Rapid reversal of hepatic steatosis, and reduction of muscle triglyceride, by rosiglitazone: MRI/S studies in Zucker fatty rats

Aims: This study aimed to chart the time course and durability of the effects of rosiglitazone, a potent thiazolidinedione-based peroxisome proliferator-activated receptor gamma agonist, on hepatic steatosis and intramyocellular lipid in an animal model of obesity, the Zucker Fatty (ZF) rat. Methods and Results: Rosiglitazone (3 mg/kg/day p.o.) significantly reduced both liver fat content (by 59%; p<0.05) and size (11.5%; p<0.05) in male ZF rats that received between 3 days and 1 week of treatment, and these reductions were maintained for at least 12 weeks. Liver fat content measured by magnetic resonance spectroscopy (MRS) correlated closely and positively with plasma insulin levels (reduced by 89% within a week, r=0.8) and with postmortem histological fat fractional volume (r=0.89). Similarly, liver volume measured by magnetic resonance imaging (MRI) correlated closely with postmortem wet weight (r=0.99). MRS also showed, and numbers of lipid vacuoles counted in transmission electron micrographs confirmed, that rosiglitazone significantly reduced the elevated intramyocellular lipid seen in ZF rat skeletal muscle by at least 40% (p<0.05). Conclusions: Localized MRS and MRI showed that rosiglitazone reversed the hepatic steatosis, hepatomegaly and intramyocellular lipid, characteristic of the ZF rat, an animal model of obesity.