Tissue-Specific Alterations in Insulin-like Growth Factor-I Concentrations in Response to 3,3′,5-Triiodo-l-thyronine Supplementation in the Growth Hormone Receptor-Deficient Sex-Linked Dwarf Chicken

Abstract

Insulin-like growth factor-I (IGF-I) mediates many of the effects of growth hormone (GH). The regulation of IGF-I, independent of GH, is methodologically difficult to assessin vivo,as hypophysectomy results in derangement of many pituitary hormone axes in addition to GH, and a gene knockout model is not available. The recessive sex-linked dwarfing (SLD) gene (dw) in chickens results in a lack of functional target tissue GH receptors due to a variety of molecular defects, which provides a unique model for evaluating GH-independent regulation of IGF-I. In the present study, the impact of 3,3′,5-triiodo-l-thyronine (T3) on circulating and tissue IGF-I was determined in normal versus SLD birds. Adult, nonovulatory female normal and SLD chickens were restrict-fed 40 g of feed/kg bw/day containing 0, 0.5, or 1.0 ppm T3, resulting in supplementation levels of 0 (control), 20 (low dose), or 40 (high dose) μg T3/kg bw/day for 10 days. Samples of GH target tissues including liver, abdominal fat pad, skeletal muscle (pectoralis major), and spleen were extracted and assayed for IGF-I. Plasma T3, T4, GH, and IGF-I were determined by homologous RIA. Tissue GH binding was determined for hepatic membranes by radioreceptor assay. Under control conditions, dwarf chickens were markedly hypersomatotropic (33.3±4.1 ng GH/ml plasma; mean±SEM) compared to normals (2.4±3.9 ng/ml), and T3supplementation reduced this to normal levels. Despite the high circulating level of GH in dwarfs, plasma IGF-I was low compared to normal controls (dwarfs 1.5±.9 ng/ml; normals 5.3±.9 ng/ml;P=0.004), but this difference was eliminated with low-dose T3. In this study, tissue IGF-I was undetectable in liver and pectoralis muscle in adults (55 weeks of age) of both genotypes, under all treatments. In contrast, adipose tissue IGF-I was relatively high and did not differ (P=0.84) between genotypes under control conditions (normals 776.5±236.7; dwarfs 844.6±236.7 pg/mg protein), but was increased in normals and decreased in dwarfs, resulting in higher levels (P=0.02) in the normal (1249.9±200.0 pg/mg protein) than in the dwarf genotype (558.4±200.0 pg/mg protein) at the higher level of T3supplementation. This relationship was somewhat reversed in spleen, where T3tended to decrease tissue IGF-I concentration in normals and increase it in dwarfs. The low level of plasma IGF-I despite nonmeasureable hepatic IGF-I tissue concentrations suggests that IGF-I synthesis by extrahepatic tissues contributes to the circulating pool of IGF-I. The relatively high control levels of adipose tissue IGF-I in the dwarf genotype further suggest that considerable IGF-I synthesis exists that is GH-independent in this extrahepatic tissue. The presence of GH action, however, may mediate the effects of other hormones that can influence local IGF-I production in this tissue, as reflected by the differential response to T3supplementation between genotypes. The tissue-specific nature of the effect of T3on IGF-I production supports an additional point of regulation of hormone action at the target tissue level.