The facts of the matter: What is a hormone?

Autoři: Gerard Karsenty aff001
Působiště autorů: Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, United States of America aff001
Vyšlo v časopise: The facts of the matter: What is a hormone?. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008938
Kategorie: Formal Comment


1. Knudsen LB. Inventing Liraglutide, a Glucagon-Like Peptide-1 Analogue, for the Treatment of Diabetes and Obesity. ACS Pharmacol Transl Sci. 2019;2(6):468–84. doi: 10.1021/acsptsci.9b00048 32259078

2. Al Rifai O, Chow J, Lacombe J, Julien C, Faubert D, Susan-Resiga D, et al. Proprotein convertase furin regulates osteocalcin and bone endocrine function. J Clin Invest. 2017;127(11):4104–17. doi: 10.1172/JCI93437 28972540

3. Boraschi-Diaz I, Tauer JT, El-Rifai O, Guillemette D, Lefebvre G, Rauch F, et al. Metabolic phenotype in the mouse model of osteogenesis imperfecta. J Endocrinol. 2017;234(3):279–89. doi: 10.1530/JOE-17-0335 28716975

4. Brennan-Speranza TC, Henneicke H, Gasparini SJ, Blankenstein KI, Heinevetter U, Cogger VC, et al. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest. 2012;122(11):4172–89. doi: 10.1172/JCI63377 23093779

5. Du J, Zhang M, Lu J, Zhang X, Xiong Q, Xu Y, et al. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK. Endocrine. 2016;53(3):701–9. doi: 10.1007/s12020-016-0926-5 26994931

6. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142(2):309–19. doi: 10.1016/j.cell.2010.06.002 20655471

7. Glatigny M, Moriceau S, Rivagorda M, Ramos-Brossier M, Nascimbeni AC, Lante F, et al. Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline. Curr Biol. 2019;29(3):435–48 e8. doi: 10.1016/j.cub.2018.12.021 30661803

8. Guedes JAC, Esteves JV, Morais MR, Zorn TM, Furuya DT. Osteocalcin improves insulin resistance and inflammation in obese mice: Participation of white adipose tissue and bone. Bone. 2018;115:68–82. doi: 10.1016/j.bone.2017.11.020 29183784

9. Guo Q, Li H, Xu L, Wu S, Sun H, Zhou B. Undercarboxylated osteocalcin reverts insulin resistance induced by endoplasmic reticulum stress in human umbilical vein endothelial cells. Sci Rep. 2017;7(1):46. doi: 10.1038/s41598-017-00163-2 28246389

10. Guo XZ, Shan C, Hou YF, Zhu G, Tao B, Sun LH, et al. Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson's Disease Rat Model Through AKT/GSK3beta Signaling. Front Mol Neurosci. 2018;11:343. doi: 10.3389/fnmol.2018.00343 30319352

11. Gupte AA, Sabek OM, Fraga D, Minze LJ, Nishimoto SK, Liu JZ, et al. Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology. 2014;155(12):4697–705. doi: 10.1210/en.2014-1430 25279794

12. Hayashi Y, Kawakubo-Yasukochi T, Mizokami A, Hazekawa M, Yakura T, Naito M, et al. Uncarboxylated Osteocalcin Induces Antitumor Immunity against Mouse Melanoma Cell Growth. J Cancer. 2017;8(13):2478–86. doi: 10.7150/jca.18648 28900485

13. Hayashi Y, Kawakubo-Yasukochi T, Mizokami A, Takeuchi H, Nakamura S, Hirata M. Differential Roles of Carboxylated and Uncarboxylated Osteocalcin in Prostate Cancer Growth. J Cancer. 2016;7(12):1605–9. doi: 10.7150/jca.15523 27698897

14. Huesa C, Zhu D, Glover JD, Ferron M, Karsenty G, Milne EM, et al. Deficiency of the bone mineralization inhibitor NPP1 protects mice against obesity and diabetes. Dis Model Mech. 2014;7(12):1341–50. doi: 10.1242/dmm.017905 25368121

15. Kawakubo-Yasukochi T, Kondo A, Mizokami A, Hayashi Y, Chishaki S, Nakamura S, et al. Maternal oral administration of osteocalcin protects offspring from metabolic impairment in adulthood. Obesity (Silver Spring). 2016;24(4):895–907.

