Melián E, González B, Ajo R, González N, Sánchez Franco F
Servicio de Endocrinología, CIC, Instituto de Salud Carlos III, Madrid, Spain.
J Endocrinol. 1999 Jan;160(1):49-56. doi: 10.1677/joe.0.1600049.
Diminished GH secretion is a well known association of obesity. As in obese humans, Zucker fatty rats develop a progressive GH deficiency, present at 6 weeks of age and maximal at 10 to 12 weeks. The aim of this study was to investigate the GH dependence of IGF-I gene expression in liver and extrahepatic tissues of the obese Zucker rat as a model of progressive GH reduction during adult life. Six- and 11-week-old obese Zucker rats and their lean littermates were used to compare body weight, glycemia, insulinemia, serum GH and IGF-I levels and IGF-I mRNA expression in liver, heart, aorta, kidney and skeletal muscle. In comparison with lean controls, obese Zucker rats showed at both ages comparable glycemia, severe hyperinsulinemia (mU/ml, mean+/-s.e.m.; 6 weeks 138+/-10 vs 45+/-6 P<0.001; 11 weeks 147+/-14 vs 46+/-3, P<0.001) and lower GH (ng/ml; 6 weeks 1.7+/-0.9 vs 2.7+/-1.1; 11 weeks 1.5+/-0.9 vs 4.2+/-1.2) in the presence of similar circulating IGF-I levels (ng/ml; 6 weeks 774+/-26 vs 694+/-28; 11 weeks 1439+/-182 vs 1516+/-121). Hepatic IGF-I mRNA expression was already reduced at 6 weeks of age due to a significant decrease in the IGF-Ib transcript compared with lean controls (relative units; IGF-Ia: 99+/-2% vs 100+/-5%; IGF-Ib: 69+/-10% vs 100+/-2%, P<0.05) and this reduction was more marked in 11-week-old animals when both IGF-I transcripts were significantly diminished (relative units; IGF-Ia: 80+/-6% vs 100+/-1%, P<0.05; IGF-Ib: 65+/-5% vs 100+/-2%, P<0.01). Extrahepatic tissues expressed almost exclusively the IGF-Ia transcript, the amount of which relative to controls was: (1) similar at 6 weeks and decreased at 11 weeks in kidney and skeletal muscle extracts (relative units; kidney: 6 weeks 88+/-10% vs 100+/-2%; 11 weeks 76+/-3% vs 100+/-4%, P<0.05; vastus lateralis: 6 weeks 95+/-7% vs 100+/-10%; 11 weeks 59+/-4% vs 100+/-2%, P<0.001); (2) similar at both ages in thoracic aorta (relative units; 6 weeks 121+/-6% vs 105+/-5%; 11 weeks: 91+/-14% vs 100+/-4%); and (3) increased at both ages in left ventricle extracts (relative units; 6 weeks 114+/-2% vs 99+/-9%, P<0. 05; 11 weeks 119+/-7% vs 95+/-3%, P<0.05). -specific dependence of IGF-I mRNA on GH levels during adulthood, reflected by the different behavior of IGF-I expression for each tissue in conditions of progressive decrease of GH levels.
生长激素（GH）分泌减少是肥胖症的一个众所周知的关联因素。与肥胖人类一样，Zucker肥胖大鼠会逐渐出现GH缺乏，在6周龄时出现，10至12周时最为严重。本研究的目的是调查肥胖Zucker大鼠肝脏和肝外组织中IGF-I基因表达对GH的依赖性，以此作为成年期GH逐渐减少的模型。使用6周龄和11周龄的肥胖Zucker大鼠及其瘦的同窝仔鼠来比较体重、血糖、胰岛素血症、血清GH和IGF-I水平以及肝脏、心脏、主动脉、肾脏和骨骼肌中IGF-I mRNA的表达。与瘦对照组相比，肥胖Zucker大鼠在两个年龄段的血糖水平相当，但存在严重的高胰岛素血症（mU/ml，平均值±标准误；6周龄时138±10 vs 45±6，P<0.001；11周龄时147±14 vs 46±3，P<0.001），并且GH水平较低（ng/ml；6周龄时1 .7±0.9 vs 2.7±1.1；11周龄时1.5±0.9 vs 4.2±1.2），而循环IGF-I水平相似（ng/ml；6周龄时774±26 vs 694±28；11周龄时1439±182 vs 1516±121）。由于与瘦对照组相比，IGF-Ib转录本显著减少，肝脏IGF-I mRNA表达在6周龄时就已降低（相对单位；IGF-Ia：99±2% vs 100±5%；IGF-Ib：69±10% vs 100±2%，P<0.05），并且在11周龄动物中这种降低更为明显，此时两种IGF-I转录本均显著减少（相对单位；IGF-Ia：80±6% vs 100±1%，P<0.05；IGF-Ib：65±5% vs 100±2%，P<0.01）。肝外组织几乎只表达IGF-Ia转录本，相对于对照组其含量为：（1）在肾脏和骨骼肌提取物中，6周龄时相似，11周龄时降低（相对单位；肾脏：6周龄时88±10% vs 100±2%；11周龄时76±3% vs 100±4%，P<0.05；股外侧肌：6周龄时95±7% vs 100±10%；11周龄时59±4% vs 100±2%，P<0.001）；（2）在胸主动脉中两个年龄段相似（相对单位；6周龄时121±6% vs 105±5%；11周龄时：91±14% vs 100±4%）；（3）在左心室提取物中两个年龄段均增加（相对单位；6周龄时114±2% vs 99±9%，P<0.05；11周龄时119±7% vs 95±3%，P<0.05）。成年期IGF-I mRNA对GH水平的组织特异性依赖性，表现为在GH水平逐渐降低的情况下，每个组织中IGF-I表达的不同行为。
