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1.
EBioMedicine ; 37: 344-355, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30348622

RESUMO

BACKGROUND: The pharmacological activation of thermogenesis in brown adipose tissue has long been considered promising strategies to treat obesity. However, identification of safe and effective agents remains a challenge. In this study, we addressed this challenge by developing a cellular system with a fluorescence readout, and applied in a high-throughput manner to screen for FDA-approved drugs that may activate endogenous UCP1 expression in adipocytes. METHODS: We have generated a Ucp1-2A-GFP reporter mouse, in which GFP intensity serves as a surrogate of the endogenous expression level of UCP1 protein; and immortalized brown adipocytes were derived from this mouse model and applied in drug screening. Candidate drugs were further tested in mouse models either fed with normal chow or high fat diet to induce obesity. FINDINGS: By using the cellular screening platform, we identified a group of FDA-approved drugs that can upregulate UCP1 expression in brown adipocyte, including previously known UCP1 activators and new candidate drugs. Further studies focusing on a previously unreported drug-sutent, revealed that sutent treatment could increase the energy expenditure and inhibit lipid synthesis in mouse adipose and liver tissues, resulting in improved metabolism and resistance to obesity. INTERPRETATION: This study offered an easy-to-use cellular screening system for UCP1 activators, and provided a candidate list of FDA-approved drugs that can potentially treat obesity. Further study of these candidates may shed new light on the drug discovery towards obesity. FUND: National Key Research and Development Program and the Strategic Priority Research Program of the Chinese Academy of Sciences, etc. (250 words).


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/patologia , Animais , Linhagem Celular Transformada , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Transgênicos , Proteína Desacopladora 1/genética , Estados Unidos , United States Food and Drug Administration
2.
J Nutr Biochem ; 61: 56-67, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30189364

RESUMO

The seminal discovery of browning of white adipose tissue (WAT) holds great promise for the treatment of obesity and metabolic syndrome. DJ-1 is evolutionarily conserved across species, and mutations in DJ-1 have been identified in Parkinson's disease. Higher levels of DJ-1 are associated with obesity, but the underlying mechanism is less understood. Here, we report the previously unappreciated role of DJ-1 in white adipocyte biology in mature models of obesity. We used DJ-1 knockout (KO) mouse models and wild-type littermates maintained on a normal diet or high-fat diet as well as in vitro cell models to show the direct effects of DJ-1 depletion on adipocyte phenotype, thermogenic capacity, fat metabolism, and microenvironment profile. Global DJ-1 KO mice show increased sympathetic input to WAT and ß3-adrenergic receptor intracellular signaling, leading to a previously unrecognized compensatory mechanism through browning of WAT with associated characteristics, including high mitochondrial contents, reduced lipid accumulation, adequate vascularization and attenuated autophagy. DJ-1 KO mice had normal body weight, energy balance, and adiposity, which were associated with protective effects on healthy WAT expansion by hyperplasia. Our findings revealed that browning of inguinal WAT occurred in DJ-1 KO mice that do not show increased predisposition to obesity and suggest that such potential mechanism may overcome the adverse metabolic consequences of obesity independent of an effect on body weight. Here, we provide the first direct evidence that targeting DJ-1 in adipocyte metabolic health may offer a unique therapeutic strategy for the treatment of obesity.


Assuntos
Adipócitos Marrons/patologia , Tecido Adiposo Branco/patologia , Obesidade/etiologia , Proteína Desglicase DJ-1/genética , Células 3T3-L1 , Adipócitos Marrons/fisiologia , Adipócitos Brancos/citologia , Animais , Autofagia , Peso Corporal/genética , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Proteína Desglicase DJ-1/metabolismo
3.
Nutrients ; 10(6)2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29865208

