adverse events detected by FDG PET/computed tomography were also recorded. The SUV values of reference organs and lymphoid cell-rich organs did not change significantly during the immunotherapy process. The intersubject variability of these values ranged from 13.0 to 28.5%. Meanwhile, metabolism of reference organs was affected by neither the tumor burden nor clinical response. SUV change of lymphoid cell-rich organs was associated with clinical response to immunotherapy. Responders showed decreased metabolism, while nonresponders showed a reverse trend (spleen SUVmaximum: -0.30 ± 0.47 vs. 0.18 ± 0.39, P = 0.001, spleen SUVmean: -0.24 ± 0.39 vs. 0.14 ± 0.31, P = 0.001; and bone marrow SUVmaximum: -0.14 ± 0.37 vs. 0.07 ± 0.46, P = 0.042, respectively). The influence of immune-related adverse events on the SUV change in evaluated organs was NS. During programmed cell death-1 immunotherapy, metabolism change of reference organs is influenced neither by tumor burden nor by clinical response, while FDG uptake change of lymphoid cell-rich organs is significantly associated with clinical response.

Diabetic ketoacidosis in type 1 diabetes mellitus in children and adolescents

Background: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Although T1DM can occur in children and adults, DKA caused by T1DM is more severe in children and adolescents and metabolic changes occur more rapidly. This review discusses clinical factors associated with DKA assessed during diagnosis in children and adolescents with T1DM.Current Concepts: DKA is a severe complication that can occur in children with T1DM because of insulin deficiency, leading to high levels of catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, muscle proteolysis, hyperglycemia, and osmotic diuresis. High levels of counterregulatory hormones that enhance ketogenesis have also been noted. High blood sugar levels, dehydration, and the release of ketone bodies into the circulation cause high occurrence of acidosis. DKA can lead to life-threatening complications, such as cerebral edema, which is more common in children than in adults. Other potential complications include kidney failure, respiratory distress, and cardiovascular collapse. Children with T1DM are at a higher risk of developing DKA, particularly during times of illness or stress, or when insulin doses are missed or insufficient. In addition, undiagnosed T1DM in children can lead to DKA when the body enters a state of severe insulin deficiency.Discussion and Conclusion: The risks should be detected earlier and the pathogenesis of T1DM should be understood and assessed by physicians in children and adolescents during check-ups. Furthermore, efforts to increase public awareness are required to reduce the cognitive delays associated with DKA.

Potential of MALDI-TOF MS biotyping to detect deltamethrin resistance in the dengue vector Aedes aegypti.

Insecticide resistance in mosquitoes is spreading worldwide and represents a growing threat to vector control. Insecticide resistance is caused by different mechanisms including higher metabolic detoxication, target-site modification, reduced penetration and behavioral changes that are not easily detectable with simple diagnostic methods. Indeed, most molecular resistance diagnostic tools are costly and labor intensive and then difficult to use for routine monitoring of insecticide resistance. The present study aims to determine whether mosquito susceptibility status against the pyrethroid insecticides (mostly used for mosquito control) could be established by the protein signatures of legs and/or thoraxes submitted to MALDI-TOF Mass Spectrometry (MS). The quality of MS spectra for both body parts was controlled to avoid any bias due to unconformity protein profiling. The comparison of MS profiles from three inbreeds Ae. aegypti lines from French Guiana (IRF, IR03, IR13), with distinct deltamethrin resistance genotype / phenotype and the susceptible reference laboratory line BORA (French Polynesia), showed different protein signatures. On both body parts, the analysis of whole protein profiles revealed a singularity of BORA line compared to the three inbreeding lines from French Guiana origin, suggesting that the first criteria of differentiation is the geographical origin and/or the breeding history rather than the insecticide susceptibility profile. However, a deeper analysis of the protein profiles allowed to identify 10 and 11 discriminating peaks from leg and thorax spectra, respectively. Among them, a specific peak around 4870 Da was detected in legs and thoraxes of pyrethroid resistant lines compared to the susceptible counterparts hence suggesting that MS profiling may be promising to rapidly distinguish resistant and susceptible phenotypes. Further work is needed to confirm the nature of this peak as a deltamethrin resistant marker and to validate the routine use of MS profiling to track insecticide resistance in Ae. aegypti field populations.

