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1.
Chemosphere ; 258: 127360, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554016

RESUMO

Environmental pollutants are thought to be a risk factor for the prevalence of hepatic steatosis. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous, and human exposure is inevitable. In the present study, phenanthrene (Phe) was used as a representative PAH to investigate the effects of in utero exposure to PAH on hepatic lipid metabolism and the toxicological mechanism involved. Pregnant mice (C57BL/6J) were orally administered Phe (0, 60, 600 and 6000 µg kg-1 body weight) once every 3 days with 6 doses in total. F1 female mice aged 125 days showed significantly elevated hepatic lipid levels in the liver. The protein expression of hepatic peroxisome proliferator-activated receptors (PPARß and PPARγ) and retinoid X receptors (RXRs) was upregulated; the transcription of genes related to lipogenesis, such as srebp1 (encoding sterol regulatory element binding proteins), acca (acetyl-CoA carboxylase), fasn (fatty acid synthase) and pcsk9 (proprotein convertase subtilisin/kexin type 9), showed an upregulation, while the mRNA levels of the lipolysis gene lcat (encoding lecithin cholesterol acyl transferase) were downregulated. These results could be responsible for lipid accumulation. The promoter methylation levels of pparγ were reduced and were the lowest in the 600 µg kg-1 group, and the promoter methylation levels of lcat were significantly increased in all the Phe treatments. These changes were matched with the alterations in their mRNA levels, suggesting that prenatal Phe exposure could induce abnormal lipid metabolism in later life via epigenetic modification.


Assuntos
Poluentes Ambientais/toxicidade , Epigênese Genética/efeitos dos fármacos , Fígado Gorduroso/virologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenantrenos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/virologia , Idoso de 80 Anos ou mais , Animais , Fígado Gorduroso/embriologia , Fígado Gorduroso/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipólise/efeitos dos fármacos , Lipólise/genética , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Transcrição Genética/genética
2.
Food Chem ; 326: 127024, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428856

RESUMO

This study aimed to analyze the effect of elderly gastrointestinal (GI) conditions on proteolysis, lipolysis and calcium and vitamins A and D3 bioaccessibility in salmon, sardine, sea bass and hake. For this purpose, cooked fishes were in vitro subjected to three elderly in vitro digestion models: E1 (oral elderly conditions), E2 (oral and gastric elderly conditions) and E3 (oral, gastric and intestinal elderly conditions)). In parallel, samples were digested under standardized GI conditions of a healthy adult as a control. Proteolysis was highly affected by elderly GI alterations (p < 0.05) (50% of reduction compared to control), being salmon and sea bass proteolysis extent (40 and 33%, respectively) the most affected with an important descend in leucine release. Calcium and vitamins bioaccessibility seemed to be also compromised for elders; however, the extent of the reduction highly depends on the fish type. Finally, these GI disorders did not negatively influence the bioabsorbable lipids of the fishes.


Assuntos
Cálcio/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Vitaminas/farmacologia , Idoso , Animais , Bass , Digestão , Gadiformes , Humanos , Salmão , Alimentos Marinhos/análise
3.
Arterioscler Thromb Vasc Biol ; 40(7): 1695-1704, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32404008

RESUMO

OBJECTIVE: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg; P<0.001) and fat percentage (3.5%; P<0.001) but did not affect glucose uptake nor lipolysis. The hypercaloric diet increased adipose tissue microvascular recruitment (P=0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia (P=0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls (P<0.001). The hypocaloric diet reversed all of these changes, except the increase in adipose tissue microvascular recruitment. CONCLUSIONS: In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02628301.


Assuntos
Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/metabolismo , Arteríolas/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Restrição Calórica , Ingestão de Energia , Insulina/administração & dosagem , Lipólise/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Adiposidade , Adolescente , Adulto , Arteríolas/fisiologia , Glicemia/metabolismo , Estudos de Casos e Controles , Voluntários Saudáveis , Humanos , Resistência à Insulina , Masculino , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Ganho de Peso , Perda de Peso , Adulto Jovem
4.
Nature ; 579(7798): 279-283, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132708

RESUMO

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.


