Circulating levels of insulin-like growth factor I (IGF-I) and serum albumin are decreased under conditions of chronic dietary protein limitation. To investigate the biochemical mechanism(s) involved in the regulation of IGF-I and serum albumin synthesis by dietary protein, we studied the effects of protein limitation on IGF-I and serum albumin gene expression in young growing rats maintained on isocaloric diets containing 20%, 12%, 8%, or 4% protein. Animals maintained on the 12%, 8%, or 4% protein diets exhibited slight, moderate, or severe growth deficiency, respectively, and a decreased abundance of hepatic IGF-I messenger RNA (mRNA). The decrease in IGF-I mRNA was most pronounced for the largest [7.7 kilobase (kb)] species, which was decreased by 87% in animals maintained on the 4% protein diet compared with animals on the 20% protein diet. The 0.9 kb species of IGF-I mRNA exhibited a smaller (46%) reduction in abundance in animals maintained on the 4% protein diet. The differential regulation of the 7.7 kb IGF-I mRNA species compared with the shorter IGF-I mRNA species suggests that a sequence or sequences within the long 3'-untranslated region of this mRNA species may play a role in regulating its abundance under conditions of protein limitation. Serum albumin mRNA was also decreased (by 62%) in the animals maintained on the 4% protein diet. The level of serum albumin gene transcription was not decreased in animals on the low protein diets, suggesting that nutrition regulates albumin mRNA at a posttranscriptional step. There was considerable animal-to-animal variability in the level of IGF-I gene transcription within each dietary group. The mean level of IGF-I gene transcription was decreased by 46% in the animals on the 4% protein diet compared with animals on the 20% protein diet, although this decrease was not statistically significant because of the animal-to-animal variability in IGF-I gene transcription within the dietary groups. Additional studies of brain RNA from animals on the four diets indicated that brain IGF-II mRNA was decreased by 57% in animals on the 4% protein diet. It has been demonstrated recently that expression of the gene for IGF binding protein-2 (IGFBP-2) is strongly induced in the liver of fasting animals. To investigate the possible regulation of the IGFBP-2 gene in the protein-limited animals, the abundance of liver and brain IGFBP-2 mRNA was analyzed in animals on the four diets.(ABSTRACT TRUNCATED AT 400 WORDS)