Characterizing human postprandial metabolic response using multiway data analysis

IntroductionAnalysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time.ObjectivesOur goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles.MethodsWe analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences.ResultsOur analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state.ConclusionThe CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.

Compartmental analysis: a new approach to estimate protein breakdown and meal response in health and critical illness

Purpose of reviewThis study aimed to discuss the use of the pulse stable isotope tracer approach to study changes in metabolism in healthy individuals and critically ill patients.Recent findings and conclusionWe found that in the postabsorptive state and healthy condition, intracellular protein breakdown and net intracellular protein breakdown, when calculated using the pulse tracer approach, are about double what has previously been reported using the more traditional primed-constant and continuous stable isotope approaches (600 versus 300 grams of protein/day). In critically ill patients, protein breakdown is even higher and calculated to be approximately 900 grams of protein/day, using the pulse tracer approach. Based on these data, we hypothesize that reducing protein breakdown in the postabsorptive state is key when trying to improve the condition of critically ill patients. Moreover, we also used the pulse tracer approach during feeding to better estimate the intracellular metabolic response to feeding. Our first observation is that endogenous protein breakdown does not seem to be reduced during feeding. We also have shown that when consuming a meal with a certain amount of protein, the biological value of that protein meal can be calculated with the pulse tracer approach. In conclusion, using the pulse stable isotope tracer approach to study protein kinetics in the postabsorptive state and during feeding expands our understanding of how dietary proteins can affect human protein metabolism. The intracellular protein synthesis stimulatory effect of a meal is an important factor to consider when calculating the exact protein requirements and needs, particularly in critical illness.

The use of medical thermal imaging in assessing the dynamics of healing of pressure ulcers in patients with severe brain damage

Patients with severe brain damage often develop pressure ulcers (PU). The phases of the wound process significantly extend in time due to the underlying disease, severity of the condition and metabolic changes. Medical thermal imaging can be used to assess the level of PU microcirculation.Aims: to study the possibility of using medical thermal imaging to predict the course of PU in patients after severe brain damage.Methods: 38 ICU patients after brain injury and stage III–IV PU (25 men, 13 women, mean age 59±17 years). The series of thermograms (native image, after the “cold test” and 3 minutes after) were recorded before treatment and after 21 days. We used an NEC ThermoTracer TH 9100 thermal imager.Results. We assessed the minimum/maximum overall temperatures and in the 1st–4th quartiles. With a positive outcome, the temperatures Q3-Q4 were higher (35.1 C–37.6 C versus 34.8 C–36.7 C for a negative outcome) and the lower thresholds of all quartiles. We hypothesized that a sign of PU healing is a narrowing of the range of temperature points on the surface of the wound. We used a point system for assessing the dynamics of temperature parameters, then checked the model using ROC analysis: the AUC was 0.932 (0.81–1.0), which indicates the high quality. The best ratio of sensitivity and specificity (0.81; 0.83) corresponds to a cut-off point of 9.5.Conclusion. The use of medical thermal imaging makes it possible to objectively assess the level of blood supply to the PU in patients after severe brain damage, as well as the prognosis of further wound healing.

