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Our objective was to interrogate mesenchymal stem cell (MSC) lipid metabolism and gestational exposures beyond maternal body mass that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n = 16) or normal weight (n = 15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24-hour excess fatty acid [24hFA]). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, TNF-α, and high-density lipoprotein and total cholesterol in fasting blood from mid and late gestation (~17 and ~27 weeks, respectively). We measured child adiposity at birth (n = 29), 4-6 months (n = 29), and 4-6 years (n = 13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster 2. All clusters increased acylcarnitines and TAGs with 24hFA, although Cluster 2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC clusters and child adiposity at 4-6 years (both highest in Cluster 3). Our data support the notion that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, although validation with larger longitudinal samples is warranted.

Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration. This study explores the effects of AdipoR1 gene deficiency in mice, revealing a striking decline in ω3 polyunsaturated fatty acids (PUFA), an increase in ω6 fatty acids, and elevated ceramides in the retina. The AdipoR1 deficiency impairs peroxisome proliferator-activated receptor α signaling, which is crucial for FA metabolism, particularly affecting proteins associated with FA transport and oxidation in the retina and retinal pigmented epithelium. Our lipidomic and proteomic analyses indicate changes that could affect membrane composition and viscosity through altered ω3 PUFA transport and synthesis, suggesting a potential influence of AdipoR1 on these properties. Furthermore, we noted a reduction in the Bardet-Biedl syndrome proteins, which are crucial for forming and maintaining photoreceptor outer segments that are PUFA-enriched ciliary structures. Diminution in Bardet-Biedl syndrome-proteins content combined with our electron microscopic observations raises the possibility that AdipoR1 deficiency might impair ciliary function. Treatment with inhibitors of ceramide synthesis led to substantial elevation of ω3 LC-PUFAs, alleviating photoreceptor degeneration and improving retinal function. These results serve as the proof of concept for a ceramide-targeted strategy to treat retinopathies linked to PUFA deficiency, including age-related macular degeneration.

Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids. [ABSTRACT FROM AUTHOR]

Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics. Author summary: Cells and viruses rely on metabolic circuits to survive and replicate. The small metabolites called polyamines support cellular homeostasis by supporting mitochondrial function. Without polyamines, lipids accumulate in cells because they are not catabolized by fatty acid oxidation. Cells depleted of polyamines switch from aerobic respiration to glycolysis for energy production, similar to cancer cells in hypoxic environments. We also show that varied viruses use lipids to replicate, and targeting lipids with small molecule inhibitors can reduce virus replication. Overall, our work makes a new connection between polyamines and lipid metabolism and highlights potential pathways to target for antiviral therapies. [ABSTRACT FROM AUTHOR]

This study aims to understand the metabolic mechanisms of unintentional weight loss in older adults. We investigated plasma metabolite associations of subsequent weight change over 2 years in 1536 previously weight stable participants (mean age 74.6 years, 50% women, 35% Black) from the Health, Aging and Body Composition (Health ABC) Study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss with/without an intention and weight gain >3% annually relative to weight stability. The metabolite associations of unintentional weight loss differed from those of intentional weight loss and weight gain. Lower levels of aromatic amino acids, phospholipids, long‐chain poly‐unsaturated triglycerides, and higher levels of amino acid derivatives, poly‐unsaturated fatty acids, and carbohydrates were associated with higher odds of unintentional weight loss after adjusting for age, sex, race, and BMI categories. Prevalent diseases attenuated four and lower mid‐thigh muscle mass and poorer appetite each attenuated 2 of 77 identified metabolite associations by >20%, respectively. Other factors (e.g., energy expenditure, diet, and medication) attenuated all associations by <20%. While 16 metabolite associations were attenuated by 20%–48% when adjusting for all these risk factors, 47 metabolite associations remained significant. Altered amino acid metabolism, impaired mitochondrial fatty acid oxidation, and inflammaging implicated by identified metabolites appear to precede unintentional weight loss in Health ABC older adults. Furthermore, these pathways seem to be associated with prevalent diseases especially diabetes, lower muscle mass, and poorer appetite. [ABSTRACT FROM AUTHOR]

Summary Metabolic dysfunction‐associated steatohepatitis (MASH) is a condition characterized by hepatosteatosis, inflammation, and tissue damage, with steatosis as the initial stage, which involves chronic, excess deposition of lipids in hepatic lipid droplets. Despite the growing prevalence and serious risks it poses, including liver decompensation, the need for transplantation, and increased patient mortality, MASH currently faces no approved pharmacotherapy. Several promising treatment candidates have emerged from recent clinical trials, including analogs of FGF21 and agonists of the associated FGFR1‐KLB complex. These agents were well‐tolerated in trials and have demonstrated significant improvements in both histological and biochemical markers of liver fat content, inflammation, injury, and fibrosis in patients with MASH. Endocrine FGF21 plays a vital role in maintaining homeostasis of lipid, glucose, and energy metabolism. It achieves this through pathways that target lipids or lipid droplets in adipocytes and hepatocytes. Mechanistically, pharmacological FGF21 acts as a potent catabolic factor to promote lipid or lipid droplet lipolysis, fatty acid oxidation, mitochondrial catabolic flux, and heat‐dissipating energy expenditure, leading to effective clearance of hepatic and systemic gluco‐lipotoxicity and inflammatory stress, thereby preventing obesity, diabetes, and MASH pathologies. In this review, we aim to provide an update on the outcomes of clinical trials for several FGF21 mimetics. We compare these outcomes with preclinical studies and offer a lipid‐centric perspective on the mechanisms underlying the clinical benefits of these agents for MASH. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSC) are considered an aberrant population of immature myeloid cells that have attracted considerable attention in recent years due to their potent immunosuppressive activity. These cells are typically absent or present in very low numbers in healthy individuals but become abundant under pathological conditions such as chronic infection, chronic inflammation and cancer. The immunosuppressive activity of MDSC helps to control excessive immune responses that might otherwise lead to tissue damage. This same immunosuppressive activity can be detrimental, particularly in cancer and chronic infection. In the cancer setting, tumors can secrete factors that promote the expansion and recruitment of MDSC, thereby creating a local environment that favors tumor progression by inhibiting the effective immune responses against cancer cells. This has made MDSC a target of interest in cancer therapy, with researchers exploring strategies to inhibit their function or reduce their numbers to improve the efficacy of cancer immunotherapies. In the context of chronic infections, MDSC can lead to persistent infections by suppressing protective immune responses thereby preventing the clearance of pathogens. Therefore, targeting MDSC may provide a novel approach to improve pathogen clearance during chronic infections. Ongoing research on MDSC aims to elucidate the exact processes behind their expansion, recruitment, activation and suppressive mechanisms. In this context, it is becoming increasingly clear that the metabolism of MDSC is closely linked to their immunosuppressive function. For example, MDSC exhibit high rates of glycolysis, which not only provides energy but also generates metabolites that facilitate their immunosuppressive activity. In addition, fatty acid metabolic pathways, such as fatty acid oxidation (FAO), have been implicated in the regulation of MDSC suppressive activity. Furthermore, amino acid metabolism, particularly arginine metabolism mediated by enzymes such as arginase-1, plays a critical role in MDSC-mediated immunosuppression. In this review, we discuss the metabolic signature of MDSC and highlight the therapeutic implications of targeting MDSC metabolism as a novel approach to modulate their immunosuppressive functions. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a devastating disease characterized by vascular remodeling, resulting in right ventricular failure and death. Dysregulation of energy metabolism is linked to PH pathogenesis. Trimetazidine (TMZ), a selective long-chain 3-ketoacyl coenzyme A thiolase inhibitor, is critical in maintaining energy metabolism. Despite the indicated TMZ's inhibitory effect on pulmonary vascular remodeling in PH development, the integrated evaluation of the changes in biomolecules, such as metabolites and transcripts, that TMZ induces in the lung and heart tissues is largely unknown in vivo. For an improved understanding of the molecular mechanism involving the effects of TMZ on PH development, we performed a comprehensive analysis of the changes in cardiac metabolites and pulmonary transcripts of SU5416-Hypoxia (Su/Hx) rats treated with TMZ. Metabolomic analysis of the Su/Hx-induced PH hearts demonstrated that TMZ reduced the long-chain fatty acid concentration. Additionally, TMZ alleviated PH degree and excessive strain on the right heart functions in rats with Su/Hx-induced PH. We identified the candidate target genes for TMZ treatment during PH development. Interestingly, the mRNA levels of the fatty acid transporters were substantially downregulated by TMZ administration in the lungs with Su/Hx-induced PH. Notably, TMZ suppressed excessive proliferation of human pulmonary artery smooth muscle cells under hypoxic conditions. Our study suggests that TMZ ameliorates PH development by involving energy metabolism in the lungs and heart. [ABSTRACT FROM AUTHOR]

