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首页> 外文期刊>Cell cycle >Pocket proteins control white versus brown fat cell differentiation.
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Pocket proteins control white versus brown fat cell differentiation.

机译：口袋蛋白控制着白色脂肪细胞与棕色脂肪细胞的分化。

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摘要

White and brown fat cells carry out largely opposite functions. White adipocytes store energy through lipid accumulation, whereas brown adipocytes store much less Hpid and can dissipate energy through adaptive thermogenesis. Thermogenesis is mediated by uncoupling protein-1 (UCP1), which is uniquely present in mitochondria of brown fat cells. A few factors have been reported to selectively modulate white versus brown adipocyte differentiation. These include the nuclear receptor cofactors peroxisome proliferator-activated receptor y (PPARy) coactivator-lalpha (PGC-lalpha), transcriptional intermediary factor-2, steroid receptor coactivator-1 and receptor-interacting protein 140 as well as the retinoblastoma protein (pRB), a tumor suppressor and cell cycle regulator known to be involved in differentiation of many cell types, including adipocytes. In retrospect, a disparate role of the pocket protein pRB in white and brown adipogenesis was suggested by the findings that expression of simian virus 40 largeT antigen (TAg) inhibits differentiation of white preadipocyte cell lines, whereas most brown preadipocyte cell lines were established eidaer from TAg-expressing brown adipose tissue (BAT) tumors or by forced expression of TAg in primary brown preadipocytes. In addition, transgenic mice expressing TAg in adipose tissue exhibit a partial conversion of white adipose tissue (WAT) into BAT. An important target of TAg is pRB that is functionally inactivated by TAg. Expression of wild-type TAg, but not a pRB-binding-defective point mutant of TAg, in white preadipocyte cell lines resulted in expression of UCPl in the adipose state when differentiation was induced by an exogenous PPARy Hgand. Accordingly, pRB-deficient and wild-type mouse embryo fibroblasts (MEFs) differentiated into brown and white fat cells, respectively. Adipocytes with targeted disruption of the retinoblastoma gene (Rb~/J) expressed UCPl protein as well as PGC-la mRNA at levels comparable to those in BAT and they accumulated substantially more mitochondria than wild-type fat cells. These data establish pRB as an inhibitor of brown fat cell differentiation and as a molecular switch involved in adipose lineage determination, at least in vitro. Besides the phenotype of the TAg transgenic mice, three observations point to the involvement of pRB in determining white versus brown adipose conversion in vivo: pRB is present in preadipocytes of epi-didymal WAT, but not in preadipocytes of interscapular BAT; pRB is downregulated during transdifferentiation of retroperitoneal white fat cells into brown-like adipocytes; pRB is inactivated by phosphorylation during cold-induced activation and recruitment of BAT. However, definite proof that pRB differentially regulates the formation of white and brown fat cells in vivo has remained elusive.
机译：白色和棕色脂肪细胞执行的功能却截然相反。白色的脂肪细胞通过脂质的积累来储存能量，而棕色的脂肪细胞的Hpid则要少得多，并且可以通过适应性产热来消散能量。生热是由解偶联蛋白1（UCP1）介导的，该蛋白独特地存在于棕色脂肪细胞的线粒体中。已经报道了一些因素选择性地调节白色与棕色脂肪细胞的分化。这些包括核受体辅因子过氧化物酶体增殖物激活受体y（PPARy）辅激活物-lalpha（PGC-1alpha），转录中介因子2，类固醇受体辅激活物-1和受体相互作用蛋白140以及成视网膜细胞瘤蛋白（pRB） ，一种肿瘤抑制因子和细胞周期调节因子，已知与许多细胞类型（包括脂肪细胞）的分化有关。回顾一下，发现猿猴病毒40 largeT抗原（TAg）的表达抑制了白色脂肪前体细胞系的分化，而大多数棕色脂肪前体细胞系的建立是通过发现发现了口袋蛋白pRB在白色和棕色脂肪形成中的不同作用。表达TAg的棕色脂肪组织（BAT）肿瘤或通过在初级棕色前脂肪细胞中强制表达TAg来实现。另外，在脂肪组织中表达TAg的转基因小鼠表现出白色脂肪组织（WAT）部分转化为BAT。 TAg的重要目标是被TAg功能性失活的pRB。当通过外源PPARγ配体诱导分化时，在白色前脂肪细胞系中野生型TAg的表达，而不是TAg的pRB结合缺陷点突变体的表达导致UCP1以脂肪状态表达。因此，pRB缺陷和野生型小鼠胚胎成纤维细胞（MEF）分别分化为棕色和白色脂肪细胞。有针对性地破坏视网膜母细胞瘤基因（Rb1- / J）的脂肪细胞以与BAT中相当的水平表达UCP1蛋白和PGC-1a mRNA，并且其线粒体比野生型脂肪细胞积累更多。这些数据证明至少在体外，pRB作为棕色脂肪细胞分化的抑制剂和参与脂肪谱系确定的分子开关。除TAg转基因小鼠的表型外，三项观察结果表明pRB参与了体内白脂肪与棕色脂肪转化的确定：pRB存在于附睾WAT的前脂肪细胞中，但不存在于肩cap间BAT的前脂肪细胞中。在腹膜后白色脂肪细胞转分化为褐色脂肪细胞的过程中，pRB被下调。在冷诱导的BAT活化和募集过程中，磷酸化使pRB失活。然而，关于pRB在体内差异性调节白色和棕色脂肪细胞形成的确切证据仍然难以捉摸。

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