Search Results (172)

Increased CT-derived fat tissue radiodensity has been indicated as a poor prognostic factor in oncological settings, although the reasons are not clear. One hypothesis is that increased radiodensity may reflect the loss of fat droplets within adipocytes, being a proxy of recent weight loss. This study aims to test this hypothesis by evaluating the association between longitudinal variations in fat tissue radiodensity and area in a cohort of COVID-19 patients. Baseline and 2–3-month follow-up chest CT scans of severe COVID-19 pneumonia survivors were retrospectively reviewed to measure subcutaneous, visceral, and intermuscular adipose tissue (SAT, VAT, and IMAT) areas and densities at the T7–T8 vertebrae, and longitudinal variations were computed for each variable. The associations between each compartment area and radiodensity variations (standardized values) were evaluated in univariate linear models and models adjusted by age and sex. A total of 196 COVID-19 survivors with suitable baseline and follow-up CT scans were included (mean age 65 ± 11 years, 62 (31.6%) females, 25% with diabetes and 2.6% with morbid obesity). Longitudinal variation in SAT area was inversely associated with longitudinal variation in SAT radiodensity in univariate models (coeff −0.91, 95%CI = −1.70/−0.12, p = 0.02) and after adjustment by age and sex (coeff −0.89, 95%CI = −1.7/−0.09, p = 0.03). The effect was similar and stronger for IMAT (coeff −2.1, 95%CI = −3.06/−1.19, p < 0.01 in adjusted models), and absent for VAT. Longitudinal variations in subcutaneous and intermuscular adipose tissue areas and densities are inversely associated. Higher adipose tissue radiodensity may be due to decrease in fat area (i.e., weight loss), explaining the poor prognostic effect found in cancer patients. Full article

Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as critical mediators in obesity-related diseases. However, the study of mature adipocyte-derived EVs (mAdipo-EVs) is limited due to the short lifespan of mature adipocytes in culture, low EV yields, and the low abundance of these EV subpopulations in the circulation. Additionally, most studies rely on rodent models, which have differences in adipose tissue biology compared to humans. To overcome these challenges, we developed a standardized approach for differentiating human preadipocytes (preAdipos) into mature differentiated adipocytes (difAdipos), which produce high-yield, human adipocyte EVs (Adipo-EVs). Using visceral adipose tissue from bariatric surgical patients, we isolated the stromal vascular fraction (SVF) and differentiated preAdipos into difAdipos. Brightfield microscopy revealed that difAdipos exhibited morphological characteristics comparable to mature adipocytes (mAdipos) directly isolated from visceral adipose tissue, confirming their structural similarity. Additionally, qPCR analysis demonstrated decreased preadipocyte markers and increased mature adipocyte markers, further validating successful differentiation. Functionally, difAdipos exhibited lipolytic activity comparable to mAdipos, supporting their functional resemblance to native adipocytes. We then isolated preAdipo-EVs and difAdipo-EVs using tangential flow filtration and characterized them using bulk and single EV analysis. DifAdipo-EVs displayed classical EV and adipocyte-specific markers, with significant differences in biomarker expression compared to preAdipo-EVs. These findings demonstrate that difAdipos serve as a reliable surrogate for mature adipocytes, offering a consistent and scalable source of adipocyte-derived EVs for studying obesity and its associated disorders. Full article

Obesity (OB) has become a serious health issue owing to its ever-increasing prevalence over the past few decades due to its contribution to severe metabolic and inflammatory disorders such as cardiovascular disease, type 2 diabetes, and cancer. The unbalanced energy metabolism in OB is associated with substantial epigenetic changes mediated by the gut microbiome (GM) structure and composition alterations. Remarkably, experimental evidence also indicates that OB-induced epigenetic modifications in adipocytes can lead to cellular “memory” alterations, predisposing individuals to weight regain after caloric restriction and subsequently inducing inflammatory pathways in the liver. Various environmental factors, especially diet, play key roles in the progression or prevention of OB and OB-related disorders by modulating the GM structure and composition and affecting epigenetic mechanisms. Here, we will first focus on the key role of epigenetic aberrations in the development of OB. Then, we discuss the association between abnormal alterations in the composition of the microbiome and OB and the interplays between the microbiome and the epigenome in the development of OB. Finally, we review promising strategies, including prebiotics, probiotics, a methyl-rich diet, polyphenols, and herbal foods for the prevention and/or treatment of OB via modulating the GM and their metabolites influencing the epigenome. Full article

