Estrogen and tamoxifen differentially regulate beta-endorphin and cFos expression and neuronal colocalization in the arcuate nucleus of the rat.
Estrogen regulates hypothalamic gene expression, synthesis and release of the endogenous opioid peptide beta-endorphin (betaEND), although a consensus estrogen response element sequence has not been identified in the rat proopiomelanocortin (POMC) gene. POMC gene expression is also regulated by the activation of AP-1 promoter elements, which are known to be estrogen sensitive. The present studies examine whether estrogen modulates the hypothalamic POMC system through a non-classical mechanism involving AP-1 binding proteins such as cFos. Immunohistochemical double-labeling for betaEND and cFos was used and immunoreactive (-ir) populations were quantified in the arcuate nucleus and periarcuate area across time using unbiased stereological methods. Ovariectomized rats were injected with 50 microg estradiol (E2), 500 microg tamoxifen citrate (TAM) or both (E2+TAM) and were perfused 1, 2, 4 or 48 h later. E2 rapidly increased numbers of cFos-ir, betaEND-ir and doubly-labeled cells after 4 h, and the number of betaEND-ir cells remained high 48 h later, suggesting that the stimulatory effects of cFos on POMC in the hypothalamus persist after the cFos signal decays. Treatment with TAM alone did not affect the numbers of immunoreactive cells, although E2+TAM blocked the E2-mediated induction in all immunoreactive populations. Similar effects were seen at the transcriptional level. E2 increased hypothalamic POMC mRNA after 4 h, while TAM treatment or coadministration of E2+TAM did not significantly change the levels of POMC mRNA. Cellular colocalization of betaEND-ir and cFos-ir supports a possible intracellular co-regulation of these peptides by an estrogen-dependent mechanism within a subset of hypothalamic neurons. It does not, however, appear that E2 acts directly through an AP-1 site within the POMC gene.
Priest
C A
CA
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Roberts
J L
JL
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000737:chemistry*; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics*; D007150:Immunohistochemistry; D009474:Neurons / Q000737:chemistry*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology*; D001615:beta-Endorphin / Q000032:analysis / Q000235:genetics*
D004967:Estrogens; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D013629:Tamoxifen; D004958:Estradiol; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin