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Basal and Growth Hormone-Induced Hepatic Messenger Ribonucleic Acid Expression of Insulin-Like Growth Factor-I (IGF-I) and IGF-Binding Protein-3 Is Independent of Hyperinsulinemia and Increased Energy Status in the Genetically Obese Zucker Rat¹

Servicio de Endocrinología, Centro Nacional de Investigacion Clinica, Instituto de Salud Carlos III (E.M., B.V., F.S-F.); and Servicio de Pediatría, Hospital Ramón y Cajal (R.B.), Madrid, Spain

Address all correspondence and requests for reprints to: Elvira M. Melián Pérez, Servicio de Endocrinología, Centro Nacional de Investigacion Clinica, Instituto Carlos III, C/Sinesio Delgado, 10, 28029 Madrid, Spain.

Genetically obese Zucker rats, like obese humans, have normal or elevated circulating insulin-like growth factor-I (IGF-I) levels in the presence of low GH secretion. Hyperinsulinemia, increased energy status, or other nutritional factors associated with obesity could be responsible for these findings directly by increasing hepatic IGF-I production at the transcriptional or posttranscriptional level. Alternatively, circulating IGF-I could be modulated indirectly by affecting its binding proteins. To further elucidate this point, we quantitated hepatic IGF-I, IGF binding protein-3 (IGFBP-3), and GH receptor messenger RNAs (mRNAs) expression in obese Zucker rats under different serum GH and insulin conditions using lean rats as controls. Eleven-week-old male rats were studied basally (intact) or after hypophysectomy (hx) at 9 weeks. In each condition, animals were killed before or 6 h after one dose of recombinant human GH (1.5 µg/g body weight ip). At this time, in addition to the mRNA expression of the above-mentioned genes, body weight, glycemia, insulinemia, serum GH (rat and human), and serum IGF-I levels were determined. Obese Zucker rats were significantly heavier than controls in all the conditions studied and did not show differences in glycemia. Severely hyperinsulinemic intact obese rats (146.9 ± 14 vs. 46.3 ± 3 µU/ml, P < 0.001) showed compared with intact lean rats significantly lower serum GH (2.39 ± 0.9 vs. 4.98 ± 0.68 ng/ml, P < 0.01), decreased hepatic IGF-I mRNA and IGFBP-3 mRNA accumulation (IGF-Ia: 79 ± 5.9% vs. 100 ± 0.9%, P < 0.05; IGF-Ib: 67 ± 5.5% vs. 100.1 ± 1.9%,P < 0.001; IGFBP-3: 54.7 ± 2.75% vs. 100.5 ± 1.55%, P < 0.001), and similar circulating IGF-I levels (1439 ± 182 vs. 1516 ± 121 ng/ml). Under comparable serum GH levels in GH-treated intact, hx, and GH-treated hx animals, hyperinsulinemia and/or increased body weight present in obese rats were not associated with increased hepatic IGF-I and IGFBP-3 mRNA amount. No differences in GH receptor/GH-binding protein mRNAs were found in any experimental condition. These results suggest that in vivo the imbalance of the serum GH/IGF-I axis present in obesity is primarily due to events distal to the hepatic IGF-I and IGFBP-3 mRNAs expression, which is tightly correlated to GH levels.

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