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1.
Science ; 368(6486): 54-60, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32193362

RESUMO

The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic "megamitochondria" with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.


Assuntos
Adipócitos Marrons/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Degradação Associada com o Retículo Endoplasmático/fisiologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Termogênese/fisiologia , Adipócitos Marrons/metabolismo , Animais , Temperatura Baixa , Estresse do Retículo Endoplasmático/genética , Degradação Associada com o Retículo Endoplasmático/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Mutantes , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/metabolismo , Receptores sigma/metabolismo , Termogênese/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
2.
Metabolism ; 105: 154173, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035087

RESUMO

OBJECTIVE: Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. METHODS: We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. RESULTS: We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. CONCLUSION: These results suggested that the IDH1-α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Histonas/metabolismo , Isocitrato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , Adipogenia , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Termogênese/genética , Termogênese/fisiologia
3.
Biosci Biotechnol Biochem ; 84(2): 305-313, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31601163

RESUMO

Specific conditions, such as exposure to cold, can induce the production of brown-like adipocytes in white adipose tissue. These adipocytes express high levels of uncoupling protein 1 (UCP1) and energy expended by generating heat. Thus, these are a potential target for the prevention or treatment of obesity. The present study involved a comprehensive analysis of the adipose tissue to understand the relationship between long non-coding RNA (lncRNA) 2310069B03Rik and UCP1. Cold exposure increased both lncRNA 2310069B03Rik and Ucp1 expression in inguinal white adipose tissue (iWAT). However, overexpression of lncRNA 2310069B03Rik suppressed the Ucp1 mRNA expression and the promoter activity of UCP1 in the iWAT primary adipocytes. In addition, compared to the early induction of Ucp1 expression by cold stimulation, the induction of lncRNA 2310069B03Rik expression was later. These results suggest that lncRNA 2310069B03Rik functions as a suppression factor of Ucp1 expression.


Assuntos
Temperatura Baixa , RNA Longo não Codificante/metabolismo , Proteína Desacopladora 1/genética , Adipócitos Bege , Agonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Termogênese/genética , Proteína Desacopladora 1/metabolismo
4.
Metabolism ; 102: 154011, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734274

RESUMO

OBJECTIVE: The gut microbiota regulates thermogenesis to benefit metabolic homeostasis at least partially via its metabolite butyrate, and the underlying mechanisms of this regulation are still unclear. In this study, we aim to investigate the role of lysine specific demethylase (LSD1), a histone demethylase and important regulator of thermogenesis, in mediating gut microbial metabolite butyrate regulation of thermogenesis. METHODS: The antibiotic cocktail (ABX) was administrated to deplete gut microbiota. Adipose-specific LSD1 knockout mice (LSD1 aKO) were generated by crossing LSD1-lox/lox with adiponectin-cre mice and sodium butyrate and dietary fiber inulin was administrated through oral-gavage. Primary stromal vascular cells were isolated from adipose tissues and differentiated to adipocytes for studying butyrate effects on adipocyte thermogenesis. RESULTS: The antibiotic cocktail (ABX)-mediated depletion of the gut microbiota in mice downregulated the expression of LSD1 in both brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT) in addition to uncoupling protein 1 (UCP1) and body temperature. Gavage of the microbial metabolite butyrate in ABX-treated mice reversed the thermogenic functional impairment and LSD1 expression. The adipose-specific ablation of LSD1 in mice attenuated the butyrate-mediated induction of thermogenesis and energy expenditure. Notably, our results showed that butyrate directly increased the expression of LSD1 and UCP1 as well as butyrate transporter monocarboxylate transporter 1 (MCT1) and catabolic enzyme acyl-CoA medium-chain synthetase 3 (ACSM3) in ex vivo cultured adipocytes. The inhibition of MCT1 blocked the effects of butyrate in adipocytes. Furthermore, the butyrate-mediated prevention of diet-induced obesity (DIO) through increased thermogenesis was attenuated in LSD1 aKO mice. Moreover, after gavaging HFD-fed mice with the dietary fiber inulin, a substrate of microbial fermentation that rapidly produces butyrate, thermogenesis in both BAT and scWAT was increased, and DIO was decreased; however, these beneficial metabolic effects were blocked in LSD1 aKO mice. CONCLUSIONS: Together, our results indicate that the microbial metabolite butyrate regulates thermogenesis in BAT and scWAT through the activation of LSD1.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Butiratos/farmacologia , Microbioma Gastrointestinal/fisiologia , Histona Desmetilases/fisiologia , Termogênese/efeitos dos fármacos , Termogênese/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Butiratos/metabolismo , Células Cultivadas , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gordura Subcutânea/metabolismo
5.
Metabolism ; 103: 154048, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31843339