Background: Studying the effect of dietary Spirulina and lysozyme supplementation on the metabolome and proteome of liver tissue contributes to understanding potential hepatic adaptations of piglets to these novel diets. This study aimed to understand the influence of including 10% Spirulina on the metabolome and proteome of piglet liver tissue. Three groups of 10 post-weaned piglets, housed in pairs, were fed for 28 days with one of three experimental diets: a cereal and soybean meal-based diet (Control), a base diet with 10% Spirulina (SP), and an SP diet supplemented with 0.01% lysozyme (SP + L). At the end of the trial, animals were sacrificed and liver tissue was collected. Metabolomics analysis (n = 10) was performed using NMR data analysed with PCA and PLS-DA. Proteomics analysis (n = 5) was conducted using a filter aided sample preparation (FASP) protocol and Tandem Mass Tag (TMT)-based quantitative approach with an Orbitrap mass spectrometer. Results: Growth performance showed an average daily gain reduction of 9.5% and a feed conversion ratio increase of 10.6% in groups fed Spirulina compared to the control group. Metabolomic analysis revealed no significant differences among the groups and identified 60 metabolites in the liver tissue. Proteomics analysis identified 2,560 proteins, with 132, 11, and 52 differentially expressed in the Control vs. SP, Control vs. SP + L and SP vs. SP + L comparisons, respectively. This study demonstrated that Spirulina enhances liver energy conversion efficiency, detoxification and cellular secretion. It improves hepatic metabolic efficiency through alterations in fatty acid oxidation (e.g., upregulation of enzymes like fatty acid synthase and increased acetyl-CoA levels), carbohydrate catabolism (e.g., increased glucose and glucose-6-phosphate), pyruvate metabolism (e.g., higher levels of pyruvate and phosphoenolpyruvate carboxykinase), and cellular defence mechanisms (e.g., upregulation of glutathione and metallothionein). Lysozyme supplementation mitigates some adverse effects of Spirulina, bringing physiological responses closer to control levels. This includes fewer differentially expressed proteins and improved dry matter, organic matter and energy digestibility. Lysozyme also enhances coenzyme availability, skeletal myofibril assembly, actin-mediated cell contraction, tissue regeneration and development through mesenchymal migration and nucleic acid synthesis pathways. Conclusions: While Spirulina inclusion had some adverse effects on growth performance, it also enhanced hepatic metabolic efficiency by improving fatty acid oxidation, carbohydrate catabolism and cellular defence mechanisms. The addition of lysozyme further improved these benefits by reducing some of the negative impacts on growth and enhancing nutrient digestibility, tissue regeneration, and overall metabolic balance. Together, Spirulina and lysozyme demonstrate potential as functional dietary components, but further optimization is needed to fully realize their benefits without compromising growth performance. [ABSTRACT FROM AUTHOR]

Sortilin‐related receptor 1 (SorL1) deficiency is a genetic predisposition to familial Alzheimer's disease (AD), but its pathology is poorly understood. In SorL1‐null rats, a disorder of the global endosome‐lysosome network (ELN) is found in hippocampal neurons. Deletion of amyloid precursor protein (APP) in SorL1‐null rats could not completely rescue the neuronal abnormalities in the ELN of the hippocampus and the impairment of spatial memory in SorL1‐null young rats. These in vivo observations indicated that APP is one of the cargoes of SorL1 in the regulation of the ELN, which affects hippocampal‐dependent memory. When SorL1 is depleted, the endolysosome takes up more of the lysosome flux and damages lysosomal digestion, leading to pathological lysosomal storage and disturbance of cholesterol and iron homeostasis in the hippocampus. These disturbances disrupt the original homeostasis of the material‐energy‐subcellular structure and reprogram energy metabolism based on fatty acids in the SorL1‐null hippocampus, instead of glucose. Although fatty acid oxidation increases ATP supply, it cannot reduce the levels of the harmful byproduct ROS during oxidative phosphorylation, as it does in glucose catabolism. Therefore, the SorL1‐null rats exhibit hippocampal degeneration, and their spatial memory is impaired. Our research sheds light on the pathology of SorL1 deficiency in AD. [ABSTRACT FROM AUTHOR]

Group 2 Innate Lymphoid Cells (ILC2) are critical drivers of both innate and adaptive type 2 immune responses, known to orchestrate processes involved in tissue restoration and wound healing. In addition, ILC2 have been implicated in chronic inflammatory barrier disorders in type 2 immunopathologies such as allergic rhinitis and asthma. ILC2 in the context of allergen-driven airway inflammation have recently been shown to influence local and systemic metabolism, as well as being rich in lipid-storing organelles called lipid droplets. However, mechanisms of ILC2 lipid anabolism and catabolism remain largely unknown and the impact of these metabolic processes in regulating ILC2 phenotypes and effector functions has not been extensively characterized. ILC2 phenotypes and effector functions are shaped by their metabolic status, and determining the metabolic requirements of ILC2 is critical in understanding their role in type 2 immune responses and their associated pathophysiology. We detail here a novel experimental method of implementing flow cytometry for large scale analysis of fatty acid uptake, storage of neutral lipids, and fatty acid oxidation in primary murine ILC2 with complementary morphological analysis of lipid storage using confocal microscopy. By combining flow cytometry and confocal microscopy, we can identify the metabolic lipid requirements for ILC2 functions as well as characterize the phenotype of lipid storage in ILC2. Linking lipid metabolism pathways to ILC2 phenotypes and effector functions is critical for the assessment of novel pharmaceutical strategies to regulate ILC2 functions in type 2 immunopathologies. [ABSTRACT FROM AUTHOR]

Oxidative metabolism declines with aging in humans leading to multiple metabolic ailments and subsequent inflammation. In mice, there is evidence of age-related suppression of fatty acid oxidation and oxidative phosphorylation in the liver, heart, and muscles. Many interventions that extend healthy lifespan of mice have been developed, including genetic, pharmacological, and dietary interventions. In this article, we review the literature on oxidative metabolism changes in response to those interventions. We also discuss the molecular pathways that mediate those changes, and their potential as targets for future longevity interventions. [Display omitted] • Oxidative metabolism is downregulated in multiple tissues with aging and age-related diseases. • Lifespan extending interventions upregulated OXPHOS and fatty acid oxidation enzymes at the transcriptional level. • Molecular pathways that mediate those effects include activation of PGC-1α and PPARs, and inhibition of NCOR1 and mTORC1. [ABSTRACT FROM AUTHOR]

