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

Abstract

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 this evidence in humans, it was reported that heterozygous PPARγ knockout mice have increased insulin sensitivity and that mice with heterozygous PPARγ dominant-negative mutation have normal insulin sensitivity and improved glucose tolerance. In the context of the interspecies intranslatability of PPARγ-related findings, we generated a PPARγ 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 PPARγ agonists and phenotypes of patients with the PPARγ mutation. This report is the first in our knowledge to clearly demonstrate that both alleles of PPARγ are required for normal adipocyte development and insulin sensitivity in vivo. Furthermore, the study indicates 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.

CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats

“…As we have reported previously, for example, while Het Pparg KO mice have increased insulin sensitivity, Het Pparg KO rats show insulin resistance like patients with Het Pparg dominant-negative mutation (30). In this context, we have thus far generated KO rats for Leptin (31) and Bscl2/Seipin (32) besides Pparg (30) and investigated the roles of each gene. Therefore, we generated a rat model to analyze the functions of ANGPTL8.…”

“…Rats are considered to be a better model than mice in terms of their physiologic and behavioral characteristics, which are in some respects more relevant to humans (20,28,29). As we have reported previously, for example, while Het Pparg KO mice have increased insulin sensitivity, Het Pparg KO rats show insulin resistance like patients with Het Pparg dominant-negative mutation (30). In this context, we have thus far generated KO rats for Leptin (31) and Bscl2/Seipin (32) besides Pparg (30) and investigated the roles of each gene.…”

Effect of Enzymatic Treatment of Chrysanthemum Indicum Linné Extracts on Lipid Accumulation and Adipogenesis in High-Fat-Diet-Induced Obese Male Mice

“…Adipogenesis is a differentiation process that converts pre-adipocytes (mesenchymal precursor cells) into mature adipocytes, accompanied by adipocyte morphology changes and lipid accumulation [ 10 ]. To differentiate pre-adipocytes into adipocytes, transcription factors are needed; these transcription factors include PPAR-(peroxisome proliferation activated receptor-) and C/EBP-(CCAAT / enhancer binding protein-) [ 11 , 12 ]. In addition, increased expression of transcription factors activates adipocyte specific genes, such as leptin and adiponectin, to regulate adipogenesis [ 13 ].…”

Role of Peroxisome Proliferator‐Activated Receptor (PPARγ) in Metabolic Disorders in SGA with Catch‐Up Growth

“…Previous studies suggest that treatment with the PPARγ agonist TZDs increases fat mass, and the effect of TZDs on adiposity varies with the location of fat. It generally increases subcutaneous fat mass but decreases intra‐abdominal fat mass in type 2 diabetes mellitus patients or Pparg mkyo/+ rats . In our study, the different results in the two groups after intervention, combined with the CUG‐SGA individuals being at high risk for metabolic disease, suggest that pioglitazone may prohibit the visceral fat CUG through PPARγ activation in SGA rats.…”