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

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 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.

本研究旨在识别瘦素（leptin）靶基因及其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，对比两种瘦素给药方案：一种为外周皮下（subcutaneous, SQ）给药，可发挥直接刺激效应；另一种为中枢脑室内（intracerebroventricular, ICV）给药，通过下丘脑通路间接抑制摄食行为。

本研究报道了中枢与外周给予瘦素对ob/ob小鼠摄食、体重及体脂组成的影响，同时报道了中枢与外周瘦素给药诱导的肝脏基因表达变化。

关键词：对比研究
瘦素缺陷型（ob/ob）小鼠通过中枢（脑室内）或外周（皮下）给药途径持续给予瘦素，时长共计12天。提取肝脏RNA并与Illumina微阵列进行杂交，随后分析基因表达数据。我们对比了ob/ob小鼠经中枢与外周瘦素处理后的全基因表达谱，并以C57BL/6小鼠作为基线基因表达的对照。

具体分组如下：
Liver_B6：C57BL/6小鼠组
Liver_VEH_SQ：ob/ob小鼠皮下给予赋形剂组
Liver_LEP_SQ：ob/ob小鼠皮下给予瘦素组
Liver_VEH_ICV：ob/ob小鼠脑室内给予赋形剂组
Liver_LEP_ICV：ob/ob小鼠脑室内给予瘦素组
Liver_LEP_ICVN：代表LEP_ICV组中的4只小鼠，该组小鼠给药失败或导管未正确置入。在分析表型数据时，我们发现这4只小鼠未出现体重减轻；脑组织切片无法确认导管是否置入，其基因表达与赋形剂处理组极为相似。