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1.
Biochem Biophys Res Commun ; 575: 20-27, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34454176

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a common disease with a multitude of complications. Increasing evidence shows that the dietary supplement with betaine, a natural chemical molecule, can effectively reduce the fat accumulation in the liver. Translational regulation is considered to play a vital role in gene expression, but whether betaine functions through the regulation of gene translational level is still unclear. To this end, RNC-seq (mRNAs bound to ribosome-nascent chain complex sequencing) and RNA-seq co-analyses were performed to identify betaine target genes by using the liver samples from high-fat diet adding betaine treated and high-fat diet treated mice. The results showed that betaine does play a lipid-lowering role by regulating the expression of gene translation levels; some NAFLD- and lipid metabolism-associated genes were differentially expressed at translational level, for example. And the translation ratio (TR) of gene significantly increased after betaine treatment. Finally, we identified a novel function gene, Gpc1, which may mediate the lipid-lowering effect of betaine in the liver. To sum up, this study depicted the molecular portrait of mice liver with or without betaine treatment from the angel of translatome and transcriptome, giving insights into the molecular mechanism of betaine-mediated lipid-lowering effect and also providing new clues for understanding and prevention of NAFLD.


Assuntos
Betaína/farmacologia , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Metabolismo dos Lipídeos , Lipotrópicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Biossíntese de Proteínas , Distribuição Aleatória , Análise de Sequência de RNA/métodos , Transcriptoma
2.
Mol Biol Rep ; 47(8): 5729-5735, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32833184

RESUMO

Allergic asthma is a chronic inflammatory airway disease concomitant with oxidative stress. The aim of this study was to evaluate the effects of betaine against asthma-induced oxidative stress in experimentally animal model. 32 BALB/C mice were divided into four equal groups as: control, asthma, prednisolone and betaine groups. 100 µl of the solution (Ova albumin (OVA, 400 µg and AL(OH)3 gel in 1 ml of phosphate buffer) was injected intraperitoneally to each mouse on days 0, 7, 14 and 21 and sensitized with OVA drop, three times a week from days 27 until 84 in asthma, prednisolone and betaine groups. Prednisolone (3 mg/kg) and betaine (1% of the total diet) were administered at day 27 to 84 as orally once daily and vehicle to controls and asthma group. Sera were collected for IgE detection and lung tissue was taken for histopathology assessment. Glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) activities, and glutathione content (GSH) as well as malondialdehyde (MDA) concentration as lipid peroxidation marker were also measured in the liver and kidney tissues. Pathological changes of the lung tissue were observed in the asthma and prednisolone groups. Prednisolone also caused significant increase level of anti-OVA IgE. The GPx activity increased significantly in the liver and kidney of asthmatic group when compared to the control and prednisolone groups. Liver MDA as lipid peroxidation marker was also significantly higher in the prednisolone-treated mice when compared to the other groups. Although the CAT and SOD activities as well as GSH content increased in the betaine and prednisolone-treated mice, these enhancements were not statically significant. Predinsolone as first choice in asthma treatment showed some oxidative properties. In contrast, betaine improved airway inflammation of lung tissue which may be associated with the antioxidant properties of betaine. This study provides a potential promising effect of betaine for treatment of asthma in future studies.


Assuntos
Asma/tratamento farmacológico , Betaína/farmacologia , Inflamação/prevenção & controle , Nefropatias/tratamento farmacológico , Lipotrópicos/farmacologia , Hepatopatias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Asma/metabolismo , Modelos Animais de Doenças , Feminino , Glucocorticoides/farmacologia , Inflamação/etiologia , Inflamação/patologia , Nefropatias/etiologia , Nefropatias/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Camundongos , Camundongos Endogâmicos BALB C , Prednisolona/farmacologia
3.
Eur J Nutr ; 59(4): 1707-1716, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31201489

RESUMO

PURPOSE: Excessive exposure of glucocorticoids activates adipose lipolysis, increases circulating free fatty acids, and contributes to ectopic lipid deposition in liver and skeletal muscle. Our previous study demonstrated that maternal betaine supplementation attenuates glucocorticoid-induced hepatic lipid accumulation in rat offspring. However, it is unclear whether maternal betaine supplementation is effective in preventing glucocorticoid-induced lipolysis in the adipose tissue of offspring. METHODS: In this study, 20 pregnant rats were fed with basal or betaine-supplemented (10 g/kg) diets throughout gestation and lactation, and the offspring rats were raised on the basal diet from weaning till 3 months of age followed by daily intraperitoneal injection of saline or 0.1 mg/kg dexamethasone (DEX) for 3 weeks. RESULTS: Chronic DEX treatment significantly (P < 0.05) decreased serum corticosterone level and increased proinflammatory cytokines, such as TNFα, IL-1ß, and IL-6. Meanwhile, GR protein content in adipose tissue was increased in response to DEX treatment, which was associated with a significant (P < 0.05) up-regulation of ATGL and HSL expression at both mRNA and protein levels. All these DEX-induced changes were significantly (P < 0.05) attenuated in progeny rats derived from betaine-supplemented dams. Furthermore, DEX-induced hypomethylation of ATGL and HSL gene promoters was reversed by maternal betaine supplementation. CONCLUSIONS: Taken together, these results suggest that maternal betaine supplementation is effective in alleviating glucocorticoid-induced lipolysis in adipose tissue with modification of DNA methylation on the promoter of lipolytic genes.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Betaína/farmacologia , Metilação de DNA/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Lipotrópicos/farmacologia , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Tecido Adiposo/metabolismo , Animais , Betaína/metabolismo , Suplementos Nutricionais , Feminino , Glucocorticoides , Lipotrópicos/metabolismo , Masculino , Gravidez , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Alcohol Clin Exp Res ; 43(9): 1887-1897, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31329297

RESUMO

BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis. METHODS: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline. RESULTS: We found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. CONCLUSIONS: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Proteínas Circadianas Period/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Pró-Opiomelanocortina/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Colina/farmacologia , Colina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais , Epigênese Genética/efeitos dos fármacos , Feminino , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipotrópicos/farmacologia , Lipotrópicos/uso terapêutico , Masculino , Gravidez
5.
Nutr Res ; 64: 49-55, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30802722

RESUMO

Dietary supplementation with the major lipotrope myo-inositol (MI) potently reduces triglyceride (TG) content and expression levels of the fatty acid synthesis genes, for example, fatty acid synthase (FASN), in rat nonalcoholic fatty liver induced by high-fructose diet. Fatty acid synthesis genes are regulated by the carbohydrate-responsive element-binding protein (ChREBP) that exists in 2 isoforms: ChREBP-α and ChREBP-ß. The gene encoding the latter isoform is more responsive to fructose. Because MI repressed the induction of fatty acid synthesis gene expression by high-fructose diet, we hypothesized that MI may reduce binding of ChREBP to the carbohydrate response elements (ChoREs) in the ChREBP-ß gene as well as in fatty acid synthesis genes in the liver. Rats were fed high-glucose, high-fructose, or high-fructose diets supplemented with MI (0.05% and 0.25%) for 2 weeks. Hepatic TG content and expression levels of the glucose-6-phosphate dehydrogenase, malic enzyme 1, FASN, acetyl-CoA carboxylase alpha, S14, and ChREBP-ß were remarkably elevated in rats fed with high fructose compared with the corresponding levels in high-glucose group. Notably, elevated values of these parameters in high-fructose group were reduced by MI. Similarly, high-fructose-induced ChREBP binding to the ChoREs of the ChREBP-ß and FASN genes was nominally decreased by MI. This study showed that treatment with MI reduced elevated TG content and expression of genes related to fatty acid synthesis, such as FASN and ChREBP-ß, in rat nonalcoholic fatty liver induced by high-fructose diet. Furthermore, MI treatment nominally decreased increased binding of ChREBP to the ChoREs of ChREBP-ß and FASN genes.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo , Frutose/metabolismo , Inositol/farmacologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Triglicerídeos/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Dieta/efeitos adversos , Açúcares da Dieta/administração & dosagem , Açúcares da Dieta/efeitos adversos , Açúcares da Dieta/metabolismo , Suplementos Nutricionais , Ácido Graxo Sintase Tipo I/genética , Frutose/administração & dosagem , Frutose/efeitos adversos , Expressão Gênica , Glucosefosfato Desidrogenase/metabolismo , Inositol/uso terapêutico , Lipogênese/efeitos dos fármacos , Lipotrópicos/farmacologia , Lipotrópicos/uso terapêutico , Fígado/metabolismo , Malato Desidrogenase/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Nucleares/metabolismo , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo
6.
J Physiol Biochem ; 75(1): 1-10, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30506389