RESUMO

Obesity predisposes animals towards the metabolic syndrome and diseases such as type 2 diabetes, atherosclerosis, and cardiovascular disease. Spirulina maxima is a microalga with anti-oxidant, anti-cancer, and neuroprotective activities, but the anti-obesity effect of Spirulina maxima 70% ethanol extract (SM70EE) has not yet been fully established. We investigated the effect of SM70EE on adipogenesis, lipogenesis, and browning using in vitro and in vivo obesity models. SM70EE treatment reduced lipid droplet accumulation by the oil red O staining method and downregulated the adipogenic proteins C/EBPα, PPARγ, and aP2, and the lipogenic proteins SREBP1, ACC, FAS, LPAATß, Lipin1, and DGAT1 by western blot analysis. In addition, the index components of SM70EE, chlorophyll a, and C-phycocyanin, reduced adipogenesis and lipogenesis protein levels in 3T3-L1 and C3H10T1/2 cells. High-fat diet (HFD)-fed mice administered with SM70EE demonstrated smaller adipose depots and lower blood lipid concentrations than control HFD-fed mice. The lower body mass gain in treated SM70EE-administrated mice was associated with lower protein expression of adipogenesis factors and higher expression of AMPKα-induced adipose browning proteins PRDM16, PGC1α, and UCP1. SM70EE administration ameliorates obesity, likely by reducing adipogenesis and activating the thermogenic program, in 3T3-L1 cells and HFD-induced obese mice.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Obesidade/prevenção & controle , Spirulina/química , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Animais , Fármacos Antiobesidade/isolamento & purificação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Obesidade/sangue , Obesidade/patologia , Obesidade/fisiopatologia , Termogênese/efeitos dos fármacos , Fatores de Tempo , Ganho de Peso/efeitos dos fármacos
4.
Arterioscler Thromb Vasc Biol ; 38(8): 1738-1747, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29954752

RESUMO

Objective- Perivascular adipose tissue (PVAT) contributes to vascular homeostasis by producing paracrine factors. Previously, we reported that selective deletion of PPARγ (peroxisome proliferator-activated receptor γ) in vascular smooth muscle cells resulted in concurrent loss of PVAT and enhanced atherosclerosis in mice. To address the causal relationship between loss of PVAT and atherosclerosis, we used BA-PPARγ-KO (brown adipocyte-specific PPARγ knockout) mice. Approach and Results- Deletion of PPARγ in brown adipocytes did not affect PPARγ in white adipocytes or vascular smooth muscle cells or PPARα and PPARδ expression in brown adipocytes. However, development of PVAT and interscapular brown adipose tissue was remarkably impaired, associated with reduced expression of genes encoding lipogenic enzymes in the BA-PPARγ-KO mice. Thermogenesis in brown adipose tissue was significantly impaired with reduced expression of thermogenesis genes in brown adipose tissue and compensatory increase in subcutaneous and gonadal white adipose tissues. Remarkably, basal expression of inflammatory genes and macrophage infiltration in PVAT and brown adipose tissue were significantly increased in the BA-PPARγ-KO mice. BA-PPARγ-KO mice were crossbred with ApoE KO (apolipoprotein E knockout) mice to investigate the development of atherosclerosis. Flow cytometry analysis confirmed increased systemic and PVAT inflammation. Consequently, atherosclerotic lesions were significantly increased in mice with impaired PVAT development, thus indicating that the lack of normal PVAT is sufficient to drive increased atherosclerosis. Conclusions- PPARγ is required for functional PVAT development. PPARγ deficiency in PVAT, while still expressed in vascular smooth muscle cell, enhances atherosclerosis and results in vascular and systemic inflammation, providing new insights on the specific roles of PVAT in atherosclerosis and cardiovascular disease at large.


