Johnson P R, Greenwood M R, Horwitz B A, Stern J S
Department of Nutrition, University of California, Davis 95616.
Annu Rev Nutr. 1991;11:325-53. doi: 10.1146/annurev.nu.11.070191.001545.
Among the candidate genes that have been reviewed herein, adipsin, calcitonin, cholecystokin, Gi alpha and Gs subunits of G proteins, insulin I and II, and lipoprotein lipase have all been mapped to specific chromosomes in mouse or rat or both. In none of these cases is the chromosomal location syntenic with murine obesity genes db (on chromosome 4), or ob (on chromosome 6). Thus, all of these genes that code for metabolic modulators that are altered in obese animals but not in lean animals can be ruled out as possible loci of the primary genetic defect, at least for the murine models of obesity. In the case of neuropeptide Y, growth hormone, glucose transporter GLUT-4, the insulin receptor, and glyceraldehyde-3-phosphate dehydrogenase, chromosomal mapping has not yet been reported. However, in each of these cases, the evidence available strongly argues against any one of these physiologic modulators as the likely site of the primary defect for any one of the obesity mutations. Rather, in all of these cases, regardless of whether or not the gene has been mapped, the evidence suggests that posttranscriptional and/or post-translational processes are involved in bringing about the specific alterations in level or activity of the protein product that is seen in the obese animal. Often hormonal regulation is invoked as a possible explanation for the changes observed in gene expression. The hormones most commonly identified as having a mediating effect on the particular metabolic pathways involved are insulin and/or the adrenal glucocorticoids. Since in each of the obese mutants, circulating amounts of these hormones are elevated, severely so in the case of insulin, it would not be surprising to find that they influence the levels and activities of many protein products involved in a variety of central nervous system and peripheral metabolic pathways. Glucocorticoids are known to exert direct effects on gene expression; however, with respect to adipsin gene expression, a direct effect has not been found. Furthermore, insulin itself has been considered as a candidate for the genetic lesion in these animals and has been ruled out by chromosomal localization. Thus, while it may certainly prove to be the case that both insulin and glucocorticoids affect these systems in some way, their effects appear to be indirect. The work by Platt and colleagues in transgenic mice provides the first evidence of signal transduction between an obese mutant allele and the promoter sequence for a gene that shows significantly altered expression in the obese animal.(ABSTRACT TRUNCATED AT 400 WORDS)
在本文中所回顾的候选基因中，脂肪酶、降钙素、胆囊收缩素、G蛋白的Giα和Gs亚基、胰岛素I和II以及脂蛋白脂肪酶，都已在小鼠或大鼠或两者中被定位到特定染色体上。在这些情况中，没有一个基因的染色体定位与小鼠肥胖基因db（位于第4号染色体）或ob（位于第6号染色体）是同线的。因此，所有这些在肥胖动物而非瘦动物中发生改变的编码代谢调节因子的基因，至少对于小鼠肥胖模型而言，都可以被排除作为原发性遗传缺陷的可能位点。就神经肽Y、生长激素、葡萄糖转运蛋白GLUT - 4、胰岛素受体和甘油醛 - 3 - 磷酸脱氢酶而言，尚未有染色体定位的报道。然而，在这些情况中的每一种里，现有的证据都强烈反对将这些生理调节因子中的任何一个作为任何一种肥胖突变的原发性缺陷位点。相反，在所有这些情况中，无论该基因是否已被定位，证据都表明转录后和/或翻译后过程参与导致在肥胖动物中所观察到的蛋白质产物水平或活性的特定改变。通常会援引激素调节来解释所观察到的基因表达变化。最常被确定为对所涉及的特定代谢途径有介导作用的激素是胰岛素和/或肾上腺糖皮质激素。由于在每一种肥胖突变体中，这些激素的循环量都会升高，在胰岛素的情况下更是严重升高，所以发现它们影响许多参与各种中枢神经系统和外周代谢途径的蛋白质产物的水平和活性也就不足为奇了。已知糖皮质激素对基因表达有直接作用；然而，就脂肪酶基因表达而言，尚未发现有直接作用。此外，胰岛素本身曾被认为是这些动物遗传损伤的候选因素，但已通过染色体定位被排除。因此，虽然胰岛素和糖皮质激素肯定可能在某种程度上影响这些系统，但它们的作用似乎是间接的。普拉特及其同事在转基因小鼠中的研究首次证明了肥胖突变等位基因与在肥胖动物中表达显著改变的基因的启动子序列之间的信号转导。（摘要截取自400字）
