RESUMEN
Advanced glycated end products (AGEs) are cytotoxic compounds that are mainly increased in diabetes mellitus (DM), kidney failure, inflammation, and in response to the ingestion of AGE-rich diets. AGEs can also impair glycemic homeostasis by decreasing the expression of the Slc2a4 (solute carrier family 2 member 4) gene and its GLUT4 (solute carrier family 2, facilitated glucose transporter member 4) protein in muscle. However, the mechanisms underlying AGE's effect on adipocytes have not been demonstrated yet. This study investigated the effects of AGEs upon Slc2a4/GLUT4 expression in 3T3-L1 adipocytes, as well as the potential role of NFKB (nuclear factor NF-kappa-B) activity in the effects observed. Adipocytes were cultured in the presence of control albumin (CA) or advanced glycated albumin (GA) at concentrations of 0.4, 3.6, and 5.4 mg/mL for 24 h or 72 h. Slc2a4, Rela, and Nfkb1mRNAs were measured by RT-qPCR, GLUT4, IKKA/B, and p50/p65 NFKB subunits using Western blotting, and p50/p65 binding into the Slc2a4 promoter was analyzed by chromatin immunoprecipitation (ChIP) assay. GA at 0.4 mg/mL increased Slc2a4/GLUT4 expression after 24 h and 72 h (from 50% to 100%), but at 5.4 mg/mL, Slc2a4/GLUT4 expression decreased at 72 h (by 50%). Rela and Nfkb1 expression increased after 24 h at all concentrations, but this effect was not observed at 72 h. Furthermore, 5.4 mg/mL of GA increased the p50/p65 nuclear content and binding into Slc2a4 at 72 h. In summary, this study reveals AGE-induced and NFKB-mediated repression of Slc2a4/GLUT4 expression. This can compromise the adipocyte glucose utilization, contributing not only to the worsening of glycemic control in DM subjects but also the impairment of glycemic homeostasis in non-DM subjects under the high intake of AGE-rich foods.
Asunto(s)
Células 3T3-L1 , Adipocitos , Transportador de Glucosa de Tipo 4 , Productos Finales de Glicación Avanzada , Factor de Transcripción ReIA , Animales , Transportador de Glucosa de Tipo 4/metabolismo , Transportador de Glucosa de Tipo 4/genética , Ratones , Productos Finales de Glicación Avanzada/metabolismo , Productos Finales de Glicación Avanzada/farmacología , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIA/genética , FN-kappa B/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regiones Promotoras Genéticas , Subunidad p50 de NF-kappa B/metabolismo , Subunidad p50 de NF-kappa B/genéticaRESUMEN
Malva parviflora has shown anti-inflammatory, antihypertensive, antihyperlipidemic, and hypoglycemic effects. This study is aimed to evaluate the anti-adipogenic effect of M. parviflora on 3T3-L1 adipocytes. Fibroblast differentiation was induced either in the absence or presence of M. parviflora fractions (F3, F4, F7, F12, F13, F17, F18 and F19) for 4 days; F17 and 18 were the most effective fractions in reducing intracellular lipid accumulation (by 25.6% and 23.1%, respectively). EC50 of F17 and F18 (14 µg/mL and 17 µg/mL, respectively) were used to evaluate their anti adipogenic effect. After 10 days of inducing differentiation in the absence or presence of the extracts at the EC50 of F17 and F18, lipid accumulation, the concentration of interleukin 6 (IL-6) were measured in the culture medium; the presence of PPAR-γ, AKT, and p-AKT was also determined. In differentiated adipocytes (C2), F17 maintained intracellular lipid concentration at levels comparable to metformin, while decreasing PPAR-γ and increasing p-AKT presence; it also prevented IL-6 expression. F17 consists of alanine, valine, phenylalanine, and proline. On the other hand, F18 reduced intracellular lipid concentrations, prevented the increase of PPAR-γ and p-AKT, and maintained IL-6 expression at similar levels as metformin. F18 is mainly constituted by alanine, valine, proline, and sucrose. In conclusion, M. parviflora fractions (F17 and F18) control the process of adipogenesis, lipogenesis, and cellular dysfunction.
