Abstract
Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO’s anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO’s suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT’s endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO’s improvement of obesity and glucose homeostasis can be attributed to increased iBAT thermogenic capacity and activation of BAT’s endocrine functions.
Highlights
Obesity and its comorbid diseases, including diabetes, cardiovascular disease, stroke, and some cancers, have increased dramatically and are a worldwide health problem
We demonstrate that EPO increased the mass of interscapular brown adipose tissue (BAT) and thermogenesis by enhancing the brown adipocyte differentiation pathway
EPO reduced body weight gain accompanied with reduction of white adipose tissue (WAT), ameliorated insulin resistance, and glucose intolerance in high-fat diet-induced obese mice
Summary
Obesity and its comorbid diseases, including diabetes, cardiovascular disease, stroke, and some cancers, have increased dramatically and are a worldwide health problem. Much attention has been paid to EPO because of its nonerythroid effects, including regulation of fat, glucose, and energy metabolism [2,3,4,5,6,7,8,9,10,11,12,13,14]. Previous studies that investigated the mechanism of EPO’s anti-obesity and anti-diabetes effect have focused mainly on white adipose tissue, muscle and liver [7,8,9,10,11,12,13,14,15,16]. Our study investigated the mechanism underlying EPO’s anti-obesity and anti-diabetic effects on classical brown adipose tissue (BAT)
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