Energy Metabolism Homeostasis Research Articles

Multiple omics analysis reveals the regulation of SIRT4 on lipid deposition and metabolism during the differentiation of bovine preadipocytes.

The differentiation and lipid metabolism of preadipocytes are crucial processes in IMF deposition. Studies have demonstrated that SIRT4 plays essential roles in energy metabolism and redox homeostasis, with its expression being coordinately regulated by multiple transcription factors associated with energy and lipid metabolism. In this study, the findings of multiple omics analysis reveal that SIRT4 significantly up-regulates the expression of genes involved in adipogenesis and enhances the differentiation and lipid deposition of bovine preadipocytes. Furthermore, SIRT4 profoundly influences the expression pattern of metabolites by increasing the abundance of substances involved in lipid synthesis while decreasing those that promote lipid oxidative decomposition. Additionally, SIRT4 broadly up-regulates the expression levels of various lipid classes, including glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids. These findings not only provide a theoretical basis for molecular breeding and genetic improvement in beef cattle, but also offer potential therapeutic approaches for energy homeostasis disorders and obesity.

Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway.

Cadmium (Cd2+) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd2+ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd2+ on the integrity and function of brain endothelial cells. After 24h of exposure, Cd2+ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd2+ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd2+ exposure. Cd2+ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd2+ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd2+ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.

Epilepsy therapy beyond neurons: unveiling astrocytes as cellular targets.

Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation-inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drug-resistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.

The role of acetylation and deacetylation in cancer metabolism.

As a hallmark of cancer, metabolic reprogramming adjusts macromolecular synthesis, energy metabolism and redox homeostasis processes to adapt to and promote the complex biological processes of abnormal growth and proliferation. The complexity of metabolic reprogramming lies in its precise regulation by multiple levels and factors, including the interplay of multiple signalling pathways, precise regulation of transcription factors and dynamic adjustments in metabolic enzyme activity. In this complex regulatory network, acetylation and deacetylation, which are important post-translational modifications, regulate key molecules and processes related to metabolic reprogramming by affecting protein function and stability. Dysregulation of acetylation and deacetylation may alter cancer cell metabolic patterns by affecting signalling pathways, transcription factors and metabolic enzyme activity related to metabolic reprogramming, increasing the susceptibility to rapid proliferation and survival. In this review, we focus on discussing how acetylation and deacetylation regulate cancer metabolism, thereby highlighting the central role of these post-translational modifications in metabolic reprogramming, and hoping to provide strong support for the development of novel cancer treatment strategies. KEY POINTS: Protein acetylation and deacetylation are key regulators of metabolic reprogramming in tumour cells. These modifications influence signalling pathways critical for tumour metabolism. They modulate the activity of transcription factors that drive gene expression changes. Metabolic enzymes are also affected, altering cellular metabolism to support tumour growth.

RNAi-mediated knockdown of HcCAT2 depresses the adaptive capacity of Hyphantria cunea larvae to cytisine and coumarin.

The diversity of host plants is an important reason for the global spread of Hyphantria cunea. However, no studies have explored the role of the antioxidant defense system with catalase (CAT) as the core at the molecular level in the adaptation of the H. cunea to host plant secondary metabolites. Herein, the purpose is to explore how HcCAT2, highly expressed in cytisine- or coumarin-treated H. cunea larvae, mediates the adaptation of H. cunea to cytisine and coumarin, and to develop nucleic acid pesticides targeting HcCAT2. Findings revealed that H. cunea larvae treated with dsHcCAT2 alongside cytisine or coumarin exhibited significantly reduced body weight, survival rate, and expression levels of growth-related genes, energy metabolism genes, and oxidative damage regulatory genes compared to treated with cytisine or coumarin alone. HcCAT2 overexpression enhanced cell viability, lowered apoptosis rates, Ca2+ concentrations, ROS levels, and MPTP opening, and increased mitochondrial membrane potential in cytisine or coumarin-treated SF9 cells. Encapsulation of dsHcCAT2 in chitosan (CS) improved stability and gene silencing efficacy. CS-dsHcCAT2 treatment did not significantly affect SF9 cell, Lymantria dispar larvae, and Arma chinensis nymphs. However, H. cunea larvae treated with CS-dsHcCAT2 combined with cytisine or coumarin showed significantly reduced body weight and survival compared to those receiving secondary metabolites alone. Therefore, HcCAT2 is a critical antioxidant defense gene for adaptation of H. cunea larvae to cytisine and coumarin stress, with the ability of maintaining energy metabolism homeostasis and antioxidant defense level. The constructed CS-dsHcCAT2 can be developed as a synergistic agent for plant-derived pesticides.

Mitochondrial calcium uniporter complex: An emerging therapeutic target for cardiovascular diseases (Review).

Cardiovascular disease (CVD) is currently a major factor affecting human physical and mental health. In recent years, the relationship between intracellular Ca2+ and CVD has been extensively studied. Ca2+ movement across the mitochondrial inner membrane plays a vital role as an intracellular messenger, regulating energy metabolism and calcium homeostasis. It is also involved in pathological processes such as cardiomyocyte apoptosis, hypertrophy and fibrosis in CVD. The selective mitochondrial calcium uniporter complex (MCU complex) located in the inner membrane is essential for mitochondrial Ca2+ uptake. Therefore, the MCU complex is a potential therapeutic target for CVD. In this review, recent research progress on the pathophysiological mechanisms and therapeutic potential of the MCU complex in various CVDs was summarized, including myocardial ischemia‑reperfusion injury, pulmonary arterial hypertension, other peripheral vascular diseases, myocardial remodeling and arrhythmias. This review contributes to a deeper understanding of these mechanisms at the molecular level and highlights potential intervention targets for CVD treatment in clinical practice.

SREBP1c-Mediated Transcriptional Repression of YME1L1 Contributes to Acute Kidney Injury by Inducing Mitochondrial Dysfunction in Tubular Epithelial Cells.

Acute kidney injury (AKI) is a prevalent clinical syndrome with high morbidity and mortality. Accumulating studies suggest mitochondrial dysfunction as the typical characteristics and key process of AKI, but the underlying mechanism remains elusive. The YME1-like 1 (YME1L1) ATPase, an inner mitochondrial membrane protein, is screened and identified to be downregulated in renal tubular epithelial cells of various mouse models and patients of AKI. Dramatically, restoration of YME1L1 expression significantly alleviates cisplatin-induced AKI and subsequent chronic kidney disease (CKD) through attenuating mitochondrial dysfunction via maintaining optic atrophy 1 (OPA1)-mediated mitochondrial energy metabolism homeostasis. Mechanistically, the upregulated expression of sterol regulatory element binding transcription factor 1c (SREBP1c) is demonstrated to be responsible for cisplatin-mediated transcriptional inhibition of YME1L1 via directly binding to its promoter region. Moreover, cisplatin-induced methyltransferase-like 3 (METTL3)-mediated m6A modification enhances SREBP1c mRNA stability, thereby upregulating its expression. Notably, both depletion of SREBP1c and renal tubule-specific overexpression of YME1L1 markedly ameliorate cisplatin-induced AKI and its transition to CKD. Taken together, these findings suggest that METTL3-mediated SREBP1c upregulation contributes to AKI and its progression to CKD through disrupting mitochondrial energy metabolism via transcriptionally suppressing YME1L1. Targeting the SREBP1c/YME1L1 signaling may serve as a novel therapeutic strategy against AKI.

Layered Double Hydroxide (LDH)-Based Nanotripod for High-Entropydynamic Therapy Associated with Metabolism Homeostasis.

Multielemental transition metal compounds represent a class of promising candidates for the biomedical field due to their unique structure and biomedical application potential. However, their synthesis process remains challenging, which was subject to the high-temperature treatment of the multimetallic elements integrated within one system. Herein, for the first time, we have fabricated the nanotripod, i.e., (FeCoNiCuZnAl)Ox (denoted as HEO) agent, via the structural topotactic transformation of layered double hydroxide (LDH) precursors with the tunable disorder degree, for highly efficient high-entropydynamic therapy associated with metabolism homeostasis. By virtue of this unique high-entropy structure, the outburst reactive oxygen species (ROS) generation can be regulated via turbulence. These unique high-entropy oxides not only presented outstanding ROS generation efficiency but also broke the intracellular metabolic balance cycle (NADH/NAD+) by NOx-like activity, which can disturb the tumor energy metabolism homeostasis, leading to cell apoptosis. Furthermore, in vitro and in vivo experiments both indicate that this agent was a satisfying candidate for magnetic resonance imaging (MRI)-guided therapy. The findings offer a strategy for the development of high-entropydynamic therapy.

Beta-aminoisobutyric acid improves bovine oocyte maturation and subsequent embryonic development by promoting lipid catabolism.

Energy metabolism homeostasis is essential for oocyte maturation and acquisition of developmental capacity. However, bovine oocyte in vitro maturation (IVM) is highly susceptible to metabolic stress and lipid accumulation. β-Aminoisobutyric acid (BAIBA), a metabolite produced in response to skeletal muscle exercise, has been reported to be involved in lipid and glucose metabolism, as well as inflammation and oxidative stress. This work aimed to evaluate the potential effects of BAIBA on bovine oocyte IVM and its mechanisms. Different concentrations of BAIBA (10, 20, 50, 100, and 200μmol/L) were supplemented to bovine oocyte IVM medium. Results shown the BAIBA (50μmol/L) had no effect on the extrusion rate of the first polar body of oocytes but significantly improved the subsequent blastocyst formation rate and embryo quality. Further revealed that supplementing BAIBA significantly up-regulated expression levels of genes to fatty acid β-oxidation metabolism (CPT1A, CPT1B and CPT2), promoted lipid metabolism, lowered lipid content, and improved mitochondrial membrane potential and active mitochondria content. Importantly, BAIBA stimulation significantly increased the phosphorylation of AMP-activated protein kinase (AMPK); and the inhibition of AMPK activity (Compound C, AMPK inhibitor) suppressed the ability of BAIBA to promote lipid metabolism in oocytes. Besides, inhibition of AMPK lowered the oocyte maturation rate and the subsequent zygote cleavage and blastocyst formation rate when compared to that of the BAIBA treatment. The results indicated that BAIBA was mainly involved in promoting lipid catabolism by activation of AMPK, consequently enhancing oocyte development potential.

Energy metabolism, antioxidant defense system, metal transport, and ion homeostasis are key contributors to Cd tolerance in SSSL derived from wild rice.

Cadmium (Cd) toxicity poses major challenges to rice cultivation, affecting plant growth and development. Wild rice and nanoparticles offer promising strategies to enhance Cd tolerance, yet little is known about their combined effects. This study evaluates the single segment substitution line (SG004) from Oryza glumaepatula (wild rice) and its response to Cd stress compared to cultivated rice (HJX74). Both genotypes were also treated with calcium oxide nanoparticles (np-CaO). Results showed that Cd exposure disrupts reactive oxygen species (ROS) metabolism in both lines, such as malondialdehyde (MDA) increases by 57 % in HJX74 compared to SG004. Moreover, SG004 exhibited a 26 % reduction in shoot length compared to 41 % in HJX74 and a 42 % decline in chlorophyll ab content versus 53 % in HJX74. Antioxidant activity such as glutathione (GSH) decreased 25 % more in HJX74 than SG004 under Cd toxicity. Additionally, SG004 had lower Cd accumulation in roots (70 %) and shoots (85 %) than HJX74, indicating its enhanced tolerance to Cd toxicity. The root cell cytology reveals several deformations in different organelles of HJX74 but less in SG004. RNAseq analysis identifies key pathways, including energy metabolism, antioxidant defense, metal transport, and ion homeostasis, which may be critical for SG004 enhanced tolerance. Notably, two distinct metallothionein-like genes (BGIOSGA019338, BGIOSGA035982), a peroxidase (BGIOSGA019133), ammonium (BGIOSGA008640, BGIOSGA008641, and potassium transporters (BGIOSGA030867), NRAMP1 (BGIOSGA025476), and an aluminum-activated malate transporter (BGIOSGA014531), showed differential expressions in SG004 under Cd stress. Genes within the substituted fragment, including those for peroxidase 25 (BGIOSGA002866), metallothionein (BGIOSGA002389), and reductase (BGIOSGA002387), are also upregulated in SG004, reinforcing the role of antioxidant and ion homeostasis pathways. The utilization of np-CaO alleviates Cd-induced stress in both genotypes, hence reinforcing the application of wild rice and nanoparticles to improve Cd tolerance.

Cinnamon Polyphenols Ameliorate the Dysregulation of Cardiac Energy and Autophagic Homeostasis in Rats with Diabetic Cardiomyopathy via the mTOR/PGC1α Pathway

Background Inflammation mediated by hyperglycemia, lipid metabolism disorders, abnormal myocardial energy metabolism, myocardial cell damage, and changes in ventricular structure are important mechanisms in the occurrence and development of diabetic cardiomyopathy (DCM). Cinnamon polyphenols (CP) are extracted from the traditional Chinese medicine cinnamon, which is believed to have cardioprotective effects and has been used in China for hundreds of years. Purpose This study aimed to investigate the therapeutic effects of CP on DCM and its possible mechanisms. Methods The DCM model was established by a single intraperitoneal injection of 85 mg/kg 1% streptozotocin in rats. The treatment group was orally administered 135 mg/kg CP for 28 consecutive days, a dosage verified by experiments on AC16 myocardial cells and detecting liver and kidney injury markers. Results CP could reduce high blood sugar, high blood lipids, left ventricular mass index, levels of myocardial injury markers, adenosine diphosphate (ADP), and cyclic adenosine monophosphate (cAMP) in the model group. It also improved weight loss, and increased myocardial adenosine triphosphate (ATP), adenosine monophosphate (AMP), phosphocreatine (PCr), and ATP/ADP, AMP/ATP, and PCr/ATP ratios. The expression of p-mTOR/mammalian target of rapamycin (mTOR), p62, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in the myocardium of the CP group was enhanced, while the expression of LC3II/LC3I was inhibited. Conclusion CPs can alleviate myocardial damage by reducing blood sugar, blood lipids, and abnormal autophagy levels while promoting the restoration of myocardial energy metabolism homeostasis.

Treating metabolic dysfunction-associated steatohepatitis: The fat-trimming FGF21 approach.

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.

Integrated physiological, energy metabolism, and metabonomic responses indicate the stress response in the hepatopancreas of Litopenaeus vannamei to nitrite stress

Nitrite is a toxic substance found in rearing water that affects shrimp health. The hepatopancreas is an important digestive, immune, and metabolic organ in the shrimp. In this study, shrimps (Litopenaeus vannamei) were separately exposed to 1 and 5 mg/L nitrite stress for 48 h, and the toxicity of nitrite in the hepatopancreas was explored by integrating histology, physiological indicators, energy metabolism, and metabolomics. Nitrite stress induced morphological changes and stress responses in the hepatopancreas. Specifically, physiology-related indices, such as the relative gene expression levels of antioxidants (ROMO1, Nrf2, GPx), endoplasmic reticulum stress (Bip, IRE1 and XBP1), and immune genes (ALF, Pen-3, Lys) were decreased, whereas the gene expression of apoptosis (Casp-3), detoxification (CYP450), and glutamic oxaloacetic transaminase (GOT) activity were increased. The activities of osmotic adjustment-related enzymes (NKA, CMA, and ATPase) also decreased. Energy metabolism-related indices, such as pyruvate and hepatic glycogen contents, increased, whereas glucose, lactic acid, triglyceride, and ATP contents and ATPase activity decreased, and the relative gene expression levels of carbohydrate metabolism (PDH, HK, and LDH) and electron-transport chain genes (CytC, COI and CCO) decreased, and the expressions of lipid metabolism (AMPK, SREBP, and FAS), tricarboxylic acid cycle (MDH, CS, IDH and FH) genes were also disturbed. The metabolic pattern of the hepatopancreas was affected by nitrite stress. Glycine, serine, and threonine metabolism were highly affected, and more functional amino acids varied in the 5 mg/L nitrite stress group. These results reveal the toxic effects of nitrite stress on the stress response, physiology, energy metabolism, and metabolite homeostasis in the hepatopancreas of shrimp. Several potential metabolite biomarker candidates were identified for toxicological evaluation.

Low Phosphorus Causes Hepatic Energy Metabolism Disorder Through Dynamin-Related Protein 1–Mediated Mitochondrial Fission in Fish

