The adipocyte specific transcription factor C/EBP alpha modulates human ob gene expression
The adipocyte specific transcription factor C/EBP alpha modulates human ob gene expression
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DOI：
10.1073/pnas.93.11.5507
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发表时间：
1996-05-28
影响因子：
11.1
通讯作者：
Auwerx, J
中科院分区：
文献类型：
--
作者：
Miller, SG;DEVos, P;Auwerx, J
ob基因产物瘦素（leptin）是一种调节体重稳态和能量平衡的信号因子，其明显地仅在脂肪组织中表达。肥胖啮齿类动物中ob基因表达增加，并受进食、胰岛素和糖皮质激素的调节，这支持了ob基因表达受激素控制的概念，预期这是控制体重稳态和能量平衡的关键因素。在人类中，肥胖症患者ob mRNA表达增加;然而，上述因素对人ob表达的影响尚不清楚。我们描述了人ob基因的结构及其启动子的初步功能分析。人ob基因的三个外显子覆盖约15 kb的基因组DNA。整个编码区包含在外显子2和3中，它们被一个2-kb的内含子分开。第一个小的30-bp非翻译外显子位于起始ATG密码子上游>10.5 kb处。已克隆并表征了转录起始位点上游的DNA的三种酶。ob基因的基础脂肪组织特异性表达以及C/EBP α的增强表达仅需要217 bp的5'序列。在该区域的单个C/EBP α位点的突变废除了在共转染试验中由C/EBP α诱导的启动子。基因结构将有助于我们分析在人类肥胖的ob突变，而知识的序列元件和因子调节ob基因的表达应该是非常重要的预防和治疗肥胖。
The ob gene product, leptin, apparently exclusively expressed in adipose tissue, is a signaling factor regulating body weight homeostasis and energy balance. ob gene expression is increased in obese rodents and regulated by feeding, insulin, and glucocorticoids, which supports the concept that ob gene expression is under hormonal control, which is expected for a key factor controlling body weight homeostasis and energy balance. In humans, ob mRNA expression is increased in gross obesity; however, the effects of the above factors on human ob expression are unknown. We describe the structure of the human ob gene and initial functional analysis of its promoter. The human ob gene's three exons cover approximate to 15 kb of genomic DNA. The entire coding region is contained in exons 2 and 3, which are separated by a 2-kb intron. The first small 30-bp untranslated exon is located >10.5 kb upstream of the initiator ATG codon. Three kilobases of DNA upstream of the transcription start site has been cloned and characterized. Only 217 bp of 5' sequence are required for basal adipose tissue-specific expression of the ob gene as well as enhanced expression by C/EBP alpha. Mutation of the single C/EBP alpha site in this region abolished inducibility of the promoter by C/EBP alpha in cotransfection assays. The gene structure will facilitate our analysis of ob mutations in human obesity, whereas knowledge of sequence elements and factors regulating ob gene expression should be of major importance in the prevention and treatment of obesity.