Search Results (120)

Prostate cancer progression and therapy response are strongly influenced by the tumor microenvironment (TME), particularly stromal fibroblasts that regulate survival signaling, metabolism, and drug resistance. In this study, we investigated whether extracts from three Lepidium meyenii (maca) morphotypes, yellow (MY), red (MR), and black (MB), modulate doxorubicin (DOX) responses in 22Rv1 prostate cancer cells under mono-culture and co-culture conditions with human dermal fibroblasts (HDFa). Cell viability, proliferation, apoptosis-related proteins, lipid droplets (LDs) accumulation, and selected signaling markers were analyzed. In mono-culture, maca extracts exhibited limited cytotoxicity, with MB showing the strongest but still moderate effect. Co-treatment with DOX did not enhance cytotoxicity and resulted in context-dependent modulation of caspase-3 and caspase-8. In co-culture, HDFa cells reduced DOX sensitivity, suggesting altered treatment responses under co-culture conditions. Morphometric analysis suggested fibroblast activation-like changes. Across models, maca reduced LDs accumulation, while increased adipose triglyceride lipase (ATGL) levels in co-culture suggested altered lipid utilization. Additionally, maca extracts modulated PI3K, PSMA, FOXO1, FAP, and HAT1 in a morphotype-dependent manner. Overall, maca extracts acted primarily as context-dependent modulators of signaling and lipid metabolism markers rather than direct cytotoxic agents with their effects strongly dependent on both extract type and microenvironmental context. Full article

The increasing demand for premium-quality meat has intensified interest in the molecular regulators that govern lipid deposition and sensory quality. Lipid metabolism, encompassing synthesis, oxidation, and storage, represents a key biological process affecting intramuscular fat content, tenderness, and flavor. G0/G1 Switch Gene 2 (G0S2) is widely recognized as an endogenous, non-competitive inhibitor of adipose triglyceride lipase. By inhibiting this key lipase, G0S2 restrains triglyceride hydrolysis and helps preserve lipid storage. Recent studies further suggest that G0S2 participates in adipocyte differentiation, mitochondrial regulation, apoptosis, and inflammatory signaling. Together, these findings indicate that G0S2 functions not only in lipolysis control but also as a multifunctional regulator of energy metabolism and cellular homeostasis. Despite its pleiotropic roles, which position G0S2 as a key integrator of lipid metabolism and cellular signaling networks, the specific roles and regulatory mechanisms by which G0S2 influences lipid metabolism and meat quality remain incompletely understood. This review summarized recent advances in G0S2-mediated lipid metabolism with emphasis on its regulatory network in livestock species. The physiological mechanisms by which G0S2 modulated lipolysis, lipid deposition, and intramuscular adipogenesis were discussed, along with nutritional, hormonal, and epigenetic factors controlling its expression. Moreover, its functional implications for meat quality improvement, marbling formation, and feed efficiency were highlighted. Understanding the molecular and regulatory features of G0S2 provided a foundation for developing genetic and nutritional strategies to optimize lipid utilization and enhance meat quality in modern animal production systems. Full article

