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1.
J Agric Food Chem ; 67(51): 14056-14065, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31789021

RESUMO

The main purpose of the present study was to investigate the browning effect of 6-gingerol (6G), one of the main functional compounds in the ethyl acetate extract of ginger (ginger ethyl acetate fraction, GEF), and its underlying mechanisms. In this study, we first discovered that GEF stimulated brown adipocyte differentiation by upregulating the expression levels of browning-specific transcription makers (UCP1, PRDM16, and PGC-1α), thereby reducing lipogenesis transcriptional regulator (C/EBPα) expression in 3T3-L1-differentiated adipocytes. Then, 6G (47.81 ± 0.62 mg/g) was identified as one of the main functional compounds in GEF using high-performance liquid chromatography. 6G promoted adipocyte browning, as evidenced by an increase in some brown/beige fat-specific genes (PGC-1α, Cidea, Prdm16, Cited1, SIRT1, Tmem26, and Ucp1) and proteins (UCP1, CEBP/ß, PGC-1α, and PRDM16) expression levels. Moreover, 6G greatly improved mitochondrial respiration and energy metabolism by upregulating the expression levels of some mitochondrial biogenesis markers (Tfam, Nrf1, SIRT1, and p-AMPK/AMPK) and increasing the uncoupled oxygen consumption rate of protons leaked in 3T3-L1 cells. Comparison of the experimental results obtained with an inhibitor (dorsomorphin) and an activator (5-aminoimidazole-4-carboxamide ribonucleotide) suggested that the 6G-associated regulation of the energy metabolism effect was mediated partly through the AMPK signaling pathway. This study provides new insight into the promotion of fat browning and regulation of lipid metabolism by 6G and suggests that 6G likely has potential therapeutic effects on obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/efeitos dos fármacos , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Gengibre/química , Extratos Vegetais/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipócitos Marrons/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
2.
J Agric Food Chem ; 67(49): 13605-13616, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31735033

RESUMO

Obesity is a global public health issue. Thermogenesis is a novel way to promote anti-obesity by consuming energy as heat rather than storing it as triacylglycerols. The browning program allows mitochondrial biosynthesis and thermogenesis-related gene expression to occur in subcutaneous white adipose tissue, which results in the formation of beige adipose tissue. Some phytochemicals have exerted the capability to activate the fat browning process. Resveratrol and oxyresveratrol are both natural stilbenoids that have been reported for their anti-obesity efficacy. However, the comparison between the two as they relate to thermogenesis as well as the differences in their underlying mechanisms are still not widely discussed. Our result reveals that both resveratrol and oxyresveratrol could elevate the expression of thermogenesis-related protein expression including UCP1 (uncoupling protein-1) and PRDM (PR domain containing 16) via Sirt1/PGC-1α (sirtuin 1/peroxisome proliferation gamma coactivator-1 α) activation. However, it is suggested that the transcriptional factor PPARα (peroxisome proliferator-activator receptor α) was activated by resveratrol (1.38 ± 0.07 fold) but not oxyresveratrol. Conversely, C/EBPß (CCAAT/enhancer-binding protein ß) was upregulated by oxyresveratrol (1.58 ± 0.05 fold) but not by resveratrol. On the other hand, CPT1 (carnitine palmitoyltransferase) was found to be significantly activated at lower concentrations of oxyresveratrol up to 1.89 ± 0.04 fold as compared to high-fat diet, and it could be a leading reason for UCP1 activation. Lastly, adiponectin expression was promoted in all experimental groups (1.53 ± 0.08 and 1.49 ± 0.11-fold in resveratrol (RES) and high oxyresveratrol (HOXY), respectively), which could be an activator for mitochondrial biosynthesis and UCP1 expression.


