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1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443613

RESUMO

Adipogenesis is a complex process in which cell commitment and mitotic clonal expansion (MCE) are in-sequence crucial events leading to terminal adipocyte differentiation. The molecules able to block some key signals in this cascade can hamper adipogenesis becoming promising agents to counteract hyperplasia and hypertrophy of adipose tissue. Mono- and di-caffeoylquinic acid isomers are biologically active polyphenols, displaying in vitro and in vivo antioxidant, hepatoprotective, anti-diabetic and anti-obesity properties. Among these isomers, 3,5-dicaffeoylquinic acid (DCQA) has been reported to inhibit lipid accumulation in adipose cells more successfully than others. Thus, we investigated DCQA effects and molecular mechanisms on 3T3-L1 pre-adipocytes induced to differentiate with a hormonal cocktail (MDI). Oil Red O incorporation assessed that DCQA pre-treatment inhibited lipid accumulation in 3T3-L1 cells induced to differentiate for 10 days. At this time, an increased phosphorylation of both AMP-activated kinase and acetyl-CoA carboxylase, as well as a strong decrease in fatty acid synthase protein level, were registered by immunoblotting, thereby suggesting that DCQA treatment can reduce fatty acid anabolism in 3T3-L1 adipocytes. Furthermore, BrdU incorporation assay, performed 48 h after hormonal stimulation, revealed that DCQA treatment was also able to hinder the 3T3-L1 cell proliferation during the MCE, which is an essential step in the adipogenic process. Thus, we focused our attention on early signals triggered by the differentiation stimuli. In the first hours after hormonal cocktail administration, the activation of ERK1/2 and Akt kinases, or CREB and STAT3 transcription factors, was not affected by DCQA pre-treatment. Whereas 24 h after MDI induction, DCQA pre-treated cells showed increased level of the transcription factor Nrf2, that induced the expression of the antioxidant enzyme heme oxygenase 1 (HO-1). In control samples, the expression level of HO-1 was reduced 24 h after MDI induction in comparison with the higher amount of HO-1 protein found at 2 h. The HO-1 decrease was functional by allowing reactive oxygen species to boost and allowing cell proliferation induction at the beginning of MCE phase. Instead, in DCQA-treated cells the HO-1 expression was maintained at high levels for a further 24 h; in fact, its expression decreased only 48 h after MDI stimulation. The longer period in which HO-1 expression remained high led to a delay of the MCE phase, with a subsequent inhibition of both C/EBP-α expression and adipocyte terminal differentiation. In conclusion, DCQA counteracting an excessive adipose tissue expansion may become an attractive option in obesity treatment.


Assuntos
Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ácido Clorogênico/análogos & derivados , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Mitose/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Ácido Clorogênico/farmacologia , Camundongos
2.
Biol Aujourdhui ; 215(1-2): 63-72, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34397376

RESUMO

Obesity is considered a pandemic responsible for millions of deaths worldwide for many years. At the end of 2019, the Coronavirus disease 2019 (COVID-19) appeared, causing the death of more than a million people in less than a year. Numerous studies suggest that obesity could be defined as key to the onset of severe forms of this emerging disease. Indeed, SARS-CoV2 infects the host by binding to ACE2 receptors present on the surface of the cells and causes excessive secretion of pro-inflammatory cytokines including IL-1, IL-6 and TNF-α, which lead to developing acute respiratory distress syndrome (ARDS). It therefore seems essential to make up effective preventive strategies to protect this part of the population from the risk of developing a severe form of COVID-19. The ketogenic diet, which is low in sugars and high in fat, has interesting properties, both in the fight against obesity but also against severe infections. This article focuses on the latest scientific advances that make it possible to consider the ketogenic diet as a preventive strategy that simultaneously reduces the development of obesity while strengthening the immune system, two key actions in the fight against SARS-CoV2 infections and severe forms of COVID-19.