This experiment investigated the effects of dietary Artemisia ordosica Krasch. (AOK) supplementation on the n3-polyunsaturated fatty acid (n3-PUFA) profile of subcutaneous adipose tissue (SADT) in Arbas cashmere goats and explored the underlying transcriptional mechanisms. Forty healthy, weaned kids (120 ± 10 days of age; similar body weight) were randomly allocated to two groups (n = 20): a control group (CON, basal diet) and an AOK group (AOK, basal diet with 3% of the roughage replaced by AOK). The feeding trial spanned 104 days, consisting of a 14-day adaptation period and 90 days of data acquisition. Compared with the CON group, AOK significantly reduced the content of saturated fatty acids (SFAs) and n6-polyunsaturated fatty acids (n6-PUFAs)/n3-PUFAs (n6/n3). In contrast, the levels of n3-PUFAs in the SADT of cashmere goats increased markedly (p < 0.05). Compared with the CON group, AOK exhibited significantly higher activities of hormone-sensitive lipase (HSL) (p = 0.027), adenylyl cyclase 2 (ADCY2) (p = 0.010), adenylyl cyclase 5 (ADCY5) (p = 0.046), cluster of differentiation 36 (CD36) (p = 0.013), solute carrier family 27 member 4 (SLC27A4) (p = 0.021), and fatty acid binding protein 4 (FABP4) (p = 0.040), along with significantly lower activities of fatty acid synthase (FAS) (p = 0.002), lipoprotein lipase (LPL) (p = 0.048), and stearoyl-coa desaturase (SCD) (p = 0.026) in SADT. Compared with the CON group, the activities of superoxide dismutase (SOD) (p = 0.032), catalase (CAT) (p = 0.010), glutathione peroxidase (GSH-PX) (p = 0.029), and total antioxidant capacity (T-AOC) (p = 0.002) were significantly increased in the AOK group. Transcriptomic profiling revealed that AOK supplementation downregulated mRNA levels of ADCY2, ADCY5, LPL, FAS, SCD, stearoyl-CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2), glycogen synthase 1 (GYS1), acyl-CoA oxidase 1 (ACOX1), acetyl-CoA carboxylase (ACC), diacylglycerol acyltransferase 1 (DGAT1), fatty acid desaturase 1 (FADS1), solute carrier family 27 member 2 (SLC27A2), erythroblastic leukemia viral oncogene homolog 4 (ERBB4), and carnitine palmitoyltransferase 1B (CPT1B) (p < 0.05). It also markedly induced acyl-CoA synthetase long-chain family member 4 (ACSL4) (p < 0.01) in SADT. Genes significantly enriched in the adenosine-monophosphate-activated protein kinase (AMPK) signaling pathway included LPL, SCD1, CPT1B, and GYS1 (p = 0.010). Genes significantly enriched in the phosphatidylinositol 3-kinase-akt (PI3K-Akt) signaling pathway included GYS1 and ERBB4 (p = 0.015). CPT1B, ADCY2, and GYS1 were identified as the genes significantly enriched in the insulin resistance signaling pathway (p = 0.048). LPL was the only gene significantly enriched in the cholesterol metabolism pathway (p = 0.049). Genes showing a tendency toward significant enrichment in the peroxisome-proliferator-activated receptor (PPAR) signaling pathway included ACSL4, CPT1B, SCD1, and LPL (p = 0.051). These interconnected cascades improve insulin sensitivity, stimulate triglyceride (TG) hydrolysis, and modulate n3-PUFA levels. Supplementation with AOK enhances n3-PUFA content by accelerating TG breakdown while simultaneously restraining FA oxidation in SADT. Consequently, AOK supplementation can be effectively used to enhance the nutritional value of cashmere goat meat through improved n3-PUFA deposition in SADT. Full article

Cardiovascular disease is the leading cause of mortality in insulin-resistant individuals, with metabolic cardiomyopathy preceding overt heart failure in a substantial proportion of patients with diabetes. Skeletal muscle accounts for approximately 40% of body mass and nearly 80% of insulin-stimulated glucose disposal, positioning it as a major determinant of systemic lipid flux. Dysregulation of lipid droplet dynamics, lipolysis, and fatty acid trafficking in skeletal muscle alters circulating lipid availability and promotes ectopic lipid deposition and mitochondrial stress in the myocardium. Intramyocellular lipid handling is governed by coordinated actions of lipid droplets, perilipin proteins (PLIN2 and PLIN3), adipose triglyceride lipase (ATGL), and diacylglycerol acyltransferases (DGAT1/2), which together regulate the rate and composition of fatty acid release into the circulation. Impaired coupling between intramyocellular lipid droplet turnover and mitochondrial oxidation in insulin-resistant muscle increases circulating free fatty acids, reducing cardiac oxidative capacity. In response, the myocardium undergoes mitochondrial lipid remodeling, including alterations in cardiolipin composition that impair cristae structure and electron transport chain efficiency. Excess lipid exposure activates apoptosis signal-regulating kinase-1 (ASK-1), promoting cardiomyocyte apoptosis and inflammatory signaling, while peroxisome proliferator-activated receptor gamma (PPARγ) modulates lipid uptake, storage, and mitochondrial oxidation in a context-dependent manner. This review integrates skeletal muscle–cardiac lipid crosstalk with ASK-1 and PPARγ signaling to define mechanisms linking peripheral insulin resistance to early myocardial dysfunction and to identify targets for intervention before irreversible cardiac remodeling develops. Full article