Assuntos
Obesidade/tratamento farmacológico , Obesidade/genética , Resveratrol/administração & dosagem , Termogênese/efeitos dos fármacos , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Obesidade/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
3.
BMC Complement Altern Med ; 19(1): 243, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488120

RESUMO

BACKGROUND: Brown adipocytes are known to promote energy expenditure and limit weight gain to combat obesity. Averrhoa bilimbi, locally called belimbing buluh (DBB), is mainly used as an ethnomedicine in the treatment of metabolic disorders including diabetes mellitus, hypertension and obesity. The present study aims to investigate the browning activity on white adipocytes by A. bilimbi leaf extract and to evaluate the potential mechanisms. METHODS: Ethanolic leaf extract of A. bilimbi was exposed to Myf5 lineage precursor cells to stimulate adipocyte differentiation. Protein expressions of brown adipocyte markers were determined through high content screening analysis and validated through western blotting. Mito Stress Test assay was conducted to evaluate the cellular oxygen consumption rate upon A. bilimbi treatment. RESULTS: A. bilimbi ethanolic leaf extract exhibited an adipogenesis effect similar to a PPARgamma agonist. It also demonstrated brown adipocyte differentiation in myoblastic Myf5-positive precursor cells. Expression of UCP1 and PRDM16 were induced. The basal metabolic rate and respiratory capacity of mitochondria were increased upon A. bilimbi treatment. CONCLUSIONS: The findings suggest that Averrhoa bilimbi ethanolic leaf extract induces adipocyte browning through PRDM16 activation and enhances mitochondria activity due to UCP1 up-regulation.


Assuntos
Adipogenia/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Averrhoa/química , Obesidade/fisiopatologia , Extratos Vegetais/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Camundongos , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Folhas de Planta/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
4.
Biomed Environ Sci ; 32(8): 578-591, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31488234

RESUMO

OBJECTIVE: We aimed to explore how fermented barley extracts with Lactobacillus plantarum dy-1 (LFBE) affected the browning in adipocytes and obese rats. METHODS: In vitro, 3T3-L1 cells were induced by LFBE, raw barley extraction (RBE) and polyphenol compounds (PC) from LFBE to evaluate the adipocyte differentiation. In vivo, obese SD rats induced by high fat diet (HFD) were randomly divided into three groups treated with oral gavage: (a) normal control diet with distilled water, (b) HFD with distilled water, (c) HFD with 800 mg LFBE/kg body weight (bw). RESULTS: In vitro, LFBE and the PC in the extraction significantly inhibited adipogenesis and potentiated browning of 3T3-L1 preadipocytes, rather than RBE. In vivo, we observed remarkable decreases in the body weight, serum lipid levels, white adipose tissue (WAT) weights and cell sizes of brown adipose tissues (BAT) in the LFBE group after 10 weeks. LFBE group could gain more mass of interscapular BAT (IBAT) and promote the dehydrogenase activity in the mitochondria. And LFBE may potentiate process of the IBAT thermogenesis and epididymis adipose tissue (EAT) browning via activating the uncoupling protein 1 (UCP1)-dependent mechanism to suppress the obesity. CONCLUSION: These results demonstrated that LFBE decreased obesity partly by increasing the BAT mass and the energy expenditure by activating BAT thermogenesis and WAT browning in a UCP1-dependent mechanism.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/metabolismo , Lactobacillus plantarum/química , Obesidade/tratamento farmacológico , Probióticos/metabolismo , Proteína Desacopladora 1/metabolismo , Células 3T3 , Adipócitos/fisiologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/fisiologia , Ração Animal/análise , Animais , Fármacos Antiobesidade/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Dieta , Fermentação , Hordeum/química , Masculino , Camundongos , Obesidade/genética , Extratos Vegetais/química , Probióticos/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteína Desacopladora 1/genética
5.
J Agric Food Chem ; 67(38): 10595-10603, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31475817

RESUMO

While ß-cryptoxanthin is hypothesized to have a preventive effect on lifestyle-related diseases, its underlying mechanisms are unknown. We investigated the effect of ß-cryptoxanthin on energy metabolism in adipose tissues and its underlying mechanism. C57BL/6J mice were fed a high-fat diet (60% kcal fat) containing 0 or 0.05% ß-cryptoxanthin for 12 weeks. ß-cryptoxanthin treatment was found to reduce body fat gain and plasma glucose level, while increasing energy expenditure. The expression of uncoupling protein (UCP) 1 was elevated in adipose tissues in the treatment group. Furthermore, the in vivo assays showed that the Ucp1 mRNA expression was higher in the ß-cryptoxanthin treatment group, an effect that disappeared upon cotreatment with a retinoic acid receptor (RAR) antagonist. In conclusion, we report that ß-cryptoxanthin reduces body fat and body weight gain and that ß-cryptoxanthin increases the expression of UCP1 via the RAR pathway.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , beta-Criptoxantina/administração & dosagem , Obesidade/tratamento farmacológico , Receptores do Ácido Retinoico/metabolismo , Proteína Desacopladora 1/genética , Animais , Metabolismo Energético/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Receptores do Ácido Retinoico/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo
6.
J Agric Food Chem ; 67(36): 10107-10115, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31434473

RESUMO

We examined the antiobesity effect of a limonoid 7-deacetoxy-7-oxogedunin, named CG-1, purified from the seeds of Carapa guianensis, Meliaceae, known as andiroba in high-fat-diet (HFD)-fed mice. C57BL/6 mice were fed a low-fat diet or an HFD and orally administered CG-1 (20 mg/kg) for 7 weeks. CG-1 lowered the body weight gain and improved the serum triglyceride level and insulin sensitivity in HFD-fed mice. The expression level of the adipogenesis-related genes was lowered by CG-1 in the visceral white adipose tissue (vWAT). The mRNA expression level of the macrophage-related genes decreased in vWAT following the administration of CG-1 to HFD-fed mice. It is noteworthy that CG-1 activated the brown adipose tissue (BAT) with enhanced expression of uncoupling protein 1 and increased the rectal temperature in HFD-fed mice. These results indicate that the limonoid CG-1 decreased body weight gain and ameliorated hypertriglyceridemia and insulin resistance with the activation of BAT in HFD-fed mice.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fármacos Antiobesidade/administração & dosagem , Resistência à Insulina , Limoninas/administração & dosagem , Meliaceae/química , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Sementes/química , Triglicerídeos/sangue , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Ganho de Peso/efeitos dos fármacos
7.
Food Funct ; 10(8): 4771-4781, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31312821

RESUMO

The increased prevalence of obesity significantly affects human health worldwide. Improvement of glycometabolism by dietotherapy/herbal remedy is an effective approach to ameliorate obesity. In this study, high-fat-diet induced obese (DIO) mice were treated with mulberry leaves for 13 weeks. The results showed that mulberry leaves significantly alleviated adiposity of DIO mice including reducing body weight gain, fat accumulation and fasting blood glucose, and improving insulin sensitivity. In addition, mulberry leaves had protective effects on liver and kidneys. The abundant flavonoids, polyphenols and 1-deoxynojirimycin in mulberry leaves were likely responsible for their beneficial effects. Mechanistically, we found that mulberry leaves could alleviate obesity by enhancing brown adipose tissue (BAT) activity partly indicated by elevated thermogenesis and overexpression of uncoupling protein 1 in BAT. Moreover, mulberry leaves significantly increased the Bacteroidetes/Firmicutes ratio and Akkermansia level that were closely associated with obesity development and progression, and decreased the potential proinflammatory Proteobacteria in feces. These findings reveal that the mulberry leaf is an edible plant food with therapeutic potential for obesity and may provide dietotherapy/herbal remedy to the treatment of obesity and its complications.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Morus/química , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tecido Adiposo Marrom/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/microbiologia , Folhas de Planta/química , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
8.
Mol Cell ; 74(4): 844-857.e7, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31000437

