title: Erythropoietin negatively regulates pituitary ACTH secretion.
abstract: Erythropoietin (Epo) and Epo-receptor (EpoR) signaling, in addition to its classical role in erythropoiesis, exhibit a protective response in non-hematopoietic tissues. Mice with EpoR expression restricted to only hematopoietic tissues (ΔEpoRE), become obese, have low energy expenditure, and are glucose intolerant and insulin resistant. In the arcuate nucleus of the mouse hypothalamus, EpoR expression co-localizes in proopiomelanocortin (POMC) neurons. In vivo high-dose Epo treatment increases hypothalamus POMC, reduces food intake and fat mass accumulation. Here we report that Epo treatment also decreases plasma concentration of the pituitary derived POMC peptide, adrenocorticotropic hormone (ACTH). Conversely, ΔEpoRE mice show reduced hypothalamus POMC and high plasma concentrations of ACTH. In the pituitary, POMC is synthesized in the corticotroph cells, and here we examine Epo effect on pituitary POMC expression using the AtT-20 mouse corticotroph pituitary cell line. In AtT-20 cells, enzyme immunoassay analysis showed that Epo inhibits ACTH secretion. This effect is post-translational, as Epo treatment did not affect POMC mRNA expression but increased intracellular levels of ACTH peptide. Moreover, Epo reduced the basal intracellular calcium (Ca(2+)) levels, suggesting an effect in the Ca(2+)-signaling pathway. In summary, our studies suggest a novel regulatory pathway of ACTH secretion in the pituitary via EpoR-signaling. The higher plasma ACTH level in ΔEpoRE mice also suggests a possible mechanism of deregulated pituitary function with loss of Epo-signaling.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Soumyadeep
authors.initials: S
authors.lastname: Dey
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Scullen
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: cnoguchi@helix.nih.gov.
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D052680:Corticotrophs / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D002118:Calcium
keywords: Adrenocorticotropic hormone; Erythropoietin; Pituitary gland