Deciphering the Therapeutic Role of Lactate in Combating Disuse-Induced Muscle Atrophy: An NMR-Based Metabolomic Study in Mice

Disuse muscle atrophy (DMA) is a significant healthcare challenge characterized by progressive loss of muscle mass and function resulting from prolonged inactivity. The development of effective strategies for muscle recovery is essential. In this study, we established a DMA mouse model through hindlimb suspension to evaluate the therapeutic potential of lactate in alleviating the detrimental effects on the gastrocnemius muscle. Using NMR-based metabolomic analysis, we investigated the metabolic changes in DMA-injured gastrocnemius muscles compared to controls and evaluated the beneficial effects of lactate treatment. Our results show that lactate significantly reduced muscle mass loss and improved muscle function by downregulating Murf1 expression, decreasing protein ubiquitination and hydrolysis, and increasing myosin heavy chain levels. Crucially, lactate corrected perturbations in four key metabolic pathways in the DMA gastrocnemius: the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; histidine metabolism; and arginine and proline metabolism. In addition to phenylalanine-related pathways, lactate also plays a role in regulating branched-chain amino acid metabolism and energy metabolism. Notably, lactate treatment normalized the levels of eight essential metabolites in DMA mice, underscoring its potential as a therapeutic agent against the consequences of prolonged inactivity and muscle wasting. This study not only advances our understanding of the therapeutic benefits of lactate but also provides a foundation for novel treatment approaches aimed at metabolic restoration and muscle recovery in conditions of muscle wasting.

Finding a Direct Method for a Dynamic Process: The DD (Direct and Dynamic) Cell-Tox Method

The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic substances, the cell triggers multiple signals in response. With this in mind, we have developed a promising cell-based toxicity method that observes various cell responses when exposed to toxic substances (either death, division, or remain viable). Based on the collective cell response, we observed and predicted the dynamics of the cell population to determine the toxicity of the toxicant. The method was tested with two different conformations: In the first conformation, we exposed a monoculture model of blood macrophages to UV light, hydrogen peroxide, nutrient deprivation, tetrabromobisphenol A, fatty acids, and 5-fluorouracil. In the second, we exposed a coculture liver model consisting of hepatocytes, hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells to rifampicin, ibuprofen, and 5-fluorouracil. The method showed good accuracy compared to established toxicity assessment methods. In addition, this approach provided more representative information on the toxic effects of the compounds, as it considers the different cellular responses induced by toxic agents.

Changes in Lipid Profiles with the Progression of Pregnancy in Black Women

Background/Objectives: Lipid metabolism plays an important role in maternal health and fetal development. There is a gap in the knowledge of how lipid metabolism changes during pregnancy for Black women who are at a higher risk of adverse outcomes. We hypothesized that the comprehensive lipidome profiles would show variation across pregnancy indicative of requirements during gestation and fetal development. Methods: Black women were recruited at prenatal clinics. Plasma samples were collected at 8–18 weeks (T1), 22–29 weeks (T2), and 30–36 weeks (T3) of pregnancy. Samples from 64 women who had term births (≥37 weeks gestation) were subjected to “shotgun” Orbitrap mass spectrometry. Mixed-effects models were used to quantify systematic changes and dimensionality reduction models were used to visualize patterns and identify reliable lipid signatures. Results: Total lipids and major lipid classes showed significant increases with the progression of pregnancy. Phospholipids and glycerolipids exhibited a gradual increase from T1 to T2 to T3, while sphingolipids and total sterol lipids displayed a more pronounced increase from T2 to T3. Acylcarnitines, hydroxy acylcarnitines, and Lyso phospholipid levels significantly decreased from T1 to T3. A deviation was that non-esterified fatty acids decreased from T1 to T2 and increased again from T2 to T3, suggestive of a potential role for these lipids during the later stages of pregnancy. The fatty acids showing this trend included key fatty acids—non-esterified Linoleic acid, Arachidonic acid, Alpha-linolenic acid, Eicosapentaenoic acid, Docosapentaenoic acid, and Docosahexaenoic acid. Conclusions: Mapping lipid patterns and identifying lipid signatures would help develop intervention strategies to reduce perinatal health disparities among pregnant Black women.

