Hepatic gene expression profiling reveals key pathways involved in leptin mediated weight loss in ob/ob mice.. Mus musculus

The purpose of this study was to identify leptin target genes and subsequent pathways correlated with leptin-mediated weight loss. We utilized the microarray technology to compare two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We report here the impact of central and peripheral administration of leptin on food intake, body weight and body fat composition in ob/ob mice. We also report hepatic gene expression changes caused by central versus peripheral leptin administration. Keywords: comparison Overall design: Leptin deficient (ob/ob) mice were continuously administered leptin over 12-days using central (intracerebroventricular) or peripheral (subcutaneous) route of administration. Liver RNA was extracted and hybridized to Illumina microarrays and gene expression data was analyzed. The global gene expression profiles were compared after the central and peripheral leptin treatments in ob/ob mice and C57BL6 mice were used for the baseline gene expression. The groups are as below: Liver_B6: C57BL6 mice Liver_VEH_SQ: ob/ob mice with vehicle subcutaneous treatment Liver_LEP_SQ: ob/ob mice with leptin subcutaneous treatment Liver_VEH_ICV: ob/ob mice with vehicle intracerebroventricular treatment, Liver_LEP_ICV: ob/ob mice with leptin intracerebroventricular treatment, Liver_LEP_ICVN: represents four animals from LEP_ICV group in which treatment failed or the cannula may not have been in place. While analyzing the phenotype data, we found that there was no weight loss in these four animals. Sectioning of the brain could not confirm placement of the cannula in these animals. The expression of these animals is very similar to the vehicle treated animals.

本研究旨在鉴定瘦素（leptin）的靶基因及与瘦素介导的体重减轻相关的下游通路。我们采用微阵列技术（microarray technology），对比两种瘦素给药方案：一种为外周皮下（subcutaneous: SQ）给药，可直接发挥刺激作用；另一种为中枢脑室内（intracerebroventricular: ICV）给药，通过下丘脑信号通路间接抑制摄食。本研究报道了中枢与外周给予瘦素对ob/ob小鼠摄食行为、体重及体脂组成的影响，同时也分析了中枢与外周瘦素给药所诱导的肝脏基因表达变化。

关键词：对比研究
整体实验设计：瘦素缺陷型ob/ob小鼠通过中枢（脑室内）或外周（皮下）途径持续给予瘦素，给药周期为12天。提取肝脏总RNA并与Illumina微阵列（Illumina microarrays）杂交，随后进行基因表达数据分析。对比ob/ob小鼠经中枢与外周瘦素处理后的全局基因表达谱，并以C57BL/6小鼠作为基线基因表达的对照群体。实验分组如下：
1. Liver_B6：C57BL/6小鼠
2. Liver_VEH_SQ：接受皮下赋形剂处理的ob/ob小鼠
3. Liver_LEP_SQ：接受皮下瘦素处理的ob/ob小鼠
4. Liver_VEH_ICV：接受脑室内赋形剂处理的ob/ob小鼠
5. Liver_LEP_ICV：接受脑室内瘦素处理的ob/ob小鼠
6. Liver_LEP_ICVN：该组包含4只来自LEP_ICV组的小鼠，其给药未成功或埋植套管未正确就位。表型数据分析显示，该4只小鼠未出现体重减轻；脑组织切片无法确认该组小鼠的套管植入位置，其基因表达谱与赋形剂处理组小鼠高度相似。