HORMONAL CONTROL OF ADIPOSE GENE EXPRESSION

这项研究的长期目标是了解胰岛素和 反调节剂控制基因的表达， 胰岛素作用和脂肪细胞中的能量储存。 我们克隆了， 确定了一个家族的结构并研究了其调控机制， 编码蛋白质的小鼠差异表达脂肪细胞基因 对能量储存和胰岛素作用很重要。 其中包括 基因：胰岛素受体;胰岛素反应性葡萄糖 转运蛋白，GLUT 4（以及GLUT 1）; 422（aP 2）蛋白;两个硬脂酰辅酶A 去饱和酶（SCD 1和SCD 2）; CCAAT/增强子结合蛋白（C/EBPalpha） 和C/EBPbeta（β）。 我们现在计划研究 这些基因中的某些（GLUT 4、SCD 2和C/EBPalpha基因）是 使用3 T3-L1前脂肪细胞/脂肪细胞模型系统调节。 这 由于基因的重要性，选择了一个基因子集进行进一步研究。 在胰岛素作用和/或前脂肪细胞中的基因产物 差异化，因为我们已经取得了实质性进展， 其特点是规范。 本研究的具体目标是： 1.阐明GLUT 4基因调控的分子基础： 激素的作用是通过cAMP介导的， 分化的脂肪细胞，和 转录因子C/EBPalpha（及其同源物） 在前脂肪细胞分化成脂肪细胞的过程中。 GLUT 4基因的表达受损预计会导致 葡萄糖摄取对胰岛素的抵抗类似于 伴随2型糖尿病（NIDDM）。 2.研究表达于细胞核中的核因子 前脂肪细胞而不是脂肪细胞，抑制SCD 2的转录 基因 “前脂肪细胞因子”将被纯化测序及其作用 在分化诱导的SCD 2基因表达中（可能 其他基因）将被确定。 3.为了确定C/EBPalpha表达的机制， 基因在前脂肪细胞分化为 脂肪细胞 C/EBP结合位点（一个可能的位点）的作用 自激活），并且基因中的推定阻遏物结合位点将 追究 我们已经获得了令人信服的证据， 在协调激活一组 脂肪转化过程中的脂肪特异性基因。

The LONG-TERM GOAL of this research is to understand how insulin and counter-regulatory agents control the expression of genes involved in insulin action and energy storage in the adipocyte. We have cloned, determined the structures and studied the regulation of a family of mouse differentially-expressed adipocyte genes that encode proteins important for energy storage and insulin action. These include the genes for: the insulin receptor; the insulin-responsive glucose transporter, GLUT4 (and also GLUT1); 422(aP2) protein; two stearoyl-CoA desaturases (SCD1 and SCD2); CCAAT/enhancer binding protein (C/EBPalpha) and C/EBPbeta (LAP). We now plan to investigate the mechanisms by which certain of these genes (the GLUT4, SCD2 and C/EBPalpha genes) are regulated using the 3T3-L1 preadipocyte/adipocyte model system. This subset of genes was selected for further study because of the importance of their gene products in insulin action an/or in preadipocyte differentiation and because of the substantial progress we have made in characterizing their regulation. The SPECIFIC AIMS of this research are: 1. to elucidate the molecular basis of the regulation of GLUT4 gene: by hormones whose effects are mediated through cAMP in the fully- differentiated adipocyte, and by the transcription factor, C/EBPalpha (and its homologues) during differentiation of preadipocytes into adipocytes. An impaired expression of the GLUT4 gene would be expected to cause resistance of glucose uptake to insulin similar to that which accompanies Type 2 (NIDDM) diabetes. 2. to investigate the mechanism by which a nuclear factor, expressed in preadipocytes but not adipocytes, represses transcription of the SCD2 gene. The "preadipocyte factor" will be purified sequenced and its role in differentiation-induced expression of the SCD2 gene (and possibly other genes) will be determined. 3. to determine the mechanism(s) by which expression of the C/EBPalpha gene is activated during differentiation of preadipocytes into adipocytes. The roles of the C/EBP binding site (a possible site of autoactivation) and a putative repressor binding site in the gene will be investigated. We have obtained compelling evidence that C/EBPalpha serves an essential role in the coordinate activation of a group of adipose-specific genes during adipose conversion.