Search Results (328)

Background: The causation of type 2 diabetes remains under debate, but evidence supports both abdominal lipid and ectopic lipid overspill into tissues including muscle as key. How these depots differentially alter cardiometabolic profile and change during body weight and fat loss is not known. Methods: Women with obesity scheduled to undergo bariatric surgery were assessed at baseline (BL, n = 28) and at 6-month follow-up (6m_FU, n = 26) after weight loss. Fasting plasma (Pla), subcutaneous thigh adipose (STA), subcutaneous abdominal adipose, (SAA), and thigh vastus lateralis muscle (VLM) samples were collected at BL through surgery and at 6m_FU using needle biopsy. An untargeted liquid chromatography mass spectrometry metabolomics platform was used. Pla and tissue-specific lipid and polar metabolite profiles were modelled as changes from BL and 6m_FU. Results: There was significant body weight (−24.5 kg) loss at 6m_FU (p < 0.05). BL vs. 6m_FU tissue metabolomics profiles showed the largest difference in lipid profiles in SAA tissue in response to surgery. Conversely, polar metabolites were more susceptible to change in STA and VLM. In Pla samples, both lipid and polar metabolite profiles showed significant differences between timepoints. Jaccard–Tanimoto coefficient t-tests identified a sub-group of gut microbiome and dietary-derived omega-3-fatty-acid-containing lipid species and core energy metabolism and adipose catabolism-associated polar metabolites that are trafficked between sample types in response to bariatric surgery. Conclusions: In this first report on channelling of lipids and polar metabolites to alternative tissues in bariatric-induced weight loss, adaptive shuttling of small molecules was identified, further promoting adipose processing and highlighting the dynamic and coordinated nature of post-surgical metabolic regulation. Full article

Background/Objectives: To investigate acute caffeine (CAF: 375 mg, ≈4.8 mg/kg body mass) effects on energy expenditure (EE) and substrate kinetics during high-intensity interval exercise in individuals with high (HBAT) versus low (LBAT) brown adipose tissue activity using time-trend polynomial modeling. Methods: This is a randomized, double-blind crossover study in which 35 highly-trained males [HBAT-CAF, HBAT-PLA (Placebo), LBAT-CAF, LBAT-PLA] performed 30-min treadmill HIIE. Infrared thermography (IRT) assessed BAT activity by measuring supraclavicular skin temperature (SST). Breath-by-breath ergospirometry measured EE (kcal/min) and carbohydrate (CHO), lipid (LIP), and protein (PTN) oxidation. We applied second- and third-order polynomial regression models to depict the temporal trajectories of metabolic responses. Results: HBAT groups showed 25% higher sustained EE versus LBAT (p < 0.001), amplified by CAF. CHO oxidation exhibited biphasic kinetics: HBAT had 40% higher initial rates (0.75 ± 0.05 vs. 0.45 ± 0.04 g/min; p < 0.001) with accelerated decline (k = −0.21 vs. −0.15/min; p = 0.01). LIP oxidation peaked later in LBAT (40 vs. 20 min in HBAT), with CAF increasing oxidation by 18% in LBAT (p = 0.01). HBAT-CAF uniquely showed transient PTN catabolism (peak: 0.045 g/min at 10 min; k = −0.0033/min; p < 0.001). Conclusions: BAT status determines EE magnitude and substrate-specific kinetic patterns, while CAF exerts divergent modulation, potentiating early glycogenolysis in HBAT and lipolysis in LBAT. The HBAT-CAF synergy triggers acute proteolysis, revealing BAT-mediated metabolic switching. Full article

Breast cancer (BC) is a neoplasm characterized by high heterogeneity and is influenced by intrinsic molecular subtypes and clinical stage, aspects that remain underexplored in the Colombian population. This study aimed to characterize metabolic alterations associated with subtypes and disease progression in a group of newly diagnosed, treatment-naive Colombian women using an untargeted metabolomics approach. To improve metabolite coverage, samples were analyzed using LC-QTOF-MS and GC-QTOF-MS, along with amino acid profiling. The Luminal B subtype exhibited elevated levels of long-chain acylcarnitines and higher free fatty acid concentrations than the other subtypes. It also presented elevated levels of carbohydrates and essential glycolytic intermediates, suggesting that this subtype may adopt a hybrid metabolic phenotype characterized by increased glycolytic flux as well as enhanced fatty acid catabolism. Tumor, Node, and Metastasis (TNM) staging analysis revealed progressive metabolic reprogramming of BC. In advanced stages, a sustained increase in phosphatidylcholines and a decrease in lysophosphatidylcholines were observed, reflecting lipid alterations associated with key roles in tumor progression. In early stages (I-II), plasma metabolites with high discriminatory power were identified, such as glutamic acid, ribose, and glycerol, which are associated with dysfunctions in energy and carbohydrate metabolism. These results highlight metabolomics as a promising tool for the early diagnosis, clinical follow-up, and molecular characterization of BC. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, affecting approximately 25–30% of the global adult population and highlighting the urgent need for effective therapeutics and prevention strategies. MASLD is characterized by excessive hepatic lipid accumulation and can progress, in a subset of patients, to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of liver cirrhosis and hepatocellular carcinoma. Although the molecular drivers of MASLD progression remain incompletely understood, several key metabolic pathways—such as triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy—are consistently dysregulated in MASLD livers. This narrative review summarizes primary literature and highlights insights from recent reviews on the multifaceted role of the mRNA-binding protein Human antigen R (HuR) in the post-transcriptional regulation of critical cellular processes, including nutrient metabolism, cell survival, and stress responses. Emerging evidence underscores HuR’s essential role in maintaining liver homeostasis, particularly under metabolic stress conditions characteristic of MASLD, with hepatocyte-specific HuR depletion associated with exacerbated disease severity. Moreover, comorbid conditions such as obesity, type 2 diabetes mellitus, and cardiovascular disease not only exacerbate MASLD progression but also involve HuR dysregulation in extrahepatic tissues, further contributing to liver dysfunction. A deeper understanding of HuR-regulated post-transcriptional networks across metabolic organs may enable the development of targeted therapies aimed at halting or reversing MASLD progression. Full article

Background/Objectives: The treatment of multiple myeloma (MM) remains a challenge, as almost all patients will eventually relapse. Proteasome inhibitors are a cornerstone in the management of MM. Unfortunately, validated biomarkers predicting drug response are largely missing. Therefore, we aimed to identify genes associated with drug resistance or sensitization to proteasome inhibitors. Methods: We performed genome-wide CRISPR-Cas9 knockout (KO) screens in human KMS-28-BM myeloma cells to identify genetic determinants associated with resistance or sensitization to proteasome inhibitors. Results: We show that KO of KLF13 and PSMC4 induces drug resistance, while NUDCD2, OSER1 and HERC1 KO cause drug sensitization. Subsequently, we focused on top sensitization hit, NUDCD2, which acts as a co-chaperone of Hsp90 to regulate the LIS1/dynein complex. RNA sequencing showed downregulation of genes involved in the ERAD pathway and in ER-associated ubiquitin-dependent protein catabolic processes in both untreated and carfilzomib-treated NUDCD2 KO cells, suggesting that NUDCD2 depletion alters protein degradation. Furthermore, bortezomib-treated NUDCD2 KO cells showed a decreased expression of genes that have a function in oxidative phosphorylation and the mitochondrial membrane, such as Carnitine Palmitoyltransferase 1A (CPT1A). CPT1A catalyzes the uptake of long chain fatty acids into mitochondria. Mitochondrial lipid metabolism has recently been reported as a possible therapeutic target for MM drug sensitivity. Conclusions: These results contribute to the search for therapeutic targets that can sensitize MM patients to proteasome inhibitors. Full article

Salt stress is one of the most common factors reducing the productivity of crops. We tested the effect of Rapamycin, an mTOR inhibitor and autophagy inducer, for the possible amelioration of high-salinity stress in Eruca sativa. We analyzed the germination rate, the macro- and micro-morphology of seedlings, and the ultrastructure of cotyledons with a Transmission Electron Microscope. The most striking observation was that salt stress blocked the catabolism of the lipid droplets stored in the embryos of E. sativa, also dramatically reducing the starch storage capability in the plastids. As a consequence, lipid droplets remained in the developing seedlings until a late stage. On the contrary, the catabolism of the lipid storage in the embryos in the presence of rapamycin and salt stress was comparable to the control, even if the starch stored in the plastids was lower. Rapamycin-induced autophagic activity was shown by characteristic ultrastructural changes, such as increased membrane recycling. Part of this activity was interpreted as pexophagy, i.e., the autophagy of peroxisomes, where an increase in their turnover rate could be necessary to maintain an active glyoxylate cycle. Full article

Background: Pulmonary arterial hypertension (PAH) is a rare and severe condition characterized by increased pulmonary arterial pressure and vascular resistance. Women are more susceptible to PAH yet have higher survival rates than men, a phenomenon called the “estrogen paradox”. This study aims to investigate the sex-based differences in PAH using plasma untargeted metabolomics. Methods: Plasma samples were collected from 43 PAH patients and 37 healthy controls. The samples were analyzed using two complementary analytical techniques: gas chromatography–mass spectrometry (GC-QqQ/MS) and liquid chromatography–mass spectrometry (LC-Q-ToF/MS). The metabolic differences between male and female PAH patients and controls were identified using multivariate statistical analyses. Results: Our results show changes in the lipid, fatty acid, and amino acid metabolism in both sexes. Women presented additional changes in the carbohydrate, bile acid, and nucleotide metabolism. The metabolites affected by PAH in women included decreased threonine, tryptophan, and lipid intermediates and elevated bile acids. Men were found to have additional changes in the heme catabolism, cholesterol synthesis, and lipoxygenase pathways. The metabolites affected by PAH in men included decreased branched-chain amino acids and increased bilirubin, phospholipids, and oxidized fatty acids. Conclusions: The gender differences observed in the development of PAH are likely multifactorial. While estrogens and potentially other sex hormones have been implicated in modulating relevant biological pathways, their exact role in disease progression and pathogenesis remains to be fully elucidated. The specific metabolic changes in women and men point to distinct disease mechanisms, potentially explaining the differences in prevalence, prognosis, and treatment response of patients with PAH. The obtained results should be validated with the use of targeted quantitative analyses and larger numbers of patients. Full article

An 8-week trial was conducted to investigate the effects of choline on the growth of Chinese perch (85.57 ± 0.54 g) with dietary choline supplementation at 0 (P0), 400 (P1), 800 (P2), 1600 (P3), 3200 (P4), and 6400 mg/kg (P5). Protein efficiency ratio and protein retention value (PRV) were higher in the P1–P4 groups than in the P0 group (p < 0.05). Compared to the P0 group, weight gain rate and specific growth rate (SGR) increased in the P2 and P3 groups (p < 0.05). The orexigenic gene agrp expression level rose in the P2–P4 groups (p < 0.05). The expression level of the lipolysis-related gene hsl or pparα was elevated in the P2 and P4 groups (p < 0.05). Proteolysis-related gene (ampd, mafbx, and murf1) expressions decreased in the P1–P4 groups, while tor and gk gene expressions increased in the P2 and P3 groups (p < 0.05). Broken-line analysis indicated that the optimal choline supplementation level for Chinese perch is 788.38 mg/kg based on SGR and 851.04 mg/kg based on PRV. The results demonstrate that moderate dietary choline supplementation enhances growth performance by promoting glucose and lipid catabolism and inhibiting protein catabolism in Chinese perch. Full article

Background: The limited bioavailability of free phytosterols restricts their clinical application in managing hypercholesterolemia. This study aimed to develop phytosterol nanoparticles (PNs) to enhance bioactivity and investigate their cholesterol-lowering efficacy and underlying mechanisms in vivo. Methods: Phytosterol nanoparticles (PNs) (93.35 nm) were engineered using soy protein isolate and administered orally at concentrations of 4.00–12.50 mg/mL to high-fat-diet-induced hypercholesterolemic mice (n = 60) over a 4-week period. Serum and hepatic lipid profiles, histopathology, gene/protein expression related to cholesterol metabolism, and fecal sterol content were evaluated. Results: PNs dose-dependently reduced serum total cholesterol (TC: 28.6–36.8%), triglycerides (TG: 22.4–30.1%), and LDL-C (31.2–39.5%), while increasing HDL-C by 18.7–23.4% compared to hyperlipidemic controls (p < 0.01). Hepatic TC and TG accumulation decreased by 34.2% and 41.7%, respectively, at the highest dose, with histopathology confirming attenuated fatty degeneration. Mechanistically, PNs simultaneously suppressed cholesterol synthesis through downregulating HMGCR (3.2-fold) and SREBP2 (2.8-fold), while enhancing cholesterol catabolism via CYP7A1 upregulation (2.1-fold) at protein level. Although less potent than simvastatin (p < 0.05), the nanoparticles exhibited unique dual-pathway modulation absent in conventional phytosterol formulations. Fecal analysis revealed dose-responsive cholesterol excretion (36.01 vs. 11.79 mg/g in controls), indicating enhanced enteric elimination. While slightly less potent than simvastatin (p < 0.05), PNs offered unique dual-pathway modulation absent in conventional phytosterol formulations. Conclusions: Nano-encapsulation significantly improves the bioavailability and hypocholesterolemic efficacy of phytosterols. PNs represent a promising nutraceutical strategy for cholesterol management by concurrently regulating cholesterol synthesis and catabolism, with potential application in both preventive and therapeutic contexts. Full article