Visceral fat mass is associated with a condition of chronic inflammation and can predispose the overweight to an increased cancer risk. Although it is known that adipocytes are active producers of the pro-inflammatory transforming growth factor β (TGFβ), the causes of their excessive synthesis are not clear. In this study, we reproduced two metabolic stress conditions frequently occurring in vivo, namely hypoxia and the fatty acid-driven metabolic uncoupling, and we characterized the response of an in vitro model of 3T3-L1 mouse adipocytes. For the first time, we demonstrated that the mitochondrial dysmetabolism of differentiated adipocytes induced the secretion of TGFβ. The paracrine activity of the secreted cytokine was then tested on two human pancreatic cancer cell lines. Cancer cells responded to the stimulation by increasing mitochondrial respiration, switching on the epithelial–mesenchymal transition (EMT) program and enhancing their motility. The data obtained in this proof-of-concept research show that TGFβ can be produced by dysmetabolic adipocytes, linking the altered metabolism with pro-tumorigenic inflammation. The novel observations of this study identify in metabolic stress a still unexplored cause of inflammation and cancer progression and pave the way to more detailed in vitro and clinical studies on pancreatic cancer. 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

Smilax glabra flavonoids (SGF), the active components of Smilax glabra Roxb., have been demonstrated to exhibit antioxidant activity and metabolic benefits in obesity, leading us to further explore their antitumor effects in obesity-related colorectal cancer (CRC). This study investigated the antiproliferative effects of SGF on obesity-related CRC by using a murine colon adenocarcinoma MC38 cell line. The underlying mechanisms were further explored via RNA-Seq and bioinformatics analysis in combination with experimental validation. SGF was proven to possess cytotoxic effects against MC38 cells, indicated by the inhibition of proliferation and migration, especially in an adipocyte-rich environment. In line with this, SGF exhibited much stronger antiproliferative effects on MC38-transplanted tumors in obese mice. Transcriptomics analysis showed that the cytotoxic effects of SGF might be related to the AMPK pathway and ferroptosis. On this basis, SGF was confirmed to induce ferroptosis and dictate ferroptosis sensitivity in a high-fat context mimicked by a two-step conditioned medium (CM) transfer experiment or a Transwell coculture system. The results of Western blotting validated that SGF suppressed the phosphorylation of AMPK, accompanied by alterations in the biomarkers of ferroptosis. These results demonstrate that SGF exerts in vitro and in vivo antiproliferative effects in obesity-associated CRC through inhibiting AMPK activation, thereby driving ferroptosis. Full article

Background: Aromatase inhibitors-related musculoskeletal syndrome (AIMSS) is a common side effect experienced by early breast cancer patients undergoing endocrine therapy. This condition can result in medication discontinuation and a diminished quality of life. The objective of this study was to characterize AIMSS, investigate its pathogenesis, and identify potential biomarkers at both the protein and metabolic levels. Methods: We collected peripheral blood samples from 60 women diagnosed with breast cancer undergoing aromatase inhibitor therapy, of whom 30 had AIMSS and 30 did not. The samples were analyzed using four-dimensional data-independent acquisition (DIA)-based proteomics and untargeted metabolomics, employing liquid chromatography–mass spectrometry (LC–MS) on the latest platform. Results: The mean age of participants was 49.2 (11.3) years in the AIMSS group and 50.1 (11.5) years in the non-AIMSS group. There were no statistically significant differences between the two groups in terms of age, BMI, education level, clinical stage, and treatment. In total, we identified 3473 proteins and 1247 metabolites in the samples. The chemokine signaling pathway (p = 0.015), cytokine–cytokine receptor interaction (p = 0.015), complement and coagulation cascades (p = 0.004), neuroactive ligand–receptor interaction (p = 0.004), and the estrogen signaling pathway (p = 0.004) were significant enriched in differentially expressed proteins (DEPs). GnRH secretion (p < 0.001), sphingolipid signaling pathways (p < 0.001), endocrine resistance (p < 0.001), the estrogen signaling pathway (p = 0.001), endocrine and other factor-regulated calcium reabsorption (p = 0.001), dopaminergic synapse (p = 0.003), regulation of lipolysis in adipocytes (p = 0.004), biosynthesis of cofactors (p = 0.004), thyroid hormone synthesis (p = 0.008), aldosterone synthesis and secretion (p = 0.001), taurine and hypotaurine metabolism (p = 0.011), ovarian steroidogenesis (p = 0.011), and the cAMP signaling pathway (p = 0.011) were significantly enriched in differentially expressed metabolites (DEMs). Complement C3 (p = 0.004), platelet factor 4 (p = 0.015), KRT10 (p = 0.004), KRT14 (p = 0.004), beta-estradiol (p = 0.019), testosterone (p = 0.023), sphingosine (p < 0.001), and 1-stearoyl-2-arachidonoyl-sn-glycerol (p = 0.039) could be the monitoring and therapeutic targets for AIMSS. Conclusions: This study offered new insights into the mechanisms underlying musculoskeletal symptoms associated with aromatase inhibitors. It also highlighted potential biomarkers for predicting and addressing these symptoms in breast cancer patients, paving the way for improved intervention strategies. Full article

Ovarian cancer (OC) is one of the most fatal gynecological neoplasms. Meta-analyses have shown that the relationship between body mass index (BMI) and ovarian cancer incidence was detected in some types of ovarian cancer. Chronic inflammation and excessive accumulation of free fatty acids are key adipose tissue-derived factors initiating cancer development. Cancer cells transform adipose-derived stem cells into cancer-associated adipocytes, which produce adipokines and interleukins. It was revealed that adipokines exert a pleiotropic role in ovarian cancer pathogenesis. Chemerin presents both pro-cancer and anti-cancer action in ovarian cancer development. Chemerin induces angiogenesis and increases programmed death ligand-1 (PD-L1) expression, leading to enhanced proliferation and migration of OC cells. Apelin impacts cancer cell migration and acts as a mitogenic factor. Moreover, apelin exerts influence on lipid uptake into cancer cells and accelerates fatty acid oxidation, which provides energy for cancer cells. Visfatin induces matrix metallopeptidase 2 (MMP2) expression involved in extracellular matrix degradation and suppresses claudin 3 and 4 expression. Visfatin also induces a shift to anaerobic glucose metabolism and influences poly-ADP ribose polymerase (PARP). Resistin induces MMP2 and vascular endothelial growth factor (VEGF) expression and contributes to cisplatin-resistance development. A substantial body of evidence indicates that antagonists of adipokines mitigate OC progression, and adipokines are gaining gradual recognition as a potential therapeutic aim in ovarian cancer targeted therapy. Full article

Background: Obesity and aging are associated with the progressive loss of brown adipose tissue (BAT), an increase in visceral white adipose tissue (vWAT), and a reduction in subcutaneous white adipose tissue (sWAT). The progressive expansion of visceral obesity promotes a low grade of systemic chronic inflammation (meta-inflammation), contributing to the onset of comorbidities such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and even cancer. Thus, preserving the thermogenic activity of adipose tissue and improving the metabolic flexibility of sWAT could be an effective strategy to prevent the development of metabolic chronic diseases and promote healthy aging. Precision nutrition has emerged as a complementary approach to control the metabolic alterations associated with unhealthy obesity and aging. In a previous work, we described that a silymarin-enriched extract from milk thistle (Mthistle) increased markers of browning and thermogenesis in vitro in human differentiated adipocytes (SGBS). Objectives/Methods: Therefore, this study aims to evaluate the potential of Mthistle to activate thermogenesis in a preclinical model of high-fat diet (HFD)-induced obesity (DIO). Results: Our results demonstrate that Mthistle increases systemic energy expenditure (EE), preserves body temperature after cold exposure, improves insulin resistance, and reduces inflammatory markers in WAT. Conclusions: Based on these results, silymarin-enriched extract from Mthistle may be proposed as a nutraceutical for the management of metabolic chronic diseases and/or accelerated aging. Full article

