Targeted deletion of somatotroph insulin-like growth factor-I signaling in a cell-specific knockout mouse model.
The role of IGF-I in the negative regulation of GH expression and release is demonstrated by in vitro and in vivo models; however, the targets and mechanisms of IGF-I remain unclear. We have developed a cell-specific knockout mouse in which the IGF-I receptor was ablated from the somatotroph in order to validate and characterize IGF-I negative regulation; we termed this the somatotroph IGF-I receptor knockout (SIGFRKO) mouse. The SIGFRKO mice demonstrated increased GH gene expression and secretion as well as increased serum IGF-I. Compensatory changes were noted with decreased GHRH and increased somatostatin mRNA expression levels. SIGFRKO mice had normal linear growth, but by 14 wk of age weighed significantly less than controls. Furthermore, metabolic studies revealed SIGFRKO mice had significantly less fat mass and body percent fat. These data support somatotroph IGF-I negative regulation and suggest that hypothalamic feedback limits the extent of GH release. The SIGFRKO mouse is a model delineating the mechanisms of IGF-I regulation in the hypothalamic-pituitary axis and demonstrates compensatory mechanisms that mediate growth and metabolic function in mammals.
Romero
Christopher J
CJ
Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Children's Medical and Surgical Center 4-106, 600 North Wolfe Street, Baltimore, Maryland 21208, USA. cromero5@jhmi.edu
Ng
Yewade
Y
Luque
Raul M
RM
Kineman
Rhonda D
RD
Koch
Linda
L
Bruning
Jens C
JC
Radovick
Sally
S
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics; D013004:Somatostatin / Q000235:genetics; D052683:Somatotrophs / Q000378:metabolism*
D018972:Insulin-Like Growth Factor Binding Protein 3; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D017526:Receptor, IGF Type 1; C048250:somatotropin releasing hormone receptor