¦Â-Arrestin signal complex plays a critical role in adipose differentiation

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• 作者：Icí ; a Santos-Zas^a ; ^b ; Marí ; a Lodeiro^a ; ^b ; Uxí ; a Gurriará ; n-Rodrí ; guez^a ; ^b ; Mó ; nica Bouzo-Lorenzo^a ; ^b ; Carlos S. Mosteiro^a ; ^b ; Felipe F. Casanueva^a ; ^b ; ^c ; Xesú ; s Casabiell^d ; Yolanda Pazos^a ; ^b ; Jesú ; s P. Camiñ ; a^a ; ^b ; ^{jesus.perez@usc.es} ; ^{jesus.perez.camina@sergas.es}
• 关键词：GHSR1a ; growth hormone secretagogue receptor type 1a ; PPAR¦Ã ; peroxisome proliferator-activated receptor ; C/EBP¦Á ; CCAAT/enhancer-binding protein ¦Á ; C/EBP¦Â ; CCAAT/enhancer-binding protein ¦Â ; C/EBP¦Ä ; CCAAT/enhancer-binding protein ¦Ä ; PI3K ; phosphatidy
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：45
• 期：7
• 页码：1281-1292
• 全文大小：4089 K

文摘

¦Â-Arrestins were identified as scaffold-proteins that have the capacity to desensitize G protein-coupled receptors. However, it has been found that ¦Â-arrestins activate signaling pathways independent of G protein activation. The diversity of these signaling pathways has also been recognized for receptor tyrosine kinase. The aim of the present study was to validate the ¦Â-arrestin-dependent signaling mechanism(s) responsible for regulation of adipogenesis. Two signal models were selected, ghrelin and insulin, based on its ¦Â-arrestin-associated Akt activity. Herein, we found that ¦Â-arrestin 1 and 2 were essential molecules for adipocyte differentiation. More specifically, the role of these scaffolding proteins was demonstrated by depletion of ¦Â-arrestin 1 and 2 during ghrelin-induced adipogenesis in 3T3-L1 cells, which decreased the adipocyte differentiation and the expression levels of master regulators of early, the CCAAT/enhancer-binding protein ¦Â (C/EBP¦Â) and the CCAAT/enhancer-binding protein ¦Ä (C/EBP¦Ä), and terminal, the peroxisome proliferator-activated receptor (PPAR¦Ã) and the CCAAT/enhancer-binding protein ¦Á (C/EBP¦Á), adipogenesis. Accordingly ghrelin-induced Akt activity and its downstream targets, the mammalian target of rapamycin complex 1 (mTORC1) and the ribosomal protein S6 kinase beta-1 (S6K1), were inhibited by ¦Â-arrestin 1 and 2 siRNAs. By contrast, assays performed during insulin-activated adipogenesis showed an intensifying effect on the adipocyte differentiation as well as on the expression of C/EBP¦Â, C/EBP¦Ä, PPAR¦Ã and C/EBP¦Á. The increase in insulin-induced adipogenesis by ¦Â-arrestin knock-down was concomitant to a decrease in the insulin receptor susbtrate-1 (IRS-1) serine phosphorylation, proving the loss of the negative feedback loop on IRS-1/phosphoinositide 3-kinase (PI3K)/Akt. Therefore, ¦Â-arrestins control the extent and intensity of the lipogenic and adipogenic factors associated to Akt signaling, although the mechanistic and functional principles that underlie the connection between signaling and ¦Â-arrestins are specifically associated to each receptor type.