This study offers promising insights into the anti-obesity potential of Pleurotus ferulae, an edible mushroom valued in Asian cuisine for its nutritional benefits. A hot water extract of P. ferulae (PWE) administered to high-fat diet-induced obese mice over an 8-week period significantly reduced their body weight gain and fat accumulation. PWE not only improved the body weight metrics but also positively influenced the serum lipid profile of obese mice by lowering their total cholesterol and low-density lipoprotein cholesterol levels. In vitro studies using 3T3-L1 adipocytes showed that PWE inhibited adipocyte differentiation and lipid accumulation by downregulating key adipogenic transcription factors, particularly PPARγ and C/EBPα, as well as related lipogenic genes involved in fat synthesis and storage, such as Fabp4, Fasn, and Scd1. Chemical analysis revealed that PWE is rich in polysaccharides, which have been associated with various health benefits, including anti-obesity, anti-diabetic, and anti-cancer properties. These findings suggest that the bioactive compounds in PWE may serve as functional food components that could potentially be applied for the prevention and management of obesity and other metabolic disorders. Full article

Flavanones, a class of flavonoids, are abundant in fruits, vegetables, and herbs. They are known to have several biological activities, such as anti-inflammatory and anti-cancer activities, but their effects on obesity remain unclear. Obesity is closely associated with adipocyte differentiation and lipid accumulation in adipose tissue. Therefore, in this study, we examined the effects of flavanone derivatives on adipocyte differentiation and lipid accumulation by using 3T3-L1 cells. Among the 15 flavanone derivatives studied, 4′-phenylflavanone (4PF), with a biphenyl structure, significantly inhibited adipocyte differentiation-related lipid accumulation in 3T3-L1 cells; this inhibition of lipid accumulation was dose-dependent. Gene expression analysis showed that 4PF suppressed the expression of adipogenic marker genes. Although the induction of peroxisome proliferator activator γ2 (Pparγ2), a master regulator of adipocyte differentiation, and its target genes during adipocyte differentiation was attenuated in 4PF-treated cells, 4PF did not directly regulate Pparγ2 gene expression and its activation. In contrast, 4PF suppressed mitotic clonal expansion (MCE), which is associated with changes in the expression of proliferation-related genes at the early stages of adipocyte differentiation. Taken together, these results suggest that 4PF inhibits lipid accumulation because it suppresses MCE during adipocyte differentiation. Thus, our findings may help in the development of anti-obesity drugs. Full article

American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC. Full article

Breast cancer is the leading cause of cancer death among women worldwide. The mammary gland is composed of various types of cells including luminal cells, fibroblasts, immune cells, adipocytes, and specific microbiota. The reciprocal interaction between these multiple types of cells can dictate the initiation and progression of cancer, as well as metastasis and response to therapy. In the present report, we have shown that Escherichia coli-conditioned media (E-CM) can directly activate human mammary luminal epithelial cells (HMLEs), by inducing epithelial-to-mesenchymal transition (EMT), a process associated with increased proliferation and invasion capacities, as well as stemness features. Additionally, it has been shown that E-CM has an indirect pro-carcinogenic effect, mediated by the activation of normal breast fibroblasts (NBFs). Indeed, E-CM upregulated various markers of active fibroblasts (FAP-α, GPR77, and CD10), and enhanced the proliferation, migration, and invasion capacities of NBFs. Furthermore, E-CM induced an inflammatory response in NBFs by activating the pro-inflammatory NF-kB transcription factor and several of its downstream target cytokines including IL-1β, IL-6, and IL-8. This E-CM-dependent activation of NBFs was confirmed by showing their paracrine pro-carcinogenic effects through inducing EMT and stemness features in normal breast epithelial cells. Interestingly, similar effects were obtained by recombinant human IL-1β. These results provide the first indication that E. coli can initiate breast carcinogenesis through the activation of breast stromal fibroblasts and their paracrine pro-carcinogenic effects. Full article