RESUMO

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism-all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.


Assuntos
Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Lipotrópicos/farmacologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucose/metabolismo , Humanos , Resistência à Insulina , Leptina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Melatonina/farmacologia , Peptídeos Natriuréticos/farmacologia , Termogênese/efeitos dos fármacos , Termogênese/genética , Tretinoína/farmacologia
7.
J Hepatol ; 69(3): 635-643, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29758334

RESUMO

BACKGROUND & AIMS: Dysregulation of the Keap1-Nrf2 pathway has been observed in experimental and human tumors, suggesting possible roles of the pathway in cancer development. Herein, we examined whether Nrf2 (Nfe2l2) activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma (HCC). METHODS: We used wild-type (WT) and Nrf2 knockout (Nrf2KO) rats treated with a single injection of diethylnitrosamine (DENA) followed by choline-devoid methionine-deficient (CMD) diet. This experimental model causes massive fatty liver and steatohepatitis with fibrosis and enables identification of early stages of hepatocarcinogenesis. RESULTS: We found that Nrf2 activation takes place in early preneoplastic lesions identified by the marker glutathione S-transferase placental form (GSTP). Nrf2 missense mutations, known to disrupt the Keap1-Nrf2 binding, were present in 65.7% of GSTP-positive foci. Nrf2KO rats were used to directly investigate whether Nrf2 is critical for initiation and/or clonal expansion of DENA-damaged hepatocytes. While Nrf2 genetic inactivation did not alter DENA-induced initiation, it led to increased liver injury and chronic compensatory hepatocyte regeneration when rats were fed a CMD diet. However, in spite of such a permissive environment, the livers of Nrf2KO rats did not display any preneoplastic lesion unlike those of WT rats. CONCLUSIONS: These results demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease: i) Nrf2 is activated at early steps of the tumorigenic process and ii) Nrf2 is mandatory for the clonal expansion of initiated cells, indicating that Nrf2 is critical in the onset of HCC. LAY SUMMARY: Dysregulation of the Keap1-Nrf2 molecular pathway has been observed in human tumors. In a nutritional model of hepatocarcinogenesis, the protein Nrf2 is frequently mutated/activated at early steps of the tumorigenic process. Herein, we show that Nrf2 is mandatory for the development of preneoplastic lesions. These results suggest that Nrf2 has a critical role in the onset of hepatocellular carcinoma.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular , Colina/farmacologia , Neoplasias Hepáticas , Metionina/farmacologia , Fator 2 Relacionado a NF-E2 , Alquilantes/farmacologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/prevenção & controle , Dieta/métodos , Dietilnitrosamina/farmacologia , Modelos Animais de Doenças , Inativação Gênica , Lipotrópicos/farmacologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Ratos , Resultado do Tratamento
8.
Diabetes ; 67(6): 1093-1104, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29535089

RESUMO

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.


Assuntos
Fator 3 Ativador da Transcrição/agonistas , Regulação da Expressão Gênica , Hipotálamo/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Receptores para Leptina/agonistas , Transdução de Sinais , Fator 3 Ativador da Transcrição/química , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Cruzamentos Genéticos , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Metabolismo Energético/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Leptina/análogos & derivados , Leptina/farmacologia , Leptina/uso terapêutico , Lipotrópicos/farmacologia , Lipotrópicos/uso terapêutico , Masculino , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
9.
J Cell Biochem ; 119(7): 5676-5685, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29384213

RESUMO

Fat mass and obesity-associated protein (FTO) is a RNA demethylase, whether FTO regulates fat metabolism through its demethylation is unclear. The results of this study confirmed that N6-methyladenosine (m6 A) is associated with fat accumulation both in vivo and in vitro. The data showed that FTO down-regulated m6 A levels, decreased mitochondrial content, and increased triglyceride (TG) deposition. However, an FTO (R316A) mutant lacking demethylation activity could not regulate mitochondria and TG content, indicating that FTO affects mitochondrial content and fat metabolism by modulating m6 A levels in hepatocytes. In addition, the regulatory roles of cycloleucine (methylation inhibitor) and betaine (methyl donor) could regulate m6 A levels and fat deposition. This work clarified that the demethylation function of FTO plays an essential role in the fat metabolism of hepatocytes and links the epigenetic modification of RNA with fat deposition, thereby providing a new target (m6 A) for regulation of hepatic fat metabolism.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Desmetilação/efeitos dos fármacos , Gorduras/metabolismo , Hepatócitos/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/patologia , RNA/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Betaína/farmacologia , Cicloleucina/farmacologia , Epigênese Genética , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lipotrópicos/farmacologia , Metilação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Conformação Proteica , Suínos
10.
JPEN J Parenter Enteral Nutr ; 42(2): 436-445, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-27856995

RESUMO

BACKGROUND: Deficiency of choline, a required nutrient, is related to intestinal failure-associated liver disease (IFALD). Therefore, we aimed to investigate the effects of choline supplementation on IFALD and the underlying mechanisms. METHODS: Male Sprague-Dawley rats (4 weeks old) were fed AIN-93G chow and administered intravenous 0.9% saline (control), parenteral nutrition (PN), or PN plus intravenous choline (600 mg/kg) for 7 days. We evaluated body weight, hepatic histology, biochemical indicators, triglycerides, oxidative status, methylation levels of peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, expression of PPARα and carnitine palmitoyltransferase 1 (CPT1), and levels of choline metabolites. RESULTS: The PN + choline group exhibited improved body weight compared with the PN group. PN impaired hepatic function, increased hepatic triglycerides, induced dyslipidemia, enhanced reactive oxygen species and malondialdehyde, and reduced total antioxidant capacity. The PN group had higher pathologic scores than the control group. These results were prevented by choline administration. Compared with the control group, PN increased PPARα promoter methylation and hepatic betaine concentration, reduced hepatic choline and phosphatidylcholine (PC) levels, decreased plasma choline and betaine concentrations, and downregulated PPARα and CPT1 mRNA and protein expression. Choline supplementation elevated hepatic choline and PC levels and enhanced plasma choline, betaine, and PC concentrations but reduced hepatic betaine level, reversed PPARα promoter hypermethylation, and upregulated PPARα and CPT1 mRNA and protein expression in PN-fed rats, compared with rats receiving PN alone. CONCLUSION: Choline addition to PN may prevent IFALD by reducing oxidative stress, enhancing hepatic fat export, and promoting fatty acid catabolism in immature rats receiving PN.


