These mice express tTA (tetracycline regulated transactivator) and a tetO-driven Flag-tagged Pparg from the endogenous Pparg locus. A fusion transcript (including the 5' portion of Pparg, IRES and tTA (AF1-IRES-tTA)), a Flag-Pparg transcript and a wildtype transcript are detected by Northem blot analysis of white adipose tissue from heterozygotes. The fusion transcript of AF1-IRES-tTA is also detected in brown adipose tissue. Expression of tTA is detected in adipose tissue by Western blot analysis. No Flag-PPARG1 protein was detected in adipose tissue. Weak expression of tTA and the Flag-Pparg transcript is observed in placenta and liver. Endogenous PPARG2 protein is reduced in adipose tissues of heterozygotes. Heterozygotes exhibit "buffalo humps" (swollen interscapular fat pads swollen by hypertrophy and unilocular lipid deposition in mutant brown adipocytes), absence of subcutaneous adipocytes, reduced gonadal white adipose tissue, irregularly residual adipocyte shape and size, and fibrotic white adipose tissue stroma with leukocytic infiltration of the adipose tissue. Although, mutant mice have hyperinsulinemia, pancreatic islet hyperplasia, severe glucose intolerance, and hepatomegaly, they do not develop steatosis or type II diabetes. Prepubertal male heterozygotes exhibit hyperglycemia which normalizes with age. Treatment with doxycycline prevents this phenotype when administered starting at midgestation. A 6 week doxycycline treatment administered to pubertal heterozygotes reverses most of the phenotype, except the reduction in white adipose tissue. Mice that are homozygous for the targeted mutation are not viable. This mutant mouse strain may be useful in studies of lipodystrophy.
