Rosiglitazone Requires Hepatocyte PPARγ Expression to Promote Steatosis in Male Mice With Diet-Induced Obesity

Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma 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 PPAR gamma knockout (Pparg(Delta Hep)) mice. Independent of the level of obesity and hepatic PPAR gamma 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, Pparg(Delta Hep) 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 PPAR gamma-dependent manner.Taken together, these results demonstrate that hepatocyte PPAR gamma expression offsets the antisteatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPAR gamma may limit the therapeutic potential of TZD to treat NAFLD.

Automated summary

Short-term treatment with TZD improves insulin sensitivity but may increase hepatic triglyceride content in severely obese mice, while hepatocyte-specific PPARγ knockout can reduce steatosis. These findings suggest that hepatocyte PPARγ expression may counteract the anti-steatogenic effects of TZD in severe obesity.