Obesity is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular mechanisms and effective treatments remain unclear. This study investigated whether ST32db, an inducer of activating transcription factor 3 (ATF3), affects lipid metabolism in MASLD. An in vitro model was established involving the treatment of HepG2 cells with 1 mM oleic acid (OA) with or without 20 µM ST32db. In an in vivo model, C57BL/6 mice were fed a high-fat diet (HFD) for 18 weeks to induce obesity and treated or not with ST32db (1 mg kg⁻¹). ST32db significantly decreased intracellular lipid accumulation in OA-treated HepG2 cells. In these cells, ST32db remarkably decreased mRNA and protein levels of adipogenesis- and lipogenesis-related genes and increased mRNA levels of adipose triglyceride lipase (ATGL), a lipolytic enzyme. In HFD-fed mice, the ST32db treatment significantly decreased the liver weight, serum triglycerides, and fat vacuole and triglyceride accumulation in the liver. Livers from these mice also showed significantly decreased CCAAT/enhancer-binding protein β mRNA and protein levels, increased ATF3 mRNA and protein and ATGL mRNA levels, and increased levels of phosphorylated AMP-activated protein kinase (AMPK) and protein kinase A (PKA). These findings suggest that ST32db may exert protective effects against MASLD through activating hepatic AMPK and PKA pathways. Full article

Extracellular vesicles (EVs) derived from probiotic bacteria have recently emerged as postbiotic mediators that regulate host cellular responses. This study investigated the effects of EVs from Lactobacillus rhamnosus BS-Pro-08, isolated from kefir grains (Lacto EV), on adipocyte differentiation and lipid metabolism. Lacto EV treatment markedly suppressed the differentiation of 3T3-L1 preadipocytes into mature adipocytes, as reflected by reduced lipid accumulation and decreased expression of the adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). This inhibitory effect was most pronounced at the early stage of adipogenesis. In mature adipocytes, Lacto EV enhanced lipolysis in a dose-dependent manner, accompanied by increased glycerol release and total lipase activity. Interestingly, these lipolytic responses occurred despite reduced protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), suggesting that Lacto EVs may mediate an EV-enhanced lipolysis that is not fully explained by canonical ATGL/HSL signaling. Collectively, these findings demonstrate that Lacto EV modulates both adipogenic and lipolytic processes in vitro, providing insight into the metabolic actions of probiotic-derived vesicles. Full article