Assuntos
Colina/farmacologia , Enteropatias/prevenção & controle , Lipotrópicos/farmacologia , Nutrição Parenteral/métodos , Animais , Colina/administração & dosagem , Modelos Animais de Doenças , Intestinos/efeitos dos fármacos , Lipotrópicos/administração & dosagem , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
11.
FEBS J ; 285(3): 501-517, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29197188

RESUMO

Hyperlipidemia is a chronic disorder which plays an important role in the development of cardiovascular diseases, type 2 diabetes, atherosclerosis, hypertension, and nonalcoholic fatty liver disease. Genipin (GNP) is a metabolite from genipioside, which is an active component of the traditional Chinese medicine Gardenia jasminoides Ellis, and has been recognized as a beneficial compound against metabolic disorders. However, whether it can correct overnutrition-induced dyslipidemia is still unknown. In this study, the effects of GNP on attenuating hyperlipidemia and hepatic lipid accumulation were investigated using normal and obese mice induced with a high-fat diet (HFD) and primary hepatocytes treated with free fatty acids. We also sought to identify potential targets of GNP to mediate its effects in the liver. We found that obese mice treated with GNP showed a decrease in the body weight, serum lipid levels, as well as hepatic lipid accumulation. Besides, GNP regulated hepatic expression levels of lipid metabolic genes, which are important in maintaining systemic lipid homeostasis. At the molecular level, GNP increased the expression levels of miR-142a-5p, which bound to 3' untranslated region of Srebp-1c, an important regulator of lipogenesis, which thus led to the inhibition of lipogenesis. Collectively, our data demonstrated that GNP effectively antagonized HFD-induced hyperlipidemia and hepatic lipid accumulation in mice. Such effects were achieved by regulating miR-142a-5p/SREBP-1c axis.


Assuntos
Hiperlipidemias/tratamento farmacológico , Iridoides/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipotrópicos/uso terapêutico , Fígado/efeitos dos fármacos , MicroRNAs/agonistas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Células Cultivadas , Biologia Computacional , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/efeitos adversos , Ácidos Graxos não Esterificados/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter/efeitos dos fármacos , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Resistência à Insulina , Iridoides/administração & dosagem , Iridoides/farmacologia , Lipotrópicos/administração & dosagem , Lipotrópicos/farmacologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Distribuição Aleatória , Proteína de Ligação a Elemento Regulador de Esterol 1/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
12.
Diabetes Obes Metab ; 20(2): 257-269, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28722242

RESUMO

GPR119 belongs to the G protein-coupled receptor family and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycaemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.


Assuntos
Drogas em Investigação/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Modelos Biológicos , Receptores Acoplados a Proteínas G/agonistas , Animais , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Ligantes , Lipotrópicos/efeitos adversos , Lipotrópicos/farmacologia , Lipotrópicos/uso terapêutico , Doenças Metabólicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Especificidade de Órgãos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
13.
BMC Vet Res ; 12: 210, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27646125

RESUMO

BACKGROUND: This study aimed to investigate the possible serum protein changes after endotoxin administration in healthy and choline-treated calves using proteomics. These results are expected to contribute to the understanding of the pathophysiological mechanisms of endotoxemia and the beneficial effect of choline administration in this clinical situation. METHODS: Healthy-calves (n = 20) were divided into 4 groups: Control, Choline treated (C), Lipopolysaccharide administered (LPS), and LPS + C. Control calves received 0.9 % NaCl injection. Calves in C and LPS + C groups received choline chloride (1 mg/kg/iv). Endotoxin (LPS) was injected (2 µg/kg/iv) to the calves in LPS and LPS + C groups. Serum samples were collected before and after the treatments. Differentially expressed proteins (> 1.5 fold-change relative to controls) were identified by LC-MS/MS. RESULTS: After LPS administration, 14 proteins increased, and 13 proteins decreased within 48 h as compared to controls. In the LPS group, there were significant increases in serum levels of ragulator complex protein (189-fold) and galectin-3-binding protein (10-fold), but transcription factor MafF and corticosteroid binding globulin were down regulated (≥ 5 fold). As compared with the LPS group, in LPS + C group, fibrinogen gamma-B-chain and antithrombin were up-regulated, while hemopexin and histone H4 were down-regulated. Choline treatment attenuated actin alpha cardiac muscle-1 overexpression after LPS. CONCLUSIONS: LPS administration produces changes in serum proteins associated with lipid metabolism, immune and inflammatory response, protein binding/transport, cell adhesion, venous thrombosis, cardiac contractility and blood coagulation. The administration of choline is associated with changes in proteins which can be related with its beneficial effect in this clinical situation.


Assuntos
Proteínas Sanguíneas/metabolismo , Bovinos/sangue , Colina/farmacologia , Endotoxinas/toxicidade , Proteômica , Animais , Colina/administração & dosagem , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipotrópicos/química , Lipotrópicos/farmacologia , Projetos Piloto
14.
J Hepatobiliary Pancreat Sci ; 23(5): 260-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26880573

RESUMO

BACKGROUND: We previously reported a model of non-alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline-deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long-term CD diet leads to hepatic fibrosis through oxidative stress. METHODS: Eight-week-old male SHR and normotensive Wistar Kyoto rats (WKYs) were fed a CD diet for 5 or 20 weeks, then liver histology and hepatic expression of genes related to lipid metabolism, fibrosis, and oxidative stress were assessed. Oxidative stress was assessed by hepatic thiobarbituric acid reactive substance (TBARS) levels. RESULTS: After 5 weeks on CD diet, prominent hepatic steatosis and decrease in expression of genes for lipid metabolism were observed in SHRs as compared with WKYs. SHRs on a CD diet demonstrated a downregulated expression of genes for antioxidants, along with significant increases in hepatic TBARS. After 20 weeks on CD diet, SHRs demonstrated severe liver fibrosis and upregulated expressions of genes for fibrosis when compared with WKY. CONCLUSION: Hypertension precipitated hepatic steatosis, and further, acts as an enhancer in NAFLD progression to liver fibrosis through oxidative stress.


Assuntos
Colina/farmacologia , Dieta , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Animais , Modelos Animais de Doenças , Seguimentos , Lipotrópicos/farmacologia , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
15.
Childs Nerv Syst ; 32(3): 467-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26732065

RESUMO

PURPOSE: We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring. METHODS: Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated. RESULTS: Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters. CONCLUSION: We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS.


Assuntos
Betaína/farmacologia , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Ácidos Graxos Ômega-3/farmacologia , Degeneração Neural/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Lipotrópicos/farmacologia , Degeneração Neural/prevenção & controle , Gravidez , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Ratos , Ratos Sprague-Dawley
16.
Nat Rev Drug Discov ; 15(4): 249-74, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26794269

RESUMO

Non-alcoholic fatty liver disease - the most common chronic liver disease - encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Over the next decade, NASH is projected to be the most common indication for liver transplantation. The absence of an effective pharmacological therapy for NASH is a major incentive for research into novel therapeutic approaches for this condition. The current focus areas for research include the modulation of nuclear transcription factors; agents that target lipotoxicity and oxidative stress; and the modulation of cellular energy homeostasis, metabolism and the inflammatory response. Strategies to enhance resolution of inflammation and fibrosis also show promise to reverse the advanced stages of liver disease.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Autofagia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Imunidade Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Lipotrópicos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Conduta do Tratamento Medicamentoso , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-26804769

RESUMO

Fat accumulation in the liver is a natural process in goose, which prepares goose for long-distance migration. In contrast to mammalian fatty liver that usually progresses into an irreversible status, steatohepatitis, goose fatty liver can return to normal without obvious pathological damage, suggesting a protective system exists in goose liver. This study was to identify the components of this system. We first focused on goose adiponectin receptor 1 and 2 (Adipor1/2) as they have ceramidase activity, and can cleave ceramide, a group of proinflammatory signaling lipid species. Quantitative analysis indicated that tumor necrosis factor alpha (Tnfα), a key proinflammatory cytokine, was down-regulated in goose fatty liver by overfeeding. This inhibition of Tnfα was accompanied with reduced adiponectin and increased Adipor1/2 in the adipose tissues and in the livers of the overfed geese, respectively. To investigate the regulation of goose Adipor2 in the context of fatty liver, we treated goose primary hepatocytes with fatty liver associated factors. Data indicated that Adipor2 was upregulated by glucose and oleate but not palmitate. Its expression was even suppressed by high level of insulin. The regulation of Adipor1 by these factors was quite similar to that of Adipor2 except that glucose did not induce Adipor1. Together, these findings suggest the upregulation of Adipor1/2 may, at least partially, contribute to the inhibition of inflammation in goose fatty liver, and the expression of Adipor1/2 can be regulated by fatty liver-associated factors.


Assuntos
Proteínas Aviárias/metabolismo , Fígado Gorduroso/veterinária , Gansos , Regulação da Expressão Gênica , Fígado/metabolismo , Doenças das Aves Domésticas/metabolismo , Receptores de Adiponectina/metabolismo , Gordura Abdominal/imunologia , Gordura Abdominal/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animais , Animais Endogâmicos , Proteínas Aviárias/agonistas , Proteínas Aviárias/genética , Células Cultivadas , China , Progressão da Doença , Embrião não Mamífero/citologia , Nutrição Enteral/efeitos adversos , Nutrição Enteral/veterinária , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/efeitos adversos , Glucose/metabolismo , Insulina/farmacologia , Lipotrópicos/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Ácido Oleico/efeitos adversos , Ácido Oleico/metabolismo , Doenças das Aves Domésticas/etiologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/fisiopatologia , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Pancreas ; 45(6): 836-45, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26646265

RESUMO

OBJECTIVES: To explore the effect of betaine on alcoholic pancreatic steatosis and its mechanism. METHODS: Rats were randomly assigned to control, ethanol, or ethanol + betaine groups. Changes in pancreatic morphology; serum lipid levels; and pancreatic lipid, amylase and lipase levels were determined. The serum and adipose tissue adiponectin level was measured by an enzyme-linked immunoassay. Adiponectin receptor-1 (AdipoR1), AdipoR2, sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, and fatty acid synthetase expression levels were quantified. The SREBP-1c expression in SW1990 cells treated with various concentrations of ethanol or ethanol plus betaine and/or adiponectin was assessed. RESULTS: Alcohol-induced changes in pancreatic morphology were attenuated by betaine. Pancreatic triglyceride, free fatty acid and expression levels of SREBP-1c and fatty acid synthetase were elevated after ethanol feeding but remained at control levels after betaine supplementation. Alcohol-induced decreases in serum and adipose tissue adiponectin, pancreatic AdipoR1, amylase, and lipase were attenuated by betaine. Serum triglyceride and free fatty acid levels were elevated after alcohol consumption and remained higher after betaine supplementation compared with controls. Betaine and/or adiponectin suppressed alcohol-induced SREBP-1c upregulation in vitro. CONCLUSIONS: Betaine attenuated alcoholic-induced pancreatic steatosis most likely by suppressing pancreatic SREBP-1c both directly and through the restoration of adiponectin signaling.


Assuntos
Betaína/farmacologia , Etanol/administração & dosagem , Pâncreas/efeitos dos fármacos , Pancreatopatias/prevenção & controle , Adiponectina/metabolismo , Amilases/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Insuficiência Pancreática Exócrina/sangue , Insuficiência Pancreática Exócrina/induzido quimicamente , Insuficiência Pancreática Exócrina/prevenção & controle , Humanos , Imuno-Histoquímica , Lipase/metabolismo , Lipídeos/análise , Lipídeos/sangue , Lipotrópicos/farmacologia , Masculino , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatopatias/sangue , Pancreatopatias/induzido quimicamente , Substâncias Protetoras/farmacologia , Ratos Wistar , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
19.
Biochem Cell Biol ; 93(6): 566-73, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26335364

