Hepatic enzymes associated with glucose hemostasis were studied in offspring of dams fed either a 20% protein (control) or an isocaloric 8% protein (low-protein) diet during pregnancy and lactation. Additionally, offspring were exposed to maternal 8% protein diet only during gestation (recuperated) or lactation (postnatal low-protein). Glucokinase activity decreased (approximately 50%), whereas phosphoenolpyruvate carboxykinase (PEPCK) activity increased (approximately 100%), in the low-protein and recuperated offspring compared with controls (P < 0.001) at 21 days of age. However, the postnatal low-protein offspring had enzyme activities comparable with those of controls. These changes were still evident in 11-mo-old offspring weaned onto a normal laboratory chow. Parallel changes were apparent in mRNA levels of glucokinase and PEPCK in the low-protein male offspring. Thus the effect of programming metabolism extends not only to protein biochemistry but possibly also to the regulation of gene expression. Furthermore, these changes could not be attributed to glucagon or insulin, because ratios of these hormones were comparable between the control and low-protein groups.