The mechanisms regulating hepatocyte proliferation are relevant to liver development, carcinogenesis, and regeneration. Studies of hepatocyte proliferation control during late foetal and postnatal development have been used as a model to understand such mechanisms. Since peroxisome proliferator-activated receptor gamma (PPARgamma ligands have been implicated in the inhibition of growth and differentiation of certain human cancers, in the present study, we have investigated the effect of englitazone (EG), a PPARgamma ligand, on foetal and postnatal development. Our results indicate that EG administered semi-chronically to pregnant rats, produced a body weight reduction on the progeny. This effect may be related to the diminished level of plasma IGF-I found in the neonates from treated-mothers. Surprisingly, despite receiving an anti-diabetic drug, foetus; and neonates showed high levels of insulin, and were hyperglycemic. The plasma levels of leptin, other putative mitogenic factor, were not affected by the treatment. In the liver of neonates from mothers receiving EG, the expression of PPARalpha, IR, PI3K and IRS-1 was unchanged, as was the phosphorylation of MAPK. Nevertheless, an increase on Akt phosphorylation was observed on liver of neonates from treated-mothers, confirming a remarkable change on the mitogenic insulin/IGF-I pathway. In conclusion, the growth inhibitory effect reported herein may be associated with the ability of PPARgamma ligands to reduce IGF-I concentrations and produce an insulin resistance state on foetus/neonates. These data strengthen the idea that PPARgamma ligands have potential benefits on cancer treatment.
