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Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia. Ageing leads to a loss of muscle mass and strength, called sarcopenia. Here, the authors show that fatty acid binding protein 3 (FABP3), a lipid chaperone, drives age-dependent lipidome remodeling in skeletal muscle and deteriorates muscle mass and contractility by modulating membrane fluidity and ER stress signaling.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very longchain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7 , which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment. Ferroptosis is an iron-dependent cell death mechanism that is emerging as a target for cancer therapy. Here, the authors find that lipoprotein-associated phospholipase A2 modulates ferroptosis resistance by controlling phospholipid metabolism.

Background Mass screening for gastric cancer (GC), particularly using endoscopy, may not be the most practical approach as a result of its high cost, lack of acceptance, and poor availability. Thus, novel markers that can be used in cost-effective diagnosis and noninvasive screening for GC are needed. Methods A total of 154 urine samples from GC patients and healthy individuals and 30 pairs of matched tumor and normal stomach tissues were collected. Multivariate analysis was performed on urinary and tissue metabolic profiles acquired using 1 H nuclear magnetic resonance and 1 H high-resolution magic angle spinning spectroscopy, respectively. In addition, metabolic profiling of urine from GC patients after curative surgery was performed. Results Multivariate statistical analysis showed significant separation in the urinary and tissue data of GC patients and healthy individuals. The metabolites altered in the urine of GC patients were related to amino acid and lipid metabolism, consistent with changes in GC tissue. In the external validation, the presence of GC (early or advanced) from the urine model was predicted with high accuracy, which showed much higher sensitivity than carbohydrate antigen 19-9 and carcinoembryonic antigen. Furthermore, 4-hydroxyphenylacetate, alanine, phenylacetylglycine, mannitol, glycolate, and arginine levels were significantly correlated with cancer T stage and, together with hypoxanthine level, showed a recovery tendency toward healthy controls in the postoperative samples compared to the preoperative samples. Conclusions An urinary metabolomics approach may be useful for the effective diagnosis of GC.

Recent investigations have revealed that the human microbiome plays an essential role in the occurrence of type 2 diabetes (T2D). However, despite the importance of understanding the involvement of the microbiota throughout the body in T2D, most studies have focused specifically on the intestinal microbiota. Extracellular vesicles (EVs) have been recently found to provide important evidence regarding the mechanisms of T2D pathogenesis, as they act as key messengers between intestinal microorganisms and the host. Herein, we explored microorganisms potentially associated with T2D by tracking changes in microbiota-derived EVs from patient urine samples collected three times over four years. Mendelian randomization analysis was conducted to evaluate the causal relationships among microbial organisms, metabolites, and clinical measurements to provide a comprehensive view of how microbiota can influence T2D. We also analyzed EV-derived metagenomic (N = 393), clinical (N = 5032), genomic (N = 8842), and metabolite (N = 574) data from a prospective longitudinal Korean community-based cohort. Our data revealed that GU174097_g, an unclassified Lachnospiraceae, was associated with T2D (β = −189.13; p = 0.00006), and it was associated with the ketone bodies acetoacetate and 3-hydroxybutyrate (r = −0.0938 and −0.0829, respectively; p = 0.0022 and 0.0069, respectively). Furthermore, a causal relationship was identified between acetoacetate and HbA1c levels (β = 0.0002; p = 0.0154). GU174097_g reduced ketone body levels, thus decreasing HbA1c levels and the risk of T2D. Taken together, our findings indicate that GU174097_g may lower the risk of T2D by reducing ketone body levels.Diabetes: a little help from the microbiomeA microbe that may help protect against type II diabetes has been detected by examining extracellular vesicles (EVs), tiny membrane-wrapped packages secreted by human cells and by the bacteria making up the microbiome. Examining EVs allows researchers to sample microbial populations other than the intensively studied intestinal microbiome. Sungho Won, Seoul National University, and Geum-Sook Hwang, Korea Basic Science Institute, Seoul, and coworkers studied the microbial EVs in urine samples collected from South Korean subjects over four years. They identified a previously unclassified bacterial species in the family Lachnospiraceae that was associated with lower risk of developing type II diabetes. Further investigation showed that these bacteria may break down ketone bodies, metabolic byproducts that signal disrupted sugar metabolism leading to diabetes. These results contribute to understanding how the microbiome contributes to metabolic health and disease.

Dietary restriction (DR) delays aging and the onset of age-associated diseases. However, it is yet to be determined whether and how restriction of specific nutrients promote longevity. Previous genome-wide screens isolated several Escherichia coli mutants that extended lifespan of Caenorhabditis elegans . Here, using 1 H-NMR metabolite analyses and inter-species genetics, we demonstrate that E. coli mutants depleted of intracellular glucose extend C. elegans lifespans, serving as bona fide glucose-restricted (GR) diets. Unlike general DR, GR diets don’t reduce the fecundity of animals, while still improving stress resistance and ameliorating neuro-degenerative pathologies of Aβ 42 . Interestingly, AAK-2a, a new AMPK isoform, is necessary and sufficient for GR-induced longevity. AAK-2a functions exclusively in neurons to modulate GR-mediated longevity via neuropeptide signaling. Last, we find that GR/AAK-2a prolongs longevity through PAQR-2/NHR-49/Δ9 desaturases by promoting membrane fluidity in peripheral tissues. Together, our studies identify the molecular mechanisms underlying prolonged longevity by glucose specific restriction in the context of whole animals. Although diet modulates aging, little is known about whether and how nutrient regulates longevity. Here, the authors show that glucose-restricted diets prolong longevity through series of conserved factors, such as neuronal AMPK, neuropeptide, AdipoR, PPARα, and Δ9 desaturases by promoting membrane fluidity.