Assuntos
COVID-19/prevenção & controle , Dieta Cetogênica , Inflamação/etiologia , Obesidade/prevenção & controle , Pandemias , SARS-CoV-2 , Adipócitos/metabolismo , Animais , COVID-19/complicações , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Dieta Cetogênica/efeitos adversos , Suscetibilidade a Doenças , Humanos , Inflamação/fisiopatologia , Inflamação/prevenção & controle , Leptina/fisiologia , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/epidemiologia , Síndrome do Desconforto Respiratório/etiologia
3.
Nat Commun ; 12(1): 4829, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376643

RESUMO

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Dioxóis/farmacologia , Glucose/metabolismo , Ácido Hialurônico/metabolismo , Lipólise/efeitos dos fármacos , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Intolerância à Glucose/metabolismo , Homeostase , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo
4.
FEBS Lett ; 595(16): 2085-2098, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34197627

RESUMO

Brown and beige adipocytes dissipate energy by uncoupling protein 1 (UCP1)-dependent and UCP1-independent thermogenesis, which may be utilized to develop treatments against obesity. We have found that mRNA and protein expression of the alanine/serine/cysteine transporter-1 (ASC-1) was induced during adipocyte differentiation of human brown-prone deep neck and beige-competent subcutaneous neck progenitors, and SGBS preadipocytes. cAMP stimulation of differentiated adipocytes led to elevated uptake of serine, cysteine, and glycine, in parallel with increased oxygen consumption, augmented UCP1-dependent proton leak, increased creatine-driven substrate cycle-coupled respiration, and upregulation of thermogenesis marker genes and several respiratory complex subunits; these outcomes were impeded in the presence of the specific ASC-1 inhibitor, BMS-466442. Our data suggest that ASC-1-dependent consumption of serine, cysteine, and glycine is required for efficient thermogenic stimulation of human adipocytes.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adrenérgicos/farmacologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Termogênese , Transporte Biológico/efeitos dos fármacos , Humanos , Termogênese/efeitos dos fármacos
5.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206740

RESUMO

N-Glycosylations are an important post-translational modification of proteins that can significantly impact cell function. Terminal sialic acid in hybrid or complex N-glycans has been shown to be relevant in various types of cancer, but its role in non-malignant cells remains poorly understood. We have previously shown that the motility of human bone marrow derived mesenchymal stromal cells (MSCs) can be modified by altering N-glycoforms. The goal of this study was to determine the role of sialylated N-glycans in MSCs. Here, we show that IFN-gamma or exposure to culture media low in fetal bovine serum (FBS) increases sialylated N-glycans, while PDGF-BB reduces them. These stimuli alter mRNA levels of sialyltransferases such as ST3Gal1, ST6Gal1, or ST3Gal4, suggesting that sialylation of N-glycans is regulated by transcriptional control of sialyltransferases. We next show that 2,4,7,8,9-pentaacetyl-3Fax-Neu5Ac-CO2Me (3F-Neu5Ac) effectively inhibits sialylations in MSCs. Supplementation with 3F-Neu5Ac increases adhesion and migration of MSCs, as assessed by both videomicroscopy and wound/scratch assays. Interestingly, pre-treatment with 3F-Neu5Ac also increases the survival of MSCs in an in vitro ischemia model. We also show that pre-treatment or continuous treatment with 3F-Neu5Ac inhibits both osteogenic and adipogenic differentiation of MSCs. Finally, secretion of key trophic factors by MSCs is variably affected upon exposure to 3F-Neu5Ac. Altogether, our experiments suggest that sialylation of N-glycans is tightly regulated in response to environmental cues and that glycoengineering MSCs to reduce sialylated N-glycans could be beneficial to increase both cell migration and survival, which may positively impact the therapeutic potential of the cells.


Assuntos
Movimento Celular , Células-Tronco Mesenquimais/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/metabolismo , Sialiltransferases/metabolismo , Adipócitos/metabolismo , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Interferon gama/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Osteoblastos/citologia , Sialiltransferases/antagonistas & inibidores
6.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203452

RESUMO

Adipokines secreted by hypertrophic visceral adipose tissue (VAT) instigate low-grade inflammation, followed by hyperglycemia (HG)-related metabolic disorders. The latter may develop with the participation of epigenetic modifications. Our aim was to assess how HG influences selected epigenetic modifications and the expression of interleukin 6 (IL-6) and adiponectin (APN; gene symbol ADIPOQ) during the adipogenesis of human visceral preadipocytes (HPA-v). Adipocytes (Ads) were chronically or transiently HG-treated during three stages of adipogenesis (proliferation, differentiation, maturation). We measured adipokine mRNA, protein, proven or predicted microRNA expression (RT-qPCR and ELISA), and enrichment of H3K9/14ac, H3K4me3, and H3K9me3 at gene promoter regions (chromatin immunoprecipitation). In chronic HG, we detected different expression patterns of the studied adipokines at the mRNA and protein levels. Chronic and transient HG-induced changes in miRNA (miR-26a-5p, miR-26b-5p, let-7d-5p, let-7e-5p, miR-365a-3p, miR-146a-5p) were mostly convergent to altered IL-6 transcription. Alterations in histone marks at the IL6 promoter were also in agreement with IL-6 mRNA. The open chromatin marks at the ADIPOQ promoter mostly reflected the APN transcription during NG adipogenesis, while, in the differentiation stage, HG-induced changes in all studied marks were in line with APN mRNA levels. In summary, HG dysregulated adipokine expression, promoting inflammation. Epigenetic changes coexisted with altered expression of adipokines, especially for IL-6; therefore, epigenetic marks induced by transient HG may act as epi-memory in Ads. Such changes in the epigenome and expression of adipokines could be instrumental in the development of inflammation and metabolic deregulation of VAT.


Assuntos
Adipócitos/metabolismo , Adiponectina/metabolismo , Hiperglicemia/metabolismo , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adipogenia/fisiologia , Adiponectina/genética , Imunoprecipitação da Cromatina , Ensaio de Imunoadsorção Enzimática , Epigênese Genética/genética , Epigênese Genética/fisiologia , Humanos , Hiperglicemia/genética , Interleucina-6/metabolismo
7.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199596

RESUMO

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.


Assuntos
Tecido Adiposo Branco/metabolismo , Mitocôndrias/genética , Obesidade/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adipócitos/metabolismo , Tecido Adiposo Branco/fisiologia , Restrição Calórica , Humanos , Lipogênese/genética , Mitocôndrias/metabolismo , Obesidade/patologia , Biogênese de Organelas
8.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299331

RESUMO

BACKGROUND: Due to its prominence in the regulation of metabolism and inflammation, adipose tissue is a major target to investigate alterations in insulin action. This hormone activates PI3K/AKT pathway which is essential for glucose homeostasis, cell differentiation, and proliferation in insulin-sensitive tissues, like adipose tissue. The aim of this work was to evaluate the impact of chronic and intermittent high glucose on the expression of biomolecules of insulin signaling pathway during the differentiation and maturation of human visceral preadipocytes. METHODS: Human visceral preadipocytes (HPA-V) cells were treated with high glucose (30 mM)during the proliferation and/or differentiation and/or maturation stage. The level of mRNA (by Real-Time PCR) and protein (by Elisa tests) expression of IRS1, PI3K, PTEN, AKT2, and GLUT4 was examined after each culture stage. Furthermore, we investigated whether miR-29a-3p, miR-143-3p, miR-152-3p, miR-186-5p, miR-370-3p, and miR-374b-5p may affect the expression of biomolecules of the insulin signaling pathway. RESULTS: Both chronic and intermittent hyperglycemia affects insulin signaling in visceral pre/adipocytes by upregulation of analyzed PI3K/AKT pathway molecules. Both mRNA and protein expression level is more dependent on stage-specific events than the length of the period of high glucose exposure. What is more, miRs expression changes seem to be involved in PI3K/AKT expression regulation in response to hyperglycemic stimulation.


Assuntos
Hiperglicemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hiperglicemia/patologia , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
9.
Cell Prolif ; 54(8): e13095, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34254370

RESUMO

OBJECTIVES: Scavenger receptor class A, member 3 (Scara3) was involved in adipogenesis. However, the effect of Scara3 on the switch between osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs) remains elusive. MATERIALS AND METHODS: The correlations between SCARA3 with the osteogenic-related were analysed based on the GTEx database. The effects of Scara3 on osteogenic or adipogenic differentiation of BMSCs were evaluated by qPCR, Western blot (WB) and cell staining. The mechanisms of Scara3 regulating Foxo1 and autophagy were validated by co-expression analysis, WB and immunofluorescence. In vivo, Scara3 adeno-associated virus was injected into intra-bone marrow of the aged mice and ovariectomized (OVX) mice whose phenotypes were confirmed by micro-CT, calcein double labelling and immunochemistry (HE and OCN staining). RESULTS: SCARA3 was positively correlated with osteogenic-related genes. Scara3 expression gradually decreased during adipogenesis but increased during osteogenesis. Moreover, the deletion of Scara3 favoured adipogenesis over osteogenesis, whereas overexpression of Scara3 significantly enhanced the osteogenesis at the expense of adipogenesis. Mechanistically, Scara3 controlled the cell fate by promoting Foxo1 expression and autophagy flux. In vivo, Scara3 promoted bone formation and reduced bone marrow fat accumulation in OVX mice. In the aged mice, Scara3 overexpression alleviated bone loss as well. CONCLUSIONS: This study suggested that Scara3 regulated the switch between adipocyte and osteoblast differentiation, which represented a potential therapeutic target for bone loss and osteoporosis.