RESUMO

OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)], a component of the renin angiotensin system, is a vasodilator that exerts its effects primarily through the Mas receptor. The discovery of the Mas receptor in white adipose tissue (WAT) suggests an additional role for this peptide. The aim of the present study was to assess whether Ang-(1-7) can induce the expression of thermogenic genes in white adipose tissue and increase mitochondrial respiration in adipocytes. MATERIALS/METHODS: Stromal Vascular fraction (SVF)-derived from mice adipose tissue was stimulated for one week with Ang-(1-7), then expression of beige markers and mitochondrial respiration were assessed. Mas+/+ and Mas-/- mice fed a control diet or a high fat-sucrose diet (HFSD) were exposed to a short or long term infusion of Ang-(1-7) and body weight, body fat, energy expenditure, cold resistance and expression of beige markers were assessed. Also, transgenic rats overexpressing Ang-(1-7) were fed with a control diet or a high fat-sucrose diet and the same parameters were assessed. Ang-(1-7) circulating levels from human subjects with different body mass index (BMI) or age were measured. RESULTS: Incubation of adipocytes derived from SVF with Ang-(1-7) increased the expression of beige markers. Infusion of Ang-(1-7) into lean and obese Mas+/+mice also induced the expression of Ucp1 and some beige markers, an effect not observed in Mas-/- mice. Mas-/- mice had increased body weight gain and decreased cold resistance, whereas rats overexpressing Ang-(1-7) showed the opposite effects. Overexpressing rats exposed to cold developed new thermogenic WAT in the anterior interscapular area. Finally, in human subjects the higher the BMI, low circulating concentration of Ang-(1-7) levels were detected. Similarly, the circulating levels of Ang-(1-7) peptide were reduced with age. CONCLUSION: These data indicate that Ang-(1-7) stimulates beige markers and thermogenesis via the Mas receptor, and this evidence suggests a potential therapeutic use to induce thermogenesis of WAT, particularly in obese subjects that have reduced circulating concentration of Ang-(1-7).


Assuntos
Tecido Adiposo Bege/efeitos dos fármacos , Angiotensina I/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas-G/fisiologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Células Cultivadas , Metabolismo Energético/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Proteínas Proto-Oncogênicas/genética , Ratos , Ratos Transgênicos , Receptores Acoplados a Proteínas-G/genética , Termogênese/genética , Adulto Jovem
6.
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
7.
PLoS One ; 14(11): e0223987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31751350

RESUMO

Energy consuming, heat-producing beige adipocytes, located in classic white adipose tissue (WAT), hold promise for the treatment of obesity. Few reports have quantitatively assessed the contribution of browned 'WAT' to energy expenditure. There is a need for methods to examine beige-fat thermogenesis, independently of classical brown fat. The aim of this study is to optimize an inducible lentiviral shRNA to conditionally knock-down Ucp1 and assess the effects on 'browned' WAT. Primary adipocytes from mouse inguinal WAT converted into thermogenic adipocytes when stimulated with ß-adrenergic agonist and thiazolidinedione. There was increased UCP1 protein and importantly increases in various indicators of mitochondrial bioenergetics. Next, we determined optimal transfection conditions for the UCP1-shRNA lentiviral system and subsequently applied this to 'browned' WAT. UCP1 knockdown decreased the brown/beige-fat gene profile and decreased mitochondrial respiration. In summary, this study optimizes lentiviral UCP1-shRNA technology in vitro. This technique could be applied to inguinal fat depots in vivo. This would allow investigation of contribution of depots to whole-body metabolism to help elucidate the physiological relevance of beige fat.