Asunto(s)
Células 3T3-L1 , Adipocitos , Adipogénesis , PPAR gamma , Extractos Vegetales , Animales , Ratones , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/citología , Adipogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , PPAR gamma/metabolismo , Interleucina-6/metabolismo , Diferenciación Celular/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
In this study, we undertook an extensive investigation to determine how CypB PPIase activity affects preadipocyte differentiation and lipid metabolism. Our findings revealed that inhibition of CypB's PPIase activity suppressed the expression of crucial proteins involved in adipocyte differentiation and induced changes in proteins regulating the cell cycle. Furthermore, we clarified the impact of CypB's PPIase activity on lipid metabolism via the AKT/mTOR signaling pathway. Additionally, we demonstrated the involvement of CypB's PPIase activity in lipid metabolism through the XBP1s pathway. These discoveries offer invaluable insights for devising innovative therapeutic strategies aimed at treating and averting obesity and its related health complications. Targeting CypB's PPIase activity may emerge as a promising avenue for addressing obesity-related conditions. Furthermore, our research opens up opportunities for creating new therapeutic strategies by enhancing our comprehension of the processes involved in cellular endoplasmic reticulum stress.
Asunto(s)
Células 3T3-L1 , Adipocitos , Diferenciación Celular , Metabolismo de los Lípidos , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Proteína 1 de Unión a la X-Box , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adipocitos/metabolismo , Adipogénesis , Estrés del Retículo Endoplásmico/fisiologíaRESUMEN
Sargassum horneri (S. horneri), a brown seaweed excessively proliferating along Asian coastlines, are damaging marine ecosystems. Thus, this study aimed to enhance nutritional value of S. horneri through lactic acid bacteria fermentation to increase S. horneri utilization as a functional food supplement, and consequently resolve coastal S. horneri accumulation. S. horneri supplemented fermentation was most effective with Lactiplantibacillus pentosus SH803, thus this product (F-SHWE) was used for further in vitro studies. F-SHWE normalized expressions of oxidative stress related genes NF-κB, p53, BAX, cytochrome C, caspase 9, and caspase 3, while non-fermented S. horneri (SHWE) did not, in a H2O2-induced HT-29 cell model. Moreover, in an LPS-induced HT-29 cell model, F-SHWE repaired expressions of inflammation marker genes ZO1, IL1ß, IFNγ more effectively than SHWE. For further functional assessment, F-SHWE was also treated in 3T3-L1 adipocytes. As a result, F-SHWE decreased lipid accumulation, along with gene expression of adipogenesis markers PPARγ, C/EBPα, C/EBPß, aP2, and Lpl; lipogenesis markers Lep, Akt, SREBP1, Acc, Fas; inflammation markers IFN-γ and NF-κB. Notably, gene expression of C/EBPß, IFN-γ and NF-κB were suppressed only by F-SHWE, suggesting the enhancing effect of fermentation on obesity-related properties. Compositional analysis attributed the protective effects of F-SHWE to acetate, an organic acid significantly higher in F-SHWE than SHWE. Therefore, F-SHWE is a novel potential anti-obesity agent, providing a strategy to reduce excess S. horneri populations along marine ecosystems.
Asunto(s)
Células 3T3-L1 , Adipocitos , Fermentación , Inflamación , Estrés Oxidativo , Sargassum , Sargassum/química , Ratones , Animales , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Humanos , Inflamación/metabolismo , Lactobacillus pentosus/metabolismo , Células HT29 , Adipogénesis/efectos de los fármacosRESUMEN
The study evaluated the effects of Arthrospira maxima phycobiliproteins (PBPs), rosiglitazone (RSG), and 17ß-estradiol (E) on the differentiation process of 3T3-L1 cells and on their regulation of lipogenic and inflammatory gene expression at different stages of the process. The results showed that phycobiliproteins promoted cell proliferation after 24 h of treatment. Furthermore, for all three treatments, the regulation of the highest number of markers occurred on days 6 and 12 of differentiation, regardless of when the treatment was applied. Phycobiliproteins reduced lipid droplet accumulation on days 3, 6, 10, and 13 of the adipogenic process, while rosiglitazone showed no differences compared to the control. On day 6, both phycobiliproteins and rosiglitazone positively regulated Acc1 mRNA. Meanwhile, all three treatments negatively regulated Pparγ and C/ebpα. Phycobiliproteins and estradiol also negatively regulated Ucp1 and Glut4 mRNAs. Rosiglitazone and estradiol, on the other hand, negatively regulated Ppara and Il-6 mRNAs. By day 12, phycobiliproteins and rosiglitazone upregulated Pparγ mRNA and negatively regulated Tnfα and Il-1ß. Additionally, phycobiliproteins and estradiol positively regulated Il-6 and negatively regulated Ppara, Ucp2, Acc1, and Glut4. Rosiglitazone and estradiol upregulate C/ebpα and Ucp1 mRNAs. The regulation exerted by phycobiliproteins on the mRNA expression of the studied markers was dependent on the phase of cell differentiation. The results of this study highlight that phycobiliproteins have an anti-adipogenic and anti-inflammatory effect by reducing the expression of adipogenic, lipogenic, and inflammatory genes in 3T3-L1 cells at different stages of the differentiation process.
