title: Steroid receptor coactivator-1-deficient mice exhibit altered hypothalamic-pituitary-adrenal axis function.
abstract: 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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0678, USA.
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Winnay
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000737:chemistry; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D056920:Nuclear Receptor Coactivator 1; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054339:Steroidogenic Factor 1; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D019764:Phosphoenolpyruvate Carboxykinase (ATP)