BASAL AND GROWTH HORMONE-INDUCED HEPATIC MESSENGER-RIBONUCLEIC-ACID EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I (TGF-I) AND IGF-BINDING PROTEIN-3 IS INDEPENDENT OF HYPERINSULINEMIA AND INCREASED ENERGY STATUS IN THE GENETICALLY-OBESE ZUCKER RAT

Genetically obese Zucker rats, like obese humans, have normal or eleva ted circulating insulin-like growth factor-I (IGF-I) levels in the pre sence of low GH secretion. Hyperinsulinemia, increased energy status, or other nutritional factors associated with obesity could be responsi ble for these findings directly by increasing hepatic IGF-I production at the transcriptional or posttranscriptional level. Alternatively, c irculating IGF-I could be modulated indirectly by affecting its bindin g proteins. To further elucidate this point, we quantitated hepatic IG F-I, IGF binding protein-3 (IGFBP-3), and GH receptor messenger RNAs ( mRNAs) expression in obese Zucker rats under different serum GH and in sulin conditions using lean rats as controls. Eleven-week-old male rat s were studied basally (intact) or after hypophysectomy (hx) at 9 week s. in each condition, animals were killed before or 6 h after one dose of recombinant human GH (1.5 mu g/g body weight ip). At this time, in addition to the mRNA expression of the above-mentioned genes, body we ight, 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 differenc es in glycemia. Severely hyperinsulinemic intact obese rats (146.9 +/- 14 vs; 46.3 +/- 3 mu U/ml, P < 0.001) showed compared with intact lea n rats significantly lower serum GH(2.39 +/- 0.9 us; 4.98 +/- 0.68 ng/ ml, P < 0.01), decreased hepatic IGF-I mRNA and IGFBP-3 mRNA accu mula tion (IGF-Ia: 79 +/- 5.9% vs. 100 +/- 0.9%, P < 0.05;IGF-Ib: 67 +/- 5. 5% us. 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 +/- 18 2 vs. 1516 +/- 121 ng/ml). Under comparable serum GH levels in GH-trea ted intact, hx, and OH-treated hx animals, hyperinsulinemia and/or inc reased body weight present in obese rats were not associated with incr eased hepatic IGF-I and IGFBP-3 mRNA amount. No differences in GH rece ptor/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 he patic IGF-I and IGFBP-3 mRNAs expression, which is tightly correlated to GH levels.