Asunto(s)
Células 3T3-L1 , Adipocitos , Adipogénesis , Diferenciación Celular , Estradiol , Ficobiliproteínas , Rosiglitazona , Animales , Ratones , Estradiol/farmacología , Rosiglitazona/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/citología , Diferenciación Celular/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Ficobiliproteínas/farmacología , Ficobiliproteínas/metabolismo , Ficobiliproteínas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , PPAR gamma/metabolismo , PPAR gamma/genética , Proliferación Celular/efectos de los fármacos , Inflamación/metabolismo , Inflamación/genética , SpirulinaRESUMEN
Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study evaluated the effect of silybin, the main bioactive component of silymarin, which has anti-inflammatory properties, on TNFα levels and its impact on glucose uptake in the adipocyte cell line 3T3-L1 challenged with two different inflammatory stimuli, TNFα or lipopolysaccharide (LPS). Silybin's pre-treatment effect was evaluated in adipocytes pre-incubated with silybin (30 or 80 µM) before challenging with the inflammatory stimuli (TNFα or LPS). For the post-treatment effect, the adipocytes were first challenged with the inflammatory stimuli and then post-treated with silybin. After treatments, TNFα production, glucose uptake, and GLUT4 protein expression were determined. Both inflammatory stimuli increased TNFα secretion, diminished GLUT4 expression, and significantly decreased glucose uptake. Silybin 30 µM only reduced TNFα secretion after the LPS challenge. Silybin 80 µM as post-treatment or pre-treatment decreased TNFα levels, improving glucose uptake. However, glucose uptake enhancement induced by silybin did not depend on GLUT4 protein expression. These results show that silybin importantly reduced TNFα levels and upregulates glucose uptake, independently of GLUT4 protein expression.
Asunto(s)
Células 3T3-L1 , Adipocitos , Glucosa , Lipopolisacáridos , Silibina , Factor de Necrosis Tumoral alfa , Animales , Silibina/farmacología , Ratones , Factor de Necrosis Tumoral alfa/metabolismo , Glucosa/metabolismo , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Lipopolisacáridos/farmacología , Transportador de Glucosa de Tipo 4/metabolismo , Silimarina/farmacologíaRESUMEN
This study aimed to investigate the therapeutic potential of Citrullus mucosospermus extract (CME) in counteracting adipogenesis and its associated metabolic disturbances in murine models. In vitro experiments utilizing 3T3-L1 preadipocytes revealed that CME potently inhibited adipocyte differentiation, as evidenced by a dose-dependent reduction in lipid droplet formation. Remarkably, CME also attenuated glucose uptake and intracellular triglyceride accumulation in fully differentiated adipocytes, suggesting its ability to modulate metabolic pathways in mature adipose cells. Translating these findings to an in vivo setting, we evaluated the effects of CME in C57BL/6N mice fed a high-fat diet (HFD) for 10 weeks. CME administration, concomitantly with the HFD, resulted in a significant attenuation of body weight gain compared to the HFD control group. Furthermore, CME treatment led to substantial reductions in liver weight, total fat mass, and deposits of visceral and retroperitoneal adipose tissue, underscoring its targeted impact on adipose expansion. Histological analyses revealed the remarkable effects of CME on hepatic steatosis. While the HFD group exhibited severe lipid accumulation within liver lobules, CME dose-dependently mitigated this pathology, with the highest dose virtually abolishing hepatic fat deposition. An examination of adipose tissue revealed a progressive reduction in adipocyte hypertrophy upon CME treatment, culminating in a near-normalization of adipocyte morphology at the highest dose. Notably, CME exhibited potent anti-inflammatory properties, significantly attenuating the upregulation of pro-inflammatory cytokines' mRNA levels (TNF-α, IL-1ß and IL-6) in the livers of HFD-fed mice. This suggests a potential mechanism through which CME may exert protective effects against inflammation associated with obesity and fatty liver disease.