Background/Objectives: Insomnia has been widely associated with cognitive impairment (CI). However, the relationship between the two entities (insomnia and CI) is poorly understood. In this context, adults with insomnia show metabolic changes, including alterations in the catabolism of branched-chain amino acids, glycerophospholipids, and glutathione and glutamate biosynthesis. Nevertheless, aging itself induces metabolic changes that may be amplified by chronic diseases that compromise the health of the elderly. Therefore, in the present study we aim to characterise metabolomic profiles of insomnia and CI alone in order to address a significant gap in current research regarding the pathways through which insomnia may lead to CI in older persons. Methods: In this study we perform a targeted metabolomics analysis (UPLC-MS) on 80 serum samples from the Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults (COSFOMA); these samples were classified into four groups (control, insomnia, CI, and insomnia + CI). Results: Our results show that insomnia increases the concentration of acylcarnitines (C10, C8, C14, C12:1, C18:1 and C18) as compared to CI group, while older persons with CI show a decrease the concentration of the acylcarnitines C16, C10 and C8. Finally, individuals with both conditions (insomnia + CI) show that only the concentration of the acylcarnitine C16 decreases compared to controls. Conclusions: Taken together, our results shed light on the relevance of insomnia on lipid metabolism in older persons. Full article

Toona sinensis (A. Juss.) Roem, classified under the Toona genus of the Meliaceae family, is a fast-growing, woody species endemic to China, valued as both a vegetable crop and medicinal plant. Its seeds achieve rapid germination through a cascade of interconnected physiological, metabolic, and hormonal adaptations. Initially, physiological hydration is driven and accelerated by only two distinct phases of water imbibition. This hydration surge triggers storage reserve mobilization, with soluble sugars, proteins, and lipids undergoing rapid degradation during imbibition, while starch catabolism proceeds gradually—a pattern mirrored by progressive increases in enzymatic activities (amylase, protease, and acid phosphodiesterase (ACP)) that correlate with reserve reallocation. Concurrently, a metabolic shift from glycolysis to the pentose phosphate pathway (PPP) optimizes energy utilization, supporting germination acceleration. These biochemical changes are orchestrated by hormonal coordination: elevated gibberellin A₃ (GA₃), zeatin riboside (ZR), and indole-3-acetic acid (IAA) levels, coupled with rising GA₃/ABA, IAA/ABA, and ZR/ABA ratios, temporally aligned with germination progression. Finally, structural evidence confirms successful germination completion, as cotyledon lipid droplet breakdown and starch granule synthesis directly correlate with embryonic elongation. Together, these mechanisms underscore T. sinensis’ adaptive strategy, integrating physiological plasticity, metabolic flexibility, and endocrine precision to ensure efficient germination. Full article

As the most abundant fat-derived hormone, adiponectin plays an essential role in regulating energy homeostasis. Current evidence proposes the serum levels of adiponectin as a risk factor and a diagnostic/prognostic biomarker in cancer. Moreover, distinctive antineoplastic features have also been reported as a result of adiponectin supplementation in preclinical models. Mapping of the cancer-associated metabolic changes has elucidated a highly adaptable and interconnected system that allows malignant cells to sustain their growth and survival. Along with the pyruvate into acetyl-CoA conversion, downregulation of both lactate dehydrogenase and glycolysis-related genes depicts the main adiponectin-induced perturbations affecting glucose metabolism in cancer. Meanwhile, a multi-level approach involving lipid trafficking, catabolism, and de novo synthesis has been attributed to adiponectin in malignancies. The adiponectin receptor agonist AdipoRon has recently been recognized as a promising antineoplastic compound. Remarkably, AdipoRon-mediated changes in cancer metabolism occur together with its antiproliferative potential. This review aimed at recapitulating the modulatory effects of adiponectin, as well as those of its synthetic receptor agonists, in driving metabolic alterations in cancerous cells. A critical discussion is also conducted to deduce whether the adiponectin axis could serve as a putative target to address the metabolic reprogramming in cancer progression. Full article