BackgroundLow phosphorus (LP) diets perturb hepatic energy metabolism homeostasis in fish. However, the specific mechanisms in LP-induced hepatic energy metabolism disorders remain to be fully elucidated. ObjectivesThis study sought to elucidate the underlying mechanisms of mitochondria involved in LP-induced energy metabolism disorders. MethodsSpotted seabass were fed diets with 0.72% (S-AP, control) or 0.36% (S-LP) available phosphorus for 10 wk. Drp1 was knocked down or protein kinase (PK) A was activated using 8Br-cAMP (5 μM, a PKA activator) in spotted seabass hepatocytes under LP medium. Zebrafish were fed Z-LP diets (0.30% available phosphorus) containing Mdivi-1 (5 mg/kg, a Drp1 inhibitor) or 8Br-cAMP (0.5 mg/kg) for 6 wk. Biochemical and molecular parameters, along with transmission electron microscopy and immunofluorescence, were used to assess hepatic glycolipid metabolism, mitochondrial function, and morphology. ResultsSpotted seabass fed S-LP diets showed reduced ATP (52%) and cAMP (52%) concentrations, along with reduced Drp1 (s582) (38%) and PKA (61%) phosphorylation concentrations in the liver compared with those fed S-AP diets (P < 0.05). Drp1 knockdown elevated ATP concentrations (1.99-fold), decreased mitochondrial DRP1 protein amounts (45%), and increased mitochondrial aspect ratio (1.82-fold) in LP-treated hepatocytes (P < 0.05). Furthermore, 8Br-cAMP-treated hepatocytes exhibited higher PKA phosphorylation (2.85-fold), ATP concentrations (1.60-fold), and mitochondrial aspect ratio (2.00-fold), along with decreased mitochondrial DRP1 protein concentrations (29%) under LP medium (P < 0.05). However, mutating s582 to alanine mimic Drp1 dephosphorylation decreased ATP concentrations (63%) and mitochondrial aspect ratio (53%) in 8Br-cAMP-treated hepatocytes (P < 0.05). In addition, zebrafish fed Z-LP diets containing Mdivi-1 or 8Br-cAMP had higher ATP concentrations (3.44-fold or 1.98-fold) than those fed Z-LP diets (P < 0.05). ConclusionsThese findings provide a potential mechanistic elucidation for LP-induced energy metabolism disorders through the cAMP/PKA/Drp1-mediated mitochondrial fission signaling pathway.

Ginsenoside Rg1 Promotes Wound Healing in Mice with Superficial Second-Degree Burns Through Energy Metabolism, Cell Migration, and Cell Adhesion Pathways.

Natural products are known to have distinct roles in the treatment of various diseases. However, the potential role of ginsenoside Rg1 (GRg1) in the context of scald injuries remains unclear. This study aimed to elucidate the effects of GRg1 on scald wound healing by utilizing a mouse scald wound model and administering varying concentrations of GRg1 orally. RNA sequencing (RNA-seq) was employed to identify the signaling pathways and key genes influenced by GRg1 in the wound healing process. Our findings indicate that mice treated with a low concentration of GRg1 exhibited a significantly higher wound healing rate compared with the model group and other treatment groups. Through RNA-seq, we observed that the gene expression profile in the wound tissues of the low-concentration-treated group was consistent with that of the normal control group. Furthermore, a low concentration of GRg1 was found to maintain cellular energy metabolism homeostasis by enhancing mitochondrial aerobic respiration and the tricarboxylic acid cycle. In addition, GRg1 facilitated wound healing by restoring the expression of genes associated with cell migration and adhesion. Confirming the appropriate concentration of GRg1 that accelerates tissue healing at scald sites and enhances our understanding of the efficacy and molecular mechanisms underlying the therapeutic effects of natural products in disease treatment.

Mendelian randomization and multi-omics approach analyses reveal impaired glucose metabolism and oxidative phosphorylation in visceral adipose tissue of women with polycystic ovary syndrome.