Asunto(s)
Células 3T3-L1 , Adipogénesis , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Extractos Vegetales , Aumento de Peso , Animales , Dieta Alta en Grasa/efectos adversos , Extractos Vegetales/farmacología , Ratones , Aumento de Peso/efectos de los fármacos , Masculino , Adipogénesis/efectos de los fármacos , Adipocitos/efectos de los fármacos , Obesidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismoRESUMEN
Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.
Asunto(s)
Vesículas Extracelulares , Insulina , MicroARNs , Animales , Humanos , Ratones , Células 3T3-L1 , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/genética , Insulina/metabolismo , Resistencia a la Insulina , MicroARNs/metabolismo , MicroARNs/genética , Obesidad/metabolismo , Obesidad/genética , Fosforilación , Transducción de SeñalRESUMEN
Eighteen compounds including eleven previously undescribed diterpenes were isolated from the leaves of Croton mangelong. The structures were determined by HRESIMS, IR, NMR, X-ray diffraction and ECD spectroscopic analysis. All isolates were assayed for their anti-hyperglycemic activities in insulin resistance (IR) 3T3-L1 adipocytes, and compound 4 was tested for its anti-diabetic activity in vivo. Results suggested compound 4 could effectively reduce blood glucose level in diabetic SD rats in a dose of 30 mg/kg.
Asunto(s)
Células 3T3-L1 , Croton , Diterpenos , Hipoglucemiantes , Hojas de la Planta , Ratas Sprague-Dawley , Hojas de la Planta/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Croton/química , Animales , Ratones , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Ratas , Estructura Molecular , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Resistencia a la Insulina , Glucemia/efectos de los fármacos , Adipocitos/efectos de los fármacosRESUMEN
Obesity has emerged as a significant global health burden, exacerbated by serious side effects associated with existing anti-obesity medications. Celastrol (CLT) holds promise for weight loss but encounters challenges related to poor solubility and systemic toxicity. Here, we present chondroitin sulfate (CS)-derived micelles engineered for adipocyte-specific targeting, aiming to enhance the therapeutic potential of CLT while minimizing its systemic toxicity. To further enhance adipocyte affinity, we introduced a biguanide moiety into a micellar vehicle. CS is sequentially modified with hydrophilic metformin and hydrophobic 4-aminophenylboronic acid pinacol ester (PBE), resulting in the self-assembly of CLT-encapsulated micelles (MET-CS-PBE@CLT). This innovative design imparts amphiphilicity via the PBE moieties while ensuring the outward exposure of hydrophilic metformin moieties, facilitating active interactions with adipocytes. In vitro studies confirmed the enhanced uptake of MET-CS-PBE@CLT micelles by adipocytes, while in vivo studies demonstrated increased distribution within adipose tissues. In a diet-induced obese mouse model, MET-CS-PBE@CLT exhibited remarkable efficacy in weight loss without affecting food intake. This pioneering strategy offers a promising, low-risk, and highly effective solution to address the global obesity epidemic.
Asunto(s)
Adipocitos , Micelas , Obesidad , Triterpenos Pentacíclicos , Animales , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacología , Ratones , Adipocitos/efectos de los fármacos , Obesidad/tratamiento farmacológico , Biguanidas/química , Biguanidas/farmacología , Biguanidas/uso terapéutico , Ratones Endogámicos C57BL , Células 3T3-L1 , Sistemas de Liberación de Medicamentos , Masculino , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/química , Tamaño de la Partícula , Sulfatos de Condroitina/química , Portadores de Fármacos/química , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
BACKGROUND: Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. METHODS: We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches. RESULTS: Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner. CONCLUSIONS: SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.
