C/EBPα is required for differentiation of white, but not brown, adipose tissue
C/EBPα is required for differentiation of white, but not brown, adipose tissue
复制标题
DOI：
10.1073/pnas.211416898
复制
发表时间：
2001-10-23
影响因子：
11.1
通讯作者：
Darlington, GJ
中科院分区：
文献类型：
--
作者：
Linhart, HG;Ishimura-Oka, K;Darlington, GJ
转录因子CCAAT增强子结合蛋白α（C/ EBP α）在肝脏和脂肪组织中高水平表达。细胞培养研究表明，C/EBP α足以触发前脂肪细胞分化为成熟脂肪细胞，这表明C/EBP α在脂肪组织发育中的核心作用。C/EBP α基因敲除小鼠在出生后7-12小时内死亡。肝脏再生缺陷和随后的低血糖导致这些动物的早期死亡。这种短寿命损害了对这些小鼠脂肪组织发育的研究。为了提高C/EBP α-/-动物的存活率，我们产生了在白蛋白增强子/启动子的控制下表达C/EBP α的转基因系。将该品系培育到敲除品系中以产生在肝脏中表达C/EBPa但在其它组织中不表达C/EBPa的动物。转基因的存在使C/EBP α-/-动物的存活率提高了近3倍。7日龄的转基因C/EBP α-/-动物显示不存在s.c.，肾周和附睾白色脂肪，尽管血清中有过量的脂质底物，而棕色脂肪组织有些肥大，并显示出最小的生化改变。有趣的是，乳腺脂肪组织存在并表现出正常形态。在存在高血脂水平的情况下，许多贮库中不存在白色脂肪组织，这表明C/EBP α是该组织体内发育所需的。相反，棕色脂肪组织分化与C/EBP α表达无关。棕色脂肪组织中脂质的存在作为内部营养对照，表明营养摄入或脂蛋白组成都不可能导致白色脂肪的缺乏。
The transcription factor CCAAT enhancer binding protein alpha (C/ EBP alpha) is expressed at high levels in liver and adipose tissue. Cell culture studies show that C/EBP alpha is sufficient to trigger differentiation of preadipocytes into mature adipocytes, suggesting a central role for C/EBP alpha in the development of adipose tissue. C/EBP alpha knockout mice die within 7-12 h after birth. Defective gluconeogenesis of the liver and subsequent hypoglycemia contribute to the early death of these animals. This short life span impairs investigation of the development of adipose tissue in these mice. To improve the survival of C/EBP alpha-/- animals, we generated a transgenic line that expresses C/EBP alpha under the control of the albumin enhancer/promoter. This line was bred into the knockout strain to generate animals that express C/EBPa in the liver but in no other tissue. The presence of the transgene improved survival of C/EBP alpha-/- animals almost 3-fold. Transgenic C/EBP alpha-/- animals at 7 days of age show an absence of s.c., perirenal, and epididymal white fat despite excess lipid substrate in the serum, whereas brown adipose tissue is somewhat hypertrophied and shows minimal biochemical alterations. Interestingly, mammary gland fat tissue is present and exhibits normal morphology. The absence of white adipose tissue in many depots in the presence of high serum lipid levels shows that C/EBP alpha is required for the in vivo development of this tissue. In contrast, brown adipose tissue differentiation is independent of C/EBP alpha expression. The presence of lipid in brown adipose tissue serves as an internal nutritional control, indicating that neither nutritional intake nor lipoprotein composition is likely responsible for the absence of white fat.