Assuntos
Adipócitos/citologia , Proteína Forkhead Box O1/metabolismo , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Receptores Depuradores Classe A/metabolismo , Adipócitos/metabolismo , Adipogenia , Envelhecimento , Animais , Autofagia , Diferenciação Celular , Células Cultivadas , Feminino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Osteogênese , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Depuradores Classe A/antagonistas & inibidores , Receptores Depuradores Classe A/genética
10.
FASEB J ; 35(8): e21759, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245608

RESUMO

Life-style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, especially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity. Here, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre-existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low-fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet-switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of ß3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of ß3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer-lasting benefits in obesity.


Assuntos
Receptores de Ativinas Tipo I/deficiência , Adipócitos/metabolismo , Ingestão de Alimentos , Lipólise , Obesidade/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Adipócitos/patologia , Animais , Camundongos , Camundongos Transgênicos , Obesidade/genética , Obesidade/patologia , Salicilatos/farmacologia
11.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206460

RESUMO

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.


Assuntos
Cromo/deficiência , Clozapina/farmacologia , Intolerância à Glucose/metabolismo , Nefropatias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Doenças Retinianas/metabolismo , Adipócitos/metabolismo , Animais , Biomarcadores , Pesos e Medidas Corporais , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/genética , Imunofluorescência , Expressão Gênica , Regulação da Expressão Gênica , Imuno-Histoquímica , Insulina/metabolismo , Nefropatias/etiologia , Fígado/metabolismo , Camundongos , Camundongos Obesos , Óxido Nítrico Sintase Tipo II , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Retinianas/etiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
12.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206506

RESUMO

Adipose-derived stem cells (ADSCs) came out from the regenerative medicine landscape for their ability to differentiate into several phenotypes, contributing to tissue regeneration both in vitro and in vivo. Dysregulation in stem cell recruitment and differentiation during adipogenesis is linked to a chronic low-grade inflammation and macrophage infiltration inside the adipose tissue, insulin resistance, cardiovascular disease and obesity. In the present paper we aimed to evaluate the role of metformin and vitamin D, alone or in combination, in modulating inflammation and autophagy in ADSCs during adipogenic commitment. ADSCs were cultured for 21 days in the presence of a specific adipogenic differentiation medium, together with metformin, or vitamin D, or both. We then analyzed the expression of FoxO1 and Heat Shock Proteins (HSP) and the secretion of proinflammatory cytokines IL-6 and TNF-α by ELISA. Autophagy was also assessed by specific Western blot analysis of ATG12, LC3B I, and LC3B II expression. Our results showed the ability of the conditioned media to modulate adipogenic differentiation, finely tuning the inflammatory response and autophagy. We observed a modulation in HSP mRNA levels, and a significant downregulation in cytokine secretion. Taken together, our findings suggest the possible application of these molecules in clinical practice to counteract uncontrolled lipogenesis and prevent obesity and obesity-related metabolic disorders.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Metformina/farmacologia , Vitamina D/farmacologia , Adipócitos/citologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Células-Tronco Mesenquimais/citologia
13.
Anticancer Res ; 41(8): 4071-4076, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281876

RESUMO

BACKGROUND/AIM: Increased expression of inflammatory cytokine genes through cell interactions in tissues may cause chronic inflammation, leading to the development of lifestyle-related diseases. Since the activation of inflammatory cytokine genes in monocytes/macrophages by co-culturing with cancer cells or adipocytes was suppressed by pre-treatment with low-dose lipopolysaccharide (LPS), we hypothesized that low-dose LPS-activated macrophages may regulate the expression of immune response-related genes in other cells. MATERIALS AND METHODS: Phorbol myristate acetate-treated human monocytes (THP-1) were activated by LPS. The conditioned medium of LPS-activated THP-1 cells was added to human adipocytes. After 5 days, the expression of genes encoding interleukin (IL)-6 (IL6), IL-8 (IL8), monocyte chemotactic protein (MCP)-1 (CCL2), adiponectin (ADIPOQ), and plasminogen activator inhibitor (PAI)-1 (SERPINE1) was analyzed using quantitative real-time PCR. RESULTS: The increased expression of inflammation-related genes and SERPINE1 in adipocytes was suppressed by the conditioned medium of THP-1 cells activated by low-dose LPS, whereas the expression of ADIPOQ was significantly increased. CONCLUSION: Low-dose LPS-activated macrophages convert adipocytes to anti-inflammatory phenotypes.