Asunto(s)
Células 3T3-L1 , Adipocitos , Adipogénesis , Epigénesis Genética , Sirtuinas , Sirtuinas/genética , Sirtuinas/metabolismo , Ratones , Adipocitos/metabolismo , Animales , Epigénesis Genética/genética , Adipogénesis/genética , Humanos , Mutación , Obesidad/genética , Obesidad/metabolismo , Procesamiento Proteico-Postraduccional/genética , Histonas/metabolismo , Histonas/genéticaRESUMEN
Obesity is a low-grade chronic inflammation induced by the pathological expansion of adipocytes which allows the development of obesity-associated metabolic diseases like type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease (NAFLD). However, mechanisms regulating adipocyte inflammation remain poorly understood. Here, we observed that TRIM8 was upregulated in adipocyte inflammation and insulin resistance while DUSP14 was downregulated. TRIM8 deficiency and DUSP14 over-expression decreased the level of inflammatory cytokines, increased glucose uptake content, and improved insulin signalling transduction compared to LPS treatment alone. Conversely, silencing DUSP14 increased the expression of inflammatory cytokines. It decreased the glucose uptake content and the phosphorylation level of proteins involved in insulin signalling, further impairing insulin signalling and aggravating insulin resistance. Furthermore, The decreased level of inflammatory cytokines, increased glucose uptake, and improved insulin signalling transduction caused by TRIM8 deficiency were reversed by down-regulated DUSP14. Collectively, our findings revealed that TRIM8 can regulate adipocyte inflammation and insulin resistance by regulating the MAPKs pathway which is dependent on DUSP14.
Asunto(s)
Adipocitos , Fosfatasas de Especificidad Dual , Inflamación , Resistencia a la Insulina , Animales , Adipocitos/metabolismo , Ratones , Inflamación/metabolismo , Fosfatasas de Especificidad Dual/metabolismo , Fosfatasas de Especificidad Dual/genética , Sistema de Señalización de MAP Quinasas , Células 3T3-L1 , Transducción de Señal , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: With the changes in lifestyle and diet structure, the incidence of obesity has increased year by year, and obesity is one of the inducements of many chronic metabolic diseases. Epigallocatechin gallate (EGCG), which is the most abundant component of tea polyphenols, has been used for many years to improve obesity and its complications. Though it has been reported that EGCG can improve obesity through many molecular mechanisms, EGCG may have many mechanisms yet to be explored. In this study, we explored other possible mechanisms through molecular docking and in vitro experiments. METHODS: AutoDock Vina was selected for conducting the molecular docking analysis to elucidate the interaction between EGCG and Notch1, while molecular dynamics simulations were employed to validate this interaction. Then, the new regulation mechanism of EGCG on obesity was verified with in vitro experiments, including a Western blot experiment, immunofluorescence experiment, oil red O staining, and other experiments in 3T3-L1 adipocytes. RESULTS: The molecular docking results showed that EGCG could bind to Notch1 protein through hydrogen bonding. In vitro cell experiments demonstrated that EGCG can significantly reduce the sizes of lipid droplets of 3T3-L1 adipocytes and promote UCP-1 expression by inhibiting the expression of Notch1 in 3T3-L1 adipocytes, thus promoting mitochondrial biogenesis. CONCLUSIONS: In this study, molecular docking and in vitro cell experiments were used to explore the possible mechanism of EGCG to improve obesity by inhibiting Notch1.
Asunto(s)
Adipogénesis , Catequina , Simulación del Acoplamiento Molecular , Receptor Notch1 , Animales , Ratones , Células 3T3-L1 , Adipogénesis/efectos de los fármacos , Catequina/análogos & derivados , Catequina/farmacología , Catequina/química , Regulación de la Expresión Génica/efectos de los fármacos , Simulación de Dinámica Molecular , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Receptor Notch1/metabolismo , Proteína Desacopladora 1/metabolismoRESUMEN
Corn peptide (CP) is a short, naturally occurring, and physiologically active peptide generated from corn-protease-catalyzed hydrolysis. CP plays a role in preventing obesity-related disorders, but its impact on reducing inflammation is unknown. Hence, this study examined the possible protective effects of corn peptide powder (CPP) against the harmful effects of lipopolysaccharide (LPS), with a particular emphasis on reducing oxidative damage and inflammation in adipocytes. Hence, mature 3T3-L1 adipocytes underwent exposure to 10 ng/mL LPS, with or without CPP (10 and 20 µg/mL). LPS stimulation increased reactive oxygen species and superoxide anion generation. However, this effect was reduced in a dose-dependent manner by pretreatment with CPP. CPP treatment elevated the mRNA expressions of the antioxidant enzymes manganese superoxide dismutase (mnSOD) and glutathione peroxidase 1 (Gpx1) while reducing the mRNA expressions of the cytosolic reactive oxygen species indicators p40 and p67 (NADPH oxidase 2). In addition, CPP inhibited the monocyte chemoattractant protein-1, tumor necrosis factor-alpha, Toll-like receptor 4, and nuclear factor kappa B mRNA expressions induced by LPS. These findings demonstrate that CPP may ameliorate adipocyte dysfunction by suppressing oxidative damage and inflammatory responses through a new mechanism known as Toll-like receptor 4/nuclear factor kappa B-mediated signaling.