Neurodevelopmental disorders can have long-lasting effects, causing not only early pediatric symptoms but also a range of neurological issues throughout adulthood. West syndrome is a severe neurodevelopmental disorder marked by infantile spasms, an early symptom that typically subsides with age. However, many patients progress to other seizure forms, known as seizure evolution, which is closely linked to poor long-term outcomes. Despite its clinical significance, the neurobiological mechanisms behind seizure evolution in West syndrome remain poorly understood. Recent genetic studies have consistently identified the CYFIP2 p.Arg87Cys variant in West syndrome patients, and the Cyfip2 + /R87C mouse model carrying this mutation has been shown to recapitulate key symptoms of the disorder, including infantile spasms. In this study, we aimed to gain deeper insight into seizure evolution by conducting longitudinal deep phenotyping of the Cyfip2 + /R87C mouse model from the neonatal stage to seven months of age. We tracked seizure activity through behavioral and EEG recordings and employed multi-omic analyses, including tissue and single-cell level transcriptomics, ultrastructural analysis, proteomics, and lipidomics, to capture a comprehensive view of molecular and cellular changes. Our results showed that after an initial period of neonatal spasms, Cyfip2 + /R87C mice entered a seizure-free phase, followed by spontaneous recurrent seizures in adulthood, ultimately leading to premature death. This progression was associated with synaptic remodeling, sequential activation of different glial cell types, lipid droplet accumulation in astrocytes, and significant proteomic and lipidomic changes in the brain. These findings suggest that seizure evolution in West syndrome involves complex, time-dependent interactions between neurons and glial cells, along with alterations in lipid metabolism. Our study highlights the potential of longitudinal multi-omic approaches to uncover underlying mechanisms of seizure evolution and suggests that targeting these changes could offer novel therapeutic strategies. Additionally, the dataset generated here may provide valuable insights for other epilepsy and neurodevelopmental disorder models.

Obesity is a multifactorial health problem resulting from genetic, environmental and behavioral factors. A particularly interesting aspect of obesity is the differences observed in response to the same high-fat diet (HFD). In this study, we performed lipidomic profiling on livers from HFD-fed C57BL/6J mice using ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry. Mice were divided into three groups: normal diet (ND), HFD-obesity prone (HFD-OP) and HFD-obesity resistant (HFD-OR). Principal components analyses showed a difference between the HFD-OP and HFD-OR groups. Individuals in the HFD-OR group were closer to those in the ND group compared with those in the HFD-OP group. In particular, phosphocholine (PC) and triglyceride (TG) levels differed significantly depending on the length of the acyl chain and degree of unsaturation, respectively. PC species were either positively or negatively correlated with concentrations of glucose, insulin, leptin and hepatic cholesterol according to the length of the acyl chain. Decreased expression of the scavenger receptor B1 and ATP-binding cassette A1 in HFD-OP mice indicated that the acyl chain length of PC species may be related to high-density lipoprotein cholesterol metabolism. This study demonstrates that lipidomic profiling is an effective approach to analyzing global lipid alterations as they pertain to obesity.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is increasing worldwide. One method used to restore sinus rhythm is direct current cardioversion (DCCV). Despite the high success rate of DCCV, AF typically recurs within the first 2 weeks. However, our understanding of the pathophysiology of AF recurrence, incidence, and progression are highly limited. Lipidomic profiling was applied to identify altered lipids in plasma from patients with AF using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry coupled with multivariate statistical analysis. Partial least-squares discriminant analysis revealed a clear separation between AF patients and healthy controls. The levels of several lipid species, including fatty acids and phospholipids, were different between AF patients and healthy controls, indicating that oxidative stress and inflammation are associated with the pathogenesis of AF. Similar patterns were also detected between recurrent and non-recurrent AF patients. These results suggest that the elevated saturated fatty acid and reduced polyunsaturated fatty acid levels in AF patients may be associated with enhanced inflammation and that free fatty acid levels may play a crucial role in the development and progression of AF.

Curcuma, a genus of rhizomatous herbaceous species, has been used as a spice, traditional medicine, and natural dye. In this study, the metabolite profile of Curcuma extracts was determined using gas chromatography-time of flight mass spectrometry (GC/TOF MS) and ultrahigh-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) to characterize differences between Curcuma aromatica and Curcuma longa grown on the Jeju-do or Jin-do islands, South Korea. Previous studies have performed primary metabolite profiling of Curcuma species grown in different regions using NMR-based metabolomics. This study focused on profiling of secondary metabolites from the hexane extract of Curcuma species. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) plots showed significant differences between the C. aromatica and C. longa metabolite profiles, whereas geographical location had little effect. A t-test was performed to identify statistically significant metabolites, such as terpenoids. Additionally, targeted profiling using UPLC/Q-TOF MS showed that the concentration of curcuminoids differed depending on the plant origin. Based on these results, a combination of GC- and LC-MS allowed us to analyze curcuminoids and terpenoids, the typical bioactive compounds of Curcuma, which can be used to discriminate Curcuma samples according to species or geographical origin.