Inhibition of ERK1/2 pathway suppresses adiponectin secretion via accelerating protein degradation by Ubiquitin-proteasome system: relevance to obesity-related adiponectin decline.
Metabolism
; 62(8): 1137-48, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23490586
ABSTRACT
OBJECTIVE:
Predominantly secreted by adipose tissue, adiponectin possesses insulin-sensitizing, anti-atherogenic, anti-inflammatory, and anti-angiogenic properties. Paradoxically, obesity is associated with declined plasma adiponectin levels; however, the underlying mechanisms remain elusive. In this study, we investigated the mechanistic involvement of MEK/ERK1/2 pathway in obesity-related adiponectin decrease. MATERIALS/METHODS:
C57 BL/6 mice exposed to a high-fat diet (HFD) were employed as animal obesity model. Both fully-differentiated 3T3-L1 and mouse primary adipocytes were used in the in vitro experiments.RESULTS:
Obesity and plasma adiponectin decline induced by prolonged HFD exposure were associated with suppressed ERK1/2 activation in adipose tissue. In adipocytes, specific inhibition of MEK/ERK1/2 pathway decreased intracellular and secretory adiponectin levels, whereas adiponectin gene expression was increased, suggesting that MEK/ERK1/2 inhibition may promote adiponectin protein degradation. Cycloheximide (CHX)-chase assay revealed that MEK/ERK1/2 inhibition accelerated adiponectin protein degradation, which was prevented by MG132, a potent proteasome inhibitor. Immunoprecipitation assay showed that intracellular MEK/ERK1/2 activity was negatively associated with ubiquitinated adiponectin protein levels. Consistently, long-term HFD feeing in mice increased ubiquitinated adiponectin levels in the epididymal fat pads.CONCLUSIONS:
Adipose tissue MEK/ERK1/2 activity can differentially regulate adiponectin gene expression and protein abundance and its suppression in obesity may play a mechanistic role in obesity-related plasma adiponectin decline.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema de Sinalização das MAP Quinases
/
Ubiquitina
/
Complexo de Endopeptidases do Proteassoma
/
Adiponectina
/
Obesidade
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article