A mouse model of conditional lipodystrophy.

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-PPARgamma1 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.