Steroid receptor coactivator-1-deficient mice exhibit altered hypothalamic-pituitary-adrenal axis function

Endocrinology. 2006 Mar;147(3):1322-32. doi: 10.1210/en.2005-0751. Epub 2005 Dec 8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenal Glands / metabolism
  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Chromatin Immunoprecipitation
  • DNA Primers / chemistry
  • Dexamethasone / pharmacology
  • Female
  • Histone Acetyltransferases
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology*
  • Hypothalamus / metabolism*
  • Immunohistochemistry
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Nuclear Receptor Coactivator 1
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Pituitary Gland / metabolism*
  • Pro-Opiomelanocortin / biosynthesis
  • Protein Binding
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Restraint, Physical
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroidogenic Factor 1
  • Time Factors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcription, Genetic


  • Blood Glucose
  • DNA Primers
  • Homeodomain Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Steroidogenic Factor 1
  • Transcription Factors
  • steroidogenic factor 1, mouse
  • Pro-Opiomelanocortin
  • Dexamethasone
  • Adrenocorticotropic Hormone
  • Histone Acetyltransferases
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Phosphoenolpyruvate Carboxykinase (ATP)