Erythropoietin, a novel versatile player regulating energy metabolism beyond the erythroid system

Li Wang, Lijun Di, Constance Tom Noguchi, Li Wang, Lijun Di, Constance Tom Noguchi

Abstract

Erythropoietin (EPO), the required cytokine for promoting the proliferation and differentiation of erythroid cells to stimulate erythropoiesis, has been reported to act as a pleiotropic cytokine beyond hematopoietic system. The various activities of EPO are determined by the widespread distribution of its cell surface EPO receptor (EpoR) in multiple tissues including endothelial, neural, myoblasts, adipocytes and other cell types. EPO activity has been linked to angiogenesis, neuroprotection, cardioprotection, stress protection, anti-inflammation and especially the energy metabolism regulation that is recently revealed. The investigations of EPO activity in animals and the expression analysis of EpoR provide more insights on the potential of EPO in regulating energy metabolism and homeostasis. The findings of crosstalk between EPO and some important energy sensors and the regulation of EPO in the cellular respiration and mitochondrial function further provide molecular mechanisms for EPO activity in metabolic activity regulation. In this review, we will summarize the roles of EPO in energy metabolism regulation and the activity of EPO in tissues that are tightly associated with energy metabolism. We will also discuss the effects of EPO in regulating oxidative metabolism and mitochondrial function, the interactions between EPO and important energy regulation factors, and the protective role of EPO from stresses that are related to metabolism, providing a brief overview of previously less appreciated EPO biological function in energy metabolism and homeostasis.

Keywords: Erythropoietin; erythroid system; pleiotropic cytokine.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The pleiotropic activity of EPO in multiple tissues beyond hematopoietic tissues. EpoR expression was detected on erythroid cells, adipocytes, immune system cells such as macrophages, pancreatic beta cells, skeletal muscle myoblasts, neural cells, hypothalamus neurons and endothelial cells. The primary function of the EPO/EpoR system is to stimulate erythroid progenitor cell proliferation, survival and differentiation to provide adequate red blood cells. The well documented non hematopoietic effect of EPO is cytoprotection including cardioprotection and neuroprotection, which are also contributed by the EPO activity in endothelial cells such as angiogenesis. The newly revealed biological activity of EPO includes prevention from obesity and metabolic disorders and improvement of insulin resistance and glucose intolerance. These effects are contributed by EPO promoted energy metabolism in adipocytes, anti-inflammation in macrophages, antiapoptosis in pancreatic beta cells, and the central control of energy intake in hypothalamus neurons.
Figure 2
Figure 2
The crosstalk between EPO and important energy sensors. EPO regulated AMPK activity is involved in adipocyte energy metabolism, angiogenesis, cardioprotection and skeletal muscle fiber type specification. EPO production can be regulated by Sirt1 via HIF-2 under hypoxia condition. On the other hand, EPO modulates NAD+/NADH level and ratio to regulate Sirt1 activity, which contributes to energy metabolism in adipocytes, inhibition of skeletal muscle differentiation, and brain protection from injury and mitochondrial function. EPO regulated AMPK activity may regulate Sirt1 activity via modulating NAD+/NADH ratio. As the downstream target of Sirt1and AMPK, PGC-1α may also be directly regulated by EPO or via regulating Sirt1 and AMPK activity to promote adipocyte oxidative metabolism, cardioprotection, brain protection, mitochondrial biogenesis and function and muscle fiber type specification.

References

    1. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995;83:59–67.
    1. Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. The Journal of biological chemistry. 1977;252:5558–64.
    1. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC. et al. Cloning and expression of the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America. 1985;82:7580–4.
    1. Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A. et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature. 1985;313:806–10.
    1. Noguchi CT, Wang L, Rogers HM, Teng R, Jia Y. Survival and proliferative roles of erythropoietin beyond the erythroid lineage. Expert reviews in molecular medicine. 2008;10:e36.. doi:10.1017/S1462399408000860.
    1. Teng R, Gavrilova O, Suzuki N, Chanturiya T, Schimel D, Hugendubler L. et al. Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production. Nature communications. 2011;2:520.. doi:10.1038/ncomms1526.
    1. Choi D, Schroer SA, Lu SY, Wang L, Wu X, Liu Y. et al. Erythropoietin protects against diabetes through direct effects on pancreatic beta cells. The Journal of experimental medicine. 2010;207:2831–42. doi:10.1084/jem.20100665.
    1. Yu X, Shacka JJ, Eells JB, Suarez-Quian C, Przygodzki RM, Beleslin-Cokic B. et al. Erythropoietin receptor signalling is required for normal brain development. Development. 2002;129:505–16.
    1. Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999;126:3597–605.
    1. Kertesz N, Wu J, Chen TH, Sucov HM, Wu H. The role of erythropoietin in regulating angiogenesis. Developmental biology. 2004;276:101–10. doi:10.1016/j.ydbio.2004.08.025.
    1. Wang L, Teng R, Di L, Rogers H, Wu H, Kopp JB. et al. PPARalpha and Sirt1 mediate erythropoietin action in increasing metabolic activity and browning of white adipocytes to protect against obesity and metabolic disorders. Diabetes. 2013;62:4122–31. doi:10.2337/db13-0518.
    1. Wang L, Jia Y, Rogers H, Suzuki N, Gassmann M, Wang Q. et al. Erythropoietin contributes to slow oxidative muscle fiber specification via PGC-1alpha and AMPK activation. The international journal of biochemistry & cell biology. 2013;45:1155–64. doi:10.1016/j.biocel.2013.03.007.
    1. Carraway MS, Suliman HB, Jones WS, Chen CW, Babiker A, Piantadosi CA. Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. Circulation research. 2010;106:1722–30. doi:10.1161/CIRCRESAHA.109.214353.
    1. Wang L, Jia Y, Rogers H, Wu YP, Huang S, Noguchi CT. GATA-binding protein 4 (GATA-4) and T-cell acute leukemia 1 (TAL1) regulate myogenic differentiation and erythropoietin response via cross-talk with Sirtuin1 (Sirt1) The Journal of biological chemistry. 2012;287:30157–69. doi:10.1074/jbc.M112.376640.
    1. Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin. The Journal of biological chemistry. 1986;261:3116–21.
    1. Quelle FW, Wang D, Nosaka T, Thierfelder WE, Stravopodis D, Weinstein Y. et al. Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Molecular and cellular biology. 1996;16:1622–31.
    1. Zhao W, Kitidis C, Fleming MD, Lodish HF, Ghaffari S. Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway. Blood. 2006;107:907–15. doi:10.1182/blood-2005-06-2516.
    1. Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood. 1988;71:524–7.
    1. Maxwell PH, Osmond MK, Pugh CW, Heryet A, Nicholls LG, Tan CC. et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney international. 1993;44:1149–62.
    1. Obara N, Suzuki N, Kim K, Nagasawa T, Imagawa S, Yamamoto M. Repression via the GATA box is essential for tissue-specific erythropoietin gene expression. Blood. 2008;111:5223–32. doi:10.1182/blood-2007-10-115857.
    1. Tan CC, Eckardt KU, Ratcliffe PJ. Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney international. 1991;40:69–76.
    1. Fandrey J, Bunn HF. In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood. 1993;81:617–23.
    1. Semenza GL, Koury ST, Nejfelt MK, Gearhart JD, Antonarakis SE. Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America. 1991;88:8725–9.
    1. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America. 1991;88:5680–4.
    1. Kochling J, Curtin PT, Madan A. Regulation of human erythropoietin gene induction by upstream flanking sequences in transgenic mice. British journal of haematology. 1998;103:960–8.
    1. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R. A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. The Journal of biological chemistry. 1994;269:19488–93.
    1. Marti HH, Gassmann M, Wenger RH, Kvietikova I, Morganti-Kossmann MC, Kossmann T. et al. Detection of erythropoietin in human liquor: intrinsic erythropoietin production in the brain. Kidney international. 1997;51:416–8.
    1. Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I. et al. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia. 2000;30:271–8.
    1. Chavez JC, Baranova O, Lin J, Pichiule P. The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2006;26:9471–81. doi:10.1523/JNEUROSCI.2838-06.2006.
    1. Juul SE, Anderson DK, Li Y, Christensen RD. Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatric research. 1998;43:40–9. doi:10.1203/00006450-199804001-00243.
    1. Juul SE, Yachnis AT, Christensen RD. Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early human development. 1998;52:235–49.
    1. Chikuma M, Masuda S, Kobayashi T, Nagao M, Sasaki R. Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. American journal of physiology Endocrinology and metabolism. 2000;279:E1242–8.
    1. Yasuda Y, Fujita Y, Musha T, Tanaka H, Shiokawa S, Nakamatsu K. et al. Expression of erythropoietin in human female reproductive organs. Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia. 2001;106:215–22.
    1. Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, Sasaki R. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. The Journal of biological chemistry. 1998;273:25381–7.
    1. Mukundan H, Resta TC, Kanagy NL. 17Beta-estradiol decreases hypoxic induction of erythropoietin gene expression. American journal of physiology Regulatory, integrative and comparative physiology. 2002;283:R496–504. doi:10.1152/ajpregu.00573.2001.
    1. Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT. et al. Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. The Journal of biological chemistry. 2000;275:39754–61. doi:10.1074/jbc.M004999200.
    1. Jia Y, Suzuki N, Yamamoto M, Gassmann M, Noguchi CT. Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2012;26:2847–58. doi:10.1096/fj.11-196618.
    1. Rundqvist H, Rullman E, Sundberg CJ, Fischer H, Eisleitner K, Stahlberg M. et al. Activation of the erythropoietin receptor in human skeletal muscle. European journal of endocrinology / European Federation of Endocrine Societies. 2009;161:427–34. doi:10.1530/EJE-09-0342.
    1. Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991;77:2583–90.
    1. Chiba T, Ikawa Y, Todokoro K. GATA-1 transactivates erythropoietin receptor gene, and erythropoietin receptor-mediated signals enhance GATA-1 gene expression. Nucleic acids research. 1991;19:3843–8.
    1. Fujiwara T, O'Geen H, Keles S, Blahnik K, Linnemann AK, Kang YA. et al. Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy. Molecular cell. 2009;36:667–81. doi:10.1016/j.molcel.2009.11.001.
    1. Chin K, Oda N, Shen K, Noguchi CT. Regulation of transcription of the human erythropoietin receptor gene by proteins binding to GATA-1 and Sp1 motifs. Nucleic acids research. 1995;23:3041–9.
    1. Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1990;87:5978–82.
    1. Anagnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N. et al. Erythropoietin receptor mRNA expression in human endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1994;91:3974–8.
    1. Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 2004;104:2073–80. doi:10.1182/blood-2004-02-0744.
    1. Beleslin-Cokic BB, Cokic VP, Wang L, Piknova B, Teng R, Schechter AN. et al. Erythropoietin and hypoxia increase erythropoietin receptor and nitric oxide levels in lung microvascular endothelial cells. Cytokine. 2011;54:129–35. doi:10.1016/j.cyto.2011.01.015.
    1. Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ. et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. European heart journal. 2007;28:2018–27. doi:10.1093/eurheartj/ehm177.
    1. Teng R, Calvert JW, Sibmooh N, Piknova B, Suzuki N, Sun J. et al. Acute erythropoietin cardioprotection is mediated by endothelial response. Basic research in cardiology. 2011;106:343–54. doi:10.1007/s00395-011-0158-z.
    1. Zhande R, Karsan A. Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-kappaB-independent upregulation of Bcl-xL. American journal of physiology Heart and circulatory physiology. 2007;292:H2467–74. doi:10.1152/ajpheart.00649.2006.
    1. Tsai PT, Ohab JJ, Kertesz N, Groszer M, Matter C, Gao J. et al. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2006;26:1269–74. doi:10.1523/JNEUROSCI.4480-05.2006.
    1. Liu C, Shen K, Liu Z, Noguchi CT. Regulated human erythropoietin receptor expression in mouse brain. The Journal of biological chemistry. 1997;272:32395–400.
    1. Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V. et al. Erythropoietin gene expression in human, monkey and murine brain. The European journal of neuroscience. 1996;8:666–76.
    1. Digicaylioglu M, Bichet S, Marti HH, Wenger RH, Rivas LA, Bauer C. et al. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proceedings of the National Academy of Sciences of the United States of America. 1995;92:3717–20.
    1. Nagai A, Nakagawa E, Choi HB, Hatori K, Kobayashi S, Kim SU. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. Journal of neuropathology and experimental neurology. 2001;60:386–92.
    1. Pan Y, Shu JL, Gu HF, Zhou DC, Liu XL, Qiao QY. et al. Erythropoietin improves insulin resistance via the regulation of its receptor-mediated signaling pathways in 3T3L1 adipocytes. Molecular and cellular endocrinology. 2013;367:116–23. doi:10.1016/j.mce.2012.12.027.
    1. Mikolas E, Cseh J, Pap M, Szijarto IA, Balogh A, Laczy B. et al. Effects of erythropoietin on glucose metabolism. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2012;44:279–85. doi:10.1055/s-0032-1301901.
    1. Hojman P, Brolin C, Gissel H, Brandt C, Zerahn B, Pedersen BK. et al. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles. PloS one. 2009;4:e5894.. doi:10.1371/journal.pone.0005894.
    1. Katz O, Stuible M, Golishevski N, Lifshitz L, Tremblay ML, Gassmann M. et al. Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models. The Journal of endocrinology. 2010;205:87–95. doi:10.1677/JOE-09-0425.
    1. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. American journal of physiology Endocrinology and metabolism. 2007;293:E444–52. doi:10.1152/ajpendo.00691.2006.
    1. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB. et al. Identification and importance of brown adipose tissue in adult humans. The New England journal of medicine. 2009;360:1509–17. doi:10.1056/NEJMoa0810780.
    1. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988;37:1163–7.
    1. Surwit RS, Feinglos MN, Rodin J, Sutherland A, Petro AE, Opara EC. et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism: clinical and experimental. 1995;44:645–51.
    1. Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A. et al. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia. 2005;48:675–86. doi:10.1007/s00125-005-1680-z.
    1. Luk CT, Shi SY, Choi D, Cai EP, Schroer SA, Woo M. In vivo knockdown of adipocyte erythropoietin receptor does not alter glucose or energy homeostasis. Endocrinology. 2013;154:3652–9. doi:10.1210/en.2013-1113.
    1. Fenjves ES, Ochoa MS, Cabrera O, Mendez AJ, Kenyon NS, Inverardi L. et al. Human, nonhuman primate, and rat pancreatic islets express erythropoietin receptors. Transplantation. 2003;75:1356–60. doi:10.1097/.
    1. Fenjves ES, Ochoa MS, Gay-Rabinstein C, Molano RD, Pileggi A, Mendez AJ. et al. Adenoviral gene transfer of erythropoietin confers cytoprotection to isolated pancreatic islets. Transplantation. 2004;77:13–8. doi:10.1097/01.TP.0000110422.27977.26.
    1. Bianchi R, Buyukakilli B, Brines M, Savino C, Cavaletti G, Oggioni N. et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:823–8. doi:10.1073/pnas.0307823100.
    1. Shuai H, Zhang J, Zhang J, Xie J, Zhang M, Yu Y. et al. Erythropoietin protects pancreatic beta-cell line NIT-1 cells against cytokine-induced apoptosis via phosphatidylinositol 3-kinase/Akt signaling. Endocrine research. 2011;36:25–34. doi:10.3109/07435800.2010.534753.
    1. Jia Y, Warin R, Yu X, Epstein R, Noguchi CT. Erythropoietin signaling promotes transplanted progenitor cell survival. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2009;23:3089–99. doi:10.1096/fj.09-130237.
    1. Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P. et al. Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity. European journal of applied physiology. 2007;101:481–6. doi:10.1007/s00421-007-0522-8.
    1. Plenge U, Belhage B, Guadalupe-Grau A, Andersen PR, Lundby C, Dela F. et al. Erythropoietin treatment enhances muscle mitochondrial capacity in humans. Frontiers in physiology. 2012;3:50.. doi:10.3389/fphys.2012.00050.
    1. Zierath JR, Hawley JA. Skeletal muscle fiber type: influence on contractile and metabolic properties. PLoS biology. 2004;2:e348.. doi:10.1371/journal.pbio.0020348.
    1. Gaster M, Poulsen P, Handberg A, Schroder HD, Beck-Nielsen H. Direct evidence of fiber type-dependent GLUT-4 expression in human skeletal muscle. American journal of physiology Endocrinology and metabolism. 2000;278:E910–6.
    1. Gaster M, Staehr P, Beck-Nielsen H, Schroder HD, Handberg A. GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes. 2001;50:1324–9.
    1. Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nature reviews Endocrinology. 2012;8:92–103. doi:10.1038/nrendo.2011.138.
    1. Sleigh A, Raymond-Barker P, Thackray K, Porter D, Hatunic M, Vottero A. et al. Mitochondrial dysfunction in patients with primary congenital insulin resistance. The Journal of clinical investigation. 2011;121:2457–61. doi:10.1172/JCI46405.
    1. Hoeks J, van Herpen NA, Mensink M, Moonen-Kornips E, van Beurden D, Hesselink MK. et al. Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance. Diabetes. 2010;59:2117–25. doi:10.2337/db10-0519.
    1. Cayla JL, Maire P, Duvallet A, Wahrmann JP. Erythropoietin induces a shift of muscle phenotype from fast glycolytic to slow oxidative. International journal of sports medicine. 2008;29:460–5. doi:10.1055/s-2007-965359.
    1. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O. et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002;418:797–801. doi:10.1038/nature00904.
    1. Ljubicic V, Miura P, Burt M, Boudreault L, Khogali S, Lunde JA. et al. Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle. Human molecular genetics. 2011;20:3478–93. doi:10.1093/hmg/ddr265.
    1. Suzuki N, Ohneda O, Takahashi S, Higuchi M, Mukai HY, Nakahata T. et al. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood. 2002;100:2279–88. doi:10.1182/blood-2002-01-0124.
    1. Salisch S, Klar M, Thurisch B, Bungert J, Dame C. Gata4 and Sp1 regulate expression of the erythropoietin receptor in cardiomyocytes. Journal of cellular and molecular medicine. 2011;15:1963–72. doi:10.1111/j.1582-4934.2010.01193.x.
    1. Wright GL, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy MO. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2004;18:1031–3. doi:10.1096/fj.03-1289fje.
    1. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB. et al. A novel protective effect of erythropoietin in the infarcted heart. The Journal of clinical investigation. 2003;112:999–1007. doi:10.1172/JCI18200.
    1. Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P. et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:4802–6. doi:10.1073/pnas.0630444100.
    1. Rui T, Feng Q, Lei M, Peng T, Zhang J, Xu M. et al. Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1. Cardiovascular research. 2005;65:719–27. doi:10.1016/j.cardiores.2004.11.019.
    1. Burger D, Lei M, Geoghegan-Morphet N, Lu X, Xenocostas A, Feng Q. Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase. Cardiovascular research. 2006;72:51–9. doi:10.1016/j.cardiores.2006.06.026.
    1. Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C, Wagner K. et al. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:11609–13. doi:10.1073/pnas.97.21.11609.
    1. Shen Y, Wang Y, Li D, Wang C, Xu B, Dong G. et al. Recombinant human erythropoietin pretreatment attenuates heart ischemia-reperfusion injury in rats by suppressing the systemic inflammatory response. Transplantation proceedings. 2010;42:1595–7. doi:10.1016/j.transproceed.2009.11.050.
    1. Liu X, Shen J, Jin Y, Duan M, Xu J. Recombinant human erythropoietin (rhEPO) preconditioning on nuclear factor-kappa B (NF-kB) activation & proinflammatory cytokines induced by myocardial ischaemia-reperfusion. The Indian journal of medical research. 2006;124:343–54.
    1. Yamada M, Miyakawa T, Duttaroy A, Yamanaka A, Moriguchi T, Makita R. et al. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature. 2001;410:207–12. doi:10.1038/35065604.
    1. Belgardt BF, Husch A, Rother E, Ernst MB, Wunderlich FT, Hampel B. et al. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell metabolism. 2008;7:291–301. doi:10.1016/j.cmet.2008.01.006.
    1. Mesaros A, Koralov SB, Rother E, Wunderlich FT, Ernst MB, Barsh GS. et al. Activation of Stat3 signaling in AgRP neurons promotes locomotor activity. Cell metabolism. 2008;7:236–48. doi:10.1016/j.cmet.2008.01.007.
    1. Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 1997;76:105–16.
    1. Lewczuk P, Hasselblatt M, Kamrowski-Kruck H, Heyer A, Unzicker C, Siren AL. et al. Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport. 2000;11:3485–8.
    1. Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P. et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:4044–9. doi:10.1073/pnas.051606598.
    1. Sola A, Rogido M, Lee BH, Genetta T, Wen TC. Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. Pediatric research. 2005;57:481–7. doi:10.1203/01.PDR.0000155760.88664.06.
    1. Kilic E, Kilic U, Soliz J, Bassetti CL, Gassmann M, Hermann DM. Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2005;19:2026–8. doi:10.1096/fj.05-3941fje.
    1. Suzuki N, Ohneda O, Takahashi S, Higuchi M, Mukai HY, Nakahata T. et al. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood. 2002;100:2279–88. doi:10.1182/blood-2002-01-0124.
    1. Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S. et al. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochemical and biophysical research communications. 1998;253:26–32. doi:10.1006/bbrc.1998.9748.
    1. Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard P. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. 2002;22:393–403. doi:10.1097/00004647-200204000-00003.
    1. Mohamad O, Chen D, Zhang L, Hofmann C, Wei L, Yu SP. Erythropoietin reduces neuronal cell death and hyperalgesia induced by peripheral inflammatory pain in neonatal rats. Molecular pain. 2011;7:51.. doi:10.1186/1744-8069-7-51.
    1. Wang L, Chopp M, Gregg SR, Zhang RL, Teng H, Jiang A. et al. Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. 2008;28:1361–8. doi:10.1038/jcbfm.2008.32.
    1. Chen ZY, Wang L, Asavaritkrai P, Noguchi CT. Up-regulation of erythropoietin receptor by nitric oxide mediates hypoxia preconditioning. Journal of neuroscience research. 2010;88:3180–8. doi:10.1002/jnr.22473.
    1. Penna F, Busquets S, Toledo M, Pin F, Massa D, Lopez-Soriano FJ. et al. Erythropoietin administration partially prevents adipose tissue loss in experimental cancer cachexia models. Journal of lipid research. 2013;54:3045–51. doi:10.1194/jlr.M038406.
    1. Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B, Epoetin Alfa Study G. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2001;19:2865–74.
    1. Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M. et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. Journal of the National Cancer Institute. 2002;94:1211–20.
    1. Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E. et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. British journal of haematology. 2003;122:394–403.
    1. Ribatti D, Marzullo A, Gentile A, Longo V, Nico B, Vacca A. et al. Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma. Histopathology. 2007;50:591–6. doi:10.1111/j.1365-2559.2007.02654.x.
    1. Wiesener MS, Munchenhagen P, Glaser M, Sobottka BA, Knaup KX, Jozefowski K. et al. Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia. International journal of cancer Journal international du cancer. 2007;121:2434–42. doi:10.1002/ijc.22961.
    1. Nico B, Annese T, Guidolin D, Finato N, Crivellato E, Ribatti D. Epo is involved in angiogenesis in human glioma. Journal of neuro-oncology. 2011;102:51–8. doi:10.1007/s11060-010-0294-6.
    1. Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B. et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–60. doi:10.1016/S0140-6736(03)14567-9.
    1. Leyland-Jones B, Investigators B, Study G. Breast cancer trial with erythropoietin terminated unexpectedly. The lancet oncology. 2003;4:459–60.
    1. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J. et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373:1532–42. doi:10.1016/S0140-6736(09)60502-X.
    1. Hedley BD, Allan AL, Xenocostas A. The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011;17:6373–80. doi:10.1158/1078-0432.CCR-10-2577.
    1. Janmaat ML, Heerkens JL, de Bruin AM, Klous A, de Waard V, de Vries CJ. Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood. 2010;115:1453–60. doi:10.1182/blood-2009-07-230870.
    1. Mak RH. Effect of recombinant human erythropoietin on insulin, amino acid, and lipid metabolism in uremia. The Journal of pediatrics. 1996;129:97–104.
    1. Allegra V, Mengozzi G, Martimbianco L, Vasile A. Early and late effects of erythropoietin on glucose metabolism in maintenance hemodialysis patients. American journal of nephrology. 1996;16:304–8.
    1. Bofill C, Joven J, Bages J, Vilella E, Sans T, Cavalle P. et al. Response to repeated phlebotomies in patients with non-insulin-dependent diabetes mellitus. Metabolism: clinical and experimental. 1994;43:614–20.
    1. Tuzcu A, Bahceci M, Yilmaz E, Bahceci S, Tuzcu S. The comparison of insulin sensitivity in non-diabetic hemodialysis patients treated with and without recombinant human erythropoietin. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2004;36:716–20. doi:10.1055/s-2004-826021.
    1. Prata MM, Madeira C, Vicente O, Miguel MJ. Lipid profile in haemodialysis patients treated with recombinant human erythropoietin. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 1998;13:2345–7.
    1. Lundby C, Robach P, Boushel R, Thomsen JJ, Rasmussen P, Koskolou M. et al. Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport? Journal of applied physiology. 2008;105:581–7. doi:10.1152/japplphysiol.90484.2008.
    1. Christensen B, Vendelbo MH, Krusenstjerna-Hafstrøm T, Madsen M, Pedersen SB, Jessen N. et al. Erythropoietin administration acutely stimulates resting energy expenditure in healthy young men. Journal of applied physiology (Bethesda, Md: 1985) 2012;112:1114–21. doi:10.1152/japplphysiol.01391.2011.
    1. McMahon LP, Johns JA, McKenzie A, Austin M, Fowler R, Dawborn JK. Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 1992;7:1199–206.
