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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.
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Células 3T3-L1 , Adipócitos , Transportador de Glucose Tipo 4 , Produtos Finais de Glicação Avançada , Fator de Transcrição RelA , Animais , Camundongos , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Transportador de Glucose Tipo 4/genética , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Regiões Promotoras Genéticas , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genéticaRESUMO
Obesity is a major public health issue that is associated with metabolic diseases including diabetes mellitus type 2 and metabolic syndrome. This pathology leads to detrimental cardiovascular health and secondary effects, such as lipotoxicity, inflammation, and oxidative stress. Recently, extracellular vesicles (EVs) have been highlighted as novel players participating in human physiology and pathophysiology. In obesity, adipose tissue is related to the active shedding of adipocyte-derived extracellular vesicles (AdEVs). The current review explores and highlights the role of AdEVs and their cargo in obesity and metabolic syndrome. AdEVs are proposed to play an important role in obesity and its comorbidities. AdEVs are biological nanoparticles mainly shed by visceral and subcutaneous adipose tissue, acting in physiological and pathophysiological conditions, and also carrying different cargo biomolecules, such as RNA, microRNA (miRNA), proteins, and lipids, among others. RNA and miRNA have local and systemic effects affecting gene expression in target cell types via paracrine and endocrine actions. State of the art analyses identified some miRNAs, such as miR-222, miR-23b, miR-4429, miR-148b, and miR-4269, that could potentially affect cell pathways involved in obesity-related comorbidities, such as chronic inflammation and fibrosis. Similarly, AdEVs-proteins (RBP4, perilipin-A, FABP, mimecan, TGFBI) and AdEVs-lipids (sphingolipids) have been linked to the obesity pathophysiology. The current knowledge about AdEVs along with further research would support and reveal novel pathways, potential biomarkers, and therapeutic options in obesity.
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Therapies to prevent osteoporosis are relevant since it is one of the most common non-communicable human diseases in the world and the most prevalent bone disorder in adults. Since jaboticaba peel extract (JPE) added to the culture medium enhanced the osteogenic potential of mesenchymal stem cells (MSCs) derived from osteoporotic rats, we hypothesized that JPE prevents the development of ovariectomy-induced osteoporosis. Ovariectomized rats were treated with either JPE (30 mg/kg of body weight) or its vehicle for 90 days, starting 7 days after the ovariectomy. Then, the femurs were subjected to microcomputed tomography and histological analyses, and the osteoblast and adipocyte differentiation of MSCs was evaluated. JPE attenuated ovariectomy-induced bone loss, as evidenced by higher bone volume/total volume and trabecular number, along with lower trabecular separation and bone marrow adiposity. These protective effects of JPE on bone tissue are due to its ability to prevent the imbalance between osteoblast and adipocyte differentiation of MSCs, since, compared with MSCs derived from ovariectomized rats treated with vehicle, MSCs treated with JPE exhibited higher gene and protein expression of osteogenic markers and extracellular matrix mineralization, as well as lower gene expression of adipogenic markers. These data highlight the potential therapeutic use of JPE to prevent osteoporosis.
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OBJECTIVE AND DESIGN: Kinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis. MATERIAL OR SUBJECTS: Kinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure. METHODS: Metabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice. RESULTS: B1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT. CONCLUSION: B1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.
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Tecido Adiposo Marrom , Tecido Adiposo Branco , Dioxóis , Camundongos Knockout , Receptor B1 da Bradicinina , Termogênese , Animais , Masculino , Camundongos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Temperatura Baixa , Dioxóis/farmacologia , Metabolismo Energético/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Termogênese/efeitos dos fármacos , Tiazóis/farmacologia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Introduction: Obesity is a complex disease that predisposes individuals to cardiometabolic alterations. It leads to adipose tissue (AT) dysfunction, which triggers insulin resistance (IR). This suggests that people with obesity develop local IR first and systemic IR later. AT secretes extracellular vesicles, which may be physiopathologically associated with the development of IR. Our aim was to evaluate the effect of a high-fat diet on different parameters of adiposity in a rat model of early-stage obesity and to determine if these parameters are associated with markers of systemic IR. In addition, we sought to explore the relationship between fasting blood measures of IR (Triglycerides/High Density Lipoprotein-cholesterol [TAG/HDL-c] and Triglycerides-Glucose Index [TyG Index]) with the size of adipocyte-derived extracellular vesicles (adEV). Methods: We used a model of diet-induced obesity for ten weeks in Wistar rats exposed to a high-fat diet. Final weight gain was analyzed by Dual X-ray absorptiometry. Visceral obesity was measured as epididymal AT weight. IR was evaluated with fasting TyG Index & TAG/HDL-c, and adEV were isolated from mature adipocytes on ceiling culture. Results: In the high-fat diet group, glucose and triglyceride blood concentrations were higher in comparison to the control group (Log2FC, 0.5 and 1.5 times higher, respectively). The values for TyG Index and adEV size were different between the control animals and the high-fat diet group. Multiple linear regression analyses showed that adEV size can be significantly associated with the TyG Index value, when controlling for epididymal AT weight. Conclusion: Our results show that lipid and glucose metabolism, as well as the size and zeta potential of adEV are already altered in early-stage obesity and that adEV size can be significantly associated with liver and systemic IR, estimated by TyG Index.
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BACKGROUND: Aging and obesity are associated with insulin resistance (IR) and low-grade inflammation. Molecularly, IR is characterized by a reduction in glucose uptake and insulin signaling (IRS-1/Akt/AS160 pathway), while inflammation may result from upregulated NF-κB pathway after low Tyr-IκBα phosphorylation. Upregulated phosphatase activity of PTP1B is associated with impaired insulin signaling and increased inflammation. Plasma levels of palmitic acid (PA) are elevated in obesity, triggering inflammation and disruption of insulin signaling. Traditional medicine in Northern Chile uses oral infusions of Lampaya medicinalis Phil. (Verbenaceae) to treat inflammatory conditions. Significant amounts of flavonoids are found in the hydroethanolic extract of Lampaya (HEL), which may account for its biological activity. The aim of this work was to study the effect of HEL and PA on insulin signaling and glucose uptake as well as inflammatory marker expression in human adipocytes. METHODS: We studied HEL effects on PA-induced impairment on insulin signaling, glucose uptake and inflammatory marker content in human SW872 adipocytes. HEL cytotoxicity was assessed in adipocytes at different concentrations (0.01 to 10 g/mL). Adipocytes were incubated or not with PA (0.4 mM, 24 h) with or without HEL (2 h pre-incubation), and then stimulated with insulin (10 min, 100 mM) or a vehicle. Phospho-IRS-1, phospho-Akt, phospho-AS160, phospho-NF-κB and phospho-IκBα, as well as protein levels of PTP1B, were assessed using Western blotting, and glucose uptake was evaluated using the 2-NBDG analogue. RESULTS: At the assessed HEL concentrations, no cytotoxic effects were observed. PA decreased insulin-stimulated phospho-Akt and glucose uptake, while co-treatment with HEL increased such markers. PA decreased phospho-IRS-1 and phospho-Tyr-IκBα. On the other hand, incubation with HEL+PA decreased phospho-AS160 and phospho-NF-κB compared with cells treated with PA alone. CONCLUSION: Our results suggest a beneficial effect of HEL by improving PA-induced impairment on molecular markers of insulin signaling, glucose uptake and inflammation in adipocytes. Further studies are necessary to elucidate whether lampaya may constitute a preventive strategy for people whose circulating PA levels contribute to IR and inflammation during aging and obesity.