Assuntos
Glucagon/farmacologia , Gluconeogênese/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Fígado/efeitos dos fármacos , Acetilcoenzima A/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Glucagon/sangue , Receptores de Inositol 1,4,5-Trifosfato/genética , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Lipólise/genética , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Oxirredução/efeitos dos fármacos
5.
Biochem J ; 477(5): 985-1008, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32168372

RESUMO

Fatty acids (FAs) are stored safely in the form of triacylglycerol (TAG) in lipid droplet (LD) organelles by professional storage cells called adipocytes. These lipids are mobilized during adipocyte lipolysis, the fundamental process of hydrolyzing TAG to FAs for internal or systemic energy use. Our understanding of adipocyte lipolysis has greatly increased over the past 50 years from a basic enzymatic process to a dynamic regulatory one, involving the assembly and disassembly of protein complexes on the surface of LDs. These dynamic interactions are regulated by hormonal signals such as catecholamines and insulin which have opposing effects on lipolysis. Upon stimulation, patatin-like phospholipase domain containing 2 (PNPLA2)/adipocyte triglyceride lipase (ATGL), the rate limiting enzyme for TAG hydrolysis, is activated by the interaction with its co-activator, alpha/beta hydrolase domain-containing protein 5 (ABHD5), which is normally bound to perilipin 1 (PLIN1). Recently identified negative regulators of lipolysis include G0/G1 switch gene 2 (G0S2) and PNPLA3 which interact with PNPLA2 and ABHD5, respectively. This review focuses on the dynamic protein-protein interactions involved in lipolysis and discusses some of the emerging concepts in the control of lipolysis that include allosteric regulation and protein turnover. Furthermore, recent research demonstrates that many of the proteins involved in adipocyte lipolysis are multifunctional enzymes and that lipolysis can mediate homeostatic metabolic signals at both the cellular and whole-body level to promote inter-organ communication. Finally, adipocyte lipolysis is involved in various diseases such as cancer, type 2 diabetes and fatty liver disease, and targeting adipocyte lipolysis is of therapeutic interest.


Assuntos
Adipócitos/metabolismo , Metabolismo Energético/fisiologia , Lipólise/fisiologia , Domínios e Motivos de Interação entre Proteínas/fisiologia , Adipócitos/efeitos dos fármacos , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Humanos , Lipólise/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos
6.
Mol Med Rep ; 21(3): 1383-1389, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016466

RESUMO

Iron deficiency has been associated with obesity and related metabolic disorders. The aim of the present study was to evaluate the effect of iron deficiency on fat metabolism, particularly regarding the lipolytic activity, lipolysis­related protein expression, and glucose utilization of adipocytes. Differentiated 3T3­L1 adipocytes were incubated with an iron chelator, deferoxamine mesylate (DFO), for 48 h. Subsequently, basal and isoproterenol­stimulated lipolytic activities, the proteins involved in lipolysis and glucose utilization were compared with a control (CON). The results revealed that treatment with DFO significantly decreased the free iron content but did not affect total protein and lipid contents in adipocytes. Iron deprivation caused a significant reduction in isoproterenol­stimulated lipolysis, but not basal lipolysis. Lipolysis­related proteins, including perilipin A, adipose triglyceride lipase, hormone sensitive lipase and comparative gene identification­58, were decreased in the DFO compared with the CON group. Furthermore, glucose utilization, a major precursor of 3­glycerol phosphate for micro­lipid droplet synthesis during lipolysis and the expression of glucose transporter (GLUT) 4 were significantly lower in the DFO group when compared with the CON group. However, hypoxia­inducible factor­1α and GLUT1 expressions were upregulated in DFO­treated adipocytes. In conclusion, the results indicated that low iron availability attenuated catecholamine­stimulated lipolysis by downregulating lipolytic enzymes and glucose utilization in 3T3­L1 adipocytes.


Assuntos
Catecolaminas/farmacologia , Glucose/metabolismo , Ferro/deficiência , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Obesidade/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Desferroxamina/química , Regulação para Baixo , Ferro/química , Isoproterenol/metabolismo , Lipase/metabolismo , Camundongos , Perilipina-1/metabolismo , Sideróforos/química , Esterol Esterase/metabolismo
7.
Nat Commun ; 11(1): 181, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924761

RESUMO

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O-linked ß-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O-GlcNAcylation during fasting. Loss of OGT decreases O-GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O-GlcNAc signaling in the treatment of obesity.


