Abstract
The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high-fat diet-induced (HFD-induced) obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive overexpression of human EPO solely in the brain (Tg21) were used to assess the neuroendocrine EPO effect without increasing the hematocrit. Male Tg21 mice resisted HFD-induced weight gain; showed lower serum adrenocorticotropic hormone, corticosterone, and C-reactive protein levels; and prevented myeloid cell recruitment to the hypothalamus compared with WT male mice. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21 male mice exhibited a lower increase in HI than WT male mice. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Female estrogen production blocked reduced weight gain and HI. Targeted deletion of EpoR gene expression in neuronal cells worsened HFD-induced glucose intolerance in both male and female mice but increased weight gain and HI in the hypothalamus in male mice only. Both male and female Tg21 mice kept on normal chow and HFD showed significantly improved glycemic control. Our data indicate that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.
Highlights
Erythropoietin (EPO), the blood hormone produced primarily in fetal liver and adult kidneys upon hypoxic stimulation, is required for erythrocyte propagation and maturation and functions through binding to its specific transmembrane receptor (EpoR) [1]
We previously found that EPO treatment in WT mice decreases body weight and fat mass by increasing energy expenditure [12, 15] and can directly activate POMC expression by inducing the STAT3 signaling pathways after subcutaneous administration of recombinant human EPO at 3000 U/kg body weight dose [13]
Endogenous physiological EPO/EpoR signaling regulates metabolism, as mice lacking the EpoR gene in nonhematopoietic tissues exhibit fat gain, glucose intolerance, and insulin resistance, resulting from low energy expenditure that is primarily due to loss of endogenous EPO response in white adipose tissue (WAT) and hypothalamus [12]
Summary
Erythropoietin (EPO), the blood hormone produced primarily in fetal liver and adult kidneys upon hypoxic stimulation, is required for erythrocyte propagation and maturation and functions through binding to its specific transmembrane receptor (EpoR) [1]. Beyond erythroid progenitor/precursor cells, EpoR expression and EPO activity has been detected in nonhematopoietic cells [4, 5], including macrophages [6, 7], osteoclasts [8], microglial cells [9], neurons [10], endothelial cells [11], and adipocytes [12]. This produces several nonerythroid physiological effects of EPO
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