RESUMO

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of lesions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). The excess influx of fatty acids (FAs) into the liver is recognized as a main cause of simple steatosis formation and progression to NASH. Recently, administration of lactoferrin (LF), a glycoprotein present in milk, was suggested to prevent NAFLD development. However, the effect of LF on the contribution of FA to NAFLD development remains unclear. In this study, the effects of LF on FA mixture (FAm)-induced lipotoxicity using human hepatocarcinoma G2 cells were assessed. FAm significantly decreased cell viability and increased intracellular lipid accumulation, whereas LF significantly recovered cell viability without affecting lipid accumulation. FAm-induced lactic dehydrogenase (LDH) and caspase-3/7 activities were significantly decreased by LF and SP600125, a c-Jun N-terminal kinase (JNK) specific inhibitor. We also found that LF added to FAm-treated cells induced Akt phosphorylation, which contributed to inhibition of JNK signaling pathway-dependent apoptosis. Akt inhibitor VIII, an allosteric Akt inhibitor, significantly attenuated the effect of LF on LDH activity and abrogated the ones on cell viability and caspase-3/7 activity. In summary, the present study has revealed that LF has a protective effect on FAm-induced lipotoxicity in a HepG2 model of NAFLD and identified the activation of the Akt signaling pathway as a possibly major mechanism.


Assuntos
Lactoferrina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipotrópicos/farmacologia , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/agonistas , Animais , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Bovinos , Ácidos Graxos não Esterificados/efeitos adversos , Ácidos Graxos não Esterificados/antagonistas & inibidores , Ácidos Graxos não Esterificados/metabolismo , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lactoferrina/antagonistas & inibidores , Lactoferrina/química , Lactoferrina/metabolismo , Lipotrópicos/química , Lipotrópicos/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinoxalinas/farmacologia
20.
J Endocrinol ; 225(3): 147-58, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25869616

RESUMO

Mitochondrial dysfunction in hypertrophic adipocytes can reduce adiponectin synthesis. We investigated whether 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression is increased in hypertrophic adipocytes and whether this is responsible for mitochondrial dysfunction and reduced adiponectin synthesis. Differentiated 3T3L1 adipocytes were cultured for up to 21 days. The effect of AZD6925, a selective 11ß-HSD1 inhibitor, on metabolism was examined. db/db mice were administered 600 mg/kg AZD6925 daily for 4 weeks via gastric lavage. Mitochondrial DNA (mtDNA) content, mRNA expression levels of 11 ß -H sd1 and mitochondrial biogenesis factors, adiponectin synthesis, fatty acid oxidation (FAO), oxygen consumption rate and glycolysis were measured. Adipocyte hypertrophy in 3T3L1 cells exposed to a long duration of culture was associated with increased 11 ß -Hsd1 mRNA expression and reduced mtDNA content, mitochondrial biogenesis factor expression and adiponectin synthesis. These cells displayed reduced mitochondrial respiration and increased glycolysis. Treatment of these cells with AZD6925 increased adiponectin synthesis and mitochondrial respiration. Inhibition of FAO by etomoxir blocked the AZD6925-induced increase in adiponectin synthesis, indicating that 11ß-HSD1-mediated reductions in FAO are responsible for the reduction in adiponectin synthesis. The expression level of 11 ß -Hsd1 was higher in adipose tissues of db/db mice. Administration of AZD6925 to db/db mice increased the plasma adiponectin level and adipose tissue FAO. In conclusion, increased 11ß-HSD1 expression contributes to reduced mitochondrial respiration and adiponectin synthesis in hypertrophic adipocytes.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Obesidade/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Células 3T3-L1 , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Adiponectina/sangue , Adiponectina/genética , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hipertrofia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipotrópicos/farmacologia , Lipotrópicos/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Mutantes , Dinâmica Mitocondrial , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/tratamento farmacológico , Obesidade/patologia , Obesidade/fisiopatologia , Consumo de Oxigênio/efeitos dos fármacos
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