Electronic cigarettes (E-Cig) are a new way of delivering nicotine, gaining popularity among adolescents and young adults, who often do not realize their harmful effects. Although the adverse effects of E-Cigs on the liver and heart have been demonstrated, their effects on the skeletal muscle have not been well studied. In this study, we evaluated the skeletal muscle effects of E-Cig aerosol, delivered in a manner similar to human vaping, in a mouse model of obesity induced by a high-fat diet (HFD). C57BL/6 mice, fed either a normal chow diet (NCD) or HFD, were exposed to either saline aerosol control or aerosol generated from Blu PLUS^TM containing 0% or 2.4% nicotine for 12 weeks. Mice fed an NCD were included to distinguish whether E-Cig effects on the skeletal muscle required the presence of obesity induced by an HFD. The soleus muscle, an oxidative muscle rich in mitochondria, was assessed by Western blotting, electron microscopy, and biochemical assays. An NCD group was included to assess the baseline effects of HFD-induced obesity, on the skeletal muscle. The skeletal muscle from HFD-fed mice exposed to E-Cig 2.4% had reduced levels of phospho-AMPK compared with saline and E-Cig 0% groups, while E-Cigs had no effect on NCD-fed mice. Levels of phospho-adipose triglyceride lipase were also reduced in both E-Cig 2.4% and 0% compared with the saline group. These metabolic protein impairments were accompanied by increased levels of oxidative stress and phospho-p38 MAPK. Deregulation of the autophagy markers, microtubule-associated protein 1A/1B-light chain 3 (LC3-I; inactive form) and LC3-II (active form), was also observed, evidenced by decreased levels of LC3-II, ratio LC3-II/LC3-I, and increased levels of p62. Transmission electron microscopy analysis showed that E-Cig 2.4% induced damage to mitochondrial structure compared with the saline or E-Cig 0% groups. These findings suggest that E-Cig exposure on HFD impairs the skeletal muscle, adding to the growing list of affected organs for ongoing regulatory efforts concerning nicotine-containing substances. Full article

Alopecia is a highly prevalent hair loss disorder characterized by an abnormality in hair cycling. Induction of autophagy and secretion of growth factors by adipocyte precursors are sufficient to activate quiescent hair follicles, yet therapies targeting these processes remain limited. Here, we identify rebamipide—a drug originally intended for gastric ulcer treatment—as a promising candidate for hair regeneration by modulating dermal adipocyte metabolism. Topical rebamipide treatment induces autophagy and adipose triglyceride lipase (ATGL)-mediated lipolysis in dermal adipocytes. Using primary culture systems, we demonstrate that rebamipide-driven lipolysis triggers adipocyte dedifferentiation, activating hair follicle stem cells (HFSCs) via elevated platelet-derived growth factor (PDGF) levels. Mechanistically, computer simulations and target validation experiments confirm that rebamipide directly binds to the prostaglandin E receptor EP4, triggering PI3K/ERK-dependent autophagy and lipolysis. Collectively, our findings highlight EP4 as a novel therapeutic target for hair loss and position rebamipide as an agent that couples lipid metabolism remodeling with HFSC activation. Full article

