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1.
Clin Sci (Lond) ; 134(7): 921-939, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32239178

RESUMO

Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Adiposidade , Dieta Hiperlipídica , Metabolismo Energético , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Adipócitos Brancos/patologia , Adipogenia/genética , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Tamanho Celular , Modelos Animais de Doenças , Metabolismo Energético/genética , Feminino , Regulação da Expressão Gênica , Hipertrofia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos Endogâmicos C57BL , Estado Nutricional , Obesidade Materna/genética , Obesidade Materna/patologia , Obesidade Materna/fisiopatologia , Gravidez , Caracteres Sexuais , Fatores Sexuais , Transdução de Sinais , Fatores de Tempo
2.
Microvasc Res ; 130: 104003, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32199946

RESUMO

OBJECTIVE: This study aimed to determine the effects of physical exercise on the angio-adaptive response in adipose tissue following weight loss in a mouse model of diet-induced obesity. We hypothesized that physical exercise stimulates angiogenesis through the regulation of Vascular endothelial growth factor-A (VEGF-A) pro-/Thrombospondin-1 (TSP-1) anti-angiogenic signal under the control of the Murine double-minute 2/Forkhead box Os (Mdm2/FoxOs) axis, as reported in skeletal muscle. METHODS: We studied the effects of 7 weeks-voluntary exercise (Ex) in C57Bl/6 control or diet-induced obese (HFS) mice on vascularization of white adipose tissue (AT). RESULTS: Diet-induced obese sedentary (HFSsed) mice presented a powerful angiostatic control in all adipose tissues, under FoxOs protein regulation, leading to capillary rarefaction. Exercise increased expression of Mdm2, repressing the angiostatic control in favor of adipose vascular regrowth in normal chow (NCex) and HFSex mice. This phenomenon was associated with adipocytes microenvironment improvement, such as decreased adipocytes hypertrophy and adipose tissue inflammation. In addition, adipose angiogenesis stimulation by exercise through Mdm2 pro-angiogenic action, improved visceral adipose insulin sensitivity, activated browning process within subcutaneous adipose tissue (ScWAT) and decreased ectopic fat deposition (muscle, heart and liver) in obese HFSex mice. The overall result of this approach of therapy by physical exercise is an improvement of all systemic cardiometabolic parameters. CONCLUSIONS: These data demonstrated the therapeutic efficacy of physical exercise against obesity-associated pathologies, and also offer new prospects for molecular therapies targeting the adipose angio-adaptation in obese humans.


Assuntos
Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/irrigação sanguínea , Tecido Adiposo Branco/metabolismo , Dieta Hiperlipídica , Terapia por Exercício , Neovascularização Fisiológica , Obesidade/terapia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Animais , Microambiente Celular , Modelos Animais de Doenças , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Transdução de Sinais , Trombospondina 1/metabolismo , Técnicas de Cultura de Tecidos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Perda de Peso
3.
Nat Commun ; 11(1): 463, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974364

RESUMO

Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. Increasing thermogenic brown and beige adipose tissue futile cycling may be an important strategy to increase energy expenditure in obesity, however, brown adipose tissue metabolic activity is lower with obesity. Herein, we report that the exposure of mice to thermoneutrality promotes the infiltration of white adipose tissue with mast cells that are highly enriched with tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme regulating peripheral serotonin synthesis. Engraftment of mast cell-deficient mice with Tph1-/- mast cells or selective mast cell deletion of Tph1 enhances uncoupling protein 1 (Ucp1) expression in white adipose tissue and protects mice from developing obesity and insulin resistance. These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes.