What is the significance of visceral adipose tissue (VAT) in the pathogenesis of polycystic ovary syndrome (PCOS) and its impact on the regulation of metabolic disorders in women with PCOS? We revealed a potentially causal relationship between increased genetically predicted VAT and PCOS-related traits, and found that VAT exhibited impaired glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in women with PCOS. PCOS is a common reproductive endocrine disorder accompanied by many metabolic abnormalities. Adipose tissue is a metabolically active endocrine organ that regulates multiple physiological processes, and VAT has a much stronger association with metabolism than subcutaneous adipose tissue does. Mendelian randomization (MR) analysis was used to investigate the potential causal association between genetically predicted VAT and the risk of PCOS. Data for MR analysis were extracted from European population cohorts. VAT samples from sixteen PCOS patients and eight control women who underwent laparoscopic surgery were collected for proteomics and targeted metabolomics analyses. PCOS was diagnosed according to the 2003 Rotterdam Criteria. The control subjects were women who underwent laparoscopic investigation for infertility or benign indications. Proteomics was performed by TMT labeling and liquid chromatography-tandem mass spectrometry analysis, and targeted metabolomics was performed by ultra-performance liquid chromatography-tandem mass spectrometry analysis. The key differentially expressed proteins (DEPs) were validated by immunoblotting. MR analysis revealed a potentially causal relationship between increased genetically predicted VAT and PCOS, as well as related traits, such as polycystic ovaries, total testosterone, bioavailable testosterone, and anti-Müllerian hormone, while a negative relationship was found with sex hormone-binding globulin. Enrichment pathway analysis of DEPs indicated the inhibition of glycolysis and activation of mitochondrial OXPHOS in the VAT of PCOS patients. MR analysis revealed that key DEPs involved in glycolysis and OXPHOS were significantly linked to PCOS and its related traits. Dot blot assay confirmed a significant decrease in glycolysis enzymes PKM2 and HK1, and an increase in mitochondrial Complex I and III subunits, NDUFS3 and UQCR10. Moreover, metabolomics analysis confirmed down-regulated metabolites of energy metabolic pathways, in particular glycolysis. Further analysis of PCOS and control subjects of normal weight revealed that dysregulation of glucose metabolism and OXPHOS in VAT of women with PCOS was independent of obesity. The mass spectrometry proteomics data have been deposited to the iProX database (http://www.iprox.org) with the iProX accession: IPX0005774001. There may be an overlap in some exposure and outcome data, which might affect the results in the MR analysis. The changes in protein expression of key enzymes affect their activities and disrupt the energy metabolic homeostasis in VAT, providing valuable insight for identifying potential intervention targets of PCOS. This work was supported by the National Key Research and Development Project of China (2021YFC2700402), the National Natural Science Foundation of China (82071608, 82271665), the Key Clinical Projects of Peking University Third Hospital (BYSY2022043), and the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001). All authors report no conflict of interest. N/A.

Serum Autotaxin Level Positively Associates with Metabolic-Associated Fatty Liver Disease and Hyperuricemia in Postmenopausal Women

Introduction: Autotaxin (ATX) is an adipokine known to affect energy metabolism and lipid homeostasis. We aimed to evaluate serum ATX levels in metabolic-associated fatty liver disease (MAFLD) and other metabolic disorders in postmenopausal women. Methods: Postmenopausal women who received an annual health examination were included. The metabolic and demographic characteristics of the subjects were collected, including age, gender, weight, height, blood pressure, and biochemical parameters. Serum ATX level was determined by ELISA. Results: This cross-sectional includes 20 postmenopausal women and 20 age-paired healthy controls. MAFLD patients showed significant metabolic disturbance presented with increased body mass index (BMI), blood pressure (p < 0.001) and decreased high-density lipoprotein cholesterol (p < 0.05), as well as liver injury companied by elevated ALT (p < 0.05). Serum ATX levels were statistically higher in MAFLD (253.1 ± 52.1 vs. 202.2 ± 53.2 ng/mL; p < 0.01) and positively correlated with ALT (p < 0.001), γ-glutamyltransferase and BMI (p < 0.01), SBP and TG (p < 0.05). Higher ATX group demonstrated worsen metabolic states with greater proportion of MAFLD, higher BMI (p < 0.01), and ALT (p < 0.05). Logistic regression analysis revealed that serum ATX levels would positively independently predicted MAFLD (OR 1.049, 95% CI: 1.001–1.098, p < 0.05) with AUC of 0.763. Serum level of ATX is significantly elevated in hyperuricemia group (257.3 ± 60.9 vs. 214.5 ± 49.4 ng/mL; p < 0.05) and positively correlated with uric acid level (p < 0.01). Serum ATX would also act as diagnosing parameter of hyperuricemia with AUC of 0.706. Conclusions: Among postmenopausal women, serum ATX level is significantly elevated in MAFLD and related to multiple metabolic characteristics, especially hyperuricemia, which would thus serve as a potential noninvasive biomarker as well as a therapeutic target.