Atherosclerotic cardiovascular disease treatment is being reevaluated, since a residual cardiovascular risk (RCR) persists even in patients who achieve optimal LDL-C values. Underlying causes are metabolic dysfunction, lipoprotein(a), inflammation, and triglyceride-rich lipoproteins and their remnants. Dietary treatment options like time-restricted eating (TRE) are becoming more widely acknowledged for their potential advantages in metabolic health and weight control, as a treatment of atherosclerosis expanding beyond LDL-C medication. Beyond weight loss, TRE (which restricts meals to a window of 6 to 8 h) appears as the most accessible treatment, and has been shown to improve blood pressure, lipid profiles, and glucose regulation through mechanisms like metabolic switching and circadian synchronization. We hypothesize, and will present our arguments, that a key mechanism underlying the cardiovascular and weight-related benefits of TRE is its impact on the circadian regulation of angiopoietin-like protein 4 (ANGPTL4) activity within adipose tissue. Additionally, lipolysis is accelerated by ANGPTL4 activation. TRE, via its actions on ANGPTL4, therefore not only inhibits adipose fatty acid uptake but stimulates their release as well. Additionally, TRE may increase intravascular very low-density lipoprotein (VLDL) catabolism by muscle due to the reduced exposure of lipoprotein lipase (LPL) to competing chylomicrons, known to slow the rate of VLDL catabolism. During the prolonged fasting, VLDL residence time is thus shortened, limiting the exposure to endothelium and hepatic lipases and thus reducing the amount of atherogenic remnant particles. Larger, longer-term randomized controlled studies in a variety of groups are required to further clarify TRE’s function in RCR prevention and therapy. As knowledge of triglyceride lipoprotein (TRL) metabolism expands, a comprehensive strategy for the management of RCR emerges, and a broader spectrum of LPL regulator-based therapeutics is created. Consequently, it is advisable to prioritize further research into the influence of TRE on LPL modulation via ANGPTL4 and ANGPTL8, which provides a natural, accessible, and low-cost alternative. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), driven by obesity and metabolic syndrome, is increasingly prevalent and a significant contributor to liver fibrosis, cirrhosis, and liver-related mortality. Emerging research implicates the gut microbiome as a critical player in MASLD progression, yet specific microbial drivers remain poorly understood. Here, we explore the role of Prevotella copri (P. copri) in MASLD progression through both human patient cohorts and a mouse model of diet-induced obesity. Methods/Results: Using 16S rRNA sequencing, we identified elevated P. copri abundance in MASLD patients with advanced fibrosis, linked with significant shifts in microbial diversity and bacterial network connectivity. To investigate causality, experimental colonization of P. copri in mice on a high-fat diet worsened MASLD progression, with P. copri-colonized mice showing significant increases in hepatic steatosis, liver triglyceride accumulation, and body weight, independent of caloric intake. At the molecular level, P. copri colonization downregulated key lipid metabolism genes, such as carnitine palmitoyltransferase 1 and adipose triglyceride lipase, and impaired tight intestinal junction integrity through the downregulation of occludin. Collectively, our findings position P. copri as a possible driver of MASLD progression by promoting hepatic steatosis through lipid and triglyceride accumulation and fibrosis through decreased tight junction integrity. These insights suggest a promising therapeutic avenue to target specific microbial signatures like P. copri to curb MASLD progression and mitigate the associated risk of advanced fibrosis. Full article

Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated Wwp1 knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists. Full article

Metabolic syndrome (MetS) is a subclinical disease, resulting in increased risk of type 2 diabetes (T2D), cardiovascular diseases, cancer, and mortality. Dynamical network biomarkers (DNB) theory has been developed to provide early-warning signals of the disease state during a preclinical stage. To improve the efficiency of DNB analysis for the target genes discovery, the DNB intervention analysis based on the control theory has been proposed. However, its biological validation in a specific disease such as MetS remains unexplored. Herein, we identified eight candidate genes from adipose tissue of MetS model mice at the preclinical stage by the DNB intervention analysis. Using Drosophila, we conducted RNAi-mediated knockdown screening of these candidate genes and identified vasa (also known as DDX4), encoding a DEAD-box RNA helicase, as a fat metabolism-associated gene. Fat body-specific knockdown of vasa abrogated high-fat diet (HFD)-induced enhancement of starvation resistance through up-regulation of triglyceride lipase. We also confirmed that DDX4 expressing adipocytes are increased in HFD-fed mice and high BMI patients using the public datasets. These results prove the potential of the DNB intervention analysis to search the therapeutic targets for diseases at the preclinical stage. Full article

Antioxidant peptides are a well-known functional food exhibiting multiple biological activities in health and disease. This study investigated the effects of three peptides, LR-7 (LALFVPR), KA-8 (KLHDEEVA), and PG-7 (PSRILYG), from Harpadon nehereus bone on sodium palmitate (PANa)-induced HepG2. The findings indicated that all three peptides significantly reduced the oxidative damage and fat accumulation in the HepG2 cells while also normalizing the abnormal blood lipid levels caused by PANa. Furthermore, treatment with LR-7 resulted in a more than 100% increase in catalase (CAT), glutathione peroxidase (GSH-Px), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels within the HepG2 cells (p < 0.001). Western blot analysis showed that LR-7 treatment significantly lowered the expression of fatty acid synthase (FASN) by 59.6% (p < 0.001) while enhancing carnitine palmitoyl transferase 1 (CPT1) by 134.7% (p < 0.001) and adipose triglyceride lipase (ATGL) by 148.1% (p < 0.001). Additionally, these peptides effectively inhibited the pancreatic lipase activity. Notably, LR-7 demonstrated superior effectiveness across all of the evaluated parameters, likely due to its greater hydrophobicity. In summary, LR-7, KA-8, and PG-7 are effective at mitigating oxidative stress as well as regulating lipid metabolism, thus protecting HepG2 cells from PANa-induced injury and lipid buildup. This research indicates that these collagen-derived peptides, especially LR-7, show promise as natural agents for managing hyperlipidemia. Full article

