Agonist-induced activation of peroxisome proliferator-activated receptor γ (PPARγ) stimulates adipocyte differentiation and insulin sensitivity. Patients with heterozygous PPARγ dominant negative mutation develop partial lipodystrophy and insulin resistance. Inconsistent with these evidences in human, it was reported that heterozygous PPARγ knockout mice had increased insulin sensitivity and mice with heterozygous PPARγ dominant negative mutation had normal insulin sensitivity and improved glucose tolerance. In the context of the interspecies intranslatability of PPARγ-related findings, we generated a PPARγ mutant rat having a loss-of-function mutation (Ppargmkyo) without dominant negative activity using the method with ENU (N-ethyl-N-nitrosourea) mutagenesis. Heterozygous Ppargmkyo/+ rats showed reduced fat mass with adipocyte hypertrophy and insulin resistance, which were highly predictable from known actions of PPARγ agonists and phenotypes of patients with PPARγ mutation. This is the first report clearly demonstrating that both alleles of PPARγ are required for normal adipocyte development and insulin sensitivity in vivo. Furthermore, the present study indicated that PPARγ 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 PPARγ.
- Received October 13, 2015.
- Accepted June 28, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.