Englitazone Delays Fetal Growth in Late Gestation in the Rat

摘要

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 (PPARy) ligands have been implicated in the inhibition of growth and differentiation of certain human cancers, in the present study, we have investigated ihe effect of englitazone (EG), a PPARy Ugand, on foetal and postnatal development. Our results indicate mat, EG administered semi-chronically to pregnant rats, produced a body weight reduction on ihe 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 hypergtycemic. 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 PPARct, 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.