Effects of GH and liver-derived IGF-I on growth and metabolism

Abstract: Growth hormone (GH) exerts major effects on body growth and metabolism. Insulin-like growth factor (IGF) is expressed in response to GH and is known to mediate many of the effects of GH. The largest expression of IGF is found in the liver although it is expressed in virtually every tissue of the body. The aim of this thesis was to investigate the effects of GH and liver-derived IGF-I on growth and metabolism, especially the relative importance of liver-derived IGF-I versus IGF-I expressed locally in peripheral tissues. We have developed a transgenic mouse model with the IGF-I gene deleted specifically in the liver. To study the importance of liver-derived IGF-I for post-natal body growth, we induced deletion of the IGF-I gene in liver when the mice were three weeks old. This caused a drop in serum IGF-I levels by over 80 %, demonstrating that the major part of serum IGF-I is liver-derived. Despite this, mice grew normally up to 11 weeks of age, indicating that liver-derived IGF-I is not required for postnatal body growth. Mice with liver-specific IGF-I inactivation had a compensatory increase in GH levels. Studies of genes differentially regulated by the GH secretion pattern demonstrated that this up-regulation was probably due to increased basal levels of GH. The expression of genes regulating GH secretion was altered in the pituitary but not in the hypothalamus, indicating that the feedback regulation of GH secretion by liver-derived IGF-I is mainly at the pituitary level. IGF-I also exhibits insulin-like effects and since these mice had no obvious anomalies of body growth, we investigated the metabolic consequences. Studies of carbohydrate and lipid metabolism demonstrated that mice with a liver-specific IGF-I inactivation had decreased fat mass and were insulin resistant, with increased serum levels of leptin and cholesterol. Taken together, these data indicate that the primary role for liver-derived IGF-I is to regulate the intermediary metabolism and not to promote postnatal body growth. We also studied the long-term effects of liver-specific IGF-I inactivation on adult bone metabolism. Bone turnover was increased and detailed studies of the different types of bone showed that while the amount of cortical bone was decreased, the trabecular bone mineral density was increased. This indicates differential effects of liver-derived IGF-I on cortical versus trabecular bone. Studies in mice devoid of GH receptors confirmed the important role of GH in skeletal growth and accumulation of bone mass. These mice were severely growth retarded from 2-3 weeks of age, the femur being more affected than the crown-rump length. They had a decreased amount of cortical bone but unchanged trabecular bone mineral density. In conclusion, this thesis demonstrates that the major part of serum IGF-I is liver-derived and that the primary role of liver-derived IGF-I is to regulate the carbohydrate and lipid metabolism and not to promote postnatal body growth.