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Rho-associated kinases (ROCKs) are crucial during the adipocyte differentiation process. KD025 (Belumosudil) is a newly developed inhibitor that selectively targets ROCK2. It has exhibited consistent efficacy in impeding adipogenesis across a spectrum of in vitro models of adipogenic differentiation. Given the novelty of this treatment, a comprehensive systematic review has not been conducted yet. This systematic review aims to fill this knowledge void by providing readers with an extensive examination of the rationale behind KD025 and its impacts on adipogenesis. Preclinical evidence was gathered owing to the absence of clinical trials. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the study's quality was assessed using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews. In various in vitro models, such as 3T3-L1 cells, human orbital fibroblasts, and human adipose-derived stem cells, KD025 demonstrated potent anti-adipogenic actions. At a molecular level, KD025 had significant effects, including decreasing fibronectin (Fn) expression, inhibiting ROCK2 and CK2 activity, suppressing lipid droplet formation, and reducing the expression of proadipogenic genes peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Additionally, KD025 resulted in the suppression of fatty acid-binding protein 4 (FABP4 or AP2) expression, a decrease in sterol regulatory element binding protein 1c (SREBP-1c) and Glut-4 expression. Emphasis must be placed on the fact that while KD025 shows potential in preclinical studies and experimental models, extensive research is crucial to assess its efficacy, safety, and potential therapeutic applications thoroughly and directly in human subjects.
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Although liposarcoma is the most prevalent soft tissue sarcoma in adults, head and neck liposarcomas are rare and account for less than 5% of all liposarcomas. The primary orbital location is even more exceptional, with fewer than 100 cases documented in the medical literature. Given the scarcity of cases of orbital liposarcoma and the limited familiarity of physicians and pathologists with this pathology, there is an increased risk of non-diagnosis or misdiagnosis, which may lead to inappropriate patient management. To address these challenges, we present a case of primary orbital myxoid liposarcoma and subsequently discuss the primary findings of this case based on the evidence documented in the medical literature. This comprehensive text is designed to serve as a valuable resource for healthcare professionals and pathologists, with the goal of promoting both clinical suspicion and accurate diagnosis and treatment of this rare condition in future cases.
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Lipossarcoma Mixoide , Neoplasias de Tecidos Moles , Adulto , Humanos , Lipossarcoma Mixoide/diagnóstico , Lipossarcoma Mixoide/cirurgia , Lipossarcoma Mixoide/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Pescoço/patologiaRESUMO
Obesity is defined as excessive fat accumulation that can be detrimental to health and currently affects a large part of the global population. Obesity arises from excessive energy intake along with a sedentary lifestyle and leads to adipocytes with aggravated hypertrophy. Strategies have been designed to prevent and treat obesity. Nutrigenomics may serve a role in prevention of obesity using bioactive compounds present in certain foods with anti-obesogenic effects. Ginger (Zingiber officinale Roscoe) contains gingerols, key bioactive compounds that inhibit hypertrophy and hyperplasia of adipocytes. The present study aimed to evaluate the antiadipogenic activity of 10-gingerol (10-G) in the 3T3-L1 cell line. Three study groups were formed: Negative (3T3-L1 preadipocytes) and positive control (mature 3T3-L1 adipocytes) and 10-G (3T3-L1 preadipocytes stimulated with 10-G during adipogenic differentiation). Cell viability and lipid content were evaluated by MTT assay and Oil Red O staining, respectively. mRNA expression of CCAAT enhancer-binding protein α (C/ebpα), peroxisome proliferator-activated receptor γ (Pparγ), mechanistic target of rapamycin complex (Mtor), sterol regulatory element binding transcription factor 1 (Srebf1), acetyl-coenzyme A carboxylase (Acaca), fatty acid binding protein 4 (Fabp4), and 18S rRNA (Rn18s), was quantified by quantitative PCR. The protein expression of C/EPBα was analyzed by western blot. In the 10-G group, lipid content was decreased by 28.83% (P<0.0001) compared with the positive control; notably, cell viability was not affected (P=0.336). The mRNA expression in the 10-G group was higher for C/ebpα (P<0.001) and lower for Acaca (P<0.001), Fabp4 (P<0.001), Mtor (P<0.0001) and Srebf1 (P<0.0001) compared with the positive control group, while gene expression of Pparγ did not present significant changes. The presence of 10-G notably decreased C/EBPα protein levels in 3T3-L1 adipocytes. In summary, the antiadipogenic effect of 10-G during the differentiation of 3T3-L1 cells into adipocytes may be explained by mRNA downregulation of adipogenic transcriptional factors and lipid metabolism-associated genes.
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Abstract Objectives: Observational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. Methods: Summary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. Results: After Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (OR = 0.870, 95% CI 0.765-0.990, p = 0.035; OR = 0.732, 95% CI 0.551-0.973, p = 0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. Conclusion: The study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. Level of evidence: This was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.
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OBJECTIVES: Observational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. METHODS: Summary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. RESULTS: After Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (ORâ¯=â¯0.870, 95% CI 0.765-0.990, pâ¯=â¯0.035; ORâ¯=â¯0.732, 95% CI 0.551-0.973, pâ¯=â¯0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. CONCLUSION: The study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. LEVEL OF EVIDENCE: This was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.
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Interleucina-6 , Rinite Alérgica , Humanos , Interleucina-6/genética , Análise da Randomização Mendeliana , Adipocinas/genética , Proteínas de Ligação a Ácido Graxo , Obesidade/genética , Rinite Alérgica/genética , LipídeosRESUMO
Obesity is linked to adipose tissue dysfunction, a dynamic endocrine organ. Two-dimensional cultures present technical hurdles hampering their ability to follow individual or cell groups for metabolic disease research. Three-dimensional type I collagen microgels with embedded adipocytes have not been thoroughly investigated to evaluate adipogenic maintenance as instrument for studying metabolic disorders. We aimed to develop a novel tunable Col-I microgel simulating the adipocyte microenvironment to maintain differentiated cells with only insulin as in vitro model for obesity research. Adipocytes were cultured and encapsulated in collagen microgels at different concentrations (2, 3 and 4 mg/mL). Collagen microgels at 3 and 4 mg/mL were more stable after 8 days of culture. However, cell viability and metabolic activity were maintained at 2 and 3 mg/mL, respectively. Cell morphology, lipid mobilization and adipogenic gene expression demonstrated the maintenance of adipocyte phenotype in an in vitro microenvironment. We demonstrated the adequate stability and biocompatibility of the collagen microgel at 3 mg/mL. Cell and molecular analysis confirmed that adipocyte phenotype is maintained over time in the absence of adipogenic factors. These findings will help better understand and open new avenues for research on adipocyte metabolism and obesity. Insight box In the context of adipose tissue dysfunction research, new struggles have arisen owing to the difficulty of cellular maintenance in 2D cultures. Herein, we sought a novel approach using a 3D type I collagen-based biomaterial to adipocyte culture with only insulin. This component was tailored as a microgel in different concentrations to support the growth and survival of adipocytes. We demonstrate that adipocyte phenotype is maintained and key adipogenesis regulators and markers are over time. The cumulative results unveil the practical advantage of this microgel platform as an in vitro model to study adipocyte dysfunction and obesity.
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Colágeno Tipo I , Microgéis , Humanos , Adipócitos , Colágeno , Insulina , ObesidadeRESUMO
The prevalence of obesity has increased rapidly worldwide. Obesity is characterized by excessive adipose tissue in the body, which is related to hyperplasia and hypertrophy in adipocytes. Ginger (Zingiber officinale Roscoe) is a medicinal plant that possesses an anti-obesogenic effect mostly attributed to gingerols, the most abundant bioactive compounds in ginger. The anti-adipogenic and lipolytic effects of these phenols have been shown when investigated individually. Therefore, the present study aimed to evaluate the lipolytic and anti-adipogenic activity of a mix of the main ginger phenols 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol and 10-shogaol on the 3T3-L1 cell line. A total of four study groups were designed: Negative control (3T3-L1 preadipocytes); positive control (mature 3T3-L1 adipocytes); phenols-pre (3T3-L1 cells stimulated with the phenols mix during adipogenic differentiation); and phenols-post (mature 3T3-L1 adipocytes stimulated with the phenols mix). MTT viability cell assay and Oil Red O staining were performed. Glycerol concentration supernatants were determined using the VITROS 350 Chemistry System. Expression of mRNA was measured using qPCR. The treatment with a 2 µg/ml ginger phenol dose reduced the lipid content by 45.52±7.8 and 35.95±0.76% in the phenols-pre and -post group, respectively, compared with that in the positive control group. The phenols-post group presented a higher glycerol concentration in the supernatant compared with that in the positive control and the phenols-pre groups. The mRNA expression levels of CCAAT/enhancer-binding protein alpha, peroxisome proliferator activated receptor-γ, fatty acid-binding protein 4 and fatty acid synthase were higher in the phenols-pre and lower in the phenols-post groups, compared with those in the positive control group. To the best of our knowledge, the current study demonstrated for the first time the anti-adipogenic and lipolytic effects of a mix of the main bioactive compounds found in ginger, and it also established the basis to use this mix of phenols in in vivo studies and clinical trials.
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We investigated whether excessive retroperitoneal adipose tissue (AT) expansion programmed by maternal obesity (MO) affects adipocyte size distribution and gene expression in relation to adipocyte proliferation and differentiation in male and female offspring (F1) from control (F1C) and obese (F1MO) mothers. Female Wistar rats (F0) ate a control or high-fat diet from weaning through pregnancy and lactation. F1 were weaned onto a control diet and euthanized at 110 postnatal days. Fat depots were weighed to estimate the total AT. Serum glucose, triglyceride, leptin, insulin, and the insulin resistance index (HOMA-IR) were determined. Adipocyte size and adipogenic gene expression were examined in retroperitoneal fat. Body weight, retroperitoneal AT and adipogenesis differed between male and female F1Cs. Retroperitoneal AT, glucose, triglyceride, insulin, HOMA-IR and leptin were higher in male and female F1MO vs. F1C. Small adipocytes were reduced in F1MO females and absent in F1MO males; large adipocytes were increased in F1MO males and females vs. F1C. Wnt, PI3K-Akt, and insulin signaling pathways in F1MO males and Egr2 in F1MO females were downregulated vs. F1C. MO induced metabolic dysfunction in F1 through different sex dimorphism mechanisms, including the decreased expression of pro-adipogenic genes and reduced insulin signaling in males and lipid mobilization-related genes in females.
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Leptina , Obesidade Materna , Humanos , Ratos , Feminino , Animais , Masculino , Gravidez , Mães , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Wistar , Obesidade/etiologia , Obesidade/metabolismo , Obesidade Materna/metabolismo , Glucose/metabolismo , Insulina , Dieta Hiperlipídica/efeitos adversos , Triglicerídeos , Tecido Adiposo/metabolismoRESUMO
Adipose tissue inflammation in obesity has a deleterious impact on organs such as the liver, ultimately leading to their dysfunction. We have previously shown that activation of the calcium-sensing receptor (CaSR) in pre-adipocytes induces TNF-α and IL-1ß expression and secretion; however, it is unknown whether these factors promote hepatocyte alterations, particularly promoting cell senescence and/or mitochondrial dysfunction. We generated conditioned medium (CM) from the pre-adipocyte cell line SW872 treated with either vehicle (CMveh) or the CaSR activator cinacalcet 2 µM (CMcin), in the absence or presence of the CaSR inhibitor calhex 231 10 µM (CMcin+cal). HepG2 cells were cultured with these CM for 120 h and then assessed for cell senescence and mitochondrial dysfunction. CMcin-treated cells showed increased SA-ß-GAL staining, which was absent in TNF-α- and IL-1ß-depleted CM. Compared to CMveh, CMcin arrested cell cycle, increased IL-1ß and CCL2 mRNA, and induced p16 and p53 senescence markers, which was prevented by CMcin+cal. Crucial proteins for mitochondrial function, PGC-1α and OPA1, were decreased with CMcin treatment, concomitant with fragmentation of the mitochondrial network and decreased mitochondrial transmembrane potential. We conclude that pro-inflammatory cytokines TNF-α and IL-1ß secreted by SW872 cells after CaSR activation promote cell senescence and mitochondrial dysfunction, which is mediated by mitochondrial fragmentation in HepG2 cells and whose effects were reversed with Mdivi-1. This investigation provides new evidence about the deleterious CaSR-induced communication between pre-adipocytes and liver cells, incorporating the mechanisms involved in cellular senescence.
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Receptores de Detecção de Cálcio , Fator de Necrose Tumoral alfa , Humanos , Receptores de Detecção de Cálcio/metabolismo , Células Hep G2 , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Adipócitos/metabolismo , Senescência CelularRESUMO
Adipose tissue is an organ with metabolic and endocrine activity. White, brown and ectopic adipose tissues have different structure, location, and function. Adipose tissue regulates energy homeostasis, providing energy in nutrient-deficient conditions and storing it in high-supply conditions. To attend to the high demand for energy storage during obesity, the adipose tissue undergoes morphological, functional and molecular changes. Endoplasmic reticulum (ER) stress has been evidenced as a molecular hallmark of metabolic disorders. In this sense, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize adipose tissue dysfunction and metabolic alterations associated with obesity. In this review, we highlight the effects of TUDCA and receptors TGR5 and FXR on adipose tissue in the setting of obesity. TUDCA has been demonstrated to limit metabolic disturbs associated to obesity by inhibiting ER stress, inflammation, and apoptosis in adipocytes. The beneficial effect of TUDCA on perivascular adipose tissue (PVAT) function and adiponectin release may be related to cardiovascular protection in obesity, although more studies are needed to clarify the mechanisms. Therefore, TUDCA has emerged as a potential therapeutic strategy for obesity and comorbidities.
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Adiposidade , Ácido Tauroquenodesoxicólico , Humanos , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêutico , Ácido Tauroquenodesoxicólico/metabolismo , Tecido Adiposo/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismoRESUMO
Osteoarticular injury is the most common presentation of active brucellosis in humans. Osteoblasts and adipocytes originate from mesenchymal stem cells (MSC). Since those osteoblasts are bone-forming cells, the predilection of MSC to differentiate into adipocytes or osteoblasts is a potential factor involved in bone loss. In addition, osteoblasts and adipocytes can be converted into each other according to the surrounding microenvironment. Here, we study the incumbency of B. abortus infection in the crosstalk between adipocytes and osteoblasts during differentiation from its precursors. Our results indicate that soluble mediators present in culture supernatants from B. abotus-infected adipocytes inhibit osteoblast mineral matrix deposition in a mechanism dependent on the presence of IL-6 with the concomitant reduction of Runt-related transcription factor 2 (RUNX-2) transcription, but without altering organic matrix deposition and inducing nuclear receptor activator ligand kß (RANKL) expression. Secondly, B. abortus-infected osteoblasts stimulate adipocyte differentiation with the induction of peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT enhancer binding protein ß (C/EBP-ß). We conclude that adipocyte-osteoblast crosstalk during B. abortus infection could modulate mutual differentiation from its precursor cells, contributing to bone resorption.
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Reabsorção Óssea , Osteoblastos , Humanos , Linhagem Celular , Diferenciação Celular , Osteoblastos/metabolismo , Reabsorção Óssea/metabolismo , Adipócitos/metabolismoRESUMO
Obesity is characterized by an expansion of adipose tissue due to excessive accumulation of triglycerides in adipocytes, causing hypertrophy and hyperplasia, followed by hypoxia, alterations in adipocyte functionality, and chronic inflammation. However, current treatments require changes in lifestyle that are difficult to achieve and some treatments do not generate sustained weight loss over time. Therefore, we evaluated the effect of the essential oil (EO) of Lippia alba (Verbenaceae) carvone chemotype on viability, lipid mobilization, and adipogenesis of adipocytes in two normal and pathological cellular models in vitro. In 3T3-L1 adipocytes, a normal and a pathological model of obesity were induced, and then the cells were treated with L. alba carvone chemotype EO to evaluate cell viability, lipid mobilization, and adipogenesis. L. alba carvone chemotype EO does not decrease adipocyte viability at concentrations of 0.1, 1, and 5 µg/mL; furthermore, there was evidence of changes in lipid mobilization and adipogenesis, leading to a reversal of adipocyte hypertrophy. These results could be due to effects produced by EO on lipogenic and lipolytic pathways, as well as modifications in the expression of adipogenesis genes. L. alba carvone chemotype EO could be considered as a possible treatment for obesity, using the adipocyte as a therapeutic target.