Objective: Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare genetic inborn errors of metabolism. Clinical manifestations may result in frequent healthcare visits, hospitalizations, and early death. This retrospective cohort study assessed manifestations, healthcare resource use (HRU), direct medical costs, and the impact of COVID-19 on HRU among patients with LC-FAOD. Methods: The IQVIA PharMetrics Plus database was searched for pediatric (0–17 years) and adult (≥18 years) patients with confirmed LC-FAOD (ICD-10-CM Diagnosis Code E71.310) and ≥12 months continuous enrollment (CE) between January 2016-February 2020. A non–LC-FAOD general population cohort was randomly selected and matched using 1:20 exact matching on age, gender, payer type, and CE start year. Manifestations were identified via ICD-10 diagnosis codes (any billing position). Overall HRU and attributable costs were stratified by care setting. Pre-COVID-19 (March 2019–February 2020) and during COVID-19 (March 2020-February 2021) HRU was assessed among a subgroup of patients and the general population. Outcomes were evaluated among children and adults, respectively. Results: 423 patients with LC-FAOD (47% female; 79.7% children) were included. The mean enrollment duration was 2.6 ± 1.2 years. 22.6% of children with LC-FAOD had at least one major clinical event (MCE), consisting of rhabdomyolysis (10.1%), hypoglycemia (9.8%), or cardiomyopathy (8.6%) versus 1.5% overall occurrence in the general population. Adults with LC-FAOD had a higher incidence of MCEs (37.2%) than children with LC-FAOD. Annualized all-cause HRU in all care settings and mean total annualized medical costs (children: $17,082 vs $4144; adults: $43,602 vs $3949) were higher in patients with LC-FAOD versus the general population. Patients with LC-FAOD had substantially fewer healthcare visits during COVID-19 across care settings than during the pre-COVID-19 period. Conclusions: LC-FAOD impart a high burden on patients. Extended hospital stays and increased outpatient management were especially pronounced for adults and for patients with ≥1 MCE, resulting in substantially higher medical costs than the general population. [ABSTRACT FROM AUTHOR]

This study employed proton transfer reaction mass spectrometry (PTR-MS) and gas chromatography–mass spectrometry (GC-MS) to identify and monitor volatile organic compounds (VOCs) in frying fumes generated during the deep frying of tempeh. The research aimed to assess the impact of frying conditions, including frying temperature, oil type, and repeated use cycles, on the formation of thermal decomposition products. A total of 78 VOCs were identified, with 42 common to both rapeseed and palm oil. An algorithm based on cosine similarity was proposed to group variables, resulting in six distinct emission clusters. The findings highlighted the prominence of saturated and unsaturated aldehydes, underscoring the role of fatty acid oxidation in shaping the frying fume composition. This study not only corroborates previous research but also provides new insights into VOC emissions during deep frying, particularly regarding the specific emission profiles of certain compound groups and the influence of frying conditions on these profiles. [ABSTRACT FROM AUTHOR]

Background: Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer. Methods: We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo. Results: In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index. Conclusions: We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer. [ABSTRACT FROM AUTHOR]

Excessive lipid accumulation in the liver can cause NAFLD, leading to chronic liver injury. To relieve liver lipid accumulation by dietary proteins, this study used oleic acid (OA) induction to establish a stable in vitro LO2 cell lipid accumulation model. This model was used to explore the mechanism by which pea albumin (PA) regulates lipid levels in LO2 cells. PA has been shown to ameliorate OA-induced lipid accumulation in LO2 cells by reducing the aggregation of intracellular lipid droplets and lowering cell TG and TC levels. In addition, it can alleviate OA-induced LO2 cell damage and oxidative stress, reduce cellular ALT and AST secretion, lower cellular MDA levels, and increase GSH-Px viability. Regulation of lipid metabolism in LO2 cells involves inhibiting the cellular lipid synthesis pathway and activating the expression of proteins related to the triglyceride catabolic and fatty acid oxidation pathways. PA contributes to regulating lipid accumulation in LO2 cells. This study provides new insights into alleviating liver fat accumulation and a theoretical basis for exploring the mechanism of protein regulation of liver cell lipid metabolism. [ABSTRACT FROM AUTHOR]

Context Due to the essential role of carnitine as an intermediary in amino acid, carbohydrate, and lipid metabolism, a detailed characterization of circulating and urinary carnitine concentrations will aid in elucidating the molecular basis of impaired maternal metabolic flexibility and facilitating timely intervention for expectant mothers. Objective To investigate the association of maternal plasma and urinary free carnitine and acylcarnitines with cardiometabolic risk factors. Methods Liquid chromatography tandem mass spectrometry–based quantification of free carnitine and acylcarnitines (C2-C18) was performed on 765 plasma and 702 urine samples collected at preconception, 26 to 28 weeks' pregnancy, and 3 months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study. Results Plasma concentrations of free carnitine and acylcarnitines decreased coupled with increased renal clearance in pregnancy compared with preconception and postpartum. Renal clearance of carnitine increased with an increase in prepregnancy body mass index (ppBMI) and gestational weight gain. Plasma short-chain acylcarnitines were positively associated with ppBMI, irrespective of the physiological state, while medium- and long-chain acylcarnitines were negatively associated with ppBMI at preconception and postpartum but showed a positive association in pregnancy. Similarly, plasma short-chain acylcarnitines were positively associated with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) whereas medium- and long-chain acylcarnitines were negatively associated with HOMA-IR at preconception and in pregnancy. Mothers who developed gestational diabetes mellitus during pregnancy had ∼10% higher plasma propionylcarnitine concentration and ∼18% higher urine tiglylcarnitine concentration than mothers with normal glucose metabolism at preconception. Conclusion This study provides the metabolic and physiological basis of maternal carnitine homeostasis, which can be used in assessment of maternal cardiometabolic health at preconception to improve pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening syndrome of organ dysfunction, characterized by uncontrolled inflammatory response and immune dysregulation, often leading to multiple organ failure and even death. Specialized pro-resolving mediators (SPMs), which are typically thought to be formed via consecutive steps of oxidation of polyenoic fatty acids, have been shown to suppress inflammation and promote timely resolution of inflammation. They are mainly divided into four categories: lipoxins, resolvins, protectins, and maresins. The SPMs may improve the prognosis of sepsis by modulating the immune and inflammatory balance, thereby holding promise for clinical applications. However, their biosynthetic and pharmacological properties are very complex. Through a literature review, we aim to comprehensively elucidate the protective mechanisms of different SPMs in sepsis and its organ damage, in order to provide sufficient theoretical basis for the future clinical translation of SPMs. [ABSTRACT FROM AUTHOR]

Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy. [ABSTRACT FROM AUTHOR]

Background: Apical papilla stem cells (SCAPs) exhibit significant potential for tissue repair, characterized by their anti-inflammatory and pro-angiogenic properties. Exosomes derived from stem cells have emerged as safer alternatives that retain comparable physiological functions. This study explores the therapeutic potential of exosomes sourced from SCAPs in the treatment of non-alcoholic steatohepatitis (NASH). Methods: A NASH mouse model was established through the administration of a high-fat diet (HFD), and SCAPs were subsequently isolated for experimental purposes. A cell model of NASH was established in vitro by treating hepatocellular carcinoma cells with oleic acid (OA) and palmitic acid (PA). Exosomes were isolated via differential centrifugation. The mice were treated with exosomes injected into the tail vein, and the hepatocytes were incubated with exosomes in vitro. After the experiment, physiological and biochemical markers were analyzed to assess the effects of exosomes derived from SCAPs on the progression of NASH in both NASH mouse models and NASH cell models. Results: After exosomes treatment, the weight gain and liver damage induced by HFD were significantly reduced. Additionally, hepatic fat accumulation was markedly alleviated. Mechanistically, exosomes treatment promoted the expression of genes involved in hepatic fatty acid oxidation and transport, while simultaneously suppressing genes associated with fatty acid synthesis. Furthermore, the levels of serum inflammatory cytokines and the mRNA expression of inflammatory markers in liver tissue were significantly decreased. In vitro cell experiments produced similar results. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of mortality worldwide. Myocardial injury resulting from ischemia can be fatal because of the limited regenerative capacity of adult myocardium. Mammalian cardiomyocytes rapidly lose their proliferative capacities, with only a small fraction of adult myocardium remaining proliferative, which is insufficient to support post‐injury recovery. Recent investigations have revealed that this decline in myocardial proliferative capacity is closely linked to perinatal metabolic shifts. Predominantly glycolytic fetal myocardial metabolism transitions towards mitochondrial fatty acid oxidation postnatally, which not only enables efficient production of ATP but also causes a dramatic reduction in cardiomyocyte proliferative capacity. Extensive research has elucidated the mechanisms behind this metabolic shift, as well as methods to modulate these metabolic pathways. Some of these methods have been successfully applied to enhance metabolic reprogramming and myocardial regeneration. This review discusses recently acquired insights into the interplay between metabolism and myocardial proliferation, emphasizing postnatal metabolic transitions. [ABSTRACT FROM AUTHOR]

The impact of Lacticaseibacillus paracasei NWAFU334 and Limosilactobacillus fermentum NWAFU0035 on the amelioration of liver function, oxidative stress reduction, and lipid metabolism modulation in mice subjected to an obesity‐inducing high‐fat diet (HFD) model was investigated. L. paracasei NWAFU334 and L. fermentum NWAFU0035 supplementations over 12 weeks have been shown to have numerous beneficial effects in mice with induced obesity. These effects comprise the restoration of liver function and the reduction of oxidative stress within the liver. Furthermore, the supplementation led to a decreased content of fat accumulation in the liver, mitigation of the expression of inflammatory cytokines in the liver and colon, and a decrease in the expression levels of tight‐junction proteins, for example, claudin‐1, PPARγ, occludin, and ZO‐1. Additionally, a notable improvement in the colonic expression proteins, including IL‐6, TNF‐α, IL‐1β, Muc‐2, Muc‐3, Zo‐1, claudin‐1, and occludin. These proposed strains considerably decreased proinflammatory cytokines and influenced the regulation of lipid metabolism in the liver. These findings indicate that the potential mechanisms, primarily the impact of L. paracasei NWAFU334 and L. fermentum NWAFU0035 on obesity‐induced liver function in mice, involve two regulated pathways: downregulation of lipogenesis and upregulation of gene expression related to fatty acid oxidation and lipolysis. In other words, these probiotic bacterial strains might be beneficial in reducing fat production and increasing fat breakdown in the liver. They may serve as effective therapeutic supplements for alleviating abnormalities induced by an HFD. [ABSTRACT FROM AUTHOR]

The article "Corrigendum: Exosomal CD44 transmits lymph node metastatic capacity between gastric cancer cells via YAP-CPT1A-mediated FAO reprogramming" published in Frontiers in Oncology on October 11, 2024, addresses errors in Figures 1E, 3C, and 4L-M, which were corrected due to image pasting mistakes. The authors conducted repeat experiments for Figure 3C and found consistent results with the original findings. The scientific conclusions of the article remain unchanged despite these errors, and the original article has been updated accordingly. [Extracted from the article]

Background: Lymph node metastasis (LNM) commonly occurs in gastric cancer (GC) and is tightly associated with poor prognosis. Exosome-mediated lymphangiogenesis has been considered an important driver of LNM. Whether exosomes directly transmit the LNM phenotype between GC cells and its mechanisms remain elusive. Methods: A highly lymphatic metastatic GC cell line (HGC-27-L) was established by serial passage of parental HGC-27 cells in BALB/c nude mice. The capacities of migration, invasion and LNM; fatty acid oxidation (FAO) levels; and the role of exosome-transferred LNM phenotype were compared among HGC-27-L, HGC-27 and primary GC cell line AGS. Exosomes derived from GC cells and sera were separately isolated using ultracentrifugation and ExoQuick exosome precipitation solution, and were characterized by transmission electron microscopy, Nanosight and western blotting. Transwell assay and LNM models were conducted to evaluate the capacities of migration, invasion and LNM of GC cells in vitro and in vivo. b-oxidation rate and CPT1 activity were measured to assess FAO. CPT1A inhibitor etomoxir was used to determine the role of FAO. Label-free LC-MS/MS proteome analysis screened the differential protein profiling between HGC-27-exosomes and AGS-exosomes. Small interference RNAs and YAP inhibitor verteporfin were used to elucidate the role and mechanism of exosomal CD44. TCGA data analysis, immunochemistry staining and ELISA were performed to analyze the expression correlation and clinical significance of CD44/YAP/CPT1A. Results: FAO was increased in lymphatic metastatic GC cells and indispensable for sustaining LNM capacity. Lymphatic metastatic GC cell-exosomes conferred LNM capacity on primary GC cells in an FAO-dependent way. Mechanistically, CD44 was identified to be enriched in HGC-27-exosomes and was a critical cargo protein regulating exosome-mediated transmission, possibly by modulating the RhoA/YAP/Prox1/CPT1A signaling axis. Abnormal expression of CD44/YAP/CPT1A in GC tissues was correlated with each other and associated with LNM status, stages, invasion and poor survival. Serum exosomal CD44 concentration was positively correlated with tumor burden in lymph nodes. Conclusions: We uncovered a novel mechanism: exosomal CD44 transmits LNM capacity between GC cells via YAP-CPT1A-mediated FAO reprogramming from the perspective of exosomes-transferred LNM phenotype. This provides potential therapeutic targets and a non-invasive biomarker for GC patients with LNM. [ABSTRACT FROM AUTHOR]

Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression. Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity. Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions. Monocytes participate in plaque formation, and adapt to metabolic changes to alter their functions. Here the authors show, using genetic mouse models and functional analyses, that Glut1-mediated glucose metabolism is important for regulating monocyte homeostasis and migration, but curiously has no impact on atherosclerotic plaque formation. [ABSTRACT FROM AUTHOR]

The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate‐limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1Cre‐driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1aMTG) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1aMTG mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7CreER‐driven, tamoxifen‐inducible Cpt1a‐OE in QSCs of adult muscles (Cpt1aPTG) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a‐OE SCs is associated with elevated level of acyl‐carnitine, and acyl‐carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl‐carnitine to impair the maintenance, proliferation and regenerative function of SCs. [ABSTRACT FROM AUTHOR]

The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30‐s all‐out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial‐related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early‐stage inhibition of the mitochondria, potentially as a protective mechanism against SIT‐induced oxidative stress. [ABSTRACT FROM AUTHOR]

Lipoxygenases (LOXs) from lower organisms have substrate flexibility and function versatility in fatty acid oxidation, but it is not clear how these LOXs acquired the ability to execute multiple functions within only one catalytic domain. This work studied a multifunctional LOX from red alga Pyropia haitanensis (PhLOX) which combined hydroperoxidelyase (HPL) and allene oxide synthase (AOS) activity in its active pocket. Molecular docking and site-directed mutagenesis revealed that Phe642 and Phe826 jointly regulated the double peroxidation of fatty acid, Gln777 and Asn575 were essential to the AOS function, and the HPL activity was improved when Asn575, Gln777, or Phe826 was replaced by leucine. Phylogenetic analysis indicated that Asn575 and Phe826 were unique amino acid sites in the separated clades clustered with PhLOX, whereas Phe642 and Gln777 were conserved in plant or animal LOXs. The N-terminal START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC (SRPBCC) domain of PhLOX was another key variable, as the absence of this domain disrupted the versatility of PhLOX. Moreover, the functions of two homologous LOXs from marine bacterium Shewanella violacea and red alga Chondrus crispus were examined. The HPL activity of PhLOX appeared to be inherited from a common ancestor, and the AOS function was likely acquired through mutations in some key residues in the active pocket. Taken together, our results suggested that some LOXs from red algae attained their versatility by amalgamating functional domains of ancestral origin and unique amino acid mutations. [ABSTRACT FROM AUTHOR]

Electron transfer flavoprotein (ETF) plays an important function in fatty acid beta oxidation and the amino acid metabolic pathway. It can provide pathogenicity to some opportunistic fungi via modulating cellular metabolite composition. Arthrobotrys oligospora is a typical invasion fungus to nematodes. Its ETF characterization is still unknown. Here, we showed that the mutations of A. oligospora ETF (Aoetfα and Aoetfβ) and its dehydrogenase (Aoetfdh) led to severe defects in mitochondrial integrity and blocked fatty acid metabolism. The pathogenicity-associated trap structures were completely suppressed when exposed to nematode-derived ascarosides and nutrition signals, including ammonia and urea. Compared to the wild-type strain, the nematode predatory activity was significantly reduced and delayed. But surprisingly, the rich nutrition could restore the massive trap and robust predatory activity in the mutant Aoetfβ beyond all induction cues. Moreover, the deletion of Aoetfβ has led to the accumulation of butyrate-like smell, which has a strong attraction to Caenorhabditis elegans nematodes. Ultimately, ETF and its dehydrogenase play a crucial role in nematode-trapping fungi, highlighting mitochondrial metabolite fluctuations that are connected to pathogenesis and further regulating the interactions between fungi and nematodes. [ABSTRACT FROM AUTHOR]

The oral microbiome is crucial for human health. Although oral dysbiosis may contribute to oral cancer (OC), the detailed relationships between the microbiome and OC remain unclear. In this case-control study, we aimed to elucidate the connection between the oral microbiome and mechanisms potentially involved in oral cancer. The study analyzed 1022 oral saliva samples, including 157 from oral cancer patients and 865 from healthy controls, using 16S ribosomal RNA (16S rRNA) sequencing and a Light Gradient Boosting Machine (LightGBM) model to identify four bacterial genera significantly associated with oral cancer. In patients with oral cancer, the relative abundance of Streptococcus and Parvimonas was higher; Corynebacterium and Prevotella showed decreased relative abundance; and levels of fatty acid oxidation enzymes, including Carnitine palmitoyltransferase 1A (CPT1A), long-chain acyl-CoA synthetase, acyl-CoA dehydrogenase, diacylglycerol choline phosphotransferase, and H+-transporting ATPase, were significantly higher compared to controls. Conversely, healthy controls exhibited increased levels of short-chain fatty acids (SCFAs) and CD4+T-helper cell counts. Survival analysis revealed that higher abundance of Streptococcus and Parvimonas, which correlated positively with interleukin-6, tumor necrosis factor-alpha, and CPT1A, were linked to poorer disease-free survival (DFS) and overall survival (OS) rates, while Prevotella and Corynebacterium were associated with better outcomes. These findings suggest that changes in these bacterial genera are associated with alterations in specific cytokines, CPT1A levels, SCFAs in oral cancer, with lower SCFA levels in patients reinforcing this link. Overall, these microbiome changes, along with cytokine and enzyme alterations, may serve as predictive markers, enhancing diagnostic accuracy for oral cancer. [ABSTRACT FROM AUTHOR]

Many studies have been carried out on the antioxidant effects of medicinal plants in edible oils. One of those plants is turmeric, which, due to its biological and antioxidant compounds such as curcuminoids, has a strong antioxidant effect and prevents oxidation of unsaturated fatty acids (FAs). In this study, turmeric at different levels (5% and 10% w/w) was used to increase the oxidative stability of the milk thistle (Silybum marianum L.) seed oil (MTSO). Additionally, to improve the performance of turmeric, cold plasma (CP) treatment was used at different durations (5 and 10 min). The effect of turmeric on the quality parameters of MTSO was investigated during different storage times (1, 30, and 60 days). The results indicated that the addition of turmeric treated with CP significantly (p < 0.05) decreased the acidity value (AV) (1.00–0.62 mg NaOH/g oil) and the peroxide value (PV) (4.47–3.65 mEq O2/kg oil) and also increased the total phenolic content (1003.23–1116.90 mg/GAE/100 g oil), antioxidant activity, α‐tocopherol, and finally the oxidative stability compared to the control sample and oil containing untreated turmeric. Furthermore, gas chromatography (GC) analysis of the oil sample of the FA profile containing CP‐treated turmeric revealed the higher ratio of unsaturated FAs (i.e., linoleic and arachidonic acid) and lower saturated FA content (palmitic and stearic acid) compared to oil samples containing untreated turmeric. To conclude, CP treatment increased turmeric performance and improved the quality characteristics of MTSO. [ABSTRACT FROM AUTHOR]

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Understanding the genetic background behind fat-tail development in sheep can be useful to develop breeding programs for genetic improvement, while the genetic basis of fat-tail formation is still not well understood. Here, to identify genomic regions influencing fat-tail size in sheep, a comprehensive selection signature identification analysis was performed through comparison of fat- and thin-tailed sheep breeds. Furthermore, to gain the first insights into the potential use of RNA-Seq for selection signature identification analysis, SNP calling was performed using RNA-Seq datasets. In total, 45 RNA-Seq samples from seven cohort studies were analyzed, and the FST method was used to detect selection signatures. Our findings indicated that RNA-Seq could be of potential utility for selection signature identification analysis. In total, 877 SNPs related to 103 genes were found to be under selection in 92 genomic regions. Functional annotation analysis reinforced the hypothesis that genes involved in fatty acid oxidation May modulate fat accumulation in the tail of sheep and highlighted the potential regulatory role of angiogenesis process in the fat deposition. In agreement with most previous studies, our results re-emphasize that the BMP2 gene is targeted by selection during sheep evolution. Further gene annotation analysis of the regions targeted by the sheep evolution process revealed that a large number of genes included in these regions are directly associated with fat metabolism, including those previously reported as candidates involved in sheep fat-tail morphology, such as NID2, IKBKG, RGMA, IGFBP7, UBR5, VEGFD and WLS. Moreover, a number of genes, including BDH2, ECHS1, AUH, ERBIN and CYP4V2 were of particular interest because they are well-known fat metabolism-associated genes and are considered novel candidates involved in fat-tail size. Consistent with the selection signature identification analysis, principal component analysis clustered the samples into two completely separate groups according to fat- and thin-tailed breeds. Our results provide novel insights into the genomic basis of phenotypic diversity related to the fat-tail of sheep breeds and can be used to determine directions for improving breeding strategies in the future. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission–dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings. [ABSTRACT FROM AUTHOR]

The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti-PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti-PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification-dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions. Author summary: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a significant global health issue. Neutrophils, immune cells that rapidly enter the lungs during Mtb infection, contribute both to fighting the infection and exacerbating lung damage. Their metabolic state, especially the way they produce energy, is crucial for their function during TB. However, the specific impact of Mtb on neutrophil metabolism and its role in TB progression has been unclear. In this study, we investigated the roles of glycolysis and fatty acid metabolism in neutrophil responses to Mtb infection. We found that inhibiting glycolysis worsens TB outcomes, while blocking fatty acid oxidation (FAO) provides protection, reducing lung damage, bacterial load, and overall disease severity. Notably, FAO inhibition specifically disrupts the accumulation of an immature neutrophil population that is more susceptible to Mtb, thereby improving infection control. Targeting carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in fatty acid metabolism, impaired neutrophil migration to infection sites and enhanced their antimicrobial activity. These findings suggest that modulating neutrophil metabolism, particularly through FAO inhibition, could be a promising strategy for developing host-directed TB therapies. [ABSTRACT FROM AUTHOR]

Objective: Multiple acyl‐coenzyme A dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation and considered an inborn error of metabolism. In recent years, we have diagnosed an increasing number of patients where, despite extensive investigation, no disease‐causing mutations have been found. We therefore investigated a cohort of consecutive patients, with the objective to detect possible non‐genetic causes. Methods: We searched the patient records and the registry of muscle biopsies, for patients with MADD, diagnosed within the past 10 years. The patient records were reviewed regarding symptoms, clinical findings, comorbidities, drugs, diagnostic investigations, and response to treatment. In addition, complementary investigations of muscle tissue were performed. Results: We identified 9 patients diagnosed with late‐onset MADD. All presented with muscle weakness and elevated levels of creatine kinase. A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood. Despite thorough genetic investigations, a probable genetic cause was found in only 2 patients. Remarkably, all 7 patients without disease‐causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved. Interpretation: Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. ANN NEUROL 2024;96:802–811 [ABSTRACT FROM AUTHOR]

Lipid-rich deposits called drusen accumulate under the retinal pigment epithelium (RPE) in the eyes of patients with age-related macular degeneration and Sorsby's fundus dystrophy (SFD). Drusen may contribute to photoreceptor degeneration in these blinding diseases. Stimulating b-oxidation of fatty acids could decrease the availability of lipid with which RPE cells generate drusen. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate b-oxidation and diminish lipid accumulation in fatty liver disease. In this report, we test the hypothesis that an ACC inhibitor, Firsocostat, can diminish lipid deposition by RPE cells. We probed metabolism and cellular function in mouse RPE-choroid tissue and human RPE cells. We used 13C6-glucose, 13C16-palmitate, and gas chromatography-linked mass spectrometry to monitor effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism. We quantified lipid abundance, apolipoprotein E levels, and vascular endothelial growth factor release using liquid chromatography-mass spectrometry, ELISAs, and immunostaining. RPE barrier function was assessed by trans-epithelial electrical resistance (TEER). Firsocostat-mediated ACC inhibition increases boxidation, decreases intracellular lipid levels, diminishes lipoprotein release, and increases TEER. When human serum or outer segments are used to stimulate lipoprotein release, fewer lipoproteins are released in the presence of Firsocostat. In a culture model of SFD, Firsocostat stimulates fatty acid oxidation, increases TEER, and decreases apolipoprotein E release. We conclude that Firsocostat remodels RPE metabolism and can limit lipid deposition. This suggests that ACC inhibition could be an effective strategy for diminishing pathologic drusen in the eyes of patients with age-related macular degeneration or SFD. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes (T2D) are associated with metabolic inflexibility, characterized by an impaired ability to switch between substrate storage and utilization pathways. Metabolic inflexibility during obesity is typified by lower engagement of fatty acid metabolism despite an ample supply of stored lipids. Intermittent fasting (IF) can promote metabolic flexibility. However, it is not clear how obesity and T2D alter metabolic flexibility after repeated IF. Male obese db/db and control db/+ mice were fasted for 24 h twice a week for 10 wk. This 5:2 IF regimen did not alter body mass, body composition, food intake, or physical activity in db/db or db/+ mice. After IF, db/db mice had lower fatty acid oxidation and higher carbohydrate oxidation in the fed state, indicating metabolic inflexibility to metabolize lipids. After IF, control db/+ mice had higher fatty acid oxidation and lower carbohydrate oxidation in the fed state, characteristic of metabolic flexibility, and increased engagement of lipid metabolism. In the fasted state, IF lowered carbohydrate oxidation and increased fatty acid oxidation in control db/+ mice but not in obese db/db mice. After IF, db/db mice also had lower serum β-hydroxybutyrate than control db/+ mice. Ten weeks of IF decreased adipocyte size in visceral adipose tissue of control db/+ mice, but this IF regimen did not change adipocyte size in obese db/db mice. Therefore, IF increases fatty acid oxidation and metabolic flexibility in lean mice, but this adaptation is absent in a mouse model of obesity and type 2 diabetes. NEW & NOTEWORTHY: We show that a 5:2 intermittent fasting regimen can increase lipid oxidation without altering body mass in lean mice. Therefore, repeated intermittent fasting can increase metabolic flexibility without the need for (or prior to) weight loss. Intermittent fasting did not increase lipid oxidation in mice with obesity and type 2 diabetes, highlighting that obesity and/or type 2 diabetes limit changes in metabolic flexibility and mitigate increased fatty acid oxidation without weight loss during intermittent fasting. [ABSTRACT FROM AUTHOR]

Black African-Caribbean (BAC) populations are at greater risk of cardiometabolic disease than White Europeans (WE), despite exhibiting lower fasting triacylglycerol (TAG) concentrations. However, limited data exist regarding postprandial fatty acid metabolism in BAC populations. This study determined the ethnic differences in postprandial fatty acid metabolism between overweight and obese WE and BAC men. WE [n = 10, age 33.3 ± 1.7 yr; body mass index (BMI) = 26.8 (25.8–31.0) kg/m2] and BAC [n = 9, age 27.9 ± 1.0 yr; BMI = 27.5 (26.0–28.6) kg/m2] men consumed two consecutive (at 0 and 300 min) moderate-to-high-fat meals—the first labeled with [U-13C]palmitate. The plasma concentration and appearance of meal-derived fatty acids in very-low-density lipoprotein (VLDL)-TAG, chylomicron-TAG, and nonesterified fatty acid (NEFA) were determined over an 8-h postprandial period. Indirect calorimetry with 13CO2 enrichment determined total and meal-derived fatty acid oxidation rates, and plasma β-hydroxybutyrate (3-OHB) concentration was measured to assess ketogenesis. BAC exhibited lower postprandial TAG [area under the curve (AUC0–480) = 671 (563–802) vs. 469 (354–623) mmol/L/min, P = 0.022] and VLDL-TAG [AUC0–480 = 288 ± 30 vs. 145 ± 27 mmol/L/min, P = 0.003] concentrations than WE. The appearance of meal-derived fatty acids in VLDL-TAG was lower in BAC than in WE (AUC0–480 = 133 ± 12 vs. 78 ± 13 mmol/L/min, P = 0.007). Following the second meal, BAC showed a trend for lower chylomicron-TAG concentration [AUC300–480 = 69 (51–93) vs. 43 (28–67) mmol/L/min, P = 0.057]. There were no ethnic differences in the appearance of chylomicron-TAG, cumulative fatty acid oxidation, and the NEFA:3-OHB ratio (P > 0.05). In conclusion, BAC exhibit lower postprandial TAG concentrations compared with WE men, driven by lower VLDL-TAG concentrations and possibly lower chylomicron-TAG in the late postprandial period. These findings suggest that postprandial fatty acid trafficking may be a less important determinant of cardiometabolic risk in BAC than in WE men. NEW & NOTEWORTHY: Postprandial TAG is lower in Black African-Caribbean men than in White European men, and this is likely driven by lower meal-derived VLDL-TAG in Black African-Caribbean men. This observation could suggest that fatty acid trafficking may be a less important determinant of cardiometabolic risk in Black Africans than in White European men. [ABSTRACT FROM AUTHOR]

Lipotoxicity is defined as a prolonged metabolic imbalance of lipids that results in ectopic fat distribution in peripheral organs such as the liver, heart, and kidney. The harmful consequences of excessive lipid accumulation in cardiomyocytes cause cardiac lipotoxicity, which alters the structure and function of the heart. Obesity and diabetes are linked to lipotoxic cardiomyopathy. These anomalies might be caused by a harmful metabolic shift that accumulates toxic lipids and shifts glucose oxidation to less fatty acid oxidation. Research has linked fatty acids, fatty acyl coenzyme A, diacylglycerol, and ceramide to lipotoxic stress in cells. This stress can be brought on by apoptosis, impaired insulin signaling, endoplasmic reticulum stress, protein kinase C activation, p38 Ras-mitogen-activated protein kinase (MAPK) activation, or modification of peroxisome proliferator–activated receptors (PPARs) family members. Curcuma longa is used to extract curcumin, a hydrophobic polyphenol derivative with a variety of pharmacological characteristics. Throughout the years, curcumin has been utilized as an anti-inflammatory, antioxidant, anticancer, hepatoprotective, cardioprotective, anti-diabetic, and anti-obesity drug. Curcumin reduces cardiac lipotoxicity by inhibiting apoptosis and decreasing the expression of apoptosis-related proteins, reducing the expression of inflammatory cytokines, activating the autophagy signaling pathway, and inhibiting the expression of endoplasmic reticulum stress marker proteins. [ABSTRACT FROM AUTHOR]

Objective This study aims to investigate the therapeutic effect and mechanism of Naoxinqing on non- alcohol fatty liver disease (NAFLD) induced by a high-fat diet through network pharmacology, molecular docking and in vitro and in vivo experiments. Methods ApoE-/- mice were given a high-fat diet for 12 weeks to establish the NAFLD model, followed by a 12-week Naoxinqing administration. To evaluate the therapeutic effect of Naoxinqing on NAFLD induced by a high-fat diet, biochemical and histopathological experiments were performed, including assessment of blood lipids, liver function, serum inflammatory factors, as well as Hematoxylin and eosin (HE), Oil red O, and Sirius red staining of liver. Subsequently, network pharmacology and molecular docking techniques were employed to predict the key targets of Naoxinqing. Finally, the mechanism of Naoxinqing was validated by Western Blot in HepG2 cells and liver tissue. Results The results of serum biochemistry and liver tissue pathology showed that Naoxinqing can significantly improve high-fat diet-induced hepatic lipid accumulation, hepatocellular injury, and inflammation. Network pharmacology and molecular docking analysis results suggested that Naoxinqing may affect lipid metabolism through the AMP-activated protein kinase (AMPK) /Sirtuin 1 (SIRT1) pathway. Finally, in vitro cell experiment confirmed that the main mechanism of Naoxinqing is to activative the AMPK/SIRT1 pathway, upregulate the expression of downstream carnitine palmitoyltransferase 1 (CPT1A), promote fatty acid oxidation, and ultimately improve NAFLD. Conclusion This study demonstrated that Naoxinqing improved NAFLD by promoting fatty acid oxidation through the activation of the AMPK/SIRT1 pathway. [ABSTRACT FROM AUTHOR]

Mitochondria respond acutely to elevations in cytosolic Ca2+ levels, leading to increases in mitochondrial matrix Ca2+ and an increase in oxidative phosphorylation rates. Mitochondrial activity and substrate usage within skeletal muscle – the largest energy-requiring tissue – can impact total body metabolism and obesity. Mitochondrial deletion of the mitochondrial Ca2+ uniporter (MCU) complex in skeletal muscle blocks acute matrix Ca2+ uptake in genetically altered mice, which paradoxically increases fatty acid oxidation (FAO) and reduces obesity. Deletion of the MCU inhibitor gene Mcub in skeletal muscle mitochondria increases acute matrix Ca2+ uptake in genetically altered mice, which decreases FAO and promotes obesity. Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca2+ increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca2+ uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca2+ uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca2+ uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca2+ regulates metabolism. [ABSTRACT FROM AUTHOR]

Exercise is increasingly recognized as an effective strategy to counteract skeletal muscle aging and conditions such as sarcopenia. However, the specific exercise-induced genes responsible for these protective effects remain unclear. To address this, we conducted an eight-week aerobic exercise regimen on late-middle-aged mice and developed an integrated approach that combines mouse exercise-induced genes with human GWAS datasets to identify causal genes for sarcopenia. This approach led to significant improvements in the skeletal muscle phenotype of the mice and the identification of exercise-induced genes and miRNAs. By constructing a miRNA regulatory network enriched with transcription factors and GWAS signals related to muscle function and traits, we focused on 896 exercise-induced genes. Using human skeletal muscle cis-eQTLs as instrumental variables, 250 of these exercise-induced genes underwent two-sample Mendelian randomization analysis, identifying 40, 68, and 62 causal genes associated with sarcopenia and its clinical indicators—appendicular lean mass (ALM) and hand grip strength (HGS), respectively. Sensitivity analyses and cross-phenotype validation confirmed the robustness of our findings. Consistently across the three outcomes, RXRA, MDM1, RBL2, KCNJ2, and ADHFE1 were identified as risk factors, while NMB, TECPR2, MGAT3, ECHDC2, and GINM1 were identified as protective factors, all with potential as biomarkers for sarcopenia progression. Biological activity and disease association analyses suggested that exercise exerts its anti-sarcopenia effects primarily through the regulation of fatty acid oxidation. Based on available drug–gene interaction data, 21 of the causal genes are druggable, offering potential therapeutic targets. Our findings highlight key genes and molecular pathways potentially responsible for the anti-sarcopenia benefits of exercise, offering insights into future therapeutic strategies that could mimic the safe and mild protective effects of exercise on age-related skeletal muscle degeneration. [ABSTRACT FROM AUTHOR]

Background and Aim: Lipid metabolism disorder is the primary feature of numerous refractory chronic diseases. Fatty acid oxidation, an essential aerobic biological process, is closely related to the progression of NAFLD. The forkhead transcription factor FOXO1 has been reported to play an important role in lipid metabolism. However, the molecular mechanism through which FOXO1 regulates fatty acid oxidation remains unclear. Methods: Transcriptomic analysis was performed to examine the cellular expression profile to determine the functional role of FOXO1 in HepG2 cells with palmitic acid (PA)‐induced lipid accumulation. FOXO1‐binding motifs at the promoter region of aldehyde dehydrogenase 1 family member L2 (ALDH1L2) were predicted via bioinformatic analysis and confirmed via luciferase reporter assay. Overexpression of ALDH1L2 was induced to recover the impaired fatty acid oxidation in FOXO1‐knockout cells. Results: Knockout of FOXO1 aggravated lipid deposition in hepatic cells. Transcriptomic profiling revealed that knockout of FOXO1 increased the expression of genes associated with fatty acid synthesis but decreased the expression of carnitine palmitoyltransferase1a (CPT1α) and adipose triglyceride lipase (ATGL), which contribute to fatty acid oxidation. Mechanistically, FOXO1 was identified as a transcription factor of ALDH1L2. Knockout of FOXO1 significantly decreased the protein expression of ALDH1L2 and CPT1α in vitro and in vivo. Furthermore, overexpression of ALDH1L2 restored fatty acid oxidation in FOXO1‐knockout cells. Conclusion: The findings of this study indicate that FOXO1 modulates fatty acid oxidation by targeting ALDH1L2. [ABSTRACT FROM AUTHOR]

Hemp seed oil (HSO) is an edible oil low in saturated fat and rich in polyunsaturated fatty acids (PUFAs) such as omega‐6 and omega‐3 fatty acids. When they are in contact with oxygen in the air, PUFAs are easily oxidized even at room temperature due to the multiple double bonds that facilitate the formation of reactive radicals when exposed to air. This study aimed to evaluate the oxidation of HSO under different conditions and to examine the encapsulation of HSO with zein as a new method to prevent its oxidation. Peak time of weight gain monitored with thermogravimetric analysis and oxidation products detected with high‐performance liquid chromatography were used to determine the oxidation of fatty acids and HSO. It was found that the thermal decomposition of fatty acids prevailed over autoxidation beyond a certain temperature (at about 100–140°C). Encapsulating HSO into zein microcapsules, which isolates oil droplets from contact with oxygen in the air, effectively prevented its oxidation. The induction period of HSO oxidation was delayed by 7.3–9.3 times with the zein‐to‐HSO ratio of 0.5–1.25. In contrast, 0.5% (w/w) α‐tocopherol could prolong the induction period up to 2.5 times indicating that the encapsulation method was much more effective than α‐tocopherol in preventing the oxidation of HSO. This method may also be applied for other oils susceptible to oxidation such as omega‐3 oils. Practical Application: This research compares the effects of three schemes that stabilize hemp seed oil from oxidation: (1) lowering temperature to slow down the oxidation reaction, (2) adding antioxidant to deactivate the initiation of oxidation reaction, and (3) encapsulating oil droplets into protein microcapsules to keep the oil from contact with oxygen. The experimental result showed the encapsulation of oils in protein microcapsules is more effective than the other two. The stabilization approaches applied to hemp seed oil can also be applied to other edible oils that are unstable. [ABSTRACT FROM AUTHOR]

Summary: Fish can justify a healthy human diet. Spoilage is caused due to microbial degradation and oxidative rancidity. Herbs and spices (H&S) are common ingredients in fish marination to improve quality and appeal to consumers globally. The given review delves into the potential of H&S to extend the freshness of fish while also addressing challenges in maximising their effectiveness for preservation and proposing innovative solutions. H&S with antimicrobial (AM) and antioxidative (AO) effects reduce biogenic amine (BA) formation by inhibiting the decarboxylation of free amino acids through microbial reduction and retarding lipid oxidation of free fatty acids by countering free radicals. Combining organoleptically standardised H&S with diverse microbial hurdle techniques supports extensive domestic utilisation, extending the shelf life of fish significantly compared to using them alone. The present findings recommend that H&S can maintain fish quality for 6–20 days, depending on the fish species, packaging, and AO/AM potential in refrigeration conditions. Thyme, garlic, ginger, stevia, turmeric, laurel, sage, cinnamon, cumin, mint, and rosemary are found to be the most potent preservatives that could be utilised commercially to increase fish's shelf life. Variations in H&S extracts and fish muscle composition pose challenges in optimising the effectiveness of bioactive compounds in fish preservation. Innovative approaches for utilising H&S essential oils (EOs) and advanced delivery techniques offer solutions to these challenges, leading to improved fish quality and limited shelf life. [ABSTRACT FROM AUTHOR]

Introduction: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches. Objective: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC–MS) metabolomics. Methods: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC–MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups. Results: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients. Conclusion: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations. [ABSTRACT FROM AUTHOR]

Aristolochic acid nephropathy (AAN) is a rapidly progressive kidney disease caused by medical or environmental exposure to aristolochic acids (AAs). This study aimed to identify serum metabolites associated with the severity of acute AAN and investigate the underlying mechanisms. Male C57BL/6 mice were treated with vehicle and 3 doses of aristolochic acid I (AAI) (1.25, 2.5, and 5 mg/kg/d) for 5 days by intraperitoneal injection. The results showed that AAI dose-dependently increased blood urea nitrogen (BUN) and serum creatinine (Scr) levels and renal pathological damage. Non-targeted metabolomics revealed that differences in serum metabolite profiles from controls increased with increasing AAI doses. Compared with the control group, 56 differentially expressed metabolites (DEMs) that could be affected by all 3 doses of AAI were obtained. We further identified 13 DEMs whose abundance significantly correlated with Scr and BUN levels and had good predictive values for diagnosing AAI exposure. Among the 13 DEMs, lipids and lipid-like molecules constituted the majority. Western blotting found that AAI suppressed renal fatty acid oxidation (FAO)-related enzymes expression. In conclusion, these findings provided evidence for developing biomarkers for monitoring AAs exposure and AAN diagnosis and indicated activation of FAO as a potential direction for the treatment of AAN. [Display omitted] • AAI induced nephrotoxicity in a dose-dependent manner. • AAI exposure exacerbated serum metabolic profile disturbances in a dose-dependent manner. • 13 DEMs were identified to be correlated with Scr and BUN levels and had good predictive values for diagnosing AAI exposure. • AAI suppressed renal fatty acid oxidation. [ABSTRACT FROM AUTHOR]

The liver of mammals is a critical organ that houses numerous physiological processes, including macronutrient metabolism. Regarding nutrient metabolism, the liver shows a quick response to nutrient status fluctuation, such as feeding and fasting. Indeed, fasting is a powerful tool to uncover the molecular mechanism through which the expression of hepatic genes is regulated. The most widely applied approach to test gene expression at the RNA level is relative quantitative polymerase chain reaction (qPCR) using stably expressed genes as an internal reference. In this study, we leveraged transcriptomic analysis to screen the hepatic genes whose expression levels were stable in response to fasting. Our data suggested that expression levels of several well-known reference genes such as beta-actin and Eef1a1 are dramatically altered upon fasting. Further assessment indicated that Itm2b is the most stably expressed hepatic gene showing no alteration to fasting. Compared to beta-actin and Eef1a1, similar results and conclusions as transcriptomic analysis were obtained using Itm2b as an internal reference in qPCR when we assessed the effect of fasting on the expression of genes involved in peroxisomal fatty acid oxidation, fatty acid synthesis, and gluconeogenesis. [ABSTRACT FROM AUTHOR]