Assuntos
Dieta/efeitos adversos , Gordura Intra-Abdominal/efeitos dos fármacos , Lipólise/efeitos dos fármacos , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Obesidade/metabolismo , Acetilglucosamina/metabolismo , Animais , Linhagem Celular Tumoral , Jejum , Deleção de Genes , Células HEK293 , Células HeLa , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Perilipina-1/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais
8.
Nat Commun ; 11(1): 220, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924786

RESUMO

Cancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.


Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Antineoplásicos/imunologia , Metabolismo dos Lipídeos/fisiologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fator 1 de Ribosilação do ADP/genética , Fator 1 de Ribosilação do ADP/farmacologia , Alarminas , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Técnicas de Silenciamento de Genes , Humanos , Lipólise/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Células-Tronco Neoplásicas/citologia , Linfócitos T/imunologia , Tamoxifeno/farmacologia , Vacinação
9.
Int J Mol Med ; 45(2): 589-596, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894306

RESUMO

Acer okamotoanum is reported to have various antioxidant, anti­inflammatory and beneficial immune system effects. The anti­adipocyte differentiation effects and mechanisms of the ethyl acetate (EtOAc) fraction of an A. okamotoanum extraction was investigated in 3T3­L1 adipocyte cells. Treatment with differentiation inducers increased the level of triglycerides (TGs) in 3T3­L1 adipocyte cells compared with an untreated control. However, the EtOAc fraction of A. okamotoanum significantly decreased TGs. Treatment with 1, 2.5 and 5 µg/ml showed weak activity, but TG production was inhibited at 10 µg/ml compared with the control. In addition, A. okamotoanum caused a significant downregulation of proteins related to adipogenesis, such as γ­cytidine­cytidine­adenosine­adenosine­thymidine/enhancer binding protein­α, ­ß and peroxisome proliferator­activated receptor­Î³, compared with the untreated control. Furthermore, A. okamotoanum significantly upregulated lipolysis related protein, hormone­sensitive lipase and the phosphorylation of adenosine monophosphate­activated protein kinase (AMPK). Therefore, these results indicate that A. okamotoanum suppressed adipogenesis and increased lipolysis and the activation of AMPK, suggesting a protective role in adipocyte differentiation.


Assuntos
Acer , Adipogenia/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Lipólise/efeitos dos fármacos , Extratos Vegetais/farmacologia , Células 3T3-L1 , Acer/química , Animais , Ativadores de Enzimas/química , Camundongos , Extratos Vegetais/química , Proteínas Quinases/metabolismo
10.
Clin Hemorheol Microcirc ; 75(2): 189-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31985455

RESUMO

BACKGROUND: Lipolytic injectables for body contouring procedures have been reported for necrotic effects on adipose tissue causing side effects as swelling, pain and hematoma. Deoxycholic acid is widely used as a solvent in lipolytic injectables and is associated with necrosis when applied to cells. A new lipolytic preparation (NWL-10) containing only polyenylphosphatidylcholine in nano particle size, glycerrhizinate and maltose has been reported for its lipolytic action on adipose tissue. However, no data exist whether the NWL-10 mixture is responsible for apoptosis or necrosis in adipose tissue which can be associated with severer side effects as reported for deoxycholic acid preparation. METHODS: 3T3-L1 mouse cells and human adipose tissue derived stem cells were exposed to the NWL-10 mixture and to each ingredient of the mix in order to investigate cytotoxic, lipolytic, necrotic or apoptotic effects. Furthermore, a Balb/C mouse animal model was used to investigate inflammatory responses to NWL-10 by bioluminescence monitoring and histological examination. RESULTS: A high extent of lipolysis was detected for the NWL-10 mixture when applied to both cell types with no cytotoxic effect. Interestingly, low concentration of NWL-10 resulted in necrosis whereas high concentration of NWL-10 showed a certain amount of apoptosis. Application of single ingredients of NWL-10 or various combinations of two component mixtures did not result in any apoptosis or necrosis. In addition, no inflammatory effects of NWL-10 were observed in the mouse model. CONCLUSIONS: The NWL-10 mixture provided promising results regarding lipolysis on adipose tissue with limited apoptosis and necrosis when compared to currently available injectables. These first promising results require further fundamental and more detailed research on essentials for drug approval. NWL-10 has the potential to become a second generation product for future lipolytic injectables.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Fosfatidilcolinas/metabolismo , Tecido Adiposo/metabolismo , Animais , Humanos , Camundongos , Nanopartículas/metabolismo
11.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G428-G438, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928222

