This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 147/3/1322    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Winnay, J. N. Articles by Hammer, G. D. Search for Related Content PubMed PubMed Citation Articles by Winnay, J. N. Articles by Hammer, G. D.

Steroid Receptor Coactivator-1-Deficient Mice Exhibit Altered Hypothalamic-Pituitary-Adrenal Axis Function

Departments of Molecular and Integrative Physiology (H.N.W., G.D.H.) and Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48109-0678; and Department of Molecular and Cellular Biology, Baylor College of Medicine (J.X., B.W.O.), Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Gary D. Hammer, 1150 West Medical Center Drive, Office 5560A MSRB II, Ann Arbor, Michigan 48109-0678. E-mail: ghammer{at}umich.edu.

Steroidogenic factor-1 (SF-1), has emerged as a critical nuclear receptor regulating development and differentiation at several levels of the hypothalamic-pituitary-steroidogenic axis. Although many coregulatory factors have been shown to physically and functionally interact with SF-1, the relative importance of these interactions in SF-1 target tissues has not been thoroughly established. In this study we assessed roles of steroid receptor coactivator-1 (SRC-1) in hypothalamic-pituitary-adrenal (HPA) axis function using SRC-1-deficient (SRC-1^–/–) mice in the absence or presence of SF-1 haploinsufficiency. Surprisingly, SRC-1 deficiency did not alter baseline HPA axis function or the acute rise in corticosterone after ACTH administration and failed to exacerbate adrenocortical dysfunction in SF-1^+/– mice. However, after exposure to paradigms of acute and chronic stress, SRC-1^–/– mice exhibited an elevation in serum corticosterone despite normal (nonsuppressed) ACTH, suggesting an increase in adrenal sensitivity as well as a concomitant defect in glucocorticoid-mediated feedback inhibition of the HPA axis. An examination of potential compensatory mechanism(s) revealed an increase in adrenal weight, selective elevation of melanocortin 2 receptor mRNA, and a coincident increase in SRC-2 and SRC-3 expression in SRC-1^–/– adrenals. A reduction in blood glucose was observed in SRC-1^–/– mice after chronic stress, consistent with a generalized state of glucocorticoid resistance. Dexamethasone suppression tests confirmed a weakened ability of glucocorticoids to 1) elevate serum glucose levels and induce hepatic phosphoenolpyruvate carboxykinase transcription and 2) suppress pituitary proopiomelanocortin transcript levels in SRC-1^–/– animals. Collectively, these data are consistent with an indispensable role for SRC-1 in mediating actions of glucocorticoids in pituitary and liver.

This article has been cited by other articles:

				S. van der Laan, S. B. Lachize, E. Vreugdenhil, E. R. de Kloet, and O. C. Meijer Nuclear Receptor Coregulators Differentially Modulate Induction and Glucocorticoid Receptor-Mediated Repression of the Corticotropin-Releasing Hormone Gene Endocrinology, February 1, 2008; 149(2): 725 - 732. [Abstract] [Full Text] [PDF]

				A. V. Patchev, D. Fischer, S. S. Wolf, M. Herkenham, F. Gotz, M. Gehin, P. Chambon, V. K. Patchev, and O. F. X. Almeida Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice FASEB J, January 1, 2007; 21(1): 231 - 238. [Abstract] [Full Text] [PDF]