title: A mouse model of conditional lipodystrophy.
abstract: 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.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Suyeon
authors.initials: S
authors.lastname: Kim
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Huang
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Snow
authors.forename: Vitaly
authors.initials: V
authors.lastname: Ablamunits
authors.forename: Muneer G
authors.initials: MG
authors.lastname: Hasham
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Young
authors.forename: Angelique C
authors.initials: AC
authors.lastname: Paulk
authors.forename: Joel E
authors.initials: JE
authors.lastname: Richardson
authors.forename: Jason P
authors.initials: JP
authors.lastname: Affourtit
authors.forename: Tali
authors.initials: T
authors.lastname: Shalom-Barak
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Bult
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Barak
mesh_terms: 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
chemical_list: D047495:PPAR gamma; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D013752:Tetracycline; D004318:Doxycycline