Assuntos
Adipócitos Marrons/metabolismo , Adipogenia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , PPAR gama/deficiência , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Lipogênese/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , PPAR gama/genética , Placa Aterosclerótica , Transdução de Sinais , Termogênese
5.
J Gastroenterol Hepatol ; 33(12): 1990-2000, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29663549

RESUMO

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Deposition of excess triglycerides in liver cells, a hallmark of NAFLD, is associated with loss of insulin sensitivity. Ostreolysin (Oly) is a 15-kDa fungal protein known to interact with cholesterol-enriched raft-like membrane domains. We aim to test whether a recombinant version of Oly (rOly) can induce functional changes in vitro in adipocytes or in vivo in mice fed a high-fat diet (HFD). METHODS: White preadipocyte 3T3-L1 cells or mouse primary adipocytes treated with rOly. Male C57BL/6 mice were fed a control or HFD and treated with saline or with rOly (1 mg/kg BW) every other day for 4 weeks. RESULTS: White preadipocyte 3T3-L1 cells or mouse primary adipocytes treated with rOly acquire a browning phenotype through activation of 5' adenosine monophosphate-activated protein kinase and downregulation of tumor necrosis factor α-mediated activation of IκB kinase ε and TANK-binding kinase 1. HFD-fed mice treated with rOly showed a 10% reduction in BW and improved glucose tolerance, which paralleled improved expression of liver and adipose functionality, metabolism, and inflammation status, mimicking the in vitro findings. CONCLUSION: This study provides first evidence of rOly's prevention of HFD-induced NAFLD by stimulating liver and adipose muscle tissue functionality and oxidative potential, improving glucose tolerance, and ameliorating the metabolic profile of diet-induced obese mice.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Proteínas Hemolisinas/farmacologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ativação Enzimática , Proteínas Fúngicas/farmacologia , Quinase I-kappa B/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Diabetes ; 67(6): 1045-1056, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29519872

RESUMO

Obesity induces profound transcriptome changes in adipocytes, and recent evidence suggests that long-noncoding RNAs (lncRNAs) play key roles in this process. We performed a comprehensive transcriptome study by RNA sequencing in adipocytes isolated from interscapular brown, inguinal, and epididymal white adipose tissue in diet-induced obese mice. The analysis revealed a set of obesity-dysregulated lncRNAs, many of which exhibit dynamic changes in the fed versus fasted state, potentially serving as novel molecular markers of adipose energy status. Among the most prominent lncRNAs is Lnc-leptin, which is transcribed from an enhancer region upstream of leptin (Lep). Expression of Lnc-leptin is sensitive to insulin and closely correlates to Lep expression across diverse pathophysiological conditions. Functionally, induction of Lnc-leptin is essential for adipogenesis, and its presence is required for the maintenance of Lep expression in vitro and in vivo. Direct interaction was detected between DNA loci of Lnc-leptin and Lep in mature adipocytes, which diminished upon Lnc-leptin knockdown. Our study establishes Lnc-leptin as a new regulator of Lep.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adipogenia , Regulação da Expressão Gênica , Leptina/agonistas , Obesidade/metabolismo , RNA Longo não Codificante/metabolismo , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/patologia , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/patologia , Adipogenia/efeitos dos fármacos , Animais , Sequência de Bases , Biomarcadores/metabolismo , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Elementos Facilitadores Genéticos/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Leptina/antagonistas & inibidores , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/patologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/química , RNA Interferente Pequeno/metabolismo
7.
Diabetes ; 67(6): 1068-1078, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29581126

RESUMO

Insulin desensitization occurs not only under the obese diabetic condition but also in the fasting state. However, little is known about the common secretory factor(s) that are regulated under these two insulin-desensitized conditions. Here, using database analysis and in vitro and in vivo experiments, we identified stromal derived factor-1 (SDF-1) as an insulin-desensitizing factor in adipocytes, overexpressed in both fasting and obese adipose tissues. Exogenously added SDF-1 induced extracellular signal-regulated kinase signal, which phosphorylated and degraded IRS-1 protein in adipocytes, decreasing insulin-mediated signaling and glucose uptake. In contrast, knockdown of endogenous SDF-1 or inhibition of its receptor in adipocytes markedly increased IRS-1 protein levels and enhanced insulin sensitivity, indicating the autocrine action of SDF-1. In agreement with these findings, adipocyte-specific ablation of SDF-1 enhanced insulin sensitivity in adipose tissues and in the whole body. These results point to a novel regulatory mechanism of insulin sensitivity mediated by adipose autocrine SDF-1 action and provide a new insight into the process of insulin desensitization in adipocytes.


Assuntos
Adipócitos Brancos/metabolismo , Quimiocina CXCL12/metabolismo , Regulação da Expressão Gênica , Resistência à Insulina , Obesidade/metabolismo , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipócitos Brancos/patologia , Animais , Células Cultivadas , Quimiocina CXCL12/antagonistas & inibidores , Quimiocina CXCL12/genética , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/etiologia , Obesidade/patologia , Especificidade de Órgãos , Interferência de RNA
8.
Horm Mol Biol Clin Investig ; 33(2)2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29425108

RESUMO

Upper body adipose tissue accumulation has been associated with clustering of metabolic disorders and increased cardiovascular risk. Neck circumference (NC) indicated that subcutaneous adipose tissue (SAT) in that region is an independent pathogenic depot that might account for the additional risk missed by visceral adipose tissue (VAT). Neck adipose tissue (NAT) is not only one more ectopic depot but has several particular features that might modulate its metabolic role. Besides a controversial impact on obstructive apnea syndrome, neck fat encompasses carotid arteries as an important perivascular adipose tissue (PVAT) depot. With dysfunctional changes in obesity, physiologic vascular regulation is lost and inflammatory signals accelerate atherogenesis. Unexpected was the discovery of brown and beige adipocytes in the neck of human adults. When stimulated, brown adipose tissue (BAT) dissipates energy through thermogenesis and it is associated with other favorable metabolic effects. Moreover, the neck is the region where the browning mechanism was disclosed. With this unique plastic nature, NAT revealed multiple ties, challenging dynamics and potential new therapeutic targets that might have significant implications on metabolic outcomes and vascular risk.


Assuntos
Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Pescoço/patologia , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Tecido Adiposo/anatomia & histologia , Animais , Humanos , Doenças Metabólicas/terapia , Pescoço/anatomia & histologia
9.
Ann Hepatol ; 17(2): 182-186, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29469051

RESUMO

Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue may be important in inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines or batokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance. Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory cytokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adipocinas/metabolismo , Metabolismo Energético , Cirrose Hepática/etiologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Adipócitos Marrons/patologia , Adipócitos Brancos/patologia , Animais , Citocinas/metabolismo , Progressão da Doença , Humanos , Mediadores da Inflamação/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Neurregulinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Fenótipo , Índice de Gravidade de Doença , Transdução de Sinais
10.
Exp Mol Med ; 50(1): e432, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29371695

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformin's action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Reumatoide/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/genética , Metformina/farmacologia , Obesidade/complicações , Adipócitos Marrons/patologia , Adipócitos Marrons/transplante , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/genética , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
11.
Diabetes ; 67(3): 400-411, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29298809

RESUMO

Sucrose nonfermenting-related kinase (SNRK) is a member of the AMPK-related kinase family, and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white adipose tissue (WAT) and brown adipose tissue (BAT), but SNRK expression diminishes in adipose tissue in obesity. In this study we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival; SNRK globally deficient pups die within 24 h after birth. Heterozygous mice are characterized by inflamed WAT and less BAT. Adipocyte-specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impaired adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, higher body weight, and insulin resistance. We further confirm the significant association of common variants of the SNRK gene with obesity risk in humans. Through applying a phosphoproteomic approach, we identified eukaryotic elongation factor 1δ and histone deacetylase 1/2 as potential SNRK substrates. Taking these data together, we conclude that SNRK represses WAT inflammation and is essential to maintain BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated metabolic disorders.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Metabolismo Energético , Mitocôndrias/metabolismo , Paniculite/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Adipócitos Marrons/imunologia , Adipócitos Marrons/patologia , Adipócitos Marrons/ultraestrutura , Adipócitos Brancos/imunologia , Adipócitos Brancos/patologia , Adipócitos Brancos/ultraestrutura , Animais , Índice de Massa Corporal , Células Cultivadas , Cruzamentos Genéticos , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Mitocôndrias/imunologia , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Obesidade/genética , Obesidade/fisiopatologia , Paniculite/etiologia , Paniculite/imunologia , Paniculite/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Termogênese
12.
Endocrinology ; 159(1): 557-569, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29077876

RESUMO

Increasing brown adipose tissue (BAT) activity is regarded as a potential treatment of obese, hyperglycemic patients with metabolic syndrome. Triiodothyronine (T3) is known to stimulate BAT activity by increasing mitochondrial uncoupling protein 1 (Ucp1) gene transcription, leading to increased thermogenesis and decreased body weight. Here we report our studies on the effects of T3 and glucose in two mouse models and in mouse immortalized brown preadipocytes in culture. We identified carbohydrate response element binding protein (ChREBP) as a T3 target gene in BAT by RNA sequencing and studied its effects in brown adipocytes. We found that ChREBP was upregulated by T3 in BAT in both hyperglycemic mouse models. In brown preadipocytes, T3 and glucose synergistically and dose dependently upregulated Ucp1 messenger RNA 1000-fold compared with low glucose concentrations. Additionally, we observed increased ChREBP and Ucp1 protein 11.7- and 19.9-fold, respectively, along with concomitant induction of a hypermetabolic state. Moreover, downregulation of ChREBP inhibited T3 and glucose upregulation of Ucp1 100-fold, whereas overexpression of ChREBP upregulated Ucp1 5.2-fold. We conclude that T3 and glucose signaling pathways coordinately regulate the metabolic state of BAT and suggest that ChREBP is a target for therapeutic regulation of BAT activity.


Assuntos
Adipócitos Marrons/metabolismo , Hiperglicemia/metabolismo , Proteínas Nucleares/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Tri-Iodotironina/metabolismo , Proteína Desacopladora 1/agonistas , Regulação para Cima , Transporte Ativo do Núcleo Celular , Adipócitos Marrons/citologia , Adipócitos Marrons/patologia , Adipogenia , Animais , Linhagem Celular Transformada , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Ácido Graxo Sintase Tipo I/química , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Transportador de Glucose Tipo 4/agonistas , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hiperglicemia/etiologia , Hiperglicemia/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Obesidade/etiologia , Obesidade/patologia , Regiões Promotoras Genéticas , Interferência de RNA , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Tri-Iodotironina/administração & dosagem , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
13.
Endocrinology ; 159(1): 227-237, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29059354

RESUMO

The prevalence of primary aldosteronism is much higher than previously thought. Recent studies have shown that primary aldosteronism is related to a higher risk of cardiovascular events. However, the underlying mechanism is not yet clear. Here we investigate the characteristics, including inflammation, fibrosis, and adipokine expression, of adipose tissues from different deposits in patients with aldosterone-producing adenoma (APA). Inflammation and fibrosis changes were evaluated in perirenal and subcutaneous adipose tissues obtained from patients with APA (n = 16), normotension (NT; n = 10), and essential hypertension (EH; n = 5) undergoing laparoscopic surgery. We also evaluated the effect of aldosterone in isolated human perirenal adipose tissue stromal vascular fraction (SVF) cells and investigated the effect of aldosterone in mouse 3T3-L1 and brown preadipocytes. Compared with the EH group, significantly higher levels of interleukin-6 (IL-6) and tumor necrosis factor-α messenger RNA (mRNA) and protein were observed in perirenal adipose tissue of patients with APA. Expression of genes related to fibrosis and adipogenesis in perirenal adipose tissue was notably higher in patients with APA than in patients with NT and EH. Aldosterone significantly induced IL-6 and fibrosis gene mRNA expression in differentiated SVF cells. Aldosterone treatment enhanced mRNA expression of genes associated with inflammation and fibrosis and stimulated differentiation of 3T3-L1 and brown preadipocytes. In conclusion, these data indicate that high aldosterone in patients with APA may induce perirenal adipose tissue dysfunction and lead to inflammation and fibrosis, which may be involved in the high risk of cardiovascular events observed in patients with primary aldosteronism.


Assuntos
Adenoma/fisiopatologia , Aldosterona/metabolismo , Hipertensão Essencial/complicações , Hiperaldosteronismo/etiologia , Gordura Intra-Abdominal/patologia , Paniculite/etiologia , Células 3T3-L1 , Adenoma/complicações , Adenoma/metabolismo , Adenoma/cirurgia , Adipócitos Marrons/imunologia , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipogenia , Adipocinas/metabolismo , Adrenalectomia , Animais , Células Cultivadas , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Fibrose , Humanos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Paniculite/imunologia , Paniculite/metabolismo , Paniculite/patologia , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Gordura Subcutânea Abdominal/imunologia , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia
14.
Endocrinology ; 159(1): 535-546, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938459

RESUMO

Glucocorticoids influence a wide range of metabolic processes in the human body, and excessive glucocorticoid exposure is known to contribute to the development of metabolic disease. We evaluated the utility of the novel glucocorticoid receptor (GR) antagonist CORT125281 for its potential to overcome adiposity, glucose intolerance, and dyslipidemia and compared this head-to-head with the classic GR antagonist RU486 (mifepristone). We show that, although RU486 displays cross-reactivity to the progesterone and androgen receptor, CORT125281 selectively inhibits GR transcriptional activity. In a mouse model for diet-induced obesity, rhythmicity of circulating corticosterone levels was disturbed. CORT125281 restored this disturbed rhythmicity, in contrast to RU486, which further inhibited endogenous corticosterone levels and suppressed adrenal weight. Both CORT125281 and RU486 reduced body weight gain and fat mass. In addition, CORT125281, but not RU486, lowered plasma levels of triglycerides, cholesterol, and free fatty acids and strongly stimulated triglyceride-derived fatty acid uptake by brown adipose tissue depots. In combination with reduced lipid content in brown adipocytes, this indicates that CORT125281 enhances metabolic activity of brown adipose tissue depots. CORT125281 was also found to increase liver lipid accumulation. Taken together, CORT125281 displayed a wide range of beneficial metabolic activities that are in part distinct from RU486, but clinical utility may be limited due to liver lipid accumulation. This warrants further evaluation of GR antagonists or selective modulators that are not accompanied by liver lipid accumulation while preserving their beneficial metabolic activities.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Antagonistas de Hormônios/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores de Glucocorticoides/antagonistas & inibidores , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacologia , Células Cultivadas , Corticosterona/sangue , Corticosterona/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Mifepristona/efeitos adversos , Mifepristona/farmacologia , Mifepristona/uso terapêutico , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Ganho de Peso/efeitos dos fármacos
15.
Obes Surg ; 28(3): 820-830, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28853013

RESUMO

BACKGROUND: Bariatric surgery is an effective treatment for obesity causing changes in energy expenditure. Brown adipose tissue (BAT) is an energy-related organ, and the potential effects of bariatric surgery are yet to be investigated. We aimed to study the effects of different bariatric surgeries on growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, brown adipocyte differentiation, and energy metabolism in obese mice and explore the underlying mechanisms. METHODS: Mice were fed a high-fat diet for 12 weeks and subjected to different bariatric procedures: adjustable gastric band (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and sham operation (SO). Pre- and postoperative weight, a metabolic index, content, and metabolic activity of BAT was recorded by micro-positron emission tomography/computed tomography (micro-PET/CT). Altered energy metabolism was estimated by metabolic cage technology. Serum GH/IGF-1 level and the brown adipose cell differentiation-related gene expression were estimated. RESULTS: By postoperative week 4, serum GH and IGF-1 levels, as well as the content and metabolic activity of BAT increased postoperatively. The differentiation factors of the brown adipose cell were significantly stronger, energy consumption increased, and respiratory exchange frequency decreased postoperative. The effect was predominant in RYGB; SG demonstrated superior result to ABG. With weight regain 8-week postoperation, these parameters deteriorated in the operation groups, significantly in the GB group; the RYGB group seemed superior to the SG group. CONCLUSIONS: Bariatric surgery elevated the GH/IGF-1 levels and increased BAT volume and activity, meanwhile decreasing the respiratory exchange frequency. This may help us better understand the mechanisms of bariatric surgery.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Cirurgia Bariátrica , Metabolismo Energético , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Animais , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade Mórbida/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Período Pós-Operatório
16.
Adipocyte ; 6(2): 141-146, 2017 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-28425843

