Erythropoietin regulates POMC expression via STAT3 and potentiates leptin response

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 wild-type (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 up-regulated 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.