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.
Kim
Suyeon
S
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Huang
Li-Wen
LW
Snow
Kathy J
KJ
Ablamunits
Vitaly
V
Hasham
Muneer G
MG
Young
Timothy H
TH
Paulk
Angelique C
AC
Richardson
Joel E
JE
Affourtit
Jason P
JP
Shalom-Barak
Tali
T
Bult
Carol J
CJ
Barak
Yaacov
Y
D050156:Adipogenesis / Q000235:genetics; D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D007333:Insulin Resistance / Q000235:genetics; D008060:Lipodystrophy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics
D047495:PPAR gamma; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D013752:Tetracycline; D004318:Doxycycline