Effect of fasting on insulin-like growth factor-I (IGF-I) and growth hormone receptor mRNA levels and IGF-I gene transcription in rat liver.

Previous studies have indicated that the concentration of circulating insulin-like growth factor-I (IGF-I) declines in young growing rats that have been fasted or maintained on a protein-deficient diet. To investigate the molecular mechanism(s) by which IGF-I levels are regulated by nutrition, we measured the levels of IGF-I mRNA in 6-week-old male control rats fed ad libitum, rats fasted for 24, 48, or 72 h, and rats fasted for 48 or 72 h and then refed for 24 h. The abundance of several IGF-I mRNA species (8.0, 4.0, 1.7, and 1.0 kilobases) decreased in the fasting animals and rebounded after 24 h of refeeding, although not to the initial control levels. The 1 kilobase IGF-I mRNA species exhibited a 43% decrease after 24 h of fasting, a 76% decrease after 48 h of fasting, and an 82% decrease after 72 h of fasting. Hepatic GH receptor mRNA also decreased in fasting rats. This indicates that the GH receptor down-regulation that occurs in fasting is accompanied by and probably at least partly caused by a decline in GH receptor mRNA. The magnitude and kinetics of the decline in GH receptor mRNA were similar to the magnitude and kinetics of the decline in IGF-I mRNA, suggesting that the two mRNAs may be regulated by a similar mechanism. There was no significant change in the levels of liver beta-actin or serum albumin mRNA under the same conditions, indicating that the regulation of IGF-I and GH receptor mRNA was specific. In addition, the levels of brain IGF-II, beta-actin, and alpha-tubulin mRNAs were not significantly changed by fasting. To further elucidate the molecular mechanism for regulation of hepatic IGF-I mRNA, nuclear transcription elongation assays were performed using nuclei isolated from the liver of control rats, rats fasted for 72 h, and fasted-refed rats. There was considerable animal-to-animal variability in IGF-I gene transcription within each group. The mean level of IGF-I gene transcription was lower in the fasting animals than in the fed controls. However, this decrease was not statistically significant, and the magnitude of the decrease did not account for the 79% decrease in total IGF-I mRNA. These results suggest that IGF-I mRNA is regulated at least partly at the posttranscriptional level.