The Role of Liver-Derived Insulin-Like Growth Factor-I

IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bonederived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other ( redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace ( lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity. (Endocrine Reviews 30: 494 -535, 2009) I. Introduction II. Liver-Derived IGF-I and Longitudinal Bone Growth A. Background, including the original somatomedin hypothesis B. Tissue-specific manipulation of IGF-I expression C. Target cells for GH and IGF-I in the growth plate D. Human genetic disorders and skeletal growth E. Mechanism of action for GH and IGF-I in the regulation of bone growth-an update III. Effects of Liver-Derived vs. Locally Produced IGF-I on Bone Mass A. In vivo and in vitro studies on IGF-I expression and action in bone B. Transgenic overexpression in bone C. Conditional knockout in bone D. Liver-derived IGF-I and bone mass IV. Liver-Derived IGF-I and GH Secretion A. Pulsatile GH secretion B. Negative feedback of liver-derived IGF-I on GH secretion C. Liver-derived IGF-I and sexually dimorphic effects of GH D. Human studies V. The Role of Liver-Derived IGF-I for Metabolism and Body Composition A. Carbohydrate metabolism B. Fat mass C. Lipid metabolism VI. Liver-Derived IGF-I and Other Tissues A. Brain B. Cardiovascular system C. Kidney D. Liver E. Prostate VII. Clinical Implications A. Indications for the use of IGF-I and adverse effects B. Potential indications for combined GH and IGF-I treatment C. Diabetes mellitus D. Other potential future indications