    1. Clyne N, Jogestrand T. Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron. 1992;60:390–6.
    1. Fagher B, Thysell H, Monti M. Effect of erythropoietin on muscle metabolic rate, as measured by direct microcalorimetry, and ATP in hemodialysis patients. Nephron. 1994;67:167–71.
    1. Fagher B, Thysell H, Monti M. Effect of erythropoietin on muscle metabolic rate, as measured by direct microcalorimetry, and ATP in hemodialysis patients. Nephron. 1994;67:167–71.
    1. Borissova AM, Djambazova A, Todorov K, Dakovska L, Tankova T, Kirilov G. Effect of erythropoietin on the metabolic state and peripheral insulin sensitivity in diabetic patients on haemodialysis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 1993;8:93.
    1. Chagnac A, Weinstein T, Zevin D, Korzets A, Hirsh J, Gafter U. et al. Effects of erythropoietin on glucose tolerance in hemodialysis patients. Clinical nephrology. 1994;42:398–400.
    1. Lin CS, Lim SK, D'Agati V, Costantini F. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes & development. 1996;10:154–64.
    1. Menne J, Park JK, Shushakova N, Mengel M, Meier M, Fliser D. The continuous erythropoietin receptor activator affects different pathways of diabetic renal injury. Journal of the American Society of Nephrology: JASN. 2007;18:2046–53. doi:10.1681/ASN.2006070699.
    1. Shushakova N, Park JK, Menne J, Fliser D. Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouse. European journal of clinical investigation. 2009;39:755–60. doi:10.1111/j.1365-2362.2009.02165.x.
    1. Bunn HF. Erythropoietin. Cold Spring Harbor perspectives in medicine. 2013;3:a011619.. doi:10.1101/cshperspect.a011619.
    1. Bournat JC, Brown CW. Mitochondrial dysfunction in obesity. Current opinion in endocrinology, diabetes, and obesity. 2010;17:446–52. doi:10.1097/MED.0b013e32833c3026.
    1. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7. doi:10.1126/science.1104343.
    1. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140–2. doi:10.1126/science.1082889.
    1. Qin C, Zhou S, Xiao Y, Chen L. Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway. Cell biology international. 2014;38:335–42. doi:10.1002/cbin.10205.
    1. Chong ZZ, Kang JQ, Maiese K. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation. 2002;106:2973–9.
    1. Li AC, Glass CK. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. Journal of lipid research. 2004;45:2161–73. doi:10.1194/jlr.R400010-JLR200.
    1. Christensen B, Vendelbo MH, Krusenstjerna-Hafstrom T, Madsen M, Pedersen SB, Jessen N. et al. Erythropoietin administration acutely stimulates resting energy expenditure in healthy young men. Journal of applied physiology. 2012;112:1114–21. doi:10.1152/japplphysiol.01391.2011.
    1. St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB. et al. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. The Journal of biological chemistry. 2003;278:26597–603. doi:10.1074/jbc.M301850200.
    1. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. The Journal of clinical investigation. 2000;106:847–56. doi:10.1172/JCI10268.
    1. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98:115–24. doi:10.1016/S0092-8674(00)80611-X.
    1. Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Current opinion in lipidology. 2009;20:98–105. doi:10.1097/MOL.0b013e328328d0a4.
    1. Chau MD, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:12553–8. doi:10.1073/pnas.1006962107.
    1. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423:550–5. doi:10.1038/nature01667.
    1. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413:131–8. doi:10.1038/35093050.
    1. Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Molecular and cellular biology. 2000;20:1868–76.
    1. Lage R, Dieguez C, Vidal-Puig A, Lopez M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med. 2008;14:539–49.
    1. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774–85.
    1. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–8. doi:10.1038/nature03354.
    1. Yuen CM, Sun CK, Lin YC, Chang LT, Kao YH, Yen CH. et al. Combination of cyclosporine and erythropoietin improves brain infarct size and neurological function in rats after ischemic stroke. Journal of translational medicine. 2011;9:141.. doi:10.1186/1479-5876-9-141.
    1. Menard R. Medicine: knockout malaria vaccine? Nature. 2005;433:113–4. doi:10.1038/433113a.
    1. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800. doi:10.1038/35001622.
    1. Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:5807–11. doi:10.1073/pnas.110148297.
    1. Smith JS, Brachmann CB, Celic I, Kenna MA, Muhammad S, Starai VJ. et al. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:6658–63.
    1. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006;126:941–54. doi:10.1016/j.cell.2006.06.057.
    1. Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Meneur C. et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell metabolism. 2005;2:105–17. doi:10.1016/j.cmet.2005.07.001.
    1. Kitamura YI, Kitamura T, Kruse JP, Raum JC, Stein R, Gu W. et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell metabolism. 2005;2:153–63. doi:10.1016/j.cmet.2005.08.004.
    1. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458:1056–60. doi:10.1038/nature07813.
    1. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004;429:771–6. doi:10.1038/nature02583.
    1. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–42. doi:10.1038/nature05354.
    1. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127:1109–22. doi:10.1016/j.cell.2006.11.013.
    1. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712–6. doi:10.1038/nature06261.
    1. Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:4401–6. doi:10.1073/pnas.0610615104.
    1. Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J. et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS biology. 2006;4:e31.. doi:10.1371/journal.pbio.0040031.
    1. Cakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA. Hypothalamic Sirt1 regulates food intake in a rodent model system. PloS one. 2009;4:e8322.. doi:10.1371/journal.pone.0008322.
    1. Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R. et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell metabolism. 2010;12:78–87. doi:10.1016/j.cmet.2010.05.010.
    1. Ramadori G, Gautron L, Fujikawa T, Vianna CR, Elmquist JK, Coppari R. Central administration of resveratrol improves diet-induced diabetes. Endocrinology. 2009;150:5326–33. doi:10.1210/en.2009-0528.
    1. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R. et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. The EMBO journal. 2007;26:1913–23. doi:10.1038/sj.emboj.7601633.
    1. Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD. et al. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 2009;324:1289–93. doi:10.1126/science.1169956.
    1. Hou J, Wang S, Shang YC, Chong ZZ, Maiese K. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Current neurovascular research. 2011;8:220–35.
    1. Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocrine reviews. 2010;31:194–223. doi:10.1210/er.2009-0026.
    1. Houtkooper RH, Auwerx J. Exploring the therapeutic space around NAD+ The Journal of cell biology. 2012;199:205–9. doi:10.1083/jcb.201207019.
    1. Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y. et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism. 2012;15:838–47. doi:10.1016/j.cmet.2012.04.022.
    1. Hwang JH, Kim DW, Jo EJ, Kim YK, Jo YS, Park JH. et al. Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice. Diabetes. 2009;58:965–74.
    1. Kao R, Xenocostas A, Rui T, Yu P, Huang W, Rose J. et al. Erythropoietin improves skeletal muscle microcirculation and tissue bioenergetics in a mouse sepsis model. Critical care. 2007;11:R58.. doi:10.1186/cc5920.
    1. Di LJ, Fernandez AG, De Siervi A, Longo DL, Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat Struct Mol Biol. 2010;17:1406–13.
    1. Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy. Diabetes. 2004;53:2931–8.
    1. Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y. et al. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Molecular cell. 2003;12:51–62.
    1. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E. et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134:405–15.
    1. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 2006;3:403–16.
    1. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100:328–41.
    1. Giri S, Rattan R, Haq E, Khan M, Yasmin R, Won JS. et al. AICAR inhibits adipocyte differentiation in 3T3L1 and restores metabolic alterations in diet-induced obesity mice model. Nutr Metab (Lond) 2006;3:31.
    1. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.
    1. Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem. 2002;277:25226–32.
    1. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961–7.
    1. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC. et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8.
    1. Sun L, Xie H, Mori MA, Alexander R, Yuan B, Hattangadi SM. et al. Mir193b-365 is essential for brown fat differentiation. Nat Cell Biol. 2011;13:958–65.
    1. Ahmadian M, Abbott MJ, Tang T, Hudak CS, Kim Y, Bruss M. et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 2011;13:739–48.
    1. Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 2008;22:1397–409.
    1. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121:96–105.
    1. Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. The Journal of biological chemistry. 2008;283:27628–35. doi:10.1074/jbc.M805711200.
    1. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y. et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. The Journal of biological chemistry. 2008;283:20015–26. doi:10.1074/jbc.M802187200.
    1. Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell metabolism. 2010;11:213–9. doi:10.1016/j.cmet.2010.02.006.
    1. Su KH, Yu YB, Hou HH, Zhao JF, Kou YR, Cheng LC. et al. AMP-activated protein kinase mediates erythropoietin-induced activation of endothelial nitric oxide synthase. Journal of cellular physiology. 2012;227:3053–62. doi:10.1002/jcp.23052.
    1. Li XJ, Wang XW, Du YJ. Protective effects of erythropoietin on myocardial infarction in rats: the role of AMP-activated protein kinase signaling pathway. The American journal of the medical sciences. 2011;342:153–9. doi:10.1097/MAJ.0b013e318210041d.
    1. Keijer J, van Schothorst EM. Adipose tissue failure and mitochondria as a possible target for improvement by bioactive food components. Current opinion in lipidology. 2008;19:4–10. doi:10.1097/MOL.0b013e3282f39f95.
    1. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI. et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11:407–20.
    1. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.
    1. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–61. doi:10.1172/JCI21625.
    1. Li Y, Takemura G, Okada H, Miyata S, Maruyama R, Li L. et al. Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure. Cardiovasc Res. 2006;71:684–94. doi:10.1016/j.cardiores.2006.06.003.
    1. Kim KH, Oudit GY, Backx PH. Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. The Journal of pharmacology and experimental therapeutics. 2008;324:160–9. doi:10.1124/jpet.107.125773.
    1. Amer J, Dana M, Fibach E. The antioxidant effect of erythropoietin on thalassemic blood cells. Anemia. 2010;2010:978710.. doi:10.1155/2010/978710.
    1. Shurtz-Swirski R, Kristal B, Shasha SM, Shapiro G, Geron R, Sela S. Interaction between erythropoietin and peripheral polymorphonuclear leukocytes in continuous ambulatory dialysis patients. Nephron. 2002;91:759–61. doi:65044.
    1. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20. doi:10.1038/414813a.
    1. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y. et al. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997;99:144–50. doi:10.1172/JCI119126.
    1. Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid. Diabetes. 2001;50:404–10.
    1. Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N. Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes. 1998;47:1562–9.
    1. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293:E1118–28.
    1. Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M. et al. Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes. 2009;58:95–103. doi:10.2337/db08-0457.
    1. Dang J, Jia R, Tu Y, Xiao S, Ding G. Erythropoietin prevents reactive oxygen species generation and renal tubular cell apoptosis at high glucose level. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2010;64:681–5. doi:10.1016/j.biopha.2010.06.011.
    1. Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A. et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. The Journal of experimental medicine. 2003;198:971–5. doi:10.1084/jem.20021067.
    1. Zhang J, Li Y, Cui Y, Chen J, Lu M, Elias SB. et al. Erythropoietin treatment improves neurological functional recovery in EAE mice. Brain research. 2005;1034:34–9. doi:10.1016/j.brainres.2004.11.036.
    1. Savino C, Pedotti R, Baggi F, Ubiali F, Gallo B, Nava S. et al. Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. Journal of neuroimmunology. 2006;172:27–37. doi:10.1016/j.jneuroim.2005.10.016.
    1. Agnello D, Bigini P, Villa P, Mennini T, Cerami A, Brines ML. et al. Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain research. 2002;952:128–34.
    1. Yuan R, Maeda Y, Li W, Lu W, Cook S, Dowling P. Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE. PloS one. 2008;3:e1924.. doi:10.1371/journal.pone.0001924.
    1. Chang YK, Choi DE, Na KR, Lee SJ, Suh KS, Kim SY. et al. Erythropoietin attenuates renal injury in an experimental model of rat unilateral ureteral obstruction via anti-inflammatory and anti-apoptotic effects. The Journal of urology. 2009;181:1434–43. doi:10.1016/j.juro.2008.10.105.
    1. Sepodes B, Maio R, Pinto R, Sharples E, Oliveira P, McDonald M. et al. Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat. Transplant international: official journal of the European Society for Organ Transplantation. 2006;19:919–26. doi:10.1111/j.1432-2277.2006.00366.x.
    1. Nairz M, Schroll A, Moschen AR, Sonnweber T, Theurl M, Theurl I. et al. Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-kappaB-inducible immune pathways. Immunity. 2011;34:61–74. doi:10.1016/j.immuni.2011.01.002.
    1. Zeyda M, Stulnig TM. Obesity, inflammation, and insulin resistance--a mini-review. Gerontology. 2009;55:379–86. doi:10.1159/000212758.
    1. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. The Journal of clinical investigation. 2011;121:2111–7. doi:10.1172/JCI57132.
    1. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–70. doi:10.1038/27376.
    1. Kalofoutis C, Piperi C, Zisaki A, Singh J, Harris F, Phoenix D. et al. Differences in expression of cardiovascular risk factors among type 2 diabetes mellitus patients of different age. Annals of the New York Academy of Sciences. 2006;1084:166–77. doi:10.1196/annals.1372.001.
    1. Ehses JA, Boni-Schnetzler M, Faulenbach M, Donath MY. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochemical Society transactions. 2008;36:340–2. doi:10.1042/BST0360340.
    1. Pregi N, Wenker S, Vittori D, Leiros CP, Nesse A. TNF-alpha-induced apoptosis is prevented by erythropoietin treatment on SH-SY5Y cells. Experimental cell research. 2009;315:419–31. doi:10.1016/j.yexcr.2008.11.005.
    1. Chen G, Shi JX, Hang CH, Xie W, Liu J, Liu X. Inhibitory effect on cerebral inflammatory agents that accompany traumatic brain injury in a rat model: a potential neuroprotective mechanism of recombinant human erythropoietin (rhEPO) Neuroscience letters. 2007;425:177–82. doi:10.1016/j.neulet.2007.08.022.
    1. Meng R, Zhu D, Bi Y, Yang D, Wang Y. Erythropoietin inhibits gluconeogenesis and inflammation in the liver and improves glucose intolerance in high-fat diet-fed mice. PloS one. 2013;8:e53557.. doi:10.1371/journal.pone.0053557.
    1. Carvalho G, Lefaucheur C, Cherbonnier C, Metivier D, Chapel A, Pallardy M. et al. Chemosensitization by erythropoietin through inhibition of the NF-kappaB rescue pathway. Oncogene. 2005;24:737–45. doi:10.1038/sj.onc.1208205.
    1. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.
    1. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation. 2003;112:1796–808. doi:10.1172/JCI19246.
    1. Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL. et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation. 2007;115:1029–38. doi:10.1161/CIRCULATIONAHA.106.638379.
    1. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation. 2003;112:1821–30. doi:10.1172/JCI19451.
    1. Alnaeeli M, Raaka BM, Gavrilova O, Teng R, Chanturiya T, Noguchi CT. Erythropoietin signaling: A novel regulator of white adipose tissue inflammation during diet-induced obesity. Diabetes. 2014. doi:10.2337/db13-0883.
    1. De Luisi A, Binetti L, Ria R, Ruggieri S, Berardi S, Catacchio I. et al. Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma. Angiogenesis. 2013;16:963–73. doi:10.1007/s10456-013-9369-2.
    1. Lu KY, Ching LC, Su KH, Yu YB, Kou YR, Hsiao SH. et al. Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha. Circulation. 2010;121:1828–37. doi:10.1161/CIRCULATIONAHA.109.876839.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner