Transcriptional regulation of adipogenesis.
Transcriptional regulation of adipogenesis.
复制标题
DOI：
10.1101/gad.14.11.1293
复制
发表时间：
2000-06
影响因子：
10.5
通讯作者：
E. Rosen;C. Walkey;P. Puigserver;B. Spiegelman
中科院分区：
文献类型：
--
作者：
E. Rosen;C. Walkey;P. Puigserver;B. Spiegelman
在过去的二十年里，我们对大量特定细胞类型分化的分子调控的理解取得了长足的进步。肌肉、骨骼、垂体和几种造血谱系的发育都已使用各种生化和遗传学手段进行了探索，这些研究已经产生了一般和组织特异性的见解。由于两个重要原因，脂肪组织也受到密切关注。首先，永生前脂肪细胞系的建立（见下文）提供了一个可通过实验进行的体外系统，其许多特征忠实地再现了体内的这一过程。这些特征包括形态变化、细胞生长停止、许多脂肪生成酶的表达、大量脂质积累，以及对影响该细胞类型的大多数或所有关键激素（包括胰岛素）建立敏感性。脂肪组织受到如此多关注的第二个原因是该组织在维持全身能量平衡方面提供了关键的环节。肥胖及其丑陋的继姐妹2型糖尿病的发病率持续激增，引起人们对脂肪细胞生物学各个方面的关注，包括脂肪生成（Must等人，1999）。在过去的一个世纪里，人们对多种物种体内脂肪组织的发育进行了大量观察。早期人们注意到，脂肪分布在遍布全身的许多不同部位，通常发生在由疏松结缔组织组成的区域，例如肌肉和真皮之间的皮下层。然而，心脏、肾脏和其他内脏器官周围也会形成脂肪沉积。体内脂肪分化的弥散性使得从胚胎中解剖出假定的前体细胞区域并进行离体研究变得困难。同样，缺乏识别前脂肪细胞状态的分子标记阻碍了对活体动物的研究。这些困难在 1970 年代得到了部分解决，当时 Green 和他的同事建立了永生的成纤维细胞系，当添加适当的激素诱导剂时，这些细胞系很容易分化为脂肪细胞（Green 和 Kehinde 1974、1975、1976）。这些细胞系被命名为 3T3-L1 和 3T3-F442A，是从非克隆 Swiss 3T3 细胞中分离出来的，并且已经定型（或确定）为脂肪细胞谱系。当使用包括 cAMP、胰岛素和糖皮质激素在内的经验性促分化方案进行治疗时，它们会在 4-6 天的时间内分化为成熟脂肪细胞。随后，其他人独立衍生了定型前脂肪细胞系（Negrel 等人，1978 年；Chapman 等人，1984 年）；尽管它们的最佳分化条件存在微小差异，但它们的行为与 3T3-L1 和 3T3-F442A 细胞非常相似。最近，人们利用多能干细胞进行了研究，除了其他几种谱系之外，多能干细胞还可以被诱导产生脂肪组织。根据所选条件，间充质干细胞系可以分化为肌肉、软骨和脂肪（Taylor 和 Jones，1979），并且可以诱导骨髓来源的基质细胞形成骨细胞和脂肪细胞（Pittenger 等，1999）。尽管干细胞技术正在迅速发展，但它们最近的引入和这些系统固有的复杂性阻碍了它们在脂肪生成领域的广泛应用。几乎所有关于脂肪生成的工作都利用了上述预定的克隆细胞系或从分离的脂肪垫的基质血管部分中分离出的培养的前脂肪细胞。尽管从这些模型中收集到了许多见解，但在解释结果时必须牢记一些注意事项。首先，这些细胞系几乎完全分化为白色脂肪组织（WAT）。哺乳动物有第二种类型的脂肪细胞，称为棕色脂肪细胞，其主要作用是消耗能量而不是储存能量（Lowell 和 Flier 1997）。这种能量浪费是由一种称为解偶联蛋白-1 (UCP-1) 的棕色脂肪组织 (BAT) 特异性蛋白完成的，该蛋白通过消散电子沿呼吸链通过时穿过线粒体内膜建立的质子梯度来产生热量 (Garlid 等人，1998)。从生理学角度来说，棕色脂肪的功能是适应寒冷和防止肥胖。 BAT 的培养细胞模型确实存在，但其中大多数并不像 3 通讯作者那样模仿其内源直系同源物。电子邮件 edrosen@massmed.org；传真 (617) 632-5363。电子邮件 bruce spiegelman@dfci.harvard.edu；传真 (617) 632-4655。
The past twenty years have seen great strides in our understanding of the molecular regulation of differentiation for a whole host of specific cell types. The development of muscle, bone, pituitary, and several hematopoeitic lineages have all been probed using a variety of biochemical and genetic means, and such studies have yielded both general and tissue-specific insights. Adipose tissue has also been the subject of intense scrutiny, for two important reasons. First, the establishment of immortal preadipocyte cell lines (see below) provided an experimentally accessible system in vitro, many features of which faithfully recapitulate this process in vivo. These features include morphological changes, cessation of cell growth, expression of many lipogenic enzymes, extensive lipid accumulation, and the establishment of sensitivity to most or all of the key hormones that impact on this cell type, including insulin. The second reason why adipose tissue has received so much attention is that this tissue provides a critical link in maintaining systemic energy balance. The ongoing explosion in the incidence of obesity and its ugly stepsister, type 2 diabetes, has focused attention on all aspects of adipocyte biology, including adipogenesis (Must et al. 1999). A wealth of observations on the development of adipose tissue in vivo in a variety of species have been recorded throughout the past century. Early on it was noted that fat