title: Erythropoietin regulates POMC expression via STAT3 and potentiates leptin response.
abstract: The arcuate nucleus of the hypothalamus is essential for metabolic homeostasis and responds to leptin by producing several neuropeptides including proopiomelanocortin (POMC). We previously reported that high-dose erythropoietin (Epo) treatment in mice while increasing hematocrit reduced body weight, fat mass, and food intake and increased energy expenditure. Moreover, we showed that mice with Epo receptor (EpoR) restricted to erythroid cells (ΔEpoRE) became obese and exhibited decreased energy expenditure. Epo/EpoR signaling was found to promote hypothalamus POMC expression independently from leptin. Herein we used WT and ΔEpoRE mice and hypothalamus-derived neural culture system to study the signaling pathways activated by Epo in POMC neurons. We show that Epo stimulation activated STAT3 signaling and upregulated POMC expression in WT neural cultures. ΔEpoRE mice hypothalamus showed reduced POMC levels and lower STAT3 phosphorylation, with and without leptin treatment, compared to in vivo and ex vivo WT controls. Collectively, these data show that Epo regulates hypothalamus POMC expression via STAT3 activation, and provide a previously unrecognized link between Epo and leptin response.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: Soumyadeep
authors.initials: S
authors.lastname: Dey
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Teng
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: Mawadda
authors.initials: M
authors.lastname: Alnaeeli
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: ZhiYong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: Heather
authors.initials: H
authors.lastname: Rogers
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N319, 10 Center Dr. MSC-1822, Bethesda, MD, 20892-1822, U.S.A.
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D001066:Appetite; D049109:Cell Proliferation; D002478:Cells, Cultured; D004921:Erythropoietin / Q000502:physiology*; D007031:Hypothalamus / Q000166:cytology; D020738:Leptin / Q000502:physiology*; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells; D061251:Primary Cell Culture; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D020738:Leptin; D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004921:Erythropoietin; D011333:Pro-Opiomelanocortin
keywords: POMC; erythropoietin; gene expression; hypothalamus and neuroendocrinology