RESUMO

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Superóxido Dismutase-1/administração & dosagem , Adiposidade/efeitos dos fármacos , Animais , Catalase/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Fígado Gorduroso Alcoólico/enzimologia , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Regulação da Expressão Gênica , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/patologia , Lipólise/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Nanomedicina , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Perilipina-1/genética , Perilipina-1/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/química
12.
Phytomedicine ; 66: 153129, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794911

RESUMO

BACKGROUND: Phyllanthus emblica L. (Indian gooseberry) is widely used in the Ayurveda for thousands of years to treat health complications including disorders of the immune system, diabetes, and obesity. PURPOSE: For the first time, our study aims to demonstrate the molecular mechanisms of the fruit extract of Phyllanthus emblica (PEFE) involved in the promotion of fat cell apoptosis and alleviation of adipogenesis. METHODS: The active constituents from PEFE were identified using high performance liquid chromatography-mass spectrometry (HPLC-MS). We carried out the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay to evaluate the cytotoxic effects of PEFE using 3T3-L1 pre-adipocytes. The colonogenic assay was carried out to determine the inhibitory effect of 3T3-L1 adipocytes after PEFE treatment. In addition, inhibition of pancreatic lipase activity was performed and the lipolytic activity of PEFE and digallic acid was compared with the well-known standard drug orlistat. Besides, the molecular interaction and ligand optimization between digallic and adipogenesis/apoptosis markers were also carried out. Furthermore, to confirm fat cell apoptosis we have used several detection methods that includes Hoechst staining, PI staining, Oil staining and qPCR respectively. RESULTS: Digallic acid was identified as a major component in the PEFE. The IC50 values of digallic acid and PEFE were found to be 3.82 µg/ml and 21.85 µg/ml respectively. PEFE and digallic acid showed significant anti-lipolytic activity compared to the standard drug orlistat. In the mature adipocytes, PEFE significantly decreased triglyceride accumulation by downregulating adiponectin, PPARγ, cEBPα, and FABP4 respectively. We further analyzed the expression of apoptosis related genes upon PEFE treatment. Apoptotic process initiated through upregulation of BAX and downregulation of BCL2 resulting in an increased caspase-3 activity. In addition, we have also confirmed the apoptosis and DNA fragmentation in 3T3-L1 cells using Hoechst, PI and TUNEL assays. CONCLUSION: PEFE negatively regulates adipogenesis by initiating fat cell apoptosis and therefore it can be considered as a potential herbal medicinal product for treating obesity.


Assuntos
Fármacos Antiobesidade/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Phyllanthus emblica/química , Fitoterapia , Extratos Vegetais/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Frutas/química , Humanos , Lipólise/efeitos dos fármacos , Camundongos , Extratos Vegetais/química , Triglicerídeos/metabolismo
13.
Food Chem ; 311: 126024, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855778

RESUMO

Solid lipid nanoparticles (SLNs) are emulsion-based carriers of lipophilic bioactive compounds. However, their digestibility may be affected by the solid lipid phase composition. Hence, the aim of this work was to study the in vitro lipolysis kinetics as well as the relationship between the lipid digestion, micelle fraction composition and ß-carotene bioaccessibility of SLNs with different solid lipids, being blends of medium chain triglyceride (MCT) oil, glyceryl stearate (GS) or hydrogenated palm oil (HPO) as compared to liquid lipid nanoparticles (LLNs) with pure MCT. SLNs formulated with GS were fully digested, similarly to LLNs. However, HPO-containing SLNs presented slower lipolysis kinetics during the intestinal phase at increasing HPO concentration. Despite this, HPO-SLNs showed higher ß-carotene bioaccessibility, which was related to the higher amount of monounstaturated free fatty acids in the micelle fraction. Thus, this work provides valuable insight for designing delivery systems of bioactive compounds with optimal functionality.


