Postreceptor Resistance to Exogenous Growth Hormone Exists in the Jejunal Mucosa of Parenterally Fed Rats

Abstract

Our objective was to determine whether the intestinal mucosa is resistant to the mitogenic effects of exogenous growth hormone (GH) but sensitive to exogenous insulin-like growth factor-I (IGF-I) during total parenteral nutrition (TPN) because of decreased GH receptor (GHR) binding or postreceptor responsiveness to GH. First, only continuous i.v. administration of IGF-I, but neither pulsatile subcutaneous nor continuous i.v. GH, stimulated jejunal mucosal hyperplasia; however, both GH and IGF-I increased serum IGF-I and promoted similar whole-body growth after 8 d of exclusive TPN and 6 d of growth factor treatment in rats. This suggests a tissue-specific resistance to GH action in the intestinal mucosa during TPN. Second, exogenous GH during TPN did not reduce GH-specific binding in jejunum, suggesting that the inability of GH to stimulate mucosal hyperplasia is not due to low levels of the GHR. Third, IGF-I, but not GH, induced acute expression of c-fos (P < 0.009) and c-jun (P = 0.053) mRNAs in jejunum based on Northern analysis and in situ hybridization histochemistry 60 min after a single i.v. bolus of GH or IGF-I. This suggests that IGF-I, but not GH, activates early postreceptor growth-related signaling pathways in jejunum. In summary, the lack of early c-fos and c-jun induction in response to GH in TPN rats indicates that the jejunal mucosa is resistant to exogenous GH between GHR activation and induction of immediate early genes. This may contribute to the inability of mucosal cells to respond to the trophic effects of GH.