Background: Obesity is a risk factor of several types of cancer, including breast cancer. In this study, we aimed to histologically characterize the adipose tissue of the tumor microenvironment (TME) of triple-negative breast cancer (TNBC) in overweight/obese versus normal-weight patients. Methods: TNBC tissue sections from normal-weight (BMI_<25) and overweight/obese patients (BMI_≥25) were stained with antibodies against CD68, CD163, CD31, CD34, and vimentin. At the invasive tumor front, positive cells were counted in tumor adjacent adipose tissue (AT) and within cancer tissue (CT). Further, the size of the tumor-adjacent and distant mammary adipocytes was determined in perilipin stained sections. Expression of ANGPTL4, CD36 and FABP4, proteins involved in fatty acid metabolism, was analyzed in marginal tumor cells using an immune reactive score. Results: Overweight/obese TNBC patients had significantly larger adipocytes, higher numbers of CD163+ macrophages (BMI_<25: 2.80 vs. BMI_≥25: 10.45; p = 0.011) and lower numbers of CD31+ (BMI_<25: 4.20 vs. BMI_≥25: 2.40; p = 0.018) and CD34+ (BMI_<25: 14.60 vs. BMI_≥25: 5.20; p = 0.045) cells as markers of angiogenesis in the AT as well as a higher frequency of cancer-associated-fibroblast-like cells in the AT and CT (BMI_<25: 7.60 vs. BMI_≥25: 25.39 in total; p = 0.001). Moreover, expression of CD36 (BMI_<25: 2.15 vs. BMI_≥25: 2.60; p = 0.041) and ANGPTL4 (BMI_<25: 6.00 vs. BMI_≥25: 9.80; p = 0.026) was elevated in the TNBC cells of overweight/obese patients. Conclusions: Our data suggest BMI-related changes in the TME of overweight/obese TNBC patients, including hypertrophied adipocytes, reduced vascularization, more M2-like macrophages and CAF-like cells, and an increase in the expression of fatty acid metabolizing proteins in marginal tumor cells, all contributing to a more tumor-promoting, immunosuppressive environment. Full article

Background/Objectives: Excess adiposity is associated with a higher risk of breast cancer metastasis and mortality. Evidence suggests that dietary vitamin D inhibits breast cancer metastasis. However, the mechanistic link between vitamin D’s regulation of adipocyte metabolism and metastasis has not been previously investigated. Therefore, the purpose of these experiments was to examine the effect of the active form of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)₂D), on adipocyte release of bioactive compounds and whether the impact on adipocytes leads to inhibition of breast cancer cell migration, an important step of metastasis. Methods: Differentiated 3T3-L1 adipocytes were treated with 1,25(OH)₂D for two days, followed by either harvesting the adipocytes or collecting adipocyte-conditioned media without 1,25(OH)₂D. A transwell migration assay was conducted with vehicle- or 1,25(OH)₂D-conditioned media. In order to explore the mechanism underlying effects on breast cancer metastatic capability, the mRNA expression of leptin, adiponectin, insulin-like growth factor (IGF-1), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) was measured in adipocytes following either vehicle or 1,25(OH)₂D treatment. Results: Conditioned media from 1,25(OH)₂D-treated adipocytes inhibited the migration of metastatic MDA-MB-231 breast cancer cells compared to conditioned media from vehicle-treated adipocytes. Treatment of adipocytes with 1,25(OH)₂D decreased mRNA expression of leptin, adiponectin, IGF-1, IL-6, and MCP-1. Consistent with mRNA expression, concentrations of leptin, adiponectin, IGF-1, and IL-6 in adipocyte-conditioned media were decreased with 1,25(OH)₂D treatment, although MCP-1 remained unchanged. Conclusions: In summary, these results suggest that 1,25(OH)₂D alters adipocyte secretions to prevent breast cancer metastasis. Full article