Assuntos
Lipídeos/química , Lipólise/efeitos dos fármacos , Nanopartículas/química , beta Caroteno/farmacocinética , Digestão/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Glicerídeos/metabolismo , Cinética , Micelas , beta Caroteno/metabolismo
14.
Biochem Pharmacol ; 172: 113774, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870769

RESUMO

Acetaminophen is both widely used to treat children with fever and is also responsible for thousands being hospitalised annually. Historically the antipyretic actions of acetaminophen were attributed to the inhibition of cyclooxygenase (COX-1/2) enzymes and more recently a novel COX-1 variant (COX-3) located in the brain. However, the evidence for acetaminophen-mediated COX inhibition remains contentious. This study assesses the impact of acetaminophen and other putative COX-3 inhibitors on the release of fatty acids during lipolysis as an alternative mechanism by which antipyretics can reduce body temperature during fever. 3T3-L1 adipocytes, primary brown adipocytes and isolated mitochondria were exposed to COX-3 inhibitors and lipolysis and mitochondrial electron transport chain function assessed. Acetaminophen, aminopyrine and antipyrine at 1-10 mM caused a significant decrease (up to 70%; P < 0.01, from control) in lipolysis within 1, 3 and 24 h without affecting cell viability. The inhibition was observed regardless of where along its signalling pathway lipolysis was stimulated. All three compounds were found to significantly attenuate mitochondrial function by up to 30% for complex I and 40% for complex II (P < 0.01, from control). These novel observations combined with the known limited inhibition of the COX enzymes by acetaminophen suggest both the antipyretic and hypothermia induced by acetaminophen and related compounds could be attributed to the direct inhibition of lipolysis and mitochondrial function, rather than cyclooxygenase inhibition centrally. Further these observations could provide new drug targets for reducing fever with the added bonus of fewer individuals being hospitalized by accidental acetaminophen overdose.


Assuntos
Acetaminofen/farmacologia , Adipócitos/efeitos dos fármacos , Antipiréticos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Lipólise/efeitos dos fármacos , Células 3T3-L1 , 8-Bromo Monofosfato de Adenosina Cíclica/metabolismo , Adipócitos/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Aminopirina/farmacologia , Animais , Antipirina/farmacologia , Diferenciação Celular , Colforsina/metabolismo , Isoproterenol/farmacologia , Camundongos , Ratos , Ratos Wistar
15.
Food Funct ; 11(1): 606-616, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31859303

RESUMO

The stability, in vitro digestion profile and phase behavior of Pickering emulsions stabilized by milled cellulose were evaluated to investigate their feasibility as food-grade formulations for encapsulation and delivery of lipophilic bioactive compounds. Curcumin encapsulated in Pickering emulsions exhibited good stability with less than 50% degraded after 30 days' storage. The digestion profiles of emulsions were markedly influenced by lipid type used and digestion buffer employed in simulated small intestinal experiments. The rate and extent of lipolysis of emulsions with medium chain triglycerides were greater than emulsions with long chain triglycerides (soy bean oil and canola oil), reaching complete hydrolysis under both fed and fasted conditions. For comparison, the digestion behaviors of curcumin encapsulated in conventional emulsions were also evaluated. Although the initial digestion rate of Pickering emulsions with long chain triglycerides was slower than the corresponding conventional emulsions stabilized by Tween/Span 80, their total extent of lipolysis was higher than that of conventional emulsions. The bioaccessibility of curcumin encapsulated in Pickering emulsions was higher than in corresponding small molecular weight surfactant stabilized conventional emulsions.


Assuntos
Celulose/química , Curcumina/química , Composição de Medicamentos/métodos , Curcumina/farmacologia , Digestão , Composição de Medicamentos/instrumentação , Estabilidade de Medicamentos , Emulsões/química , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiologia , Lipólise/efeitos dos fármacos , Modelos Biológicos , Tamanho da Partícula
16.
J Agric Food Chem ; 67(51): 14048-14055, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31791125

