OR14-05 Hepatocyte Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Offsets the Anti-Steatogenic Effects of Thiazolidinediones in Obese Male Mice

Abstract

Pparg is a nuclear receptor that regulates glucose and lipid metabolism. Thiazolidinediones (TZD) are PPARG agonists that may reduce hepatic steatosis through their effects in adipose tissue. However, some studies suggest that expression and activation of hepatocyte Pparg promotes steatosis. In this study, we have assessed the relevance of hepatocyte Pparg, and its TZD-mediated activation in the development and/or reduction of steatosis, with adult-onset hepatocyte-specific Pparg knockout (PpargΔHep) mice. We reported that a single iv injection of AAV8-TBG-Cre in Pparg-floxed mice, knocked out hepatocyte Pparg expression (PpargΔHep mice), and that prevented diet-induced steatosis. In this study, a group of 5 wk-old Pparg-floxed mice were fed a low fat (LF) or a high fat (HF) diet for 7 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with the TZD Rosiglitazone maleate, for 5 weeks. HF diet induced mild obesity (36.8 +/- 1.4 g of body weight [BW]), while TZD slightly increased BW (41.3 +/- 1.3 g) and insulin sensitivity. Liver weight was not altered in HF-fed mice with or without TZD, and we did not observe any effect induced by PpargΔHep. Due to the mild phenotype observed in this cohort, we generated a 2nd cohort adjusting for age and length of diet. Briefly, 10 wk-old Pparg-floxed mice were fed a LF or HF diet for 16 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with Rosiglitazone maleate for 7 weeks. In this group of mice, HF diet induced obesity (50.1 +/- 1.05 g BW), and increased liver weight independent of hepatic Pparg expression. TZD treatment exacerbated obesity (62.4 +/- 1.2g BW) and adiposity, but increased insulin sensitivity as compared to mice fed a HF diet without TZD. Interestingly, PpargΔHep mice fed a HF diet with TZD showed enlarged subcutaneous white and brown adipose tissue weight, and a dramatic reduction in liver weight and steatosis as compared to obese control mice treated with TZD. The expression of hepatic Cd36, Cidea, Cidec, and Fabp4 was increased by TZD in a Pparg-dependent manner in HF-fed mice. Altogether, this data suggest that hepatocyte Pparg expression may offset the antisteatogenic actions of TZD in mice with severe obesity. In obese and insulin resistant individuals, TZD-mediated activation of hepatocyte Pparg may exacerbate steatosis.