16. Kode A, Mosialou I, Silva BC, Joshi S, Ferron M, Rached MT, et al. FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis. J Biol Chem. 2012;287(12):8757–68. doi: 10.1074/jbc.M111.282897 22298775

17. Kosmidis S, Polyzos A, Harvey L, Youssef M, Denny CA, Dranovsky A, et al. RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss. Cell Rep. 2018;25(4):959–73 e6. doi: 10.1016/j.celrep.2018.09.077 30355501

18. Lacombe J, Karsenty G, Ferron M. In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice. Mol Metab. 2013;2(4):498–504. doi: 10.1016/j.molmet.2013.08.004 24327965

19. Levinger I, Lin X, Zhang X, Brennan-Speranza TC, Volpato B, Hayes A, et al. The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo. Osteoporos Int. 2016;27(2):653–63. doi: 10.1007/s00198-015-3273-0 26259649

20. Li H, Zhou B, Xu L, Liu J, Zang W, Wu S, et al. The reciprocal interaction between autophagic dysfunction and ER stress in adipose insulin resistance. Cell Cycle. 2014;13(4):565–79. doi: 10.4161/cc.27406 24309597

21. Lin X, Parker L, McLennan E, Hayes A, McConell G, Brennan-Speranza TC, et al. Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice. J Bone Miner Res. 2019;34(8):1517–30. doi: 10.1002/jbmr.3731 30908701

22. Lin X, Parker L, McLennan E, Zhang X, Hayes A, McConell G, et al. Recombinant Uncarboxylated Osteocalcin Per Se Enhances Mouse Skeletal Muscle Glucose Uptake in both Extensor Digitorum Longus and Soleus Muscles. Front Endocrinol (Lausanne). 2017;8:330.

23. Lin X, Parker L, McLennan E, Zhang X, Hayes A, McConell G, et al. Uncarboxylated Osteocalcin Enhances Glucose Uptake Ex Vivo in Insulin-Stimulated Mouse Oxidative But Not Glycolytic Muscle. Calcif Tissue Int. 2018;103(2):198–205. doi: 10.1007/s00223-018-0400-x 29427234

24. Matsumoto Y, La Rose J, Lim M, Adissu HA, Law N, Mao X, et al. Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism. J Clin Invest. 2017;127(7):2612–25. doi: 10.1172/JCI92233 28581440

25. Mizokami A, Mukai S, Gao J, Kawakubo-Yasukochi T, Otani T, Takeuchi H, et al. GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J Endocrinol. 2020;244(2):285–96. doi: 10.1530/JOE-19-0288 31693486

26. Mizokami A, Wang D, Tanaka M, Gao J, Takeuchi H, Matsui T, et al. An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration. Biosci Biotechnol Biochem. 2016;80(11):2176–83. doi: 10.1080/09168451.2016.1214530 27460506

27. Mizokami A, Yasutake Y, Gao J, Matsuda M, Takahashi I, Takeuchi H, et al. Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. PLoS One. 2013;8(2):e57375. doi: 10.1371/journal.pone.0057375 23437377

28. Mizokami A, Yasutake Y, Higashi S, Kawakubo-Yasukochi T, Chishaki S, Takahashi I, et al. Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion. Bone. 2014;69:68–79. doi: 10.1016/j.bone.2014.09.006 25230237

29. Namai F, Shigemori S, Sudo K, Sato T, Yamamoto Y, Nigar S, et al. Recombinant Mouse Osteocalcin Secreted by Lactococcus lactis Promotes Glucagon-Like Peptide-1 Induction in STC-1 Cells. Curr Microbiol. 2018;75(1):92–8. doi: 10.1007/s00284-017-1354-3 28905106

30. Otani T, Matsuda M, Mizokami A, Kitagawa N, Takeuchi H, Jimi E, et al. Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes via activation of p300. Cell Death Dis. 2018;9(12):1194. doi: 10.1038/s41419-018-1257-7 30546087