Assuntos
Resistência à Insulina/fisiologia , Mastócitos/metabolismo , Obesidade/etiologia , Serotonina/biossíntese , Triptofano Hidroxilase/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/prevenção & controle , Serotonina/genética , Termogênese , Triglicerídeos/metabolismo , Triptofano Hidroxilase/genética , Proteína Desacopladora 1/metabolismo
4.
Korean J Radiol ; 21(2): 248-256, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31997600

RESUMO

OBJECTIVE: The purpose of the study was to non-invasively characterize and discriminate brown adipose tissue (BAT) from white adipose tissue (WAT) in rats using spectral computed tomography (CT) with histological validation. MATERIALS AND METHODS: A lipid-containing phantom (lipid fractions from 0% to 100%) was imaged with spectral CT. An in vivo, non-enhanced spectral CT scan was performed on 24 rats, and fat concentrations of BAT and WAT were measured. The rats were randomized to receive intraperitoneal treatment with norepinephrine (NE) (n = 12) or saline (n = 12). Non-enhanced and enhanced spectral CT scans were performed after treatment to measure the elevation of iodine in BAT and WAT. The BAT/aorta and WAT/aorta ratios were calculated and compared, after which isolated BAT and WAT samples were subjected to histological and uncoupling protein 1 (UCP1) analyses. RESULTS: The ex-vivo phantom study showed excellent linear fit between measured fat concentration and the known gravimetric reference standard (r² = 0.996). In vivo, BAT had significantly lower fat concentration than WAT (p < 0.001). Compared to the saline group, the iodine concentration of BAT increased significantly (p < 0.001) after injection of NE, while the iodine concentration of WAT only changed slightly. The BAT/aorta ratio also increased significantly after exposure to NE compared to the saline group (p < 0.001). Histological and UCP1 expression analyses supported the spectral CT imaging results. CONCLUSION: The study consolidates spectral CT as a new approach for non-invasive imaging of BAT and WAT. Quantitative analyses of BAT and WAT by spectral CT revealed different characteristics and pharmacologic activations in the two types of adipose tissue.


Assuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Branco/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Processamento de Imagem Assistida por Computador , Injeções Intraperitoneais , Masculino , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Proteína Desacopladora 1/metabolismo
5.
Nat Commun ; 11(1): 481, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980643

RESUMO

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.


Assuntos
Senescência Celular , Resistência à Insulina , Progéria/metabolismo , Progéria/patologia , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Senescência Celular/genética , Senescência Celular/fisiologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Interleucina-1alfa/metabolismo , Camundongos , Camundongos Transgênicos , Estresse Oxidativo , Progéria/genética , Regiões Promotoras Genéticas , Receptor TIE-2/genética , Transdução de Sinais , Proteína 2 de Ligação a Repetições Teloméricas/deficiência , Proteína 2 de Ligação a Repetições Teloméricas/genética , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo
6.
Am J Physiol Cell Physiol ; 318(1): C63-C72, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596606

RESUMO

Endocrine-disrupting chemicals interact with transcription factors essential for adipocyte differentiation. Exposure to endocrine-disrupting chemicals corresponds with elevated risks of obesity, but the effects of these compounds on human cells remain largely undefined. Widespread use of bisphenol AF (BPAF) as a bisphenol A (BPA) alternative in the plastics industry presents unknown health risks. To this end, we discovered that BPAF interferes with the metabolic function of mature human adipocytes. Although 4-day exposures to BPAF accelerated adipocyte differentiation, we observed no effect on mature fat cell marker genes. Additional gene and protein expression analysis showed that BPAF treatment during human adipocyte differentiation failed to suppress the proinflammatory transcription factor STAT1. Microscopy and respirometry experiments demonstrated that BPAF impaired mitochondrial function and structure. To test the hypothesis that BPAF fosters vulnerabilities to STAT1 activation, we treated mature adipocytes previously exposed to BPAF with interferon-γ (IFNγ). BPAF increased IFNγ activation of STAT1 and exposed mitochondrial vulnerabilities that disrupt adipocyte lipid and carbohydrate metabolism. Collectively, our data establish that BPAF activates inflammatory signaling pathways that degrade metabolic activity in human adipocytes. These findings suggest how the BPA alternative BPAF contributes to metabolic changes that correspond with obesity.


Assuntos
Adipócitos Brancos/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Metabolismo Energético/efeitos dos fármacos , Paniculite/induzido quimicamente , Fenóis/toxicidade , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Interferon gama/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , PPAR gama/genética , PPAR gama/metabolismo , Paniculite/metabolismo , Paniculite/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
7.
Eur J Radiol ; 123: 108777, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31855655

RESUMO

PURPOSE: To characterize brown adipose tissue (BAT) in polycystic ovary syndrome (PCOS) patients in comparison to healthy subjects using Z-spectral imaging (ZSI). METHOD: ZSI data were collected on 19 normal control females (NCF), 17 males (NCM), and 13 PCOS patients. By fitting to multiple Lorentzian functions, ZSI provides fat-water fraction (FWF) of tissue in the supraclavicular area that can be used to differentiate between white adipose tissue (WAT), BAT, and muscle. The fraction of BAT over the total fat depot (BATf) and the average FWF in BAT or FWF(BAT) were then computed, reflecting relative BAT mass and BAT metabolism respectively. The parameters were compared among the three groups, and the correlations to Body Mass Index (BMI) were also quantified. RESULTS: There was an inverse correlation between BATf and BMI in normal subjects. The BATf of the PCOS group was significantly smaller than the NCF (P < 0.001). On the other hand, FWF(BAT) correlated linearly with BMI in healthy subjects. The PCOS group had higher FWF(BAT) than the NCF group (P < 0.001). CONCLUSIONS: Normal subjects with higher BMI show less BATf and have increased FWF(BAT), indicating relatively higher level of metabolic passive WAT depot and relatively reduced metabolism in their BAT depots. PCOS patients have the least BATf and the highest FWF(BAT), suggesting decreased BAT mass and function in PCOS. Novel imaging technique with ZSI for the characterization of BAT mass and function in PCOS may help to monitor treatment responses of PCOS therapies.


Assuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Síndrome do Ovário Policístico/fisiopatologia , Termogênese/fisiologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/diagnóstico por imagem , Tecido Adiposo Branco/patologia , Adulto , Análise de Variância , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino
8.
Molecules ; 24(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817377

RESUMO

Many anti-obesity chemicals have been withdrawn from the market due to serious adverse reactions, and the researchers have turned their attention to low-toxic natural products. Previous studies have demonstrated that chitosan (CTS) and chitosan oligosaccharide (COS) were low-toxic natural products for the use of weight loss. However, it is still unclear whether CTS and COS have positive effects on the thermogenesis. In this study, CTS and COS significantly reduced the weight gain of rats without affecting food intake and effectively inhibited adipose tissue hypertrophy and hyperplasia. Consistently, CTS and COS significantly increased the thermogenic capacity of obese rats induced by high-fat diet (HFD) and increased the expression of browning genes and proteins (UCP1, PGC1α, PRMD16, and ATF2) in white adipose tissue (WAT) and brown adipose tissue (BAT). In vitro, COS inhibited the formation of mature adipocytes and increased the expression of browning genes. In conclusion, COS and CTS was used to explore the function and mechanism on thermogenesis, and CTS and COS can increase the browning of WAT and the thermogenesis of BAT to inhibit obesity. This effect may be achieved by promoting the expression of browning and thermogenic genes, providing new ideas for the utilization of COS and CTS.


Assuntos
Tecido Adiposo Marrom , Tecido Adiposo Branco , Quitosana , Obesidade/tratamento farmacológico , Oligossacarídeos , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Quitosana/química , Quitosana/farmacologia , Dieta Hiperlipídica/efeitos adversos , Epididimo/metabolismo , Epididimo/patologia , Masculino , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/patologia , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Ratos , Ratos Sprague-Dawley
9.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671737