RESUMO

Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiological and genetic regulation. BAT-specific deletion of Sirt5, a mitochondrial desuccinylase and demalonylase, results in dramatic increases in global protein succinylation and malonylation. Mass spectrometry-based quantification of succinylation reveals that Sirt5 regulates the key thermogenic protein in BAT, UCP1. Mutation of the two succinylated lysines in UCP1 to acyl-mimetic glutamine and glutamic acid significantly decreases its stability and activity. The reduced function of UCP1 and other proteins in Sirt5KO BAT results in impaired mitochondria respiration, defective mitophagy, and metabolic inflexibility. Thus, succinylation of UCP1 and other mitochondrial proteins plays an important role in BAT and in regulation of energy homeostasis.


Assuntos
Metabolismo Energético/genética , Mitocôndrias/metabolismo , Obesidade/genética , Sirtuínas/genética , Proteína Desacopladora 1/genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Regulação da Expressão Gênica , Glucose/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Obesidade/metabolismo , Obesidade/patologia , Proteômica/métodos , Ácido Succínico/metabolismo , Termogênese/genética , Proteína Desacopladora 1/metabolismo
9.
Biol Sex Differ ; 10(1): 19, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987673

RESUMO

BACKGROUND: The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age. METHODS: Body composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA. RESULTS: Siah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels. CONCLUSIONS: The most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Caracteres Sexuais , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica , Receptor alfa de Estrogênio/metabolismo , Feminino , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transcriptoma , Ubiquitina-Proteína Ligases/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
10.
Infect Immun ; 87(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30962398

RESUMO

Obesity is increasingly causing lifestyle diseases in developed countries where helminthic infections are rarely seen. Here, we investigated whether an intestinal nematode, Heligmosomoides polygyrus, has a suppressive role in diet-induced obesity in mice. Infection with H. polygyrus suppressed weight gain in obese mice, which was associated with increased uncoupling protein 1 (UCP1) expression in adipocytes and a higher serum norepinephrine (NE) concentration. Blocking interactions of NE with its receptor on adipocytes resulted in the failure to prevent weight gain and to enhance UCP1 expression in obese mice infected with H. polygyrus, indicating that NE is responsible for the protective effects of H. polygyrus on obesity. In addition to sympathetic nerve-derived NE, the intestinal microbiota was involved in the increase in NE. Infection with H. polygyrus altered the composition of intestinal bacteria, and antibiotic treatment to reduce intestinal bacteria reversed the higher NE concentration, UCP1 expression, and prevention of the weight gain observed after H. polygyrus infection. Our data indicate that H. polygyrus exerts suppressive roles on obesity through modulation of microbiota that produce NE.


Assuntos
Terapia Biológica , Microbioma Gastrointestinal , Nematospiroides dubius/fisiologia , Obesidade/microbiologia , Obesidade/terapia , Adipócitos/metabolismo , Animais , Humanos , Intestinos/microbiologia , Intestinos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Norepinefrina/metabolismo , Obesidade/metabolismo , Obesidade/parasitologia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
11.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939750

RESUMO

Obesity is a major risk for diabetes. Brown adipose tissue (BAT) mediates production of heat while white adipose tissue (WAT) function in the storage of fat. Roles of BAT in the treatment of obesity and related disorders warrants more investigation. Peroxisome proliferator activator receptor gamma (PPAR-γ) is the master regulator of both BAT and WAT adipogenesis and has roles in glucose and fatty acid metabolism. Adipose tissue is the major expression site for PPAR-γ. In this study, the effects of rosiglitazone on the brown adipogenesis and the association of MAPK and PI3K pathways was investigated during the in vitro adipogenic differentiation of telomerase transformed mesenchymal stromal cells (iMSCs). Our data indicate that 2 µM rosiglitazone enhanced adipogenesis by over-expression of PPAR-γ and C/EBP-α. More specifically, brown adipogenesis was enhanced by the upregulation of EBF2 and UCP-1 and evidenced by multilocular fatty droplets morphology of the differentiated adipocytes. We also found that rosiglitazone significantly activated MAPK and PI3K pathways at the maturation stage of differentiation. Overall, the results indicate that rosiglitazone induced overexpression of PPAR-γ that in turn enhanced adipogenesis, particularly browning adipogenesis. This study reports the browning effects of rosiglitazone during the differentiation of iMSCs into adipocytes in association with the activation of MAPK and PI3K signaling pathways.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipogenia , Hipoglicemiantes/farmacologia , Sistema de Sinalização das MAP Quinases , Rosiglitazona/farmacologia , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
12.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939798