Asunto(s)
Células 3T3-L1 , Adipocitos , Inflamación , Lipopolisacáridos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Superóxido Dismutasa , Receptor Toll-Like 4 , Zea mays , Animales , Ratones , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Zea mays/química , Especies Reactivas de Oxígeno/metabolismo , Inflamación/metabolismo , Receptor Toll-Like 4/metabolismo , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Polvos , Péptidos/farmacología , Glutatión Peroxidasa/metabolismo , FN-kappa B/metabolismo , Antioxidantes/farmacología , Glutatión Peroxidasa GPX1 , Transducción de Señal/efectos de los fármacos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Factor de Necrosis Tumoral alfa/metabolismo , Antiinflamatorios/farmacologíaRESUMEN
Obesity is increasingly prevalent worldwide and is linked to metabolic diseases, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), due to excessive free fatty acids (FFAs). Although lifestyle changes are effective, they often prove to be insufficient as initial treatments for obesity. Additionally, while surgical and pharmacological interventions are available, they are not entirely safe or effective. Recently, interest has grown in utilizing food waste and plant-derived phenolic compounds for their health benefits, presenting a promising avenue for managing obesity and its related disorders. Indeed, many studies have examined the potential inhibitory effects of the natural extract on adipocyte differentiation and lipid accumulation. This study focused on the evaluation of the effects of standardized extracts obtained from red oranges and olive leaf waste on 3T3-L1 murine pre-adipocyte and adipocyte functionality. Red orange extract (ROE) and olive leaf extract (OLE), alone and in combination, were tested to assess their anti-obesity and anti-inflammatory effects, as well as their potential therapeutic benefits. Three in vitro models were established to investigate the effects of the extracts on (I) adipocyte differentiation; (II) mature and hypertrophic adipocytes challenged with palmitic acid (PA) and erastin (ER), respectively; and (III) erastin-induced cytotoxicity on pre-adipocytes.
Asunto(s)
Células 3T3-L1 , Adipocitos , Olea , Extractos Vegetales , Hojas de la Planta , Animales , Olea/química , Adipocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Ratones , Hojas de la Planta/química , Diferenciación Celular/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Adipogénesis/efectos de los fármacos , Obesidad/tratamiento farmacológicoRESUMEN
Introduction: Quercetin (QUER), a flavonoid abundant in fruits and vegetables, is emerging as a promising alternative therapeutic agent for obesity treatment due to its antioxidant and anti-adipogenic properties. However, the clinical application of QUER is limited by its poor solubility, low bioavailability, and potential toxicity at high doses. To address these challenges, this study aims to develop an advanced drug delivery system using fluorescent mesoporous silica nanoparticles (FMSNs) coated with polydopamine (PDA) for the efficient and sustained delivery of QUER to inhibit adipogenesis. Methods: The research included the synthesis of PDA-coated FMSNs for encapsulation of QUER, characterization of their mesoporous structures, and systematic investigation of the release behavior of QUER. The DPPH assay was used to evaluate the sustained radical scavenging potential. Concentration-dependent effects on 3T3-L1 cell proliferation, cellular uptake and adipogenesis inhibition were investigated. Results: PDA-coated FMSNs exhibited well-aligned mesoporous structures. The DPPH assay confirmed the sustained radical scavenging potential, with FMSNs-QUER@PDA showing 53.92 ± 3.48% inhibition at 72 h, which was higher than FMSNs-QUER (44.66 ± 0.57%) and free QUER (43.37 ± 5.04%). Concentration-dependent effects on 3T3-L1 cells highlighted the enhanced efficacy of PDA-coated FMSNs for cellular uptake, with a 1.5-fold increase compared to uncoated FMSNs. Adipogenesis inhibition was also improved, with relative lipid accumulation of 44.6 ± 4.6%, 37.3 ± 4.6%, and 36.5 ± 7.3% at 2.5, 5, and 10 µM QUER concentrations, respectively. Conclusion: The study successfully developed a tailored drug delivery system, emphasizing sustained QUER release and enhanced therapeutic effects. FMSNs, especially when coated with PDA, exhibit promising properties for efficient QUER delivery, providing a comprehensive approach that integrates advanced drug delivery technology and therapeutic efficacy.