RESUMO

Obesity and related comorbidities are a major health concern. The drugs used to treat these conditions are largely inadequate or dangerous, and a well-researched approach based on nutraceuticals would be highly useful. Pterostilbene (Pt), i.e., 3,5-dimethylresveratrol, has been reported to be effective in animal models of obesity, acting on different metabolic pathways. We investigate here its ability to induce browning of white adipose tissue. Pt (5 µM) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 µmol/kg/day) to mice fed an obesogenic high-fat diet (HFD) for 30 weeks, starting at weaning. In the cultured adipocytes, the treatment elicited a significant increase of the levels of Uncoupling Protein 1 (UCP1) protein-a key component of thermogenic, energy-dissipating beige/brown adipocytes. In vivo administration antagonized weight increase, more so in males than in females. Analysis of inguinal White Adipose Tissue (WAT) revealed a trend towards browning, with significantly increased transcription of several marker genes (Cidea, Ebf2, Pgc1α, PPARγ, Sirt1, and Tbx1) and an increase in UCP1 protein levels, which, however, did not achieve significance. Given the lack of known side effects of Pt, this study strengthens the candidacy of this natural phenol as an anti-obesity nutraceutical.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Obesidade/metabolismo , Estilbenos/farmacologia , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Proteínas Reguladoras de Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Peso Corporal , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , PPAR gama/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sirtuína 1/genética , Proteínas com Domínio T/genética , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
10.
Commun Biol ; 2: 389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667363

RESUMO

Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 (ATF3 -/- ) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein-stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Adipócitos Marrons/metabolismo , Obesidade/metabolismo , Células 3T3-L1 , Fator 3 Ativador da Transcrição/deficiência , Fator 3 Ativador da Transcrição/genética , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Fármacos Antiobesidade/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Regulação da Temperatura Corporal/fisiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Resistência à Insulina , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/prevenção & controle , Orlistate/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Salvia miltiorrhiza/química
11.
PLoS One ; 14(10): e0224403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648235

RESUMO

Muscle and bone masses are elevated by the increased mechanical stress associated with body weight gain in obesity. However, the mechanisms by which obesity affects muscle and bone remain unclear. We herein investigated the roles of obesity and humoral factors from adipose tissue in the recovery phase after reloading from disuse-induced muscle wasting and bone loss using normal diet (ND)- or high fat diet (HFD)-fed mice with hindlimb unloading (HU) and subsequent reloading. Obesity did not affect decreases in trabecular bone mineral density (BMD), muscle mass in the lower leg, or grip strength in HU mice. Obesity significantly increased trabecular BMD, muscle mass in the lower leg, and grip strength in reloading mice over those in reloading mice fed ND. Among the humoral factors in epididymal and subcutaneous adipose tissue, leptin mRNA levels were significantly higher in reloading mice fed HFD than in mice fed ND. Moreover, circulating leptin levels were significantly higher in reloading mice fed HFD than in mice fed ND. Leptin mRNA levels in epididymal adipose tissue or serum leptin levels positively correlated with the increases in trabecular BMD, total muscle mass, and grip strength in reloading mice fed ND and HFD. The present study is the first to demonstrate that obesity enhances the recovery of bone and muscle masses as well as strength decreased by disuse after reloading in mice. Leptin may contribute to the recovery of muscle and bone enhanced by obesity in mice.


Assuntos
Osso e Ossos/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Leptina/metabolismo , Músculos/fisiopatologia , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Animais , Fenômenos Biomecânicos , Peso Corporal , Densidade Óssea , Osso e Ossos/patologia , Osso Esponjoso/patologia , Osso Esponjoso/fisiopatologia , Força da Mão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/patologia , Obesidade/induzido quimicamente , Obesidade/patologia , Obesidade/fisiopatologia , Tamanho do Órgão , Tíbia/patologia , Tíbia/fisiopatologia , Suporte de Carga
12.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652943

RESUMO

Shortening of poly(A) tails triggers mRNA degradation; hence, mRNA deadenylation regulates many biological events. In the present study, we generated mice lacking the Cnot1 gene, which encodes an essential scaffold subunit of the CCR4-NOT deadenylase complex in adipose tissues (Cnot1-AKO mice) and we examined the role of CCR4-NOT in adipocyte function. Cnot1-AKO mice showed reduced masses of white adipose tissue (WAT) and brown adipose tissue (BAT), indicating abnormal organization and function of those tissues. Indeed, Cnot1-AKO mice showed hyperinsulinemia, hyperglycemia, insulin resistance, and glucose intolerance and they could not maintain a normal body temperature during cold exposure. Muscle-like fibrous material appeared in both WAT and BAT of Cnot1-AKO mice, suggesting the acquisition of non-adipose tissue characteristics. Gene expression analysis using RNA-sequencing (RNA-seq) showed that the levels of adipose tissue-related mRNAs, including those of metabolic genes, decreased, whereas the levels of inflammatory response-related mRNAs increased. These data suggest that the CCR4-NOT complex ensures proper adipose tissue function by maintaining adipocyte-specific mRNAs at appropriate levels and by simultaneously suppressing mRNAs that would impair adipocyte function if overexpressed.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Fatores de Transcrição/genética , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Animais , Temperatura Corporal , Células Cultivadas , Regulação da Expressão Gênica , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Fatores de Transcrição/deficiência
13.
Eur J Pharmacol ; 863: 172708, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31568785

