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1.
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
2.
J Microbiol Biotechnol ; 30(2): 306-312, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-31752058

RESUMO

Despite the importance of brown adipocytes as a therapeutic target for the prevention and treatment of obesity, the molecular mechanism underlying brown adipocyte differentiation is not fully understood. In particular, the role of post-translational modifications in brown adipocyte differentiation has not been extensively studied. Histidine phosphorylation is increasingly recognized an important process for protein post-translational modifications. In this study, we show that histidine phosphorylation patterns change during brown adipocyte differentiation. In addition, the expression level of protein histidine phosphatase 1 (PHPT1), a major mammalian phosphohistidine phosphatase, is reduced rapidly at the early phase of differentiation and recovers at the later phase. During white adipocyte differentiation of 3T3- L1 preadipocytes, however, the expression level of PHPT1 do not significantly change. Knockdown of PHPT1 promotes brown adipocyte differentiation, whereas ectopic expression of PHPT1 suppresses brown adipocyte differentiation. These results collectively suggest that histidine phosphorylation is closely linked to brown adipocyte differentiation and could be a therapeutic target for obesity and related metabolic diseases.


Assuntos
Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Diferenciação Celular/genética , Histidina/metabolismo , Proteína Fosfatase 1/genética , Adipogenia/genética , Animais , Biomarcadores , Expressão Ectópica do Gene , Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Fosforilação , Proteína Fosfatase 1/metabolismo , RNA Mensageiro
3.
Mol Cells ; 40(9): 667-676, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28927261

RESUMO

Abnormal differentiation of muscle is closely associated with aging (sarcopenia) and diseases such as cancer and type II diabetes. Thus, understanding the mechanisms that regulate muscle differentiation will be useful in the treatment and prevention of these conditions. Protein lysine acetylation and methylation are major post-translational modification mechanisms that regulate key cellular processes. In this study, to elucidate the relationship between myogenic differentiation and protein lysine acetylation/methylation, we performed a PCR array of enzymes related to protein lysine acetylation/methylation during C2C12 myoblast differentiation. Our results indicated that the expression pattern of HDAC11 was substantially increased during myoblast differentiation. Furthermore, ectopic expression of HDAC11 completely inhibited myoblast differentiation, concomitant with reduced expression of key myogenic transcription factors. However, the catalytically inactive mutant of HDAC11 (H142/143A) did not impede myoblast differentiation. In addition, wild-type HDAC11, but not the inactive HDAC11 mutant, suppressed MyoD-induced promoter activities of MEF2C and MYOG (Myogenin), and reduced histone acetylation near the E-boxes, the MyoD binding site, of the MEF2C and MYOG promoters. Collectively, our results indicate that HDAC11 would suppress myoblast differentiation via regulation of MyoD-dependent transcription. These findings suggest that HDAC11 is a novel critical target for controlling myoblast differentiation.


Assuntos
Diferenciação Celular/genética , Histona Desacetilases/genética , Proteína MyoD/genética , Transcrição Gênica , Acetilação , Animais , Sítios de Ligação , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição MEF2/genética , Camundongos , Desenvolvimento Muscular/genética , Mutação , Mioblastos/citologia , Mioblastos/metabolismo , Miogenina/genética
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