Fat mass reduction with adipocyte hypertrophy and insulin resistance in heterozygous PPARγ mutant rats

Abstract

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