Bone
Volume 50, Issue 2 , Pages 430-436 , February 2012

Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue

  • Yan-Chuan Shi

      Affiliations

    • Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia
  • ,
  • Paul A. Baldock

      Affiliations

    • Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia
    • Faculty of Medicine, University of New South Wales, Sydney 2052, New South Wales, Australia
    • Corresponding Author InformationCorresponding author at: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia. Fax: +61 2 9295 8241.

Received 4 July 2011 ,Revised 2 October 2011 ,Accepted 3 October 2011.

References 

  1. Kanis JA. An update on the diagnosis of osteoporosis. Curr Rheumatol Rep. 2000;2:62–66
  2. Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr Rev. 2006;27:750–761
  3. Ribot C, Tremollieres F, Pouilles JM, Bonneu M, Germain F, Louvet JP. Obesity and postmenopausal bone loss: the influence of obesity on vertebral density and bone turnover in postmenopausal women. Bone. 1987;8:327–331
  4. Reid IR, Plank LD, Evans MC. Fat mass is an important determinant of whole body bone density in premenopausal women but not in men. J Clin Endocrinol Metab. 1992;75:779–782
  5. Gilsanz V, Chalfant J, Mo AO, Lee DC, Dorey FJ, Mittelman SD. Reciprocal relations of subcutaneous and visceral fat to bone structure and strength. J Clin Endocrinol Metab. 2009;94:3387–3393
  6. Clark EM, Ness AR, Tobias JH. Adipose tissue stimulates bone growth in prepubertal children. J Clin Endocrinol Metab. 2006;91:2534–2541
  7. Timpson NJ, Sayers A, Davey-Smith G, Tobias JH. How does body fat influence bone mass in childhood? A Mendelian randomization approach. J Bone Miner Res. 2009;24:522–533
  8. Sayers A, Timpson NJ, Sattar N, Deanfield J, Hingorani AD, Davey-Smith G, et al. Adiponectin and its association with bone mass accrual in childhood. J Bone Miner Res. 2010;25:2212–2220
  9. