Fat Mass Reduction With Adipocyte Hypertrophy and Insulin Resistance in Heterozygous PPARγ Mutant Rats

Agonist-induced activation of peroxisome proliferatoractivated receptor-gamma (PPAR gamma) stimulates adipocyte differentiation and insulin sensitivity. Patients with heterozygous PPAR gamma dominant-negative mutation develop partial lipodystrophy and insulin resistance. Inconsistent with this evidence in humans, it was reported that heterozygous PPAR gamma knockout mice have increased insulin sensitivity and that mice with heterozygous PPAR gamma dominant-negative mutation have normal insulin sensitivity and improved glucose tolerance. In the context of the interspecies intranslatability of PPAR gamma-related findings, we generated a PPAR gamma mutant rat with a loss-of-function mutation (Pparg(mkyo)) without dominant-negative activity by using the ENU (N-ethyl-N-nitrosourea) mutagenesis method. Heterozygous Pparg(mkyo/+) rats showed reduced fat mass with adipocyte hypertrophy and insulin resistance, which were highly predictable from known actions of PPAR gamma agonists and phenotypes of patients with the PPAR gamma mutation. This report is the first in our knowledge to clearly demonstrate that both alleles of PPAR gamma are required for normal adipocyte development and insulin sensitivity in vivo. Furthermore, the study indicates that PPAR gamma regulates mainly adipocyte number rather than adipocyte size in vivo. The choice of appropriate species as experimental models is critical, especially for the study of PPAR gamma.