title: Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice.
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.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kodo
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.|Department of Pediatrics, Ayabe Municipal Hospital, Ayabe City, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Sugimoto
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Hisakazu
authors.identifier: http://orcid.org/0000-0002-3678-9918
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Itoh
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Shigehara
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Kitaro
authors.initials: K
authors.lastname: Kosaka
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000209:etiology*; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D004268:DNA-Binding Proteins; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D004921:Erythropoietin; D005346:Fibroblast Growth Factors