Different sites of actions make different responses to thiazolidinediones between mouse and rat models of fatty liver

Abstract

Therapeutic approach for NAFLD is limited and there are no approved drugs. Pioglitazone (PGZ), a thiazolidinedione (TZD) that acts via peroxisome proliferator activated receptor gamma (PPARγ) is the only agent that has shown consistent benefit and efficacy in clinical trials. However, the mechanism of its therapeutic effect on NAFLD remains unclear. The poor understanding may be due to problems with mouse, a species most used for animal experiments. TZDs exacerbate fatty liver in mouse models while they improve it in rat models like in human patients. Therefore, we compared the effects of TZDs including PGZ and rosiglitazone (RGZ) in ob/ob mice and Lepmkyo/Lepmkyo rats, models of leptin-deficient obesity, and A-ZIP/F-1 mice and seipin knockout (SKO) rats, models of generalized lipodystrophy. Pparg mRNA expression was markedly upregulated in fatty livers of mouse models while it was unchanged in rat models. TZDs exacerbated fatty liver in ob/ob and A-ZIP/F-1 mice, improved it in Lepmkyo/Lepmkyo rats and showed no effect in SKO rats. Gene expression analyses of Pparg and its target gene, Fsp27 revealed that PPARγ in the adipose tissue is the exclusive therapeutic target of TZDs in rats but PPARγ in the liver in addition to the adipose tissue is also a major site of actions for TZDs in mice. Although the response to TZDs in mice is the complete opposite of that in human patients, no report has pointed out the problem with TZD studies using mouse models so far. The present study might provide useful suggestions in research on TZDs.

Role of Seipin in Human Diseases and Experimental Animal Models

“…However, in SKO rats, both pioglitazone and rosiglitazone fail to rescue the fatty liver via rescuing PPARγ expression in the liver and adipocyte tissue. Therefore, whether the potential that fatty liver could be rescued by PPARγ agonists is species-dependent or related to the methodology in which SKO animals are generated remains unclear [ 145 ]. (3) In SKO mice, leptin-replacement therapy not only rescues impaired vascular function [ 141 , 146 ], but also ameliorates kidney injury secondary to metabolic disturbance [ 124 ].…”

Metformin versus metformin plus pioglitazone on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome: a single-center, open-labeled prospective randomized controlled trial

“…However, clinical options for normal-weight women with PCOS are limited. Thiazolidinediones (TZDs) are peroxisomal proliferating-activated receptor-γ (PPAR-γ) agonists, such as pioglitazone and troglitazone, which play an insulin-sensitizing role by stimulating PPAR-γ receptors in peripheral tissues [ 13 , 14 ]. TZDs can alleviate HA by upregulating the expression of liver sex hormone-binding globulin (SHBG), directly regulate ovarian function through a variety of mechanisms [ 15 , 16 ], and play a role in preventing the metabolic consequences in PCOS women [ 17 – 20 ].…”