Nutritional status is a critical factor that modulates the responsiveness of the liver to GH and the resulting production of endocrine (mostly liver-derived) IGF-I. Using a conditional Cre/lox P system, we have established a liver-specific IGF-I-deficient mouse model. Despite the reduction in the circulating IGF-I (75%), the growth parameters are normal, except for the reduced spleen size, providing a unique model to study the effect of protein restriction on the autocrine/paracrine GH/IGF-I axis. To determine the effects of protein calorie malnutrition on the spleen, liver-specific IGF-I-deficient mice were assigned to one of four isocaloric diets, differing in the protein content (20, 12, 4, and 0%), for a period of 10 d. A low protein intake decreased the nonhepatic IGF-I secretion into the circulation, whereas it caused an increase in the level of circulating GH. This supports the view that nonhepatic IGF-I production contributes to circulating IGF-I levels. The lack of dietary protein led to an up-regulation of GH and IGF-I receptors expression in the spleen, whereas the IGF-I mRNA remained unchanged, as was demonstrated by flow cytometry and ribonuclease protection assay. B lymphocytes seem to be responsible for the up-regulated GH/IGF-I receptor expression. Northern blot analysis showed an up-regulation of IGF-binding protein-3 mRNA levels, which suggests that the protein deprivation may lead to an increased sequestration of circulating or locally synthesized IGF-I. These results support the hypothesis that the splenic GH/IGF-I axis responds to the nutritional stress caused by a low protein intake, to maintain the tissue homeostasis.