Melián E, Velasco B, Barrios R, Sanchez-Franco F
Servicio de Endocrinología, Instituto de Salud Carlos III, Hospital Ramón y Cajal, Madrid, Spain.
Endocrinology. 1997 Mar;138(3):1066-71. doi: 10.1210/endo.138.3.4975.
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 micrograms/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 microU/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.
遗传性肥胖的 Zucker 大鼠与肥胖人类一样，在生长激素（GH）分泌量较低的情况下，其循环胰岛素样生长因子 -I（IGF-I）水平正常或升高。高胰岛素血症、能量状态增加或与肥胖相关的其他营养因素，可能通过在转录或转录后水平增加肝脏 IGF-I 的产生，直接导致这些结果。或者，循环中的 IGF-I 可能通过影响其结合蛋白而受到间接调节。为了进一步阐明这一点，我们以瘦大鼠作为对照，对处于不同血清 GH 和胰岛素条件下的肥胖 Zucker 大鼠肝脏中的 IGF-I、胰岛素样生长因子结合蛋白 -3（IGFBP-3）以及 GH 受体信使核糖核酸（mRNA）的表达进行了定量分析。对 11 周龄的雄性大鼠在基础状态（完整状态）下进行研究，或在 9 周龄时进行垂体切除术后（hx）进行研究。在每种情况下，在给予一剂重组人生长激素（1.5 微克/克体重，腹腔注射）之前或之后 6 小时处死动物。此时，除了上述基因的 mRNA 表达外，还测定了体重、血糖、胰岛素血症、血清 GH（大鼠和人）以及血清 IGF-I 水平。在所有研究条件下，肥胖 Zucker 大鼠均比对照大鼠明显更重，且血糖无差异。与完整的瘦大鼠相比，严重高胰岛素血症的完整肥胖大鼠（146.9±14 对 46.3±3 微单位/毫升，P<0.001）血清 GH 显著降低（2.39±0.9 对 4.98±0.68 纳克/毫升，P<0.01），肝脏 IGF-I mRNA 和 IGFBP-3 mRNA 积累减少（IGF-Ia：79±5.9%对 100±0.9%，P<0.05；IGF-Ib：67±5.5%对 100.1±1.9%，P<0.001；IGFBP-3：54.7±2.75%对 100.5±1.55%，P<0.001），而循环 IGF-I 水平相似（1439±182 对 1516±121 纳克/毫升）。在接受 GH 治疗的完整、hx 以及 GH 治疗的 hx 动物中，当血清 GH 水平相当的情况下，肥胖大鼠中存在的高胰岛素血症和/或体重增加与肝脏 IGF-I 和 IGFBP-3 mRNA 量的增加无关。在任何实验条件下，均未发现 GH 受体/GH 结合蛋白 mRNA 存在差异。这些结果表明，在体内，肥胖状态下血清 GH/IGF-I 轴的失衡主要是由于肝脏 IGF-I 和 IGFBP-3 mRNA 表达远端的事件引起的，而这与 GH 水平密切相关。