RESUMO

BMP4 has a well-established role in triggering commitment of mesenchymal stem cells into the osteogenic and adipogenic linage. We recently described an additional dual function in adipogenesis: after promoting the formation of both white and brown pre-adipocytes, Bmp4 drives terminal differentiation into mature white rather than brown fat cells. Besides this, Bmp4 seems to have a dual role in metabolism either promoting or repressing oxidative metabolism in a cell context dependent manner.


Assuntos
Adipogenia/fisiologia , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Adipócitos/citologia , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Adipogenia/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Osteogênese
17.
J Biol Chem ; 292(22): 9175-9190, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28404815

RESUMO

Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-α (PPARα) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPARα activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPARα agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such as Ucp1, Pgc1a, and Cpt1b Fenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-deficient mice. These findings indicate that FGF21 is crucial for the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hiperlipidemias/metabolismo , Obesidade/metabolismo , PPAR alfa/agonistas , Adipócitos Marrons/patologia , Tecido Adiposo/patologia , Animais , Metabolismo Energético/genética , Fenofibrato/farmacologia , Fatores de Crescimento de Fibroblastos/genética , Glucose/genética , Glucose/metabolismo , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Hiperlipidemias/patologia , Camundongos , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/patologia , PPAR alfa/genética , PPAR alfa/metabolismo
18.
Mol Cell Endocrinol ; 456: 87-94, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28412522

RESUMO

Obesity has reached epidemic proportions world-wide and constitutes a substantial risk factor for hypertension, type 2 diabetes, cardiovascular diseases and certain cancers. So far, regulation of energy intake by dietary and pharmacological treatments has met limited success. The main interest of current research is focused on understanding the role of different pathways involved in adipose tissue function and modulation of its mass. Whole-genome sequencing studies revealed that the majority of the human genome is transcribed, with thousands of non-protein-coding RNAs (ncRNA), which comprise small and long ncRNAs. ncRNAs regulate gene expression at the transcriptional and post-transcriptional level. Numerous studies described the involvement of ncRNAs in the pathogenesis of many diseases including obesity and associated metabolic disorders. ncRNAs represent potential diagnostic biomarkers and promising therapeutic targets. In this review, we focused on small ncRNAs involved in the formation and function of adipocytes and obesity.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , MicroRNAs/genética , Obesidade/genética , RNA Nucleolar Pequeno/genética , RNA de Transferência/genética , Adipócitos Marrons/patologia , Adipócitos Brancos/patologia , Adipogenia/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Biomarcadores/metabolismo , Ingestão de Energia/genética , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Obesidade/diagnóstico , Obesidade/metabolismo , Obesidade/patologia , RNA Nucleolar Pequeno/metabolismo , RNA de Transferência/metabolismo
19.
Curr Diabetes Rev ; 13(4): 386-394, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26900134

RESUMO

INTRODUCTION: Mitochondrial uncoupling is a physiological process that has direct and indirect consequences on glucose homeostasis. Non-shivering thermogenesis in brown adipose tissue, which is the most well-recognized biological process related to the physiological uncoupling of mitochondria, is caused by uncoupling protein-1 (UCP1), which mediates a regulated permeabilization of the mitochondrial inner membrane to protons. CONCLUSION: The uncoupled brown fat mitochondria are specialized to produce heat by oxidizing large amounts of substrates, making brown fat a sink that can actively drain glucose from circulation. This has been confirmed in human studies in which active brown fat was detected by glucose-derivative-based positron emission tomography scans. Thus, UCP1-mediated activation of brown fat appears to be a likely mechanism through which hyperglycemia could be ameliorated. In other tissues, mitochondria are reported to be mildly uncoupled by the UCP1-like proteins, UCP2 and UCP3. The primary role of these other UCPs does not appear to be the oxidation of a metabolic substrate (e.g., glucose) for heat production; instead, they participate in other processes, such as regulating the production of reactive oxygen species and transporting certain metabolites across the mitochondrial membrane. UCP2 activity influences glucose homeostasis by fine tuning intracellular events related to the cellular energy status, thereby controlling insulin secretion, food intake behavior and adiponectin secretion in pancreatic .- cells, brain and white adipose tissue, respectively. UCP3 appears to be more specifically involved in promoting fatty acid oxidation in muscle, and is thus likely to influence glucose metabolism indirectly. Several genetic association studies have related polymorphisms in the genes encoding UCPs with obesity and/or type 2 diabetes phenotypes. In this review, we will focus on what is known about the specific role of mitochondrial uncoupling in glucose metabolism, and its implications in diabetes.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Metabolismo Energético , Glucose/metabolismo , Mitocôndrias/genética , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/fisiopatologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Homeostase , Humanos , Mitocôndrias/patologia , Proteínas de Desacoplamento Mitocondrial/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/fisiopatologia , Transdução de Sinais , Termogênese
20.
Oncotarget ; 8(6): 9267-9279, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28030827

RESUMO

Sirtuin 1 (Sirt1) promotes adaptive thermogenesis by controlling the acetylation status of enzymes and transcriptional factors in interscapular brown adipose tissue (iBAT). However, the effects of Sirt1 on endoplasmic reticulum (ER) stress and apoptosis of iBAT remain elusive. In this study, the mRNA levels of Sirt1 and thermogenesis genes were reduced but the genes related with ER stress were elevated in iBAT of high-fat diet (HFD)-induced obese mice. Moreover, ER stress further inhibited mRNA level of Sirt1 and triggered brown adipocyte apoptosis in vitro and in vivo. Further analysis revealed that Sirt1 overexpression alleviated ER stress-induced brown adipocyte apoptosis by inhibiting Smad3 and ATF4. In addition, Smad3 bound to ATF4 promoter region and positively transcriptional regulation of ATF4. Our data also confirmed that Sirt1 reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by directly interacting with ATF4. Furthermore, Sirt1 attenuated tunicamycin-induced cold intolerance and elevating thermogenesis by inhibiting ER stress and apoptosis in iBAT. In summary, our data collectively revealed Sirt1 reduced ER stress and apoptosis of brown adipocyte in vivo and in vitro by inhibiting Smad3/ATF4 signal. These data reveal a novel mechanism that links Sirt1 to brown adipocyte apoptosis.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Adipócitos Marrons/enzimologia , Tecido Adiposo Marrom/enzimologia , Apoptose , Estresse do Retículo Endoplasmático , Hipotermia/enzimologia , Obesidade/enzimologia , Sirtuína 1/metabolismo , Proteína Smad3/metabolismo , Fator 4 Ativador da Transcrição/genética , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipotermia/genética , Hipotermia/patologia , Hipotermia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/patologia , Obesidade/fisiopatologia , Regiões Promotoras Genéticas , Interferência de RNA , Transdução de Sinais , Sirtuína 1/genética , Proteína Smad3/genética , Termogênese , Fatores de Tempo , Transcrição Genética , Ativação Transcricional , Transfecção , Tunicamicina/farmacologia
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