生物
产热
褐色脂肪组织
细胞生物学
RNA剪接
拼接因子
选择性拼接
产热素
基因敲除
基因表达
脂肪细胞
激活剂(遗传学)
脂肪组织
基因
内分泌学
信使核糖核酸
生物化学
核糖核酸
作者
Moisés Castellá,Alberto Mestres-Arenas,Aleix Gavaldà‐Navarro,Albert Blasco-Roset,Tania Quesada‐López,Inés Romero-Carramiñana,Marta Giralt,Francesc Villarroya,Rubén Cereijo
标识
DOI:10.1016/j.bcp.2023.116014
摘要
The ability of alternative splicing mechanisms to control gene expression is increasingly being recognized as relevant for adipose tissue function. The expression of SF3B1, a key component of the SF3B complex directly involved in spliceosome formation, was previously reported to be significantly induced in brown adipose tissue under cold-induced thermogenic activation. Here, we identify that noradrenergic cAMP-mediated thermogenic stimulation increases SF3B1 expression in brown and beige adipocytes. We further show that pladienolide-B, a drug that binds SF3B1 to inhibit pre-mRNA splicing by targeting the SF3B complex, down-regulates key components of the thermogenic machinery (e.g., UCP1 gene expression), differentially alters the expression of alternative splicing-regulated transcripts encoding molecular actors involved in the oxidative metabolism of brown adipocytes (e.g., peroxisome proliferator-activated receptor-gamma co-activator-alpha [PGC-1α] and cytochrome oxidase subunit 7a genes), and impairs the respiratory activity of brown adipocytes. Similar alterations were found in brown adipocytes with siRNA-mediated knockdown of SF3B1 protein levels. Our findings collectively indicate that SF3B1 is a key factor in the appropriate thermogenic activation of differentiated brown adipocytes. This work exemplifies the importance of splicing processes in adaptive thermogenesis and suggests that pharmacological tools, such as pladienolide-B, may be used to modulate brown adipocyte thermogenic activity.
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