Liquid Chromatography–Mass Spectrometry-Based Metabolomics Reveals Dynamic Metabolite Changes during Early Postmortem Aging of Donkey Meat

Background: Metabolic changes in donkey meat during the early postmortem period have not been previously reported. Methods: The LC–MS-based metabolomics technique was conducted to understand the metabolic profiles and identify the key metabolites of donkey meat in the first 48 h postmortem. Results: The pH values showed a decreasing trend followed by an increasing trend. Shear force was the lowest at 4 h and the highest at 24 h (p < 0.05). For the metabolome, some candidate biomarker metabolites were identified, such as adenine, inosine, n-acetylhistidine, citric acid, isocitrate, and malic acid. Predominant metabolic pathways, such as citrate cycle (TCA cycle), alanine, aspartate and glutamate metabolism, and purine metabolism, were affected by aging time. Overabundant n-acetylhistidine was identified in LT, declined at 12 h postmortem aging, and then increased. This may explain the significantly lower pH at 12 h postmortem. Adenine was higher at 4 h postmortem, then declined. Decreased ADP may indicate a fast consumption of ATP and subsequent purine metabolism in donkey meat. Conclusions: The results of this study provided new insights into early postmortem aging of donkey meat quality.

Clcn3 deficiency ameliorates high-fat diet-induced obesity and improves metabolism in mice

ObjectiveObesity is defined as excess body fat and is a current health epidemic associated with increased risk for type 2 diabetes and cardiovascular disease. The ClC-3 chloride channel/antiporter, encoded by the Clcn3, is associated with some diseases, like carcinoma, nervous system diseases, and metabolic diseases. To verify the relationship between the Clcn3 and weight including metabolic changes, searching for a new target for metabolic therapy of obesity, we designed the experiment.MethodsThe mice were divided into 4 different groups: Clcn3+/+ mice + high-fat diet (HFD), Clcn3−/− mice + HFD, Clcn3+/+ mice + normal diet (ND), Clcn3−/− mice + ND, and fed for 16 weeks. After the glucose tolerance test and insulin tolerance test, peripheral blood and adipose tissues were collected. Moreover, we performed transcriptome sequencing for the epididymal white adipose tissue from Clcn3+/+ and Clcn3−/− mice with the high-fat diet. Western blotting verified the changes in protein levels of relevant metabolic genes.ResultsWe found that the Clcn3−/− mice had lower body weight and visceral fat, refining glucose and lipid metabolism in HFD-induced mice, but had no effect in normal diet mice. RNA-seq and Western blotting indicated that Clcn3 deficiency may inhibit obesity through the AMPK-UCP1 axis.ConclusionModulation of Clcn3 may provide an appealing therapeutic target for obesity and associated metabolic syndrome.

Investigating the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism in participants with major depressive disorder

Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus–pituitary–adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.

Widely-targeted metabolomics and transcriptomics identify metabolites associated with flowering regulation of Choy Sum

Choy Sum, a stalk vegetable highly valued in East and Southeast Asia, is characterized by its rich flavor and nutritional profile. Metabolite accumulation is a key factor in Choy Sum stalk development; however, no research has focused on metabolic changes during the development of Choy Sum, especially in shoot tip metabolites, and their effects on growth and flowering. Therefore, in the present study, we used a widely targeted metabolomic approach to analyze metabolites in Choy Sum stalks at the seedling (S1), bolting (S3), and flowering (S5) stages. In total, we identified 493 metabolites in 31 chemical categories across all three developmental stages. We found that the levels of most carbohydrates and amino acids increased during stalk development and peaked at S5. Moreover, the accumulation of amino acids and their metabolites was closely related to G6P, whereas the expression of flowering genes was closely related to the content of T6P, which may promote flowering by upregulating the expressions of BcSOC1, BcAP1, and BcSPL5. The results of this study contribute to our understanding of the relationship between the accumulation of stem tip substances during development and flowering and of the regulatory mechanisms of stalk development in Choy Sum and other related species.