Piriformospora/Serendipita indica has been frequently proved to play a crucial role in enhancing plant adaptation to environmental stresses. However, its influence on blueberry (Vaccinium corymbosum) drought tolerance has not yet been studied. Here, we reported that P. indica colonization can significantly enhance the drought tolerance of blueberry. Physio-biochemical parameter determination results showed that, compared to non-colonized controls (CK), P. indica-colonized (PI) plants exhibited higher leaf chlorophyll and carotenoids contents, photosynthetic capacity, biomass and root antioxidant enzyme activities (superoxide dismutase and catalase), while also exhibiting lower root malondialdehyde content under drought stress (DS). To explore the underlying mechanism, comparative root transcriptome analysis of well-watered (WW) and DS-treated CK and PI blueberry plants was conducted. In total, we identified 14,587 differentially expressed genes (DEGs) across CK-WW vs. CK-DS, PI-WW vs. PI-DS, CK-WW vs. PI-WW and CK-DS vs. PI-DS comparisons. Under DS, stress-, metabolism- and regulation-related DEGs were overwhelmingly upregulated in PI, while being downregulated in CK. Weighted gene co-expression network analysis categorized DEGs into four modules. Of them, the MEblack module was significantly correlated with the PI-DS group, with DEGs enriched in the cell wall macromolecule catabolic process, carbohydrate metabolic process, phenylpropanoid biosynthesis, and so on. Several defense-related genes, including four thaumatin family proteins, were identified as hub genes of this module. DEGs in the MEblue module were expressed at the highest level in CK-DS, followed by in PI-DS. Hub genes of the MEblue module included DEG-encoding lipid transfer protein, abscisic stress ripening protein, and so on. This study demonstrates that P. indica enhances blueberry drought tolerance by enhancing antioxidant ability and mediating the expression of genes related to stress, carbohydrate and secondary metabolism, and cell wall metabolism. Full article

The global prevalence of obesity and type 2 diabetes has increased considerably in recent decades, primarily due to behavioral changes associated with societal progress, such as increased consumption of high-calorie foods and sedentary lifestyles. Obesity is a disease of the energy homeostasis system, not merely a passive accumulation of fat. The hypothalamus serves as the regulatory center for energy balance, and together with peripheral organs, such as liver, pancreas, muscle and adipose tissue, controls food intake, energy expenditure, and whole-body metabolism. Adenosine, a product of ATP catabolism, exerts its effects through various G-protein-coupled receptors: A1R, A2AR, A2BR, and A3R. It plays a key role in regulating peripheral metabolism, including glucose homeostasis, insulin sensitivity, fat beta-oxidation, and lipolysis in adipose tissue. Beyond its roles in the CNS, adenosine receptors are also crucial in metabolic tissues, where they regulate glucose and lipid homeostasis and contribute to overall metabolic function. Several studies have been analyzing the role of adenosine system, specifically the adenosine receptors in the regulation of whole-body metabolism, and the importance of adenosine receptors in context of metabolic diseases and obesity. In this review, we provide an overview of the adenosine signaling system, highlighting its role in metabolic regulation as well as the pathophysiological mechanisms underlying obesity and type 2 diabetes. Full article

Background: Muscle loss during sarcopenia and atrophy is also commonly associated with age-related insulin resistance. Interestingly, branched-chain amino acids (BCAA) which are known for stimulating muscle protein synthesis are commonly elevated during insulin resistance and sarcopenic obesity. Objectives: This study investigated the effects of the interplay between atrophy and insulin resistance on insulin sensitivity, mitochondrial metabolism, and BCAA catabolic capacity in a myotube model of skeletal muscle insulin resistance. Methods: C2C12 myotubes were treated with dexamethasone to induce atrophy. Insulin resistance was induced via hyperinsulinemia. Gene and expression were measured using qRT-PCR and Western blot, while mitochondrial and lipid content were assessed using fluorescent staining. Cell metabolism was analyzed via Seahorse metabolic assays. Results: Both dexamethasone-induced atrophy and insulin resistance independently reduced insulin-stimulated pAkt levels, as well as mitochondrial function and content. However, neither treatment affected gene or protein expression associated with mitochondrial biogenesis or content. Although dexamethasone independently reduced insulin sensitivity in otherwise previously insulin-sensitive cells, dexamethasone had no significant effect on extracellular BCAA content. Conclusions: Our findings indicate the metabolic interplay between atrophy and insulin resistance and demonstrate that both can reduce mitochondrial function, though only limited effects were observed on indicators of BCAA catabolism and utilization. This emphasizes the need for future studies to investigate the mechanisms that underlie atrophy and other metabolic disorders to develop new interventions. Full article