Purpose: Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000^TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat.
Materials and Methods: KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC).
Results: Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 (Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only.
Conclusion: These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.

Keywords: obesity, druggable, homologous recombination, gene trapping


中文翻译：

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小鼠基因敲除的高通量筛选鉴定已建立的和新型的高体脂表型

目的：肥胖是一个重大的公共卫生问题。了解哪些基因导致肥胖可以更好地预测个体风险并有助于开发新疗法。由于小鼠基因敲除 (KO) 系的肥胖预示着人类直系同源基因与肥胖的关联，因此我们回顾了 Lexicon Genome5000 ^TM高通量表型筛选 (HTS) 小鼠基因 KO 的数据，以鉴定具有高体脂的 KO 系。
材料和方法：使用同源重组或基因捕获技术产生 KO 系。对来自 3758 个具有人类直系同源物的可药物小鼠基因的成年野生型和纯合 KO 同窝小鼠进行 HTS 身体成分分析。通过 DXA 或 QMR 对来自所有 3758 个 KO 品系的饲料喂养队列进行测量，并通过 QMR 对来自 2488 个 KO 品系的独立高脂肪饮食喂养队列进行测量。在可能的情况下，与国际小鼠表型联盟 (IMPC) 的 HTS 数据进行了比较。
结果：提供了 75 个 KO 品系的体脂数据。在 46 个独立外部公开的 KO 系和/或 IMPC KO 系被报告为肥胖的 46 个 KO 系中，有 43 个体脂肪增加。对于其余 29 个新型高体脂 KO 系，Ksr2和G2e3得到来自其他独立 KO 队列的数据支持，6 个（Asnsd1、Srpk2、Dpp8、Cxxc4、Tenm3和Kiss1）得到来自其他内部队列的数据支持，其余的仅在 HTS 队列中研究了21 种基因，包括Tle4、Ak5、Ntm、Tusc3、Ankk1、Mfap3l、Prok2和Prokr2 。
结论：这些数据支持在 43 个独立的外部发表和/或 IMPC KO 系中发现高体脂肪。在另外 29 个 KO 系中发现了一种新的肥胖表型，其中 27 个仍缺乏目前为Ksr2和G2e3 KO 小鼠提供的外部确认。毫无疑问，许多哺乳动物肥胖基因仍有待鉴定和表征。

关键词:肥胖, 可药物化, 同源重组, 基因捕获