Assuntos
Adipócitos/metabolismo , Adiponectina/genética , Citocinas/genética , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Linhagem Celular , Humanos , Ativação de Macrófagos
14.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203569

RESUMO

Propolis is a honeybee product with various biological activities, including antidiabetic effects. We previously reported that artepillin C, a prenylated cinnamic acid derivative isolated from Brazilian green propolis, acts as a peroxisome proliferator-activated receptor γ (PPARγ) ligand and promotes adipocyte differentiation. In this study, we examined the effect of baccharin, another major component of Brazilian green propolis, on adipocyte differentiation. The treatment of mouse 3T3-L1 preadipocytes with baccharin resulted in increased lipid accumulation, cellular triglyceride levels, glycerol-3-phosphate dehydrogenase activity, and glucose uptake. The mRNA expression levels of PPARγ and its target genes were also increased by baccharin treatment. Furthermore, baccharin enhanced PPARγ-dependent luciferase activity, suggesting that baccharin promotes adipocyte differentiation via PPARγ activation. In diabetic ob/ob mice, intraperitoneal administration of 50 mg/kg baccharin significantly improved blood glucose levels. Our results suggest that baccharin has a hypoglycemic effect on glucose metabolic disorders, such as type 2 diabetes mellitus.


Assuntos
Adipócitos/metabolismo , Hiperglicemia/metabolismo , Própole/química , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Hiperglicemia/genética , Camundongos
15.
Biomed Pharmacother ; 139: 111687, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243611

RESUMO

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.


Assuntos
Benzofuranos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/fisiologia , Obesidade/metabolismo , Substâncias Protetoras/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Fígado Gorduroso/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Termogênese/efeitos dos fármacos
16.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198827

RESUMO

The objective of this study was to investigate molecular mechanisms underlying the ability of carnosic acid to attenuate an early increase in reactive oxygen species (ROS) levels during MDI-induced adipocyte differentiation. The levels of superoxide anion and ROS were determined using dihydroethidium (DHE) and 2'-7'-dichlorofluorescin diacetate (DCFH-DA), respectively. Both superoxide anion and ROS levels peaked on the second day of differentiation. They were suppressed by carnosic acid. Carnosic acid attenuates the translation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (Nox4), p47phox, and p22phox, and the phosphorylation of nuclear factor-kappa B (NF-κB) and NF-κB inhibitor (IkBa). The translocation of NF-κB into the nucleus was also decreased by carnosic acid. In addition, carnosic acid increased the translation of heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GCSc), and glutathione S-transferase (GST) and both the translation and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, these results indicate that carnosic acid could down-regulate ROS level in an early stage of MPI-induced adipocyte differentiation by attenuating ROS generation through suppression of NF-κB-mediated translation of Nox4 enzyme and increasing ROS neutralization through induction of Nrf2-mediated translation of phase II antioxidant enzymes such as HO-1, γ-GCS, and GST, leading to its anti-adipogenetic effect.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Abietanos/farmacologia , DNA Helicases/genética , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , NADPH Oxidase 4/genética , Inibidor de NF-kappaB alfa/genética , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Antioxidantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Grupo dos Citocromos b/genética , Etídio/análogos & derivados , Etídio/farmacologia , Fluoresceínas/farmacologia , Glutationa Transferase/genética , Camundongos , NADPH Oxidases/genética , Biossíntese de Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
17.
Front Immunol ; 12: 649359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220807

RESUMO

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.


Assuntos
COVID-19/patologia , Leptina/imunologia , Obesidade/patologia , SARS-CoV-2/imunologia , Adipócitos/metabolismo , Células Apresentadoras de Antígenos/imunologia , COVID-19/mortalidade , Citocinas/imunologia , Suscetibilidade a Doenças/patologia , Humanos , Leptina/sangue , Monócitos/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Células Th1/imunologia
18.
Electron. j. biotechnol ; 52: 67-75, July. 2021. tab, graf, ilus
Artigo em Inglês | LILACS | ID: biblio-1283594

RESUMO

BACKGROUND: Adipogenesis and fibrogenesis can be considered as a competitive process in muscle, which may affect the intramuscular fat deposition. The CCAAT/enhancer-binding protein beta (C/EBPb) plays an important role in adipogenesis, which is well-characterized in mice, but little known in bovine so far. RESULTS: In this study, real-time qPCR revealed that the level of C/EBPb was increased during the developmental stages of bovine and adipogenesis process of preadipocytes. Overexpression of C/EBPb promoted bovine fibroblast proliferation through mitotic clonal expansion (MCE), a necessary process for initiating adipogenesis, by significantly downregulating levels of p21 and p27 (p < 0.01). Also, the PPARc expression was inhibited during the MCE stage (p < 0.01). 31.28% of transfected fibroblasts adopted lipid-laden adipocyte morphology after 8 d. Real-time qPCR showed that C/EBPb activated the transcription of early stage adipogenesis markers C/EBPa and PPARc. Expression of ACCa, FASN, FABP4 and LPL was also significantly upregulated, while the expression of LEPR was weakened. CONCLUSIONS: It was concluded C/EBPb can convert bovine fibroblasts into adipocytes without hormone induction by initiating the MCE process and promoting adipogenic genes expression, which may provide new insights into the potential functions of C/EBPb in regulating intramuscular fat deposition in beef cattle.


Assuntos
Bovinos/metabolismo , Adipócitos/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Fibroblastos/metabolismo , Tecido Adiposo/metabolismo , Células Clonais , Proliferação de Células , Adipogenia , Reação em Cadeia da Polimerase em Tempo Real , Mitose , Músculos
19.
Nat Metab ; 3(6): 751-761, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34158657

RESUMO

The perception of adipose tissue, both in the scientific community and in the general population, has changed dramatically in the past 20 years. While adipose tissue was thought for a long time to be a rather simple lipid storage entity, it is now recognized as a highly heterogeneous organ and a critical regulator of systemic metabolism, composed of many different subtypes of cells, with important endocrine functions. Additionally, adipose tissue is nowadays recognized to contribute to energy turnover, due to the presence of specialized thermogenic adipocytes, which can be found in many adipose depots. This review discusses the unprecedented insights that we have gained into the heterogeneity of thermogenic adipocytes and their respective precursors due to the technical developments in single-cell and nucleus technologies. These methodological advances have increased our understanding of how adipose tissue catabolic function is influenced by developmental and intercellular communication events.


Assuntos
Tecido Adiposo/metabolismo , Plasticidade Celular , Termogênese , Adipócitos/metabolismo , Comunicação Celular , Metabolismo Energético , Humanos
20.
FASEB J ; 35(7): e21728, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34110658

RESUMO

Proliferation and differentiation of preadipocytes, and other cell types, is accompanied by an increase in glucose uptake. Previous work showed that a pulse of high glucose was required during the first 3 days of differentiation in vitro, but was not required after that. The specific glucose metabolism pathways required for adipocyte differentiation are unknown. Herein, we used 3T3-L1 adipocytes as a model system to study glucose metabolism and expansion of the adipocyte metabolome during the first 3 days of differentiation. Our primary outcome measures were GLUT4 and adiponectin, key proteins associated with healthy adipocytes. Using complete media with 0 or 5 mM glucose, we distinguished between developmental features that were dependent on the differentiation cocktail of dexamethasone, insulin, and isobutylmethylxanthine alone or the cocktail plus glucose. Cocktail alone was sufficient to activate the capacity for 2-deoxglucose uptake and glycolysis, but was unable to support the expression of GLUT4 and adiponectin in mature adipocytes. In contrast, 5 mM glucose in the media promoted a transient increase in glucose uptake and glycolysis as well as a significant expansion of the adipocyte metabolome and proteome. Using genetic and pharmacologic approaches, we found that the positive effects of 5 mM glucose on adipocyte differentiation were specifically due to increased expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key regulator of glycolysis and the ancillary glucose metabolic pathways. Our data reveal a critical role for PFKFB3 activity in regulating the cellular metabolic remodeling required for adipocyte differentiation and maturation.


Assuntos
Adipócitos/metabolismo , Glucose/metabolismo , Fosfofrutoquinase-2/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular , Dexametasona/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Xantinas/farmacologia
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