Hyporesponsiveness to glucocorticoids in mice genetically deficient for the corticosteroid binding globulin.
Corticosteroid binding globulin (CBG) is the carrier for glucocorticoids in plasma. The protein is believed to keep the steroids inactive and to regulate the amount of free hormone acting on target tissues (free hormone hypothesis). Here, we generated a mouse model genetically deficient for CBG to test the contribution of the carrier to glucocorticoid action and adrenocortical stress response. The absence of CBG resulted in a lack of corticosterone binding activity in serum and in an approximately 10-fold increase in free corticosterone levels in CBG-null mice, consistent with its role in regulation of circulating free hormone levels. Surprisingly, cbg(-/-) animals did not exhibit features seen in organisms with enhanced glucocorticoid signaling. Rather, the mice exhibited increased activity of the pituitary axis of hormonal control, normal levels of gluconeogenetic enzymes, and fatigue, as well as an aggravated response to septic shock, indicating an inability to appropriately respond to the excess free corticosterone in the absence of CBG. Thus, our data suggest an active role for CBG in bioavailability, local delivery, and/or cellular signal transduction of glucocorticoids that extends beyond a function as a mere cargo transporter.
Petersen
Helle Heibroch
HH
Max Delbrueck Center for Molecular Medicine, University Medical School, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany.
Andreassen
Thomas K
TK
Breiderhoff
Tilman
T
Bräsen
Jan Hinrich
JH
Schulz
Herbert
H
Gross
Volkmar
V
Gröne
Hermann-Josef
HJ
Nykjaer
Anders
A
Willnow
Thomas E
TE
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001835:Body Weight; D003345:Corticosterone / Q000097:blood; D005091:Exons / Q000235:genetics; D005260:Female; D005508:Food Deprivation; D015870:Gene Expression; D018390:Gene Targeting; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000166:cytology; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000166:cytology; D008297:Male; D051379:Mice; D015996:Survival Rate; D014156:Transcortin / Q000172:deficiency* / Q000378:metabolism*
D005938:Glucocorticoids; D008070:Lipopolysaccharides; D000324:Adrenocorticotropic Hormone; D014156:Transcortin; D003345:Corticosterone