Assuntos
Tecido Adiposo Bege/metabolismo , Metabolismo Energético/genética , Homeostase/genética , Lentivirus/genética , Interferência de RNA , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Adipócitos/metabolismo , Tecido Adiposo Bege/citologia , Animais , Glicólise/genética , Masculino , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Termogênese/genética
8.
Nat Commun ; 10(1): 5070, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699980

RESUMO

ß-Adrenergic receptor (ß-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the ß3-adrenergic receptor (ß3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses ß3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.


Assuntos
Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Adipogenia/genética , Metabolismo Energético/genética , Fatores de Transcrição Forkhead/genética , Receptores Adrenérgicos beta 3/genética , Proteínas Repressoras/genética , Termogênese/genética , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Camundongos , Obesidade/genética , Obesidade/metabolismo , Omento/metabolismo , Feocromocitoma/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteínas Repressoras/metabolismo
9.
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
10.
DNA Cell Biol ; 38(11): 1303-1312, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553232

RESUMO

Growth differentiation factor 5 (GDF5) was reported to regulate brown adipogenesis; however, its effects on insulin sensitivity, full metabolic syndrome spectrum, and the thermogenesis in subcutaneous white adipose tissue (sWAT) have not been elucidated yet. We thus generated fatty acid-binding protein 4 (Fabp4)-GDF5 transgenic (TG) mice and showed that GDF5 TG mice developed a relative lean phenotype on a high-fat diet (HFD) and showed increased insulin sensitivity. Over expression of GDF5 in adipose tissues greatly promoted the thermogenic process in sWAT after cold or ß3-agonist treatment. In TG mice, sWAT showed an important thermogenic effect as the thermogenic gene expression was markedly increased, which was consistent with the typical features of beige adipocytes. Moreover, knockdown of the protein GDF5 impaired browning program in sWAT after thermogenic stimuli. Enhanced mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling was also identified in sWAT of HFD-fed GDF5 mice, and thermogenesis in mature adipocytes induced by GDF5 protein could be partly blocked by a p38 MAPK inhibitor. Taken together, our data suggest that GDF5 could improve insulin sensitivity and prevent metabolic syndrome, the adaptive thermogenesis in sWAT could mediate the obesity resistance effects of GDF5 in mice and partially resulted in the activation of the p38 MAPK signaling pathway.


Assuntos
Tecido Adiposo Branco/fisiologia , Fator 5 de Diferenciação de Crescimento/fisiologia , Termogênese/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adipogenia/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Células Cultivadas , Fator 5 de Diferenciação de Crescimento/genética , Resistência à Insulina/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Transdução de Sinais/genética
11.
Am J Physiol Endocrinol Metab ; 317(6): E1158-E1171, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550180

RESUMO

Although many studies have shown that histamine and its signaling regulate energy homeostasis through the central nervous system, their roles in adipose tissues remain poorly understood. Here, we identified that the histamine H4 receptor (HrH4) was highly expressed in adipocytes at a level higher than that of the other three receptors (i.e., HrH1, HrH2, and HrH3). The HrH4 expression in adipocytes responded to cold through thermogenesis and lipolysis, supported by results from both mouse and cell models. When HrH4 expression was knocked down in the subcutaneous white adipose tissue (scWAT), browning and lipolysis effects triggered by cold were ablated, and the oxygen consumption was also lowered both at the normal and cold conditions. Moreover, mice exhibited browned scWAT, accelerated metabolic rates, and tolerance to hypothermia when 4-methylhistamine (4MH), a selective HrH4 agonist, was adjacently injected to the scWAT. Consistent with these findings, 4MH also triggered the browning and lipolytic effects in cultured C3H10T1/2 adipocytes. Mechanically, we demonstrated that p38/MAPK and ERK/MAPK pathways were involved in these processes. In conclusion, our findings have uncovered an effective role of HrH4 in adipose tissue browning.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Temperatura Baixa , Consumo de Oxigênio/genética , Receptores Histamínicos H4/genética , Gordura Subcutânea/metabolismo , Termogênese/genética , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Metabolismo Basal/efeitos dos fármacos , Metabolismo Basal/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Agonistas dos Receptores Histamínicos/farmacologia , Lipólise/efeitos dos fármacos , Lipólise/genética , Sistema de Sinalização das MAP Quinases , Metilistaminas/farmacologia , Camundongos , Consumo de Oxigênio/efeitos dos fármacos , Receptores Histamínicos H4/agonistas , Receptores Histamínicos H4/metabolismo , Gordura Subcutânea/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502571