Background/Objectives: Endothelial peroxisome proliferator-activated receptor gamma (PPARγ) regulates adipose tissue by facilitating lipid uptake into white adipocytes, but the role of endothelial lipid transport in systemic energy balance remains unclear. Ghrelin conveys nutritional information through the central nervous system and increases adiposity, while deficiency in its receptor, growth hormone secretagogue-receptor (GHSR), suppresses adiposity on a high-fat diet. This study aims to examine the effect of ghrelin/GHSR signaling in the endothelium on lipid metabolism. Methods: We compared the effects of ghrelin on adiposity and lipid uptake into adipocytes in wild-type and GHSR-null mice. Transgenic mice expressing GHSR selectively in endothelial cells were also generated and compared with global GHSR-null and wild-type mice. The impact of ghrelin on lipid uptake-related genes was assessed in cultured endothelial cells. Results: Ghrelin increased adiposity and triglyceride clearance in wild-type but not in GHSR-null mice. GHSR-null mice showed higher serum triglyceride after olive oil gavage and lower white adipose tissue (WAT) weight on a high-fat diet, suggesting impaired lipid uptake. Restoring GHSR expression in endothelial cells increased lipoprotein lipase activity, lipid uptake into WAT, and WAT weight. Ghrelin enhanced free fatty acid uptake and the expression of lipid uptake genes in cultured endothelial cells, whereas these effects were absent in GHSR-null mice-derived endothelial cells. Knockdown of PPARγ revealed that ghrelin/GHSR signaling in endothelial cells promoted lipid uptake via endothelial PPARγ. Conclusions: Endothelial GHSR is key for regulating lipid metabolism via PPARγ in response to ghrelin and for the role of endothelium in regulating white adipocyte metabolism. Targeting endothelial ghrelin signaling may be a promising therapeutic approach for managing excessive adiposity and associated metabolic disorders. Full article

Background: Lacticaseibacillus paracasei (L. paracasei) strains and their postbiotics show potential for managing metabolic disorders such as diabetes and obesity. Two newly isolated L. paracasei strains, M2.1 and P4, were yielded from Formica rufa anthills in Sinite Kamani National Park, Bulgaria. Their metabolic effects on mature 3T3-L1 adipocytes were investigated. Methods: Mature 3T3-L1 adipocytes were treated for 24 h with 10% (v/v) cell-free supernatants (CFSs) of M2.1 or P4. Two experimental (M2.1, P4) and two control groups (mature, untreated adipocytes and mature adipocytes, treated with 10% (v/v) MRS broth) were analyzed for intracellular lipid accumulation, glucose uptake, and the mRNA expression of lipid metabolism and beta-oxidation-related genes. Fold changes in gene expression were assessed using RT-qPCR. Results: Both M2.1 and P4 CFSs enhanced glucose uptake by over 30% compared to the control. P4 demonstrated a more favorable effect by significantly upregulating adipose triglyceride lipase–patatin-like phospholipase domain containing 2, adiponectin, and peroxisomal beta-oxidation enzymes—acyl-coenzyme A oxidase 1, palmitoyl. Intracellular lipid accumulation increased only with M2.1, while P4 supported improved lipid turnover without promoting excessive lipid storage or lipolysis. Conclusions: P4 CFS exhibits the potential to improve adipocyte metabolism by enhancing glucose uptake, promoting beta-oxidation, and increasing adiponectin expression, offering a promising strategy for managing metabolic dysfunctions. Full article