Asunto(s)
Células 3T3-L1 , Adipogénesis , Preparaciones de Acción Retardada , Portadores de Fármacos , Indoles , Nanopartículas , Polímeros , Quercetina , Dióxido de Silicio , Quercetina/química , Quercetina/farmacología , Quercetina/farmacocinética , Quercetina/administración & dosificación , Animales , Ratones , Adipogénesis/efectos de los fármacos , Dióxido de Silicio/química , Indoles/química , Indoles/farmacología , Indoles/farmacocinética , Indoles/administración & dosificación , Nanopartículas/química , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos/química , Polímeros/química , Porosidad , Liberación de Fármacos , Proliferación Celular/efectos de los fármacos , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/farmacocinética , Antioxidantes/administración & dosificaciónRESUMEN
Obesity and type 2 diabetes are prevalent metabolic diseases that have significant links to several chronic diseases, including cancer, diabetes, hypertension, and cardiovascular disease. Muscadine grape extracts have shown the potential to reduce adiposity and improve insulin sensitivity and glucose control. Thus, this study was designed to determine the potential of muscadine grape berries extract (Pineapple and Southern Home) for its antiobesity properties in 3T3-L1 cells as a model for obesity research. The current study's data indicated the total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydraziyl (DPPH) activity were higher in cultivar (CV) Southern Home, meanwhile, elevated the total flavonoid content (TFC) in Pineapple. Both extracts were safe across the tested range (0-5 mg/mL). A noticeable reduction in lipid accumulation was also found in extract-treated cells. In preadipocytes and adipocytes, the tested extracts showed significant alterations in various genes involved in glucose homeostasis and obesity. The most remarkable findings of the current study are the upregulation of two genes, Cntfr (+712.715-fold) and Hrh1 (+270.11-fold) in CV Pineapple extract-treated adipocytes 3T3-L1 and the high fold increase in Ramp3 induced by both Pineapple and Southern Home in pre-adipose cells. Furthermore, the tested extracts showed a potential to alter the mRNA of various genes, including Zfp91, B2m, Nr3c1, Insr, Atrn, Il6ra, Hsp90ab1, Sort1, and Npy1r. In conclusion, the data generated from the current study suggested that the two extracts under investigation are considered potential candidates for controlling insulin levels and managing obesity.
Asunto(s)
Células 3T3-L1 , Adipocitos , Fármacos Antiobesidad , Obesidad , Extractos Vegetales , Vitis , Animales , Ratones , Extractos Vegetales/farmacología , Fármacos Antiobesidad/farmacología , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/genética , Vitis/química , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Diferenciación Celular/efectos de los fármacos , Frutas/químicaRESUMEN
Obesity is a major health issue that contributes significantly to increased mortality and morbidity worldwide. Obesity is caused by uncontrolled adipogenesis and lipogenesis, leading to several metabolism-associated problems. Pancreatic lipase, an enzyme that breaks down dietary lipids, is a prominent target for obesity. Orlistat, a known inhibitor of pancreatic lipase, is commonly employed for the management of obesity. However, its side effects, such as diarrhoea, nausea and bladder pain, urge to look out for safer alternatives. Morin is a pentahydroxyflavone, exerts a broad spectrum of pharmacological effects including antioxidant, anti-inflammatory, lipid lowering, anti-diabetic, anti-fibrotic, anti-cancer, etc. This study investigated the effect of morin on pancreatic lipase activity, in vitro and in vivo adipogenesis. Molecular docking and simulation studies showed morin to have a higher binding affinity towards pancreatic lipase compared with orlistat, which also inhibited its activity in vitro. Morin also reduced lipid droplet accretion and downregulated the expression of adipogenic and lipogenic genes. The acute oral toxicity of morin was determined in C57BL/6 mice, where morin did not show toxicity up to 2000 mg/kg body weight dose. Oral administration of morin to high fat diet fed mice reduced body weight, glucose and insulin levels. Also, the histopathological examination revealed reduction in adipocyte size and decreased mRNA expression of adipogenesis markers in white adipose tissue of morin administered group compared to high fat diet group. Overall, the results suggested morin inhibited pancreatic lipase activity, adipogenesis and further studies are warranted to explore its therapeutic potential for obesity.