Integrated non-targeted metabolomics and lipidomics reveal mechanisms of fluorotelomer sulfonates-induced toxicity in human hepatocytes

Fluorotelomer sulfonates (FTSs) are widely used as novel substitutes for perfluorooctane sulfonate, inevitably leading to FTSs accumulation in various environmental media and subsequent exposure to humans. This accumulation eventually poses environmental hazards and health risks. However, their toxicity mechanisms remain unclear. Herein, the mechanisms of two FTSs (6:2 and 8:2 FTS) induced toxicity in human hepatocellular carcinoma cells were investigated via non-targeted metabolomics and lipidomics based on liquid chromatography–high resolution mass spectrometry. Our results revealed that amino acid, purine, acylcarnitine and lipid levels were significantly perturbed by 6:2 and 8:2 FTS exposure. The effects of 8:2 FTS exposure were largely characterized by up-regulation of pyruvate metabolism pathway and down-regulation of purine metabolism pathway, whereas the opposite trends were induced by 6:2 FTS exposure. The opposite trends were confirmed by the mRNA expression levels of four key genes (glyoxalase 1, adenylosuccinate lyase, inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2) determined by real-time PCR. Common lipid perturbations included significantly increased ceramide/sphingomyelin ratios, and obvious accumulation of hexosylceramides and lysoglycerophospholipids. 6:2 FTS exposure induced sharp accumulation of glycerides, including monoglycerides, diglycerides and triglycerides. 8:2 FTS exposure induced decreased levels of acylcarnitines and fatty acids. Both of 6:2 and 8:2 FTS exposure induced increased levels of intracellular reactive oxygen species, an imbalance in energy metabolism homeostasis, and mitochondrial dysfunction. The results of integrated omics analysis are expected to serve as valuable information for the health risk assessment of 6:2 FTS and 8:2 FTS.

Sputum Metabolomic Signature and Dynamic Change of Cough Variant Asthma.

Cough variant asthma (CVA), a common reason for chronic cough, is a globally prevalent and burdensome condition. The heterogeneity of CVA and a lack of knowledge concerning the exact molecular pathogenesis has hampered its clinical management. This study presented the first sputum metabolome of CVA patients, revealed the dynamic change during treatment, and explored biomarkers related to the occurrence and treatment response of CVA. We found arginine biosynthesis, purine metabolism, and pyrimidine metabolism pathways were enriched in CVA compared to healthy controls. Part of metabolic disturbances could be reversed by anti-asthmatic medication. The levels of dipeptides/tripeptides (alanyltyrosine, Gly-Tyr-Ala, Ala-Leu, and Thr-Leu) were significantly associated with sputum Neu% or Eos% of CVA patients. Differential metabolites pre-treatment between effective and ineffective groups enriched in purine metabolism, thiamine metabolism, and arginine metabolism. 2-isopropylmalate was down-regulated in CVA patients and increased after treatment, and effective group had a lower 2-isopropylmalate level pre-treatment. Random forest and logistic regression models identified glutathione, thiamine phosphate, alanyltyrosine, and 2'-deoxyadenosine as markers for distinguishing CVA from healthy controls (all AUC > 0.8). Thiamine phosphate might also be promising for predicting therapy responsiveness (AUC = 0.684). These findings implied that disturbed mitochondrial energy metabolism and imbalanced oxidation-reduction homeostasis probably underlay the metabolic pathogenesis of CVA.

Dimorphic Nature of Adipose Tissue and Role of Herbal Extracts in Lipids Metabolism

Adipose tissue, known as body fat, plays a crucial role in human health and disease. Traditionally viewed as a storage site for excess energy as body fat, advances in medical research have shown the complex and dynamic nature of adipose tissue, highlighting its critical role in the regulation of metabolism, hormone production, and immune response. Adipose tissue is subdivided into two types – lipids accumulating white adipose tissue (WAT) and brown adipose tissue (BAT), color of which is determined by the load of mitochondria; the beige adipose tissue (BeAT) is a mix of WAT and BAT cells. This review aims to explore the multifaceted aspects of WAT, focusing on key areas: the diverse cell types comprising WAT and their unique functions, the major genes expressed and secreted from adipose tissue cells, the role of adipose tissue in inflammation, and the sex-specific differences in adipose tissue transcriptomes. Understanding the intricate dynamics of adipose tissue in the context of secreted factors having systemic effects, including inflammatory response, is essential, given its central role in maintaining energy balance and metabolic homeostasis in health issues like obesity, type 2 diabetes, and cardiovascular diseases. Examining adipocyte-specific transcriptomes gives an understanding of the unique characteristics of these cells. The dimorphic nature of adipose tissue not only influences body fat distribution but also affects disease susceptibility and response to treatment. Additionally, this review will cover the increasingly recognized role and the intriguing effects of plant extracts on adipogenesis, which offer potential therapeutic avenues for treating obesity and its related disorders.