TISSUE-SPECIFIC ALTERATIONS IN INSULIN-LIKE GROWTH-FACTOR-I CONCENTRATIONS IN RESPONSE TO 3,3',5-TRIIODO-L-THYRONINE SUPPLEMENTATION IN THEGROWTH-HORMONE RECEPTOR-DEFICIENT SEX-LINKED DWARF CHICKEN

Insulin-like growth factor-I (IGF-I) mediates many of the effects of g rowth hormone (GH). The regulation of IGF-I, independent of GH, is met hodologically difficult to assess in vivo, as hypophysectomy results i n derangement of many pituitary hormone axes in addition to GH, and a gene knockout model is not available. The recessive sex-linked dwarfin g (SLD) gene (dw) in chickens results in a lack of functional target t issue GH receptors due to a variety of molecular defects, which provid es a unique model for evaluating GH-independent regulation of IGF-I. I n the present study, the impact of 3,3',5-triiodo-L-thyronine (T-3) on circulating and tissue IGF-I was determined in normal versus SLD bird s. Adult, nonovulatory female normal and SLD chickens were restrict-fe d 40 g of feed/kg bw/day containing 0, 0.5, or 1.0 ppm T-3, resulting in supplementation levels of 0 (control), 20 (low dose), or 40 (high d ose) mu g T-3/kg bw/day for 10 days. Samples of GH target tissues incl uding liver, abdominal fat pad, skeletal muscle (pectoralis major), an d spleen were extracted and assayed for IGF-I. Plasma T-3, T-4, GH, an d IGF-I were determined by homologous RIA. Tissue GH binding was deter mined for hepatic membranes by radioreceptor assay. Under control cond itions, dwarf chickens were markedly hypersomatotropic (33.3 +/- 4.1 n g GH/ml plasma; mean +/- SEM) compared to normals (2.4 +/- 3.9 ng/ml, and T-3 supplementation reduced this to normal levels. Despite the hig h 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 T-3. In thi s study, tissue IGF-I was undetectable in liver and pectoralis muscle in adults (55 weeks of age) of both genotypes, under all treatments. I n contrast, adipose tissue IGF-I was relatively high and did not diffe r (P = 0.84) between genotypes under control conditions (normals 776.5 +/- 236.7; dwarfs 844.6 +/- 236.7 pg/mg protein), but was increased i n normals and decreased in dwarfs, resulting in higher levels (P = 0.0 2) in the normal (1249.9 +/- 200.0 pg/mg protein) at the higher level of T-3 supplementation. This relationship was somewhat reversed in spl een, where T-3 tended to decrease tissue IGF-I concentration in normal s and increase it in dwarfs. The low level of plasma IGF-I despite non measureable hepatic IGF-I tissue concentrations suggests that IGF-I sy nthesis 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 e xists 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 T-3 supplementation between genotypes. Th e tissue-specific nature of the effect of T-3 on IGF-I production supp orts an additional point of regulation of hormone action at the target tissue level. (C) 1997 Academic Press