RESUMO

Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency of receptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was to compare BAT activity in RAGE knock out (Ager-/-, RKO) and wild-type (WT) mice after treated with HFD or LFD. [18F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUVmean), ratio of SUViBAT/SUVmuscle (SUVR, muscle as the reference region) and percentage ID/g were used for BAT quantification. The results showed that [18F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that in WT-LFD (1.40 +/- 0.07 and 4.03 +/- 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affected by HFD, with SUVRRKO-LFD: 2.14 +/- 0.10 and SUVRRKO-LFD: 1.52 +/- 0.13 (P = 0.3). The uptake in WT-LFD was almost double of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFD mice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 in the BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD by Ager deletion (Ager -/-).


Assuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Receptor para Produtos Finais de Glicação Avançada/genética , Termogênese/genética , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Camundongos , Camundongos Knockout , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Proteína Desacopladora 1
13.
Proc Natl Acad Sci U S A ; 116(37): 18691-18699, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451658

RESUMO

Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) including Srebp1, the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer of Srebp1 expression, and engaged circadian transcriptional repressors REV-ERBα and ß as rhythmic regulators of Srebp1 in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and ß in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.


Assuntos
Aclimatação , Tecido Adiposo Marrom/metabolismo , Ritmo Circadiano/fisiologia , Lipogênese/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Termogênese/genética , Animais , Temperatura Corporal , Temperatura Baixa/efeitos adversos , Regulação da Expressão Gênica/fisiologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Modelos Animais , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
14.
Nat Commun ; 10(1): 3536, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387996

RESUMO

Tonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases > 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of ß3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with ß3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia.


Assuntos
Epigênese Genética , Resistência à Insulina/genética , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Células 3T3 , Adipócitos/metabolismo , Tecido Adiposo Bege/citologia , Tecido Adiposo Bege/metabolismo , Animais , Índice de Massa Corporal , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/etiologia , Cultura Primária de Células , Receptores Adrenérgicos beta 3/metabolismo , Gordura Subcutânea/citologia , Gordura Subcutânea/metabolismo , Termogênese/genética , Fatores de Transcrição/genética
15.
Metabolism ; 100: 153955, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31390528

RESUMO

OBJECTIVES: The activation of brown adipose tissue (BAT) is considered as a promising therapeutic target for obesity. APPL1 (Adaptor protein containing the Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif) is an intracellular adaptor protein and its genetic variation is correlated with BMI and body fat distribution in diabetic patients. However, little is known about the roles of APPL1 in BAT thermogenesis. MATERIALS/METHODS: In this study, adipose tissue specific knockout (ASKO) mice were generated to evaluate APPL1's role in BAT thermogenesis in vivo, and possible signaling pathways were further explored in cultured brown adipocytes. RESULTS: After high fat diet challenge, APPL1 ASKO mice developed more severe obesity, glucose intolerance and insulin resistance compared with control mice. Metabolic cage study showed that APPL1 deficiency impaired energy expenditure and adaptive thermogenesis in ASKO mice. PET-CT analysis showed decreased standardized uptake value (SUV) in the inter-scapular region which indicated impaired BAT activity in ASKO mice. Further study showed deletion of APPL1 attenuated brown fat specific gene expression, such as UCP1 and PGC1α in both BAT and brown adipocytes. In cultured brown adipocytes, upon cAMP stimulation, APPL1 shuttled from cytosol to nuclei. Co-IP and ChIP study showed that APPL1 could directly interact with histone deacetylase 3 (HDAC3) to mediate chromatin remodeling and UCP1 gene expression. CONCLUSIONS: Our data demonstrated the essential role of APPL1 in regulating brown adipocytes thermogenesis via interaction with HDAC3, which may have potential therapeutic implications for treatment of obesity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Tecido Adiposo Marrom/fisiologia , Histona Desacetilases/fisiologia , Termogênese/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Dieta Hiperlipídica , Metabolismo Energético , Feminino , Regulação da Expressão Gênica , Intolerância à Glucose , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/prevenção & controle , Termogênese/genética
16.
Am J Physiol Endocrinol Metab ; 317(5): E820-E830, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31386566

