Tissue-specific response of IGF-I mRNA expression to obesity-associated GH decline in the male Zucker fatty rat

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, means 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). These data support the existence of tissue-specific dependence of IGF-I mRNA on GH levels during adulthood, reflected by the diVerent behavior of IGF-I expression for each tissue in conditions of progressive decrease of GH levels.