RESUMO

Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (UCP1) mRNA expression by real-time PCR. Among those UCP1 activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased UCP1 expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Fluvastatina/uso terapêutico , Obesidade/tratamento farmacológico , Tecido Adiposo Marrom/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Células Cultivadas , Metabolismo Energético , Fluvastatina/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
13.
J Pharmacol Exp Ther ; 369(3): 419-427, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940691

RESUMO

Mirabegron, a ß3-adrenergic receptor agonist, has been shown to stimulate the activity of brown fat and increase the resting metabolic rate in humans. However, it is unknown whether mirabegron can reduce body weight and improve metabolic health. We investigated the antiobesity effects of mirabegron using both in vitro and in vivo models. Mouse brown preadipocytes and 3T3-L1 cells were treated with different concentrations of mirabegron (0.03-3 µg/ml), and the expression of brown fat-related genes was measured by quantitative real-time polymerase chain reaction. Furthermore, male C57BL/6J mice were fed a high-fat diet for 10 weeks, and mirabegron (2 mg/kg body weight) or a vehicle control was delivered to the interscapular brown adipose tissue (iBAT) using ALZET osmotic pumps from week 7 to 10. The metabolic parameters and tissues were analyzed. In both mouse brown preadipocytes and 3T3-L1 cells, mirabegron stimulated uncoupling protein 1 (UCP1) expression. In animal studies, mirabegron-treated mice had a lower body weight and adiposity. Lipid droplets in the iBAT of mirabegron-treated mice were fewer and smaller in size compared with those from vehicle-treated mice. H&E staining and immunohistochemistry indicated that mirabegron increased the abundance of beige cells in inguinal white adipose tissue (iWAT). Compared with vehicle-treated mice, mirabegron-treated mice had a higher gene expression of UCP1 (14-fold) and cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA) (4-fold) in iWAT. Furthermore, mirabegron-treated mice had improved glucose tolerance and insulin sensitivity. Taken together, mirabegron enhances UCP1 expression and promotes browning of iWAT, which are accompanied by improved glucose tolerance and insulin sensitivity and prevention from high-fat diet-induced obesity.


Assuntos
Acetanilidas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Tiazóis/farmacologia , Células 3T3-L1 , Acetanilidas/uso terapêutico , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/patologia , Tiazóis/uso terapêutico , Proteína Desacopladora 1/genética
14.
Am J Physiol Endocrinol Metab ; 316(5): E977-E986, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30912962

RESUMO

Prevalence of obesity is exacerbated by low rates of successful long-term weight loss maintenance (WLM). In part, relapse from WLM to obesity is due to a reduction in energy expenditure (EE) that persists throughout WLM and relapse. Thus, interventions that increase EE might facilitate WLM. In obese mice that were calorically restricted to reduce body weight by ~20%, we manipulated EE throughout WLM and early relapse using intermittent cold exposure (ICE; 4°C, 90 min/day, 5 days/wk, within the last 3 h of the light cycle). EE, energy intake, and spontaneous physical activity were measured during the obese, WLM, and relapse phases. During WLM and relapse, the ICE group expended more energy during the light cycle because of cold exposure but expended less energy in the dark cycle, which led to no overall difference in total daily EE. The compensation in EE appeared to be mediated by activity, whereby the ICE group was more active during the light cycle because of cold exposure but less active during the dark cycle, which led to no overall effect on total daily activity during WLM and relapse. In brown adipose tissue of relapsing mice, the ICE group had greater mRNA expression of Dio2 and protein expression of UCP1 but lower mRNA expression of Prdm16. In summary, these findings indicate that despite robust increases in EE during cold exposures, ICE is unable to alter total daily EE during WLM or early relapse, likely due to compensatory behaviors in activity.


Assuntos
Manutenção do Peso Corporal/fisiologia , Temperatura Baixa , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Atividade Motora/fisiologia , Termogênese/fisiologia , Ganho de Peso/fisiologia , Perda de Peso/fisiologia , Tecido Adiposo Marrom/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Camundongos , Obesidade , Fotoperíodo , RNA Mensageiro/metabolismo , Recidiva , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
15.
Diabetes ; 68(6): 1178-1196, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30862682

RESUMO

Carboxylesterase 3 (Ces3) is a hydrolase with a wide range of activities in liver and adipose tissue. In this study, we identified Ces3 as a major lipid droplet surface-targeting protein in adipose tissue upon cold exposure by liquid chromatography-tandem mass spectrometry. To investigate the function of Ces3 in the ß-adrenergic signaling-activated adipocytes, we applied WWL229, a specific Ces3 inhibitor, or genetic inhibition by siRNA to Ces3 on isoproterenol (ISO)-treated 3T3-L1 and brown adipocyte cells. We found that blockage of Ces3 by WWL229 or siRNA dramatically attenuated the ISO-induced lipolytic effect in the cells. Furthermore, Ces3 inhibition led to impaired mitochondrial function measured by Seahorse. Interestingly, Ces3 inhibition attenuated an ISO-induced thermogenic program in adipocytes by downregulating Ucp1 and Pgc1α genes via peroxisome proliferator-activated receptor γ. We further confirmed the effects of Ces3 inhibition in vivo by showing that the thermogenesis in adipose tissues was significantly attenuated in WWL229-treated or adipose tissue-specific Ces3 heterozygous knockout (Adn-Cre-Ces3flx/wt) mice. As a result, the mice exhibited dramatically impaired ability to defend their body temperature in coldness. In conclusion, our study highlights a lipolytic signaling induced by Ces3 as a unique process to regulate thermogenesis in adipose tissue.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo/metabolismo , Carboxilesterase/fisiologia , Lipólise/genética , Termogênese/genética , Células 3T3-L1 , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Animais , Carboxilesterase/antagonistas & inibidores , Carboxilesterase/genética , Temperatura Baixa , Regulação para Baixo , Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , RNA Interferente Pequeno , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/genética
16.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717287

RESUMO

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.


Assuntos
Adiposidade/efeitos dos fármacos , Antipsicóticos/efeitos adversos , Cloretos/farmacologia , Compostos de Cromo/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Hiperlipidemias/metabolismo , Olanzapina/efeitos adversos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Administração Oral , Animais , Cloretos/metabolismo , Compostos de Cromo/metabolismo , Feminino , Regulação da Expressão Gênica , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/prevenção & controle , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/genética , Hiperinsulinismo/prevenção & controle , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Hiperlipidemias/prevenção & controle , Inflamação , Resistência à Insulina/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Ganho de Peso/efeitos dos fármacos
17.
Am J Physiol Endocrinol Metab ; 316(5): E729-E740, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30807213

RESUMO

The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57Bl/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 wk. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly, high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.