RESUMO

Brown adipose tissue (BAT) catabolizes glucose and fatty acids to produce heat and thereby contributes to energy expenditure. Long-term high-fat diet (HFD) feeding results in so-called 'whitening' of BAT characterized by increased lipid deposition, mitochondrial dysfunction, and reduced fat oxidation. The aim of the current study was to unravel the rate and related mechanisms by which HFD induces BAT whitening and insulin resistance. Wild-type mice were fed a HFD for 0, 1, 3, or 7 days. Within 1 day of HFD, BAT weight and lipid content were increased. HFD also immediately reduced insulin-stimulated glucose uptake by BAT, indicating rapid induction of insulin resistance. This was accompanied by a tendency toward a reduced uptake of triglyceride-derived fatty acids by BAT. Mitochondrial mass and Ucp1 expression were unaltered, whereas after 3 days of HFD, markers of mitochondrial dynamics suggested induction of a more fused mitochondrial network. Additionally, HFD also increased macrophage markers in BAT after 3 days of HFD. Counterintuitively, the switch to HFD was accompanied by an acute rise in core body temperature. We showed that a single day of HFD feeding is sufficient to induce the first signs of whitening and insulin resistance in BAT, which reduces the uptake of glucose and triglyceride-derived fatty acids. BAT whitening and insulin resistance are likely sustained by reduced mitochondrial oxidation due to changes in mitochondrial dynamics and macrophage infiltration, respectively. Likely, the switch to HFD swiftly induces thermogenesis in other metabolic organs, which allows attenuation of BAT thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Dieta Hiperlipídica , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , DNA Mitocondrial/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética , Triglicerídeos/metabolismo , Proteína Desacopladora 1/metabolismo
17.
Biomed Res Int ; 2019: 1969413, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312653

RESUMO

The positive regulatory domain containing 16 (PRDM16) gene is a dominant transcriptional regulator that favors the "browning" of white adipocytes in rodents. Since the "browning" of white fat is important in pig in terms of producing heat fighting against cold environment, avoiding obesity, and improving meat quality, understanding the critical role that PRDM16 gene played in pig adipose "browning" and energy metabolism is of great significance. However, the constitution of pig fat differs a lot from rodents and human as they do not have brown adipose tissue (BAT) even in the newborn piglets. In this study, we isolated porcine primary preadipocytes and investigated the function of PRDM16 during preadipocytes differentiation. Our results showed that overexpression of the PR domain of PRDM16 repressed the differentiation of porcine preadipocytes, indicated by oil red O staining and the deposition of the triglyceride. Overexpression of the PR domain significantly increased the level of lipolysis and mitochondrial oxidative capacity detected by Western blotting during differentiation. Furthermore, we purified the protein coded by the PR domain and demonstrated that this protein has the H3K9me1 methyltransferase activity. In conclusion, the PR domain of the porcine PRDM16 gene repressed the mature of the porcine preadipocytes by promoting its oxidative activity.


Assuntos
Tecido Adiposo Branco/crescimento & desenvolvimento , Metabolismo Energético/genética , Lipogênese/genética , Obesidade/genética , Adipócitos/metabolismo , Tecido Adiposo Marrom/crescimento & desenvolvimento , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Lipólise/genética , Obesidade/fisiopatologia , Suínos , Termogênese/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética
18.
Proc Natl Acad Sci U S A ; 116(35): 17419-17428, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31341090

RESUMO

Viperin is an interferon (IFN)-inducible multifunctional protein. Recent evidence from high-throughput analyses indicates that most IFN-inducible proteins, including viperin, are intrinsically expressed in specific tissues; however, the respective intrinsic functions are unknown. Here we show that the intrinsic expression of viperin regulates adipose tissue thermogenesis, which is known to counter metabolic disease and contribute to the febrile response to pathogen invasion. Viperin knockout mice exhibit increased heat production, resulting in a reduction of fat mass, improvement of high-fat diet (HFD)-induced glucose tolerance, and enhancement of cold tolerance. These thermogenic phenotypes are attributed to an adipocyte-autonomous mechanism that regulates fatty acid ß-oxidation. Under an HFD, viperin expression is increased, and its function is enhanced. Our findings reveal the intrinsic function of viperin as a novel mechanism regulating thermogenesis in adipose tissues, suggesting that viperin represents a molecular target for thermoregulation in clinical contexts.


Assuntos
Tecido Adiposo/metabolismo , Regulação da Expressão Gênica , Proteínas/genética , Termogênese/genética , Adipócitos/metabolismo , Animais , Metabolismo Energético/genética , Masculino , Camundongos , Camundongos Knockout
19.
Proc Natl Acad Sci U S A ; 116(30): 15184-15193, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31289229

RESUMO

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene (Klein-Zschocher [KLZ]; Yipf6 KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6 KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6 KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6 KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Fígado/metabolismo , Proteínas de Membrana/genética , Síndrome Metabólica/genética , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Animais , Temperatura Corporal , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Dieta Hiperlipídica/efeitos adversos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Metabolismo Energético/genética , Fatores de Crescimento de Fibroblastos/sangue , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lipólise/genética , Fígado/patologia , Proteínas de Membrana/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Ligação Proteica , Transdução de Sinais , Termogênese/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
20.
Am J Physiol Endocrinol Metab ; 317(3): E535-E547, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237449

RESUMO

CB1 receptor (CB1R) antagonism improves the deleterious effects of a high-fat diet (HFD) by reducing body fat mass and adipocyte cell size. Previous studies demonstrated that the beneficial effects of the CB1R antagonist rimonabant (RIM) in white adipose tissue (WAT) are partially due to an increase of mitochondria numbers and upregulation thermogenesis markers, suggesting an induction of WAT beiging. However, the molecular mechanism by which CB1R antagonism induces weight loss and WAT beiging is unclear. In this study, we probed for genes associated with beiging and explored longitudinal molecular mechanisms by which the beiging process occurs. HFD dogs received either RIM (HFD+RIM) or placebo (PL) (HFD+PL) for 16 wk. Several genes involved in beiging were increased in HFD+RIM compared with pre-fat, HFD, and HFD+PL. We evaluated lipolysis and its regulators including natriuretic peptide (NP) and its receptors (NPRs), ß-1 and ß-3 adrenergic receptor (ß1R, ß3R) genes. These genes were increased in WAT depots, accompanied by an increase in lipolysis in HFD+RIM. In addition, RIM decreased markers of inflammation and increased adiponectin receptors in WAT. We observed a small but significant increase in UCP1; therefore, we evaluated the newly discovered UCP1-independent thermogenesis pathway. We confirmed that SERCA2b and RYR2, the two key genes involved in this pathway, were upregulated in the WAT. Our data suggest that the upregulation of NPRs, ß-1R and ß-3R, lipolysis, and SERCA2b and RYR2 may be one of the mechanisms by which RIM promotes beiging and overall the improvement of metabolic homeostasis induced by RIM.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Proteína Desacopladora 1/efeitos dos fármacos , Animais , Cães , Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Inflamação/prevenção & controle , Resistência à Insulina , Masculino , Biogênese de Organelas , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Rimonabanto/farmacologia , Termogênese/efeitos dos fármacos , Termogênese/genética , Perda de Peso/efeitos dos fármacos
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