RESUMO

Chemical residues in the environment are considered to be important factors that cause obesity. Bifenthrin is one of the pyrethroid pesticides and is widely used worldwide. However, its effect on adipose tissue is ill-defined. Here, we administered bifenthrin/corn oil to adult C57BL/6 mice by gavage. After 6 weeks, the bifenthrin treatment significantly increased their body weight (P = 0.015) and fat mass (P < 0.001). Then we identified 246 differently expressed proteins by proteomic analysis, and they were highly involved in fatty acid uptake and lipid metabolism processes. Interestingly, protein hormone-sensitive lipase and adipose triacylglyceride lipase were downregulated while lipoprotein lipase is upregulated after bifenthrin treatment. Similar effects in 3T3-L1 cells treated with bifenthrin validated the in vivo results. Thus, this study suggests that long-term exposure to low-dose bifenthrin induces fat deposition in mice by improving fatty acid uptake and inhibiting lipolysis, and it may cause obesity in humans.


Assuntos
Ácidos Graxos/metabolismo , Lipólise/efeitos dos fármacos , Obesidade/metabolismo , Praguicidas/efeitos adversos , Piretrinas/efeitos adversos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Feminino , Humanos , Lipase/genética , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/fisiopatologia , Praguicidas/metabolismo , Piretrinas/metabolismo , Esterol Esterase/genética , Esterol Esterase/metabolismo
17.
Int J Mol Sci ; 20(23)2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810173

RESUMO

The PPARs (peroxisome proliferator-activated receptors) play critical roles in the regulation of lipid and glucose metabolism. PPARδ, a member of the PPARs family, is associated with decreased susceptibility to ectopic lipid deposition and is implicated in the regulation of mitochondrial processes. The current study aimed to determine the role of PPARδ in fatty acid ß-oxidation and its influence on PEPCK for the lipogenic/lipolytic balance during in vitro bovine oocyte maturation and embryo development. Activation of PPARδ by GW501516, but not 2-BP, was indicated by intact embryonic PEPCK (cytosolic) and CPT1 expression and the balance between free fatty acids and mitochondrial ß-oxidation that reduced ROS and inhibited p-NF-κB nuclear localization. Genes involved in lipolysis, fatty acid oxidation, and apoptosis showed significant differences after the GW501516 treatment relative to the control- and 2-BP-treated embryos. GSK3787 reversed the PPARδ-induced effects by reducing PEPCK and CPT1 expression and the mitochondrial membrane potential, revealing the importance of PPARδ/PEPCK and PPARδ/CPT1 for controlling lipolysis during embryo development. In conclusion, GW501516-activated PPARδ maintained the correlation between lipolysis and lipogenesis by enhancing PEPCK and CPT1 to improve bovine embryo quality.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Desenvolvimento Embrionário/genética , PPAR delta/genética , Fosfoenolpiruvato Carboxilase/genética , Animais , Apoptose , Bovinos , Ácidos Graxos não Esterificados/metabolismo , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Oxirredução , Tiazóis/farmacologia
18.
BMC Complement Altern Med ; 19(1): 338, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783835

RESUMO

BACKGROUND: To investigate the potential of Catharanthus roseus leaf aqueous crude extract (CRACE) as a regulator of adipocyte development and function. METHODS: 3T3-L1 adipogenesis model was used to investigate the effect of CRACE on adipogenesis. 3T3-L1 preadipocytes (for adipogenic differentiation) and mature 3T3-L1 adipocytes (for adipocyte function) were treated with non-toxic doses of CRACE. The outcomes were corroborated by intracellular lipid accumulation, expression of pro-and anti-adipogenic effector molecules. To investigate CRACE mediated lipolysis, cAMP accumulation, glycerol release and phosphorylation of key effector molecules were tested in treated mature adipocytes. Finally, the extract was fractionated to identify the active molecule/s in the extract. RESULTS: CRACE significantly reduced adipocyte differentiation by modulating PPARγ expression. At early stage CRACE directly targeted Lipin1 expression and consequently impacted KLF7, subsequently expression of GATA2, CEBPα, SREBP1c were targeted, with PPARγ expression, particularly curtailed. While CRACE significantly reduced several lipogenic genes like FAS and GPD1 in mature adipocytes, concomitantly, it greatly increased lipolysis resulting in decreased lipid accumulation in mature adipocytes. The increase in lipolysis was due to decreased Akt activation, increased cAMP level, and PKA activity. The fractionation of CRACE allowed identification of two fractions with potent anti-adipogenic activity. Both the fractions contained 1α, 25-dihydroxy Vitamin D3 as major component. CONCLUSIONS: 1α, 25-dihydroxy Vitamin D3 containing CRACE can be developed into an effective anti-obesity formulation that decreases adipogenesis and increases lipid catabolism.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Calcitriol/farmacologia , Catharanthus , Lipólise/efeitos dos fármacos , Células 3T3-L1 , Animais , Camundongos , Extratos Vegetais/farmacologia , Folhas de Planta/química
19.
Metabolism ; 101: 153999, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31672447

RESUMO

BACKGROUND: Adipose tissue plays a crucial role in diet- and obesity-related insulin resistance, with implications for several metabolic diseases. Identification of novel target genes and mechanisms that regulate adipocyte function could lead to improved treatment strategies. RND3 (RhoE/Rho8), a Rho-related GTP-binding protein that inhibits Rho kinase (ROCK) signaling, has been linked to diverse diseases such as apoptotic cardiomyopathy, heart failure, cancer and type 2 diabetes, in part by regulating cytoskeleton dynamics and insulin-mediated glucose uptake. RESULTS: We here investigated the expression of RND3 in adipose tissue in human obesity, and discovered a role for RND3 in regulating adipocyte metabolism. In cross-sectional and prospective studies, we observed 5-fold increased adipocyte levels of RND3 mRNA in obesity, reduced levels after surgery-induced weight loss, and positive correlations of RND3 mRNA with adipocyte size and surrogate measures of insulin resistance (HOMA2-IR and circulating triglyceride/high-density lipoprotein cholesterol (TAG/HDL-C) ratio). By screening for RND3-dependent gene expression following siRNA-mediated RND3 knockdown in differentiating human adipocytes, we found downregulation of inflammatory genes and upregulation of genes related to adipocyte ipolysis and insulin signaling. Treatment of adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), hypoxia or cAMP analogs increased RND3 mRNA levels 1.5-2-fold. Functional assays in primary human adipocytes confirmed that RND3 knockdown reduces cAMP- and isoproterenol-induced lipolysis, which were mimicked by treating cells with ROCK inhibitor. This effect could partly be explained by reduced protein expression of adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase (HSL). CONCLUSION: We here uncovered a novel differential expression of adipose RND3 in obesity and insulin resistance, which may at least partly depend on a causal effect of RND3 on adipocyte lipolysis.


Assuntos
Adipócitos/metabolismo , Lipólise/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/fisiologia , Animais , Células Cultivadas , Estudos Transversais , Regulação da Expressão Gênica , Humanos , Resistência à Insulina , Obesidade/metabolismo , Estudos Prospectivos , RNA Mensageiro/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo
20.
Phytomedicine ; 65: 153064, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31645009

RESUMO

BACKGROUND: Obesity develops when dietary energy intake exceeds energy expenditure, and can be associated with metabolic syndrome. Recent studies have shown that dietary phytochemicals can promote energy expenditure by inducing the browning of white adipose tissue (WAT). PURPOSE: This study investigated whether cardamonin induces the browning of 3T3-L1 adipocytes through the activation of protein kinase A (PKA). METHODS: Anti-obesity potential of cardamonin was evaluated in 3T3-L1 adipocytes. Adipocyte-specific genes were observed using western blot, qPCR analysis and immunocytochemistry. RESULTS: Cardamonin treatment inhibited lipid droplet accumulation and reduced the expression of the adipogenic proteins C/EBPα and FABP4, and the lipogenic proteins LPAATθ, lipin 1, DGAT1, SREBP1, and FAS. Cardamonin also induced the expression of the browning marker genes PRDM16, PGC1α, and UCP1 at the mRNA and protein levels, and induced mRNA expression of CD137, a key marker of beige adipocytes. It also increased the expression of the ß-oxidation genes CPT1 and PPARα at the mRNA and protein levels. In addition, cardamonin increased PKA phosphorylation and the mRNA and protein expression of the downstream lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). CONCLUSION: Our findings demonstrate novel effects of cardamonin to stimulate adipocyte browning, suppress lipogenesis, and promote lipolysis, implying it may have potential as an anti-obesity agent.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Chalconas/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lipogênese/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Camundongos , Oxirredução/efeitos dos fármacos , Esterol Esterase/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
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