A mouse model of conditional lipodystrophy
A mouse model of conditional lipodystrophy
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DOI：
10.1073/pnas.0707797104
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发表时间：
2007-10-16
影响因子：
11.1
通讯作者：
Barak, Yaacov
中科院分区：
文献类型：
--
作者：
Kim, Suyeon;Huang, Li-Wen;Barak, Yaacov
脂肪营养不良是与脂质和葡萄糖稳态严重缺陷相关的脂肪组织变性综合征。我们在这里报告的生成和分析Pparg（ldi），一个有针对性的等位基因，赋予条件性显性脂肪代谢障碍的小鼠。Pparg（ldi）等位基因通过将泰特激活剂（tTA）和tTA调节的Flag-Pparg 1转基因插入到Pparg基因中而产生。出乎意料的是，tTA引起轻度脂肪营养不良、胰岛素抵抗和血脂异常，并且Flag-PPAR γ 1转基因令人惊讶地加剧了这些性状。强力霉素可以完全预防和逆转这些表型，提供了一种诱导型脂肪营养不良的小鼠模型。来自Pparg（ldi/+）或表型相似的aP 2-nSrebp 1c（Sr）转基因小鼠的胚胎成纤维细胞经历稳健的脂肪形成，表明由于脂肪细胞分化缺陷，两种品系都不发展脂肪营养不良。此外，Pparg（ldi/+）脂肪组织与Sr小鼠的脂肪组织具有广泛的基因表达畸变，在分子水平上验证了表型，并揭示了脂肪营养不良性脂肪的共同表达特征。因此，Pparg（ldi/+）小鼠提供了用于研究脂肪营养不良及其相关生理学和基因表达的条件性动物模型。
Lipodystrophies are syndromes of adipose tissue degeneration associated with severe defects in lipid and glucose homeostasis. We report here the generation and analysis of Pparg(ldi), a targeted allele that confers conditional dominant lipodystrophy in mice. The Pparg(ldi) allele was generated by insertion of the Tet activator (tTA) and a tTA-regulated Flag-Pparg1 transgene into the Pparg gene. Unexpectedly, tTA elicits mild lipodystrophy, insulin resistance, and dyslipidemia, and the Flag-PPAR gamma l transgene surprisingly exacerbates these traits. Doxycycline can both completely prevent and reverse these phenotypes, providing a mouse model of inducible lipodystrophy. Embryonic fibroblasts from either Pparg(ldi/+) or the phenotypically similar aP2-nSrebp1c (Sr) transgenic mice undergo robust adipogenesis, suggesting that neither strain develops lipodystrophy because of defective adipocyte differentiation. In addition, Pparg(ldi/+) adipose tissue shares extensive gene expression aberrations with that of Sr mice, authenticating the phenotype at the molecular level and revealing a common expression signature of lipodystrophic fat. Thus, the Pparg(ldi/+) mouse provides a conditional animal model for studying lipodystrophy and its associated physiology and gene expression.