31. Otani T, Mizokami A, Hayashi Y, Gao J, Mori Y, Nakamura S, et al. Signaling pathway for adiponectin expression in adipocytes by osteocalcin. Cell Signal. 2015;27(3):532–44. doi: 10.1016/j.cellsig.2014.12.018 25562427

32. Pi M, Kapoor K, Ye R, Nishimoto SK, Smith JC, Baudry J, et al. Evidence for Osteocalcin Binding and Activation of GPRC6A in beta-Cells. Endocrinology. 2016;157(5):1866–80. doi: 10.1210/en.2015-2010 27007074

33. Pi M, Wu Y, Quarles LD. GPRC6A mediates responses to osteocalcin in beta-cells in vitro and pancreas in vivo. J Bone Miner Res. 2011;26(7):1680–3. doi: 10.1002/jbmr.390 21425331

34. Pi M, Xu F, Ye R, Nishimoto SK, Williams RW, Lu L, et al. Role of GPRC6A in Regulating Hepatic Energy Metabolism in Mice. Sci Rep. 2020;10(1):7216. doi: 10.1038/s41598-020-64384-8 32350388

35. Qaradakhi T, Gadanec LK, Tacey AB, Hare DL, Buxton BF, Apostolopoulos V, et al. The Effect of Recombinant Undercarboxylated Osteocalcin on Endothelial Dysfunction. Calcif Tissue Int. 2019;105(5):546–56. doi: 10.1007/s00223-019-00600-6 31485687

36. Rached MT, Kode A, Silva BC, Jung DY, Gray S, Ong H, et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest. 2010;120(1):357–68. doi: 10.1172/JCI39901 20038793

37. Rashdan NA, Sim AM, Cui L, Phadwal K, Roberts FL, Carter R, et al. Osteocalcin Regulates Arterial Calcification Via Altered Wnt Signaling and Glucose Metabolism. J Bone Miner Res. 2020;35(2):357–67. doi: 10.1002/jbmr.3888 31596966

38. Riddle RC, Frey JL, Tomlinson RE, Ferron M, Li Y, DiGirolamo DJ, et al. Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis. Mol Cell Biol. 2014;34(10):1850–62. doi: 10.1128/MCB.00075-14 24591652

39. Sabek OM, Nishimoto SK, Fraga D, Tejpal N, Ricordi C, Gaber AO. Osteocalcin Effect on Human beta-Cells Mass and Function. Endocrinology. 2015;156(9):3137–46. doi: 10.1210/EN.2015-1143 26151356

40. Solhjoo S, Akbari M, Toolee H, Mortezaee K, Mohammadipour M, Nematollahi-Mahani SN, et al. Roles for osteocalcin in proliferation and differentiation of spermatogonial cells cocultured with somatic cells. J Cell Biochem. 2019;120(4):4924–34. doi: 10.1002/jcb.27767 30302795

41. Tsuka S, Aonuma F, Higashi S, Ohsumi T, Nagano K, Mizokami A, et al. Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin. Biochem Biophys Res Commun. 2015;459(3):437–42. doi: 10.1016/j.bbrc.2015.02.123 25735975

42. Wei J, Hanna T, Suda N, Karsenty G, Ducy P. Osteocalcin promotes beta-cell proliferation during development and adulthood through Gprc6a. Diabetes. 2014;63(3):1021–31. doi: 10.2337/db13-0887 24009262

43. Yasutake Y, Mizokami A, Kawakubo-Yasukochi T, Chishaki S, Takahashi I, Takeuchi H, et al. Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet. Am J Physiol Endocrinol Metab. 2016;310(8):E662–E75. doi: 10.1152/ajpendo.00334.2015 26884384

44. Ye R, Pi M, Cox JV, Nishimoto SK, Quarles LD. CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. J Exp Clin Cancer Res. 2017;36(1):90. doi: 10.1186/s13046-017-0561-x 28659174

