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1.
Life Sci ; 237: 116914, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622606

RESUMO

AIMS: The aim of the presente study was to examine the effects of oral gallic acid (GA) administration on the brown adipose tissue of obese mice fed with high-fat diet. New mechanisms and interactions pathways in thermogenesis were accessed through bioinformatics analyses. MAIN METHODS: Swiss male mice were divided into four groups and fed during 60 days with: standard diet, standard diet combined with gallic acid, high-fat diet and high-fat diet combined with gallic acid. Body weight, food intake, and blood parameters (glucose tolerance test, total-cholesterol, high-density low-c, triglyceride and glucose levels) were evaluated. Brown and subcutaneous white adipose tissue histological analysis were performed. SIRT1 and PGC1-α mRNA expression in the brown adipose tissue were assessed. KEY FINDINGS: Our main findings showed that the gallic acid improved glucose tolerance and metabolic parameters. These results were accompanied by bioinformatics analyses that evidenced SIRT1 as main target in the thermogenesis process, confirmed as increased SIRT1 mRNA expression was evidenced in the brown adipose tissue. SIGNIFICANCE: Together, the data suggest that the gallic acid effect in brown adipose tissue may improve body metabolism, glucose homeostasis and increase thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Biologia Computacional/métodos , Dieta Hiperlipídica/efeitos adversos , Ácido Gálico/farmacologia , Metaboloma/efeitos dos fármacos , Obesidade/metabolismo , Sirtuína 1/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Sirtuína 1/genética , Termogênese/efeitos dos fármacos
2.
Acta Diabetol ; 56(12): 1333-1339, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31506721

RESUMO

AIMS: This study aimed to evaluate the effect of pioglitazone on brown adipose tissue function and hypothalamic gliosis in humans. Brown adipose tissue and the hypothalamus are regarded as important potential pharmacological targets to metabolic diseases, and defining the impact of current therapies on their structure and/or function could provide therapeutic advance in this field. METHODS: Six patients with type 2 diabetes were treated for 24 weeks with pioglitazone 30 mg/day as an add-on therapy. Brown adipose tissue glucose uptake and volume were determined using 18F-FDG PET/CT scans; hypothalamic gliosis was determined using MRI scans; blood was collected for hormone and biochemistry measurements. All tests were performed at inclusion and six months after pioglitazone introduction. RESULTS: Pioglitazone treatment led to a significant 3% body mass increase. There were neither changes in cold-induced brown adipose tissue glucose uptake and volume nor changes in hypothalamic gliosis. CONCLUSIONS: This is a proof-of-concept study that provides clinical evidence for a lack of action of a thiazolidinedione, pioglitazone, to promote homogeneous and measurable changes in brown adipose tissue volume and also in hypothalamic gliosis after 6 months of treatment.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliose/prevenção & controle , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Pioglitazona/farmacologia , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/patologia , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Quimioterapia Combinada , Feminino , Fluordesoxiglucose F18 , Gliose/diagnóstico , Gliose/patologia , Humanos , Hipotálamo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/tratamento farmacológico , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Sobrepeso/complicações , Sobrepeso/diagnóstico , Sobrepeso/tratamento farmacológico , Sobrepeso/patologia , Pioglitazona/administração & dosagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estudo de Prova de Conceito , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologia
3.
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
4.
J Vet Med Sci ; 81(6): 799-807, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-30956272

RESUMO

Brown adipocytes, which exist in brown adipose tissue (BAT), are activated by adrenergic stimulation, depending on the activity of uncoupling protein 1 (UCP1). Beige adipocytes emerge from white adipose tissue (WAT) in response to chronic adrenergic stimulation. We investigated obesity-related changes in responses of both types of adipocytes to adrenergic stimulation in mice. Feeding of mice with high-fat diets (HFD: 45%-kcal fat) for 14 weeks resulted in significantly higher body and WAT weight compared to feeding with normal diets (ND: 10%-kcal fat). Injection with ß3-adrenergic receptor agonist CL316,243 (CL; 0.1 mg/kg, once a day) for one week elevated the mRNA and protein expression levels of UCP1 in BAT, irrespective of diet. In WAT, CL-induced UCP1 expression in ND mice; however, the responses to CL treatment were attenuated in HFD mice, indicating that CL-induced browning of WAT was impaired in obese mice. Flow cytometric analysis revealed a significant decrease in platelet-derived growth factor receptor (PDGFR) α-expressing beige adipocyte progenitors in WAT of HFD mice compared with those of ND mice. Expression of PDGF-B, a PDGFRα ligand, increased in WAT following CL-injection in ND mice, but not in HFD mice. Treatment of mice with a PDGFR inhibitor significantly decreased CL-dependent UCP1 protein induction in WAT. Our study demonstrates that ß3-adrenergic stimulation-dependent beige adipocyte induction in WAT is impaired by obesity in mice, potentially due to obesity-dependent reduction in the number of PDGFRα-expressing progenitors and decreased PDGF-B expression.


Assuntos
Adipócitos Bege/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Dioxóis/farmacologia , Obesidade/patologia , Adipócitos Bege/patologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Dieta Hiperlipídica , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas Proto-Oncogênicas c-sis/metabolismo , Proteína Desacopladora 1/metabolismo
5.
Eur J Pharmacol ; 854: 354-364, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30822393

RESUMO

Obesity results in the chronic activation of innate immune system and subsequently sets in diabetes. Aim of the study was to investigate the immunometabolic role of brown adipose tissue (BAT) in the obesity. We performed both BAT transplantation as well as extirpation experiments in the mouse model of high-fat diet (HFD)-induced obesity. We carried out immune cell profiling in the stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). BAT transplantation reversed HFD-induced increase in body weight gain and insulin resistance without altering diet intake. Importantly, BAT transplantation attenuated the obesity-associated adipose tissue inflammation in terms of decreased pro-inflammatory M1-macrophages, cytotoxic CD8a T-cells and restored anti-inflammatory regulatory T-cells (Tregs) in the eWAT. BAT transplantation also improved endogenous BAT activity by elevating protein expression of browning markers (UCP-1, PRDM16 and PGC1α) in it. In addition, BAT transplantation promoted the eWAT expression of various genes involved in fatty acid oxidation (such as Elvol3 and Tfam,). In contrast, extirpation of the interscapular BAT exacerbated HFD-induced obesity, insulin resistance and adipose tissue inflammation (by increasing M1 macrophages, CD8a T-cell and decreasing Tregs in eWAT). Taken together, our results suggested an important role of BAT in combating obesity-associated metabolic complications. These results open a novel therapeutic option to target obesity and related metabolic disorders like type 2 diabetes.


Assuntos
Tecido Adiposo Marrom/transplante , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Biomarcadores/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia
7.
Am J Pathol ; 189(3): 492-501, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30803496

RESUMO

The complex relationship between diet and metabolism is an important contributor to cellular metabolism and health. Over the past few decades, a central role for mammalian target of rapamycin (mTOR) in the regulation of multiple cellular processes, including the response to food intake, maintaining homeostasis, and the pathogenesis of disease, has been shown. Herein, we first review our current understanding of the biochemical functions of mTOR and its response to fluctuations in hormone levels, like insulin. Second, we highlight the role of mTOR in lipogenesis, adipogenesis, ß-oxidation of lipids, and ketosis of carbohydrates, lipids, and proteins. Special attention is paid to recent advances in mTOR signaling in white versus brown adipose tissues. Finally, we review how mTOR regulates cardiovascular health and disease. Together, these insights define a clearer picture of the connection between mTOR signaling, metabolic health, and disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Adipogenia , Tecido Adiposo Marrom/patologia , Animais , Doenças Cardiovasculares/patologia , Humanos , Lipogênese , Doenças Metabólicas/patologia
8.
J Physiol Biochem ; 75(1): 1-10, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30506389

RESUMO

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


Assuntos
Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Lipotrópicos/farmacologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucose/metabolismo , Humanos , Resistência à Insulina , Leptina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Melatonina/farmacologia , Peptídeos Natriuréticos/farmacologia , Termogênese/efeitos dos fármacos , Termogênese/genética , Tretinoína/farmacologia
9.
EBioMedicine ; 39: 436-447, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30502051

RESUMO

BACKGROUND: Inflammation is the most relevant mechanism linking obesity with insulin-resistance and metabolic disease. It impacts the structure and function of tissues and organs involved in metabolism, such as the liver, pancreatic islets and the hypothalamus. Brown adipose tissue has emerged as an important component of whole body energy homeostasis, controlling caloric expenditure through the regulation of non-shivering thermogenesis. However, little is known about the impact of systemic inflammation on the structure and function of brown adipose tissue. METHODS: The relations between IL10 and mitochondria structure/function and also with thermogenesis were evaluated by bioinformatics using human and rodent data. Real-time PCR, immunoblot, fluorescence and transmission electron microscopy were employed to determine the effect of IL10 in the brown adipose tissue of wild type and IL10 knockout mice. FINDINGS: IL10 knockout mice, a model of systemic inflammation, present severe structural abnormalities of brown adipose tissue mitochondria, which are round-shaped with loss of cristae structure and increased fragmentation. IL10 deficiency leads to newborn cold intolerance and impaired UCP1-dependent brown adipose tissue mitochondrial respiration. The reduction of systemic inflammation with an anti-TNFα monoclonal antibody partially rescued the structural but not the functional abnormalities of brown adipose tissue mitochondria. Using bioinformatics analyses we show that in both humans and mice, IL10 transcripts correlate with mitochondrial lipid metabolism and caspase gene expression. INTERPRETATION: IL10 and systemic inflammation play a central role in the regulation of brown adipose tissue by controlling mitochondrial structure and function. FUND: Sao Paulo Research Foundation grant 2013/07607-8.


Assuntos
Tecido Adiposo Marrom/citologia , Inflamação/patologia , Interleucina-10/genética , Mitocôndrias/patologia , Tremor por Sensação de Frio/genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Caspases/genética , Linhagem Celular , Temperatura Baixa , Biologia Computacional/métodos , Metabolismo Energético , Técnicas de Inativação de Genes , Humanos , Inflamação/genética , Inflamação/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteína Desacopladora 1/metabolismo
10.
Skeletal Radiol ; 48(3): 413-419, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30215105

RESUMO

OBJECTIVE: To determine the role of brown adipose tissue (BAT) in cancer activity. MATERIALS AND METHODS: The study group comprised 142 patients (121 female, 21 male; mean age, 49 ± 16 years) who underwent F18-FDG PET/CT (PET/CT) for staging or surveillance of cancer and who were BAT-positive on PET/CT. BAT volume by PET/CT, abdominal (visceral and subcutaneous) fat and paraspinous muscle cross-sectional areas (CSA) were assessed. Groups with and without active cancer on PET/CT were compared using a two-sided paired t test. Linear regression analyses between BAT and body composition parameters were performed. RESULTS: There were 62 patients (54 female, eight male) who had active cancer on PET/CT and 80 patients (67 female, 13 male) without active cancer. Groups were similar in age and BMI (p ≥ 0.4), abdominal fat and muscle CSA, fasting glucose, and outside temperature at time of scan (p ≥ 0.2). Patients who had active cancer on PET/CT had higher BAT volume compared to patients without active cancer (p = 0.009). In patients without active cancer, BAT was positively associated with BMI and abdominal fat depots (r = 0.46 to r = 0.59, p < 0.0001) while there were no such associations in patients with active cancer (p ≥ 0.1). No associations between BAT and age or muscle CSA were found (p ≥ 0.1). CONCLUSIONS: BAT activity is greater in patients with active cancer compared to age-, sex-, and BMI-matched BAT-positive patients without active cancer, suggesting a possible role of BAT in cancer activity.


Assuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Neoplasias/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tecido Adiposo Marrom/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Composição Corporal , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Compostos Radiofarmacêuticos , Estudos Retrospectivos
11.
Cell Rep ; 25(12): 3315-3328.e6, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30566859

RESUMO

Mutations in genes essential for mitochondrial function have pleiotropic effects. The mechanisms underlying these traits yield insights into metabolic homeostasis and potential therapies. Here we report the characterization of a mouse model harboring a mutation in the tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding the mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction, and hypertrophic cardiomyopathy. We demonstrate the tissue heterogeneity arises as a result of variable activation of the integrated stress response (ISR) pathway and the ability of certain tissues to respond to impaired mitochondrial translation. Many of the systemic metabolic effects are likely mediated through elevated fibroblast growth factor 21 (FGF21) following activation of the ISR in certain tissues. These findings demonstrate the potential pleiotropy associated with Wars2 mutations in patients.


Assuntos
Especificidade de Órgãos , Fosforilação Oxidativa , Estresse Fisiológico , Triptofano-tRNA Ligase/genética , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Adiposidade , Alelos , Processamento Alternativo/genética , Animais , Sequência de Bases , Peso Corporal , Encéfalo/patologia , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/fisiopatologia , Modelos Animais de Doenças , Transporte de Elétrons , Potenciais Evocados Auditivos do Tronco Encefálico , Éxons/genética , Fatores de Crescimento de Fibroblastos/sangue , Fibroblastos/metabolismo , Perda Auditiva/sangue , Perda Auditiva/complicações , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Camundongos , Camundongos Mutantes , Músculo Esquelético/metabolismo , Mutação/genética , Biogênese de Organelas , Triptofano-tRNA Ligase/metabolismo , Regulação para Cima
12.
J Transl Med ; 16(1): 314, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30453990

RESUMO

BACKGROUND: The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. METHODS: Il18-/- male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18+/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. RESULTS: Compared with Il18+/+ mice, BAT of Il18-/- mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18+/+ and Il18-/- mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18-/- BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18+/+ and Il18-/- mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the 'Quantity of adipocytes' identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes' size. CONCLUSIONS: This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.


Assuntos
Tecido Adiposo Marrom/patologia , Adiposidade , Diferenciação Celular , Dislipidemias/metabolismo , Dislipidemias/patologia , Interleucina-18/deficiência , Adipogenia/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/crescimento & desenvolvimento , Animais , Diferenciação Celular/efeitos dos fármacos , Fígado Gorduroso/patologia , Interleucina-18/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Termogênese/efeitos dos fármacos
13.
Cell Rep ; 25(7): 1708-1717.e5, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30428342

RESUMO

Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues.


Assuntos
Adipócitos/citologia , Tecido Adiposo/metabolismo , Autofagia , Resistência à Insulina , Peróxidos Lipídicos/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Composição Corporal , Peso Corporal , Humanos , Inflamação/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipoproteínas HDL/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
14.
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
15.
Nat Commun ; 9(1): 3622, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30190464

RESUMO

Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19-MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans.


Assuntos
Tecido Adiposo Marrom/fisiologia , Impressão Genômica , Obesidade/genética , RNA Longo não Codificante/genética , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/etiologia
16.
Toxicol Appl Pharmacol ; 359: 12-23, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30222981

RESUMO

Obesity and its related metabolic disorders including insulin resistance and fatty liver become major public health concerns in both developed and developing countries. Brown adipose tissue (BAT), a critical organ of energy expenditure due to thermogenesis, has been considered as an attractive target for prevention or treatment of obesity and obesity related diseases. Previous studies indicate Met-enkephalin (MetEnk) has the potential on adipocyte browning, however, whether MetEnk displays the impact on adipocyte browning in vivo to improve obesity associated morbidities is still unclear. In the present study, we showed that MetEnk effectively prevented high fat diet (HFD) induced C57BL/6J mice weight gain, clearly enhanced glucose tolerance and insulin sensitivity, and dramatically reduced hepatic steatosis in HFD fed mice. Mechanically, MetEnk restored protein kinase A (PKA) signaling pathway in HFD challenged mice and promoted subcutaneous white adipose tissue (WAT) browning. Our study suggests that MetEnk can be considered as a potential therapeutic peptide for diet-induced obesity and metabolic disorders.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Encefalina Metionina/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/crescimento & desenvolvimento , Tecido Adiposo Marrom/patologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/metabolismo , Intolerância à Glucose/tratamento farmacológico , Resistência à Insulina , Masculino , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Opioides delta/efeitos dos fármacos
17.
Curr Diab Rep ; 18(10): 80, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120579

RESUMO

PURPOSE OF REVIEW: The global prevalence of type 2 diabetes (T2D) is escalating at alarming rates, demanding the development of additional classes of therapeutics to further reduce the burden of disease. Recent studies have indicated that increasing the metabolic activity of brown and beige adipose tissue may represent a novel means to reduce circulating glucose and lipids in people with T2D. The AMP-activated protein kinase (AMPK) is a cellular energy sensor that has recently been demonstrated to be important in potentially regulating the metabolic activity of brown and beige adipose tissue. The goal of this review is to summarize recent work describing the role of AMPK in brown and beige adipose tissue, focusing on its role in adipogenesis and non-shivering thermogenesis. RECENT FINDINGS: Ablation of AMPK in mouse adipocytes results in cold intolerance, a reduction in non-shivering thermogenesis in brown adipose tissue (BAT), and the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance; effects associated with a defect in mitochondrial specific autophagy (mitophagy) within BAT. The effects of a ß3-adrenergic agonist on the induction of BAT thermogenesis and the browning of white adipose tissue (WAT) are also blunted in mice lacking adipose tissue AMPK. A specific AMPK activator, A-769662, also results in the activation of BAT and the browning of WAT, effects which may involve demethylation of the PR domain containing 16 (Prdm16) promoter region, which is important for BAT development. AMPK plays an important role in the development and maintenance of brown and beige adipose tissue. Adipose tissue AMPK is reduced in people with insulin resistance, consistent with findings that mice lacking adipocyte AMPK develop greater NAFLD and insulin resistance. These data suggest that pharmacologically targeting adipose tissue AMPK may represent a promising strategy to enhance energy expenditure and reduce circulating glucose and lipids, which may be effective for the treatment of NAFLD and T2D.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Bege/enzimologia , Tecido Adiposo Marrom/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Resistência à Insulina , Obesidade/enzimologia , Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/patologia , Animais , Humanos
18.
J Cell Physiol ; 234(1): 13-22, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078199

RESUMO

Cancer cachexia is a complex disorder that is driven by inflammation and metabolic imbalances, resulting in extreme weight loss. Adipose tissue, a main player in cancer cachexia, is an essential metabolic and secretory organ consisting of both white adipose tissue (WAT) and brown adipose tissue. Its secretory products, including adipokines and cytokines, affect a wide variety of central and peripheral organs, such as the skeletal muscle, brain, pancreas, and liver. Therefore, a combination of metabolic alterations, and systemic inflammation dysregulation of both anti-inflammatory and proinflammatory modulators contribute toward adipose tissue wasting in cancer cachexia. Growing evidence suggests that, during cancer cachexia, WAT undergoes a browning process, resulting in increased lipid mobilization and energy expenditure. In this review, we have summarized the characteristics of cancer cachexia and WAT browning. Furthermore, this review describes how adipose tissue becomes inflamed in cancer, shedding light on the combinatorial action of multiple secreted macromolecules, cytokines, hormones, and tumor mediators on adipose tissue dysfunction. We also highlight the inflammatory responses, energy utilization defects, and molecular mechanisms underlying the WAT dysfunction and browning in cancer cachexia. Further, the actual mechanisms behind the loss of adipose tissue are unknown, but have been attributed to increased adipocyte lipolysis, systemic inflammation, and apoptosis or reduced lipogenesis. The understanding of adipose tissue dysfunction in cancer cachexia will hopefully promote the development of new therapeutic approaches to prevent or treat this wasting syndrome.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Caquexia/metabolismo , Neoplasias/metabolismo , Adipocinas/genética , Adipocinas/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Caquexia/complicações , Caquexia/genética , Caquexia/patologia , Citocinas/genética , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neoplasias/complicações , Neoplasias/genética , Neoplasias/patologia , Pâncreas/metabolismo , Pâncreas/patologia
19.
JCI Insight ; 3(15)2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089714

RESUMO

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, improved insulin sensitivity, and reduced hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to ß-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. These findings define an epigenetic pathway for the regulation of energy homeostasis and suggest the potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fígado Gorduroso/patologia , Histona Desacetilases/metabolismo , Obesidade/patologia , Termogênese/genética , Fatores de Transcrição/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético/genética , Epigênese Genética/fisiologia , Fígado Gorduroso/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Histona Desacetilases/genética , Humanos , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética
20.
Biochimie ; 154: 107-118, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30142366

RESUMO

This study was conducted to investigate the effects of DJ-1 deficiency on brown adipose tissue (BAT) function in mice. DJ-1 knockout (KO) mouse models and wild-type littermates placed on a normal diet or high-fat diet were utilized to demonstrate the direct consequences of DJ-1 deletion on BAT characteristics, thermogenic ability, lipid metabolism, and microenvironment regulation. Global DJ-1 KO mice had defective brown adipose tissue activity culminating in a profound whitening of BAT. Despite aberrations in inactive BAT associated with greater lipid accretion, decreased sympathetic activity, mitochondrial dysfunction, reduced vascularity, and autophagy activation, we found that the body weight and energy balance were unaffected in male mice depleted of DJ-1. Taken together, the results of this study suggest that male DJ-1 KO mice exhibit defects in BAT activity but do not gain more weight, revealing that BAT activity is not necessarily required for predisposing DJ-1 KO mice to obesity. Therefore, therapeutic targeting of DJ-1 in BAT could provide novel insights into the treatment of obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Gorduras na Dieta/efeitos adversos , Metabolismo Energético , Metabolismo dos Lipídeos , Obesidade , Proteína Desglicase DJ-1/deficiência , Tecido Adiposo Marrom/patologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Gorduras na Dieta/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia
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