develops in many different sites scattered throughout the body, generally occurring in areas composed of loose connective tissue, such as the subcutaneous layers between the muscle and dermis. However, fat deposits also form around the heart, kidneys, and other internal organs. The diffuse nature of adipose differentiation in vivo has made it difficult to dissect out regions of presumptive precursor cells from embryos and study these ex vivo. Similarly, a lack of molecular markers identifying the preadipocytic state has hampered investigations in living animals. These difficulties were partially circumvented in the 1970’s when Green and his colleagues established immortal fibroblast lines that readily differentiated into adipocytes when appropriate hormonal inducers were added (Green and Kehinde 1974, 1975, 1976). These lines, designated 3T3-L1 and 3T3-F442A, were isolated from nonclonal Swiss 3T3 cells and are already committed (or determined) to the adipocytic lineage. When treated with an empirically-derived prodifferentiative regimen that includes cAMP, insulin, and glucocorticoids, they undergo differentiation to mature fat cells over a 4–6 day period. Subsequently, committed preadipocyte lines have been derived independently by others (Negrel et al. 1978; Chapman et al. 1984); despite minor differences in their optimal differentiation conditions they behave very similarly to 3T3-L1 and 3T3-F442A cells. More recently, studies have been performed using pluripotent stem cells that can be induced to yield adipose tissue in addition to several other lineages. Mesenchymal stem cell lines can be differentiated to muscle, cartilage, and fat depending upon the chosen conditions (Taylor and Jones 1979), and marrow-derived stromal cells can be induced to form both bone cells and fat cells (Pittenger et al. 1999). Although stem cell technology is developing rapidly, their recent introduction and the complexity inherent in these systems has prevented them from being extensively used in the adipogenesis field. Almost all work on adipogenesis has utilized either the aforementioned predetermined clonal cell lines or cultured preadipocytes isolated from the stromal-vascular fraction of dissociated fat pads. Despite the many insights gleaned from these models, several caveats must be kept in mind when interpreting results. First, these cell lines are differentiated to white adipose tissue (WAT) almost exclusively. Mammals have a second type of fat cell called the brown adipocyte, which serves primarily to dissipate energy instead of storing it (Lowell and Flier 1997). This energy wasting is accomplished by a brown adipose tissue (BAT)-specific protein called uncoupling protein-1 (UCP-1), which generates heat by dissipating the proton gradient that is established across the inner mitochondrial membrane during the passage of electrons along the respiratory chain (Garlid et al. 1998). In physiological terms, brown fat functions in adaptation to cold and as protection against obesity. Cultured cell models of BAT do exist, but most of these do not mimic their endogenous ortholog quite as 3Corresponding authors. E-MAIL edrosen@massmed.org; FAX (617) 632-5363. E-Mail bruce spiegelman@dfci.harvard.edu; FAX (617) 632-4655.