Differential effects of central and peripheral administration of growth hormone (GH) and insulin-like growth factor on hypothalamic GH-releasing hormone and somatostatin gene expression in GH-deficient dwarf rats.
The roles of GH and insulin-like growth factor-I (IGF-I) in the regulation of hypothalamic GH-releasing hormone (GRH) and somatostatin (SRIH) gene expression were investigated in the GH-deficient dwarf (dw) rat, in which endogenous feedback signals are lacking. Adult male and female dw rats were treated with GH or IGF-I by systemic (sc) administration or intracerebroventricular (icv) infusion, and hypothalamic GRH and SRIH mRNA were determined by Northern blotting and densitometric analysis. Systemic sc injection of rGH (75 micrograms every 12 h for 3 days) decreased GRH mRNA levels in both sexes. However, systemic sc injection of human IGF-I (150 micrograms every 12 h for 3 days) did not affect GRH mRNA levels in either sex despite significant stimulation of body weight gain. The use of a continuous sc infusion, which normalized serum IGF-I levels, and prolongation of the treatment period to 7 days also failed to change GRH mRNA levels. SRIH mRNA was unaffected by systemic administration of either GH or IGF-I. Continuous icv infusion of GH (1 microgram/h for 7 days) decreased GRH mRNA levels in both sexes, but did not alter SRIH mRNA levels. Continuous icv infusion of IGF-I (100 ng/h for 7 days) decreased GRH mRNA in both sexes. In contrast, SRIH mRNA levels were increased in both sexes. IGF-I decreased GRH mRNA levels at icv infusion rates of 100 and 300 ng/h and stimulated SRIH mRNA levels at infusion rates of 30 and 100 ng/h. Food intake was unaffected at these infusion rates. Changes in GRH and SRIH mRNA levels in response to systemic or central GH and IGF-I administration were similar in both sexes, except that the decrease in GRH mRNA levels produced by the icv infusion of IGF-I was greater in female than in male rats. The results provide evidence for a direct inhibitory feedback effect of GH in the central nervous system on the regulation of hypothalamic GRH gene expression that is independent of peripheral IGF-I. IGF-I feedback, in contrast, appears to originate with central nervous system-derived IGF-I and exhibits a stimulatory effect on SRIH mRNA as well as an inhibitory effect on GRH mRNA.
Sato
M
M
Department of Internal Medicine, University of Cincinnati, College of Medicine, Ohio 45267.
Frohman
L A
LA
D000818:Animals; D015152:Blotting, Northern; D002552:Cerebral Ventricles / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004392:Dwarfism / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology*; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D013004:Somatostatin / Q000235:genetics*
D012333:RNA, Messenger; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone