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1.
Int J Mol Sci ; 20(2)2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641938

RESUMO

Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 (Ucp1) involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of Ucp1 and peroxisome proliferator-activated receptor γ (Pparγ), which is known as a Ucp1 transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the Ucp1 enhancer, thereby downregulating Ucp1 expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on Ucp1 expression via Pparγ suppression in beige adipocytes.


Assuntos
Adipócitos Bege/metabolismo , Estresse do Retículo Endoplasmático , PPAR gama/genética , PPAR gama/metabolismo , Proteína Desacopladora 1/genética , Adipócitos Bege/citologia , Animais , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Ligação Proteica , Proteólise , Tunicamicina/farmacologia , Proteína Desacopladora 1/metabolismo , Resposta a Proteínas não Dobradas
2.
Int J Mol Sci ; 19(8)2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30126161

RESUMO

Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (Ucp1). Several reports have suggested that histone deacetylase (HDAC) might regulate Ucp1 by remodelling chromatin structure, although the mechanism remains unclear. Herein, we investigate the effect of ß-adrenergic receptor (ß-AR) activation on the chromatin state of beige adipocyte. ß-AR-stimulated Ucp1 expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within Ucp1 promoter upon isoproterenol addition, favouring open chromatin for Ucp1 transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly Hdac3 and Hdac8. Further investigation showed that although HDAC8 activity decreased, Ucp1 expression was not altered when HDAC8 was activated or inhibited. In contrast, HDAC3 mRNA and protein levels were simultaneously downregulated upon isoproterenol addition, resulting in reduced recruitment of HDAC3 to the Ucp1 enhancer region, causing an increased H3K27 acetylation for Ucp1 upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced Ucp1 expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated Ucp1 expression during ß-AR stimulation.


Assuntos
Adipócitos Bege/metabolismo , Histona Desacetilases/metabolismo , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Proteína Desacopladora 1/genética , Regulação para Cima , Acetilação , Adipócitos Bege/citologia , Animais , Regulação para Baixo , Histona Desacetilases/genética , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Ativação Transcricional
3.
Mol Nutr Food Res ; 61(10)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28544341

RESUMO

SCOPE: Recent reports indicate that gut microbiota and their metabolites may regulate host inflammatory conditions, including the chronic inflammation of obese adipose tissues. In this study, we investigated whether specific synthesized fatty acids, identical to the metabolites generated by gut microbiota, act as anti-inflammatory factors in obesity-induced inflammation. METHODS AND RESULTS: We first used lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages to examine the anti-inflammatory effect of fatty acids synthesized to resemble representative polyunsaturated fatty acid metabolites from gut microbiota. Fatty acids containing an enone structure showed the most potent anti-inflammatory activity. Enone fatty acids also displayed anti-inflammatory effects on macrophages cocultured with hypertrophied 3T3-L1 or immortalized primary adipocytes; and macrophages stimulated with 3T3-L1 adipocyte conditioned medium. Consistently, the beneficial outcome was revealed in the case of LPS- and obesity-induced inflammatory cytokine stimulation in ex vivo adipose tissues. Furthermore, these fatty acids recovered the suppression of ß-adrenergic receptor-stimulated uncoupling protein 1 expression and secretion of adiponectin in C3H10T1/2 and 3T3-L1 adipocytes, respectively, under inflammatory conditions, suggesting that enone fatty acids can ameliorate dysfunctions of adipocytes induced by inflammation. CONCLUSION: These findings indicate that synthesized enone fatty acids show potent anti-inflammatory effects, leading to the improvement of inflammation-induced dysfunctions in adipocytes.


Assuntos
Adipócitos/citologia , Anti-Inflamatórios/farmacologia , Ácidos Graxos Insaturados/farmacologia , Microbioma Gastrointestinal , Inflamação/terapia , Macrófagos/citologia , Células 3T3-L1 , Adiponectina/metabolismo , Animais , Quimiocina CCL2/metabolismo , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Lactobacillus/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Obesidade/terapia , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
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