RESUMO

Obesity is a serious public health problem characterized by abnormal or excessive fat accumulation, which is caused by an energy imbalance between calories consumed and calories expended. MiRNAs have been involved in the regulation of occurrence and progression of obesity. This study aims to investigate the role of miR-324-5p in regulating the adipose tissue mass and preliminarily probe into its effect on progression of obesity. MiR-324-5p was upregulated in the epididymal white adipose tissues (eWAT), inguinal white adipose tissues (iWAT) and brown adipose tissues (BAT) of the mice fed with high fat diet (HFD). Under room temperature (RT) or thermoneutrality (TN) condition, when tail intravenously injected with miR-324-5p antagomir (anta-miR-324-5p), the fat mass and total weight of mice were both significantly suppressed. The suppressive effect was more distinct under TN than RT. The weight of iWAT and BAT were both inhibited by anta-miR-324-5p under TN. Moreover, PM20D1 was a direct target gene of miR-324-5p. In primary iWAT cells, the expression of PM20D1 was significantly increased by anta-miR-324-5p, whereas decreased by the miR-324-5p mimic. Furthermore, anta-miR-324-5p noticeably increased the cellular oxygen consumption in primary BAT and iWAT cells. Our findings indicated that inhibition of miR-324-5p increased PM20D1-mediated fat consumption and reduced body weight in mice, suggesting that miR-324-5p may be a novel therapeutic target against obesity.


Assuntos
Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Amidoidrolases/metabolismo , Peso Corporal/genética , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Amidoidrolases/genética , Animais , Antagomirs/genética , Progressão da Doença , Camundongos , Camundongos Endogâmicos BALB C , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Consumo de Oxigênio/genética , Termogênese/genética , Regulação para Cima/genética
14.
Cells ; 8(8)2019 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405230

RESUMO

Adipose tissue accumulation is an independent and modifiable risk factor for cardiovascular disease (CVD). The recent CVD European Guidelines strongly recommend regular physical exercise (PE) as a management strategy for prevention and treatment of CVD associated with metabolic disorders and obesity. Although mutations as well as common genetic variants, including the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, are associated with increased body weight, eating and neuropsychiatric disorders, and myocardial infarction, the effect of this polymorphism on adipose tissue accumulation and regulation as well as its relation to obesity/thrombosis remains to be elucidated. Here, we showed that white adipose tissue (WAT) of humanized knock-in BDNFVal66Met (BDNFMet/Met) mice is characterized by an altered morphology and an enhanced inflammatory profile compared to wild-type BDNFVal/Val. Four weeks of voluntary PE restored the adipocyte size distribution, counteracted the inflammatory profile of adipose tissue, and prevented the prothrombotic phenotype displayed, per se, by BDNFMet/Met mice. C3H10T1/2 cells treated with the Pro-BDNFMet peptide well recapitulated the gene alterations observed in BDNFMet/Met WAT mice. In conclusion, these data indicate the strong impact of lifestyle, in particular of the beneficial effect of PE, on the management of arterial thrombosis and inflammation associated with obesity in relation to the specific BDNF Val66Met mutation.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Inflamação/metabolismo , Condicionamento Físico Animal , Trombose/metabolismo , Adipócitos/patologia , Tecido Adiposo Branco/patologia , Animais , Artérias/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Linhagem Celular , Técnicas de Introdução de Genes , Camundongos , Polimorfismo de Nucleotídeo Único , Trombose/patologia
15.
Turk J Med Sci ; 49(4): 1165-1169, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31385484