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Human adenovirus 36 (HAdV-D36) can cause obesity in animal models, induces an adipogenic effect and increased adipocyte differentiation in cell culture. HAdV-D36 infection alters gene expression and the metabolism of the infected cells resulting in increased glucose internalization and triglyceride accumulation. Although HAdV-D36 prevalence correlates with obesity in humans, whether human preadipocytes may be targeted in vivo has not been determined and metabolic reprogramming of preadipocytes has not been explored in the context of the viral replication cycle. HAdV-D36 infection of the mouse fibroblasts, 3T3-L1 cells, which can differentiate into adipocytes, promotes proliferation and differentiation, but replication of the virus in these cells is abortive as indicated by short-lived transient expression of viral mRNA and a progressive loss of viral DNA. Therefore, we have evaluated whether a productive viral replication cycle can be established in the 3T3-L1 preadipocyte model under conditions that drive the cell differentiation process. For this purpose, viral mRNA levels and viral DNA replication were measured by RT-qPCR and qPCR, respectively, and viral progeny production was determined by plaque assay. The lipogenic effect of infection was evaluated with Oil Red O (ORO) staining, and expression of genes that control lipid and glucose metabolism was measured by RT-qPCR. In the context of a viral productive cycle, HAdV-D36 modulated the expression of the adipogenic genes, C/EBPα, C/EBPß and PPARγ, as well as intracellular lipid accumulation, and the infection was accompanied by altered expression of glucolytic genes. The results show that only adipocyte-committed 3T3-L1 cells are permissive for the expression of early and late viral mRNAs, as well as viral DNA replication and progeny production, supporting productive HAdV-D36 viral replication, indicating that a greater effect on adipogenesis occurs in adipocytes that support productive viral replication.
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Infecções por Adenovirus Humanos , Adenovírus Humanos , Células 3T3-L1 , Adenovírus Humanos/genética , Adipócitos , Animais , Diferenciação Celular , Replicação do DNA , DNA Viral , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipídeos/farmacologia , Camundongos , Obesidade , PPAR gama/genética , PPAR gama/metabolismo , PPAR gama/farmacologia , RNA Mensageiro/metabolismo , Triglicerídeos/metabolismo , Replicação ViralRESUMO
Semaglutide (GLP-1 agonist) was approved for treating obesity. Although the effects on weight loss and metabolism are known, the responses of adipocytes to semaglutide are yet limited. C57BL/6 male mice (n = 20/group) were fed a control diet (C) or a high-fat (HF) diet for 16 weeks and then separated into four groups (n = 10/group) for an additional four weeks: C, C diet and semaglutide, HF, and HF diet and semaglutide. Epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (sWAT) fat pads were studied with biochemistry, immunohistochemistry/fluorescence, stereology, and reverse transcription-quantitative polymerase chain reaction. In obese mice, semaglutide reduced the fat pad masses (eWAT, -55%; sWAT, -40%), plasmatic cytokines, and proinflammatory gene expressions: tumor necrosis factor-alpha (-60%); interleukin (IL)-6 (-55%); IL-1 beta (-40%); monocyte chemoattractant protein-1 (-90%); and leptin (-80%). Semaglutide also lessened endoplasmic reticulum (ER) stress genes of activating transcription factor-4 (-85%), CCAAT enhancer-binding protein homologous protein (-55%), and growth arrest and DNA damage-inducible gene 45 (-45%). The obese mice's adipocyte hypertrophy and macrophage infiltration were equally reduced by semaglutide. Semaglutide enhanced multiloculation and uncoupled protein 1 (UCP1) labeling in obese mice: peroxisome proliferator-activated receptor-alpha (+560%) and gamma (+150%), fibronectin type III domain-containing protein 5 (+215%), peroxisome proliferator-activated receptor-alpha coactivator (+110%), nuclear respiratory factor 1 (+260%), and mitochondrial transcription factor A (+120%). Semaglutide also increased thermogenetic gene expressions for the browning phenotype maintenance: beta-3 adrenergic receptor (+520%), PR domain containing 16 (+90%), and Ucp1 (+110%). In conclusion, semaglutide showed significant beneficial effects beyond weight loss, directly on fat pads and adipocytes of obese mice, remarkably anti-inflammatory, and reduced adipocyte size and ER stress. Besides, semaglutide activated adipocyte browning, improving UCP1, mitochondrial biogenesis, and thermogenic marker expressions help weight loss.