45. Yi M, Wu Y, Long J, Liu F, Liu Z, Zhang YH, et al. Exosomes secreted from osteocalcin-overexpressing endothelial progenitor cells promote endothelial cell angiogenesis. Am J Physiol Cell Physiol. 2019;317(5):C932–C41. doi: 10.1152/ajpcell.00534.2018 31411920

46. Yoshikawa Y, Kode A, Xu L, Mosialou I, Silva BC, Ferron M, et al. Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. J Bone Miner Res. 2011;26(9):2012–25. doi: 10.1002/jbmr.417 21557308

47. Zhou B, Li H, Liu J, Xu L, Zang W, Wu S, et al. Intermittent injections of osteocalcin reverse autophagic dysfunction and endoplasmic reticulum stress resulting from diet-induced obesity in the vascular tissue via the NFkappaB-p65-dependent mechanism. Cell Cycle. 2013;12(12):1901–13. doi: 10.4161/cc.24929 23708521

48. Zhou B, Li H, Xu L, Zang W, Wu S, Sun H. Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-kappaB signaling pathway. Endocrinology. 2013;154(3):1055–68. doi: 10.1210/en.2012-2144 23407450

49. De Toni L, De Filippis V, Tescari S, Ferigo M, Ferlin A, Scattolini V, et al. Uncarboxylated osteocalcin stimulates 25-hydroxy vitamin D production in Leydig cell line through a GPRC6a-dependent pathway. Endocrinology. 2014;155(11):4266–74. doi: 10.1210/en.2014-1283 25093461

50. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130(3):456–69. doi: 10.1016/j.cell.2007.05.047 17693256

51. Chowdhury S, Schulz LC, Palmisano B, Singh P, Berger JM, Yadav VK, et al. Muscle derived interleukin-6 increases exercise capacity by signaling in osteoblasts. J Clin Invest. 2020.

52. Millar SA, Anderson SI, O'Sullivan S E. Human vascular cell responses to the circulating bone hormone osteocalcin. J Cell Physiol. 2019;234(11):21039–48. doi: 10.1002/jcp.28707 31026070

53. Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, et al. Endocrine regulation of male fertility by the skeleton. Cell. 2011;144(5):796–809. doi: 10.1016/j.cell.2011.02.004 21333348

54. Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell. 2013;155(1):228–41. doi: 10.1016/j.cell.2013.08.042 24074871

55. Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone. 2012;50(2):568–75. doi: 10.1016/j.bone.2011.04.017 21550430

56. Di Nisio A, Rocca MS, Fadini GP, De Toni L, Marcuzzo G, Marescotti MC, et al. The rs2274911 polymorphism in GPRC6A gene is associated with insulin resistance in normal weight and obese subjects. Clin Endocrinol (Oxf). 2017;86(2):185–91.

57. De Toni L, Di Nisio A, Speltra E, Rocca MS, Ghezzi M, Zuccarello D, et al. Polymorphism rs2274911 of GPRC6A as a Novel Risk Factor for Testis Failure. J Clin Endocrinol Metab. 2016;101(3):953–61. doi: 10.1210/jc.2015-3967 26735260

58. Korostishevsky M, Malkin I, Trofimov S, Pei Y, Deng HW, Livshits G. Significant association between body composition phenotypes and the osteocalcin genomic region in normative human population. Bone. 2012;51(4):688–94. doi: 10.1016/j.bone.2012.07.010 22842327

59. Das SK, Sharma NK, Elbein SC. Analysis of osteocalcin as a candidate gene for type 2 diabetes (T2D) and intermediate traits in Caucasians and African Americans. Dis Markers. 2010;28(5):281–6. doi: 10.3233/DMA-2010-0701 20592451

60. Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, et al. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Invest. 2013;123(6):2421–33. doi: 10.1172/JCI65952 23728177

61. Confavreux CB, Borel O, Lee F, Vaz G, Guyard M, Fadat C, et al. Osteoid osteoma is an osteocalcinoma affecting glucose metabolism. Osteoporos Int. 2012;23(5):1645–50. doi: 10.1007/s00198-011-1684-0 21681611

62. Manolagas SC. Osteocalcin promotes bone mineralization but is not a hormone. PLoS Genet. 2020;16(6):e1008714.

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