Assuntos
Dieta Hiperlipídica , Obesidade/genética , Termogênese/genética , Proteína Desacopladora 1/genética , Tecido Adiposo , Tecido Adiposo Marrom/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Ingestão de Alimentos , Metabolismo Energético/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Norepinefrina/farmacologia , Obesidade/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo , Ganho de Peso
18.
Mol Nutr Food Res ; 63(7): e1800813, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30632684

RESUMO

SCOPE: The mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of a high-fat diet rich in omega-3 (n-3) fatty acids are investigated. METHODS AND RESULTS: C57BL/6J mice are fed either a low-fat (control group) or one of two isocaloric high-fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis, and inguinal white and interscapular brown adipose tissue (iWAT and iBAT, respectively) gene expression, lipidome, and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances, and hyperinsulinemia. This is associated with increased energy expenditure, iWAT UCP1 expression, and incorporation of n-3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild-type and UCP1-deficient mice without recruiting other thermogenic processes in iWAT and iBAT, such as mitochondrial uncoupling and SERCA-mediated calcium and creatine-driven substrate cyclings. CONCLUSION: Intake of a high-fat diet rich in omega-3 fatty acids protects both wild-type and UCP1-deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Óleos de Peixe/farmacologia , Intolerância à Glucose/dietoterapia , Obesidade/prevenção & controle , Proteína Desacopladora 1/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Ácidos Graxos Ômega-3/análise , Ácidos Graxos Ômega-3/farmacologia , Óleos de Peixe/química , Intolerância à Glucose/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética , Proteína Desacopladora 1/metabolismo
19.
Mol Nutr Food Res ; 63(7): e1800821, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30657255

RESUMO

SCOPE: Brown adipose tissue (BAT) dissipates energy through uncoupling protein 1 (UCP1) and has been proposed as an anti-obesity target. It was reported previously that a high-fat (HF) diet enriched in eicosapentaenoic acid (EPA) significantly increased UCP1 and other thermogenic markers in BAT. It is hypothesized that these effects are mediated through UCP1-dependent regulation. METHODS AND RESULTS: Wild-type (WT) and UCP1 knockout (KO) B6 male mice were housed at thermoneutrality and fed a HF diet, without or with eicosapentaenoic acid (EPA)-enriched fish oil. HF-fed KO mice were heavier and had higher BAT lipid content than other groups. Protective effects of EPA in WT, previously observed at 22 °C (reduced adiposity, improved glucose tolerance, and increased UCP1), disappeared at thermoneutrality. Mitochondrial proteins, cytochrome c oxidase subunit 1 (COX I), COX I, II, and IV were reduced in the KO mice compared to WT. Unexpectedly, EPA attenuated weight and fat mass gain and improved glucose tolerance in the KO mice. Finally, EPA increased BAT peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein and gene expression, and whole-body oxygen consumption in KO mice, consistent with increased mitochondria DNA (mtDNA)/nuclear DNA (nucDNA) ratio. CONCLUSIONS: EPA rescued the weight gain and glucose intolerance in UCP1 KO mice at thermoneutrality, independent of UCP1; these effects may be mediated in part via increased oxygen consumption and BAT PGC1α.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Ácido Eicosapentaenoico/farmacologia , Intolerância à Glucose/tratamento farmacológico , Oxigênio/metabolismo , Proteína Desacopladora 1/genética , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Temperatura Ambiente , Proteína Desacopladora 1/metabolismo , Ganho de Peso/efeitos dos fármacos
20.
Gastroenterology ; 156(6): 1742-1752, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30677401

RESUMO

BACKGROUND & AIMS: Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. METHODS: We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS+/LSLG12D P53flox/flox mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry. RESULTS: There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. CONCLUSIONS: We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.


Assuntos
Caquexia/etiologia , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/diagnóstico , Hiperglicemia/sangue , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Glicemia/metabolismo , Temperatura Corporal , Peso Corporal , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/genética , Estudos de Casos e Controles , Células Cultivadas , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Exossomos , Humanos , Hiperglicemia/etiologia , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/patologia , Camundongos , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Gordura Subcutânea Abdominal/diagnóstico por imagem , Gordura Subcutânea Abdominal/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Triglicerídeos/sangue , Proteína Desacopladora 1/genética , Regulação para Cima
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