Englitazone delays fatal growth in late geotation in the rat.

Abstract

The mechanisms regulating hepatocyte proliferation are relevant to liver development, carcinogenesis, and regeneration. Studies of hepatocyte proliferation control dming late foetal and postnatal development bave been used as a model to tmderstand such mecbanisms. Since peroxisome proliferator-activated receptor gamma (PPARy) ligands bave been implicated in the inbibition of growth and difrerentiation of certain human cencers, in the present stud:y, we have investigated the etJect of englitazone (EG), a PPARy ligand. on foetal and postnatal development. Our results indicate tbat, EG administered semi-cbronically to pregnantrats, produced a body weight reduction on the progeny. This etlect may be related to the diminished level of plasma IGF-1 fotmd in the neonates ftom treatedmothers. 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 atJected by the treatment. In the liver of neonates ftom mothers receiving EG, the expression of PPARa, IR, Pl3K and IRS-1 was unchanged, as was the phosphorylation of MAPK. Nevertheless, an increase on Akt phosphorylation was observed on liver of neonates ftom treated-mothers, confinning a remarkable change on the mitogenic insulin/IGF-1 path.way. In conclusion, the growtb intnbitory effect reported herein may be associated with the ability of PPARy ligands to reduce IGF-1 concentrations and produce an insulin resistance state on foetus/neonates. These data strengthen the idea that PP ARy ligands have potential benefits on cancer treatment.