Thiazolidinediones (TZD) are
peroxisome proliferator-activated receptor γ (PPARγ) agonists that may reduce hepatic steatosis through their effects in adipose tissue and therefore have been assessed as potential
therapies to treat
nonalcoholic fatty liver disease (
NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a
NAFLD therapy. To further explore this possibility, we examined the impact of short-term
rosiglitazone maleate treatment after the development of moderate or severe diet-induced
obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (PpargΔHep) mice. Independent of the level of
obesity and hepatic PPARγ expression, the TZD treatment enhanced
insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic
triglyceride content only in control mice with
severe obesity. Under these conditions, PpargΔHep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of
adiponectin, while hepatic levels of phosphorylated
adenosine 5'-monophosphate-activated
protein kinase were also increased. In addition, in mice with
severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the antisteatogenic actions of TZD in mice with
severe obesity. Therefore, in obese and
insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat
NAFLD.