Asunto(s)
Adipogénesis , Flavonoides , Lipasa , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Animales , Adipogénesis/efectos de los fármacos , Flavonoides/farmacología , Ratones , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Masculino , Células 3T3-L1 , Dieta Alta en Grasa/efectos adversos , Páncreas/efectos de los fármacos , Páncreas/patología , Fármacos Antiobesidad/farmacología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Humanos , Orlistat/farmacología , FlavonasRESUMEN
Tetrabromobisphenol A (TBBPA), a widely-used brominated flame retardant, has been revealed to exert endocrine disrupting effects and induce adipogenesis. Given the high structural similarities of TBBPA analogues and their increasing exposure risks, their effects on lipid metabolism are necessary to be explored. Herein, 9 representative TBBPA analogues were screened for their interference on 3T3-L1 preadipocyte adipogenesis, differentiation of C3H10T1/2 mesenchymal stem cells (MSCs) to brown adipocytes, and lipid accumulation of HepG2 cells. TBBPA bis(2-hydroxyethyl ether) (TBBPA-BHEE), TBBPA mono(2-hydroxyethyl ether) (TBBPA-MHEE), TBBPA bis(glycidyl ether) (TBBPA-BGE), and TBBPA mono(glycidyl ether) (TBBPA-MGE) were found to induce adipogenesis in 3T3-L1 preadipocytes to different extends, as evidenced by the upregulated intracellular lipid generation and expressions of adipogenesis-related biomarkers. TBBPA-BHEE exhibited a stronger obesogenic effect than did TBBPA. In contrast, the test chemicals had a weak impact on the differentiation process of C3H10T1/2 MSCs to brown adipocytes. As for hepatic lipid formation test, only TBBPA mono(allyl ether) (TBBPA-MAE) was found to significantly promote triglyceride (TG) accumulation in HepG2 cells, and the effective exposure concentration of the chemical under oleic acid (OA) co-exposure was lower than that without OA co-exposure. Collectively, TBBPA analogues may perturb lipid metabolism in multiple tissues, which varies with the test tissues. The findings highlight the potential health risks of this kind of emerging chemicals in inducing obesity, non-alcoholic fatty liver disease (NAFLD) and other lipid metabolism disorders, especially under the conditions in conjunction with high-fat diets.
Asunto(s)
Células 3T3-L1 , Adipogénesis , Retardadores de Llama , Metabolismo de los Lípidos , Bifenilos Polibrominados , Bifenilos Polibrominados/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Ratones , Adipogénesis/efectos de los fármacos , Humanos , Retardadores de Llama/toxicidad , Células Hep G2 , Diferenciación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Adipocitos/efectos de los fármacos , Adipocitos/metabolismoRESUMEN
Glinus oppositifolius L., a member of the Molluginaceae family, has a long-standing history of utilization as both a vegetable and a medicinal agent across numerous countries. This plant possesses a diverse range of pharmacological activities and attracts scientific interest in studying its chemical profile. The present phytochemical investigation of the plant resulted in the isolation of eleven new triterpenoid saponins, accompanied by three known compounds. Their structures were elucidated by intensive spectroscopic analysis, DFT calculations, and comparison with previously reported data. The isolates were evaluated for their anti-adipogenic effect and cytotoxicity against human cancer cell lines, namely, colorectal carcinoma HCT116, hepatoblastoma cell HepG2, breast cancer cell MDA-MB-231, and human lung adenocarcinoma cell A549. Compounds 5, 7, and 13 exhibited a potent inhibitory effect against the differentiation of preadipocyte 3T3-L1. In addition, compound 13 displayed inhibitory effects against the growth of A549 cancer cells.