RESUMO

Background/aim: Several studies demonstrated that primary hyperparathyroidism is related to increased risk for cardiovascular diseases (CVDs), and risk is decreased by parathyroidectomy. Epicardial fat thickness (EFT) has been postulated as a new marker of CVD risk. We evaluated the impact of parathyroidectomy on EFT in patients with primary hyperparathyroidism (PHPT). Materials and methods: Thirty-four PHPT patients (29 female, 5 male) and 28 age- and sex-matched controls (19 female, 9 male) were included in the study. Demographic, anthropometric, and biochemical data were recorded both before parathyroidectomy and 6 months after the procedure. Epicardial fat thickness was measured by transthoracic echocardiography. Results: Mean age was 53.15 ± 8.44 years. Mean preoperative EFT was higher than mean EFT in the control group (0.49 ± 0.07 cm to 0.46 ± 0.08 cm, P: 0.0005), and EFT decreased after parathyroidectomy (0.49 ± 0.07 cm to 0.44 ± 0.08 cm, P: 0.0005). Systolic blood pressure and calcium, parathormone, and hsCRP levels decreased after parathyroidectomy (P < 0.05). Vitamin D levels increased (P < 0.05). Diastolic blood pressure, body mass index, carotid intima-media thickness, and HOMA-IR, fasting plasma glucose, and phosphorus levels were unchanged after parathyroidectomy (P > 0.05). Preoperatively, EFT was correlated with SBP (r: 0.360, P: 0.0285) and age (r: 0.466, P: 0.0036). Multiple linear regression used to identify independent predictors of change in epicardial fat did not find any predictor of change in epicardial fat (P > 0.05). Conclusion: EFT was decreased by parathyroidectomy in patients with primary hyperparathyroidism.However, the decrease in EFT was not correlated with any of the cardiovascular risk factors. More comprehensive studies evaluating the potential relation between PHPT and EFT need to be conducted.


Assuntos
Doenças Cardiovasculares/epidemiologia , Hiperparatireoidismo Primário , Paratireoidectomia/estatística & dados numéricos , Pericárdio/patologia , Tecido Adiposo Branco/patologia , Feminino , Humanos , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/fisiopatologia , Hiperparatireoidismo Primário/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
16.
Arch Biochem Biophys ; 671: 175-184, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31283909

RESUMO

Endoplasmic Reticulum Protein 44 (ERp44) is a member of the PDI family, named for a molecular weight of 44 kD. White adipose tissue has metabolic and endocrine functions that are important to metabolism. The role of ERp44 in glucose and lipid metabolism is not known yet. The current study was undertaken to investigate the implication of ERp44 in glucose and lipid metabolism. In this study, we generated and characterized ERp44-/- mice. We used type 2 diabetes models and ERp44 knockout mice to show the implication of ERp44 in glucose and lipid metabolism. Knockout newborns had lower blood glucose compared to wild-type. Adult knockouts had abnormal intraperitoneal, glucose, insulin and pyruvic acid tolerance. Lipocytes were smaller and fewer in knockout mice compared to wild-type. Knockouts resisted to high-fat diet-induced obesity. ERp44 expression in white adipose tissue decreased significantly in type 2 diabetes models. Results suggest that ERp44 is closely associated with glucose and lipid metabolism.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Metabolismo dos Lipídeos/fisiologia , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Linhagem Celular , Dieta Hiperlipídica , Feminino , Técnicas de Inativação de Genes , Ilhotas Pancreáticas/patologia , Gotículas Lipídicas/patologia , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Obesidade/metabolismo , Ratos Wistar
17.
Endocr J ; 66(10): 923-936, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31292308

RESUMO

Promoting brown adipose tissue (BAT) formation and function reduces obesity. Ellagic Acid (EA), located abundantly in plant extracts and fruits, has been shown to modulate formation and differentiation of adipocytes, although its role in the process of browning of white adipose tissue (WAT) has not been elucidated. In this study, fifty-six five-week old SD rats were randomly assigned to receive normal diet (ND, 10% lipids) or high-fat diet (HFD, 60% lipid) with or without various dosages of EA for 24 weeks. Our results showed that high fat diet intake triggered overweight, glucose intolerance and white adipocyte hypertrophy, the effects of which were mitigated by EA treatment. Meanwhile, EA supplementation reduced serum resistin levels, improved hepatic steatosis and serum lipid profile in DIO (high fat diet induced obesity) rats. Moreover, EA supplementation significantly decreased mRNA expression of Zfp423 and Aldh1a1, the key determinants of WAT plasticity. EA also increased mRNA expression of brown adipocyte markers including UCP1, PRDM16, Cidea, PGC1α, Ppar-α; beige markers including CD137and TMEM26; mitochondrial biogenesis markers including TFAM in inguinal WAT (iWAT) when compared to their counterparts. EA treatment significantly improved mitochondrial function, as measured by citrate synthase activity. More importantly, EA markedly elevated the expression of UCP1 in iWAT, which is a specific protein of brown adipocyte. In conclusion, our results provided evidence that EA improved obesity-induced dyslipidemia and hepatic steatosis in DIO rats via browning of iWAT through suppressing white adipocyte maintaining genes and promoting expression of key thermogenic genes. These findings suggest that EA could be a promising therapeutic avenue to treat metabolic diseases.


Assuntos
Adipócitos Brancos/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Ácido Elágico/administração & dosagem , Obesidade/tratamento farmacológico , Obesidade/patologia , Adipócitos Brancos/fisiologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Citrato (si)-Sintase/metabolismo , Dieta Hiperlipídica , Intolerância à Glucose/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Obesidade/etiologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Ganho de Peso/efeitos dos fármacos
18.
Cell ; 178(3): 686-698.e14, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31257031

RESUMO

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.


Assuntos
Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Dieta Hiperlipídica , Intolerância à Glucose , Humanos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Metabolismo dos Lipídeos/genética , Lipídeos/análise , Macrófagos/citologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Monócitos/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Transdução de Sinais , Análise de Célula Única
19.
EBioMedicine ; 44: 489-501, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31221584

RESUMO

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.


Assuntos
Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Antígenos CD/genética , Antígenos de Neoplasias/genética , Metabolismo Energético/genética , Hipóxia/metabolismo , Paniculite/genética , Paniculite/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Matriz Extracelular , Feminino , Fibrose , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Paniculite/patologia , Transdução de Sinais
20.
Acta Pharmacol Sin ; 40(12): 1532-1543, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31165783

RESUMO

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3-/-) mice. In the present study we investigated the role of Clcn3 in high-fat diet (HFD)-induced obesity and ATM inflammation. To establish the mouse obesity model, both Clcn3-/- mice and wild-type mice were fed a HFD for 4 or 16 weeks. The metabolic parameters were assessed and the abdominal total adipose tissue was scanned using computed tomography. Their epididymal fat pad tissue and adipose tissue stromal vascular fraction (SVF) cells were isolated for analyses. We found that the HFD-fed Clcn3-/- mice displayed a significant decrease in obesity-induced body weight gain and abdominal visceral fat accumulation as well as an improvement of glucose and lipid metabolism as compared with HFD-fed wild-type mice. Furthermore, the Clcn3 deficiency significantly attenuated HFD-induced ATM accumulation, HFD-increased F4/80+ CD11c+ CD206- SVF cells as well as HFD-activated TLR-4/NF-κB signaling in epididymal fat tissue. In cultured human THP-1 macrophages, adenovirus-mediated transfer of Clcn3 specific shRNA inhibited, whereas adenovirus-mediated cDNA overexpression of Clcn3 enhanced lipopolysaccharide-induced activation of NF-κB and TLR-4. These results demonstrate a novel role for Clcn3 in HFD-induced obesity and ATM inflammation.


Assuntos
Tecido Adiposo Branco/metabolismo , Canais de Cloreto/genética , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Animais , Linhagem Celular , Dieta Hiperlipídica , Humanos , Camundongos Knockout , NF-kappa B/metabolismo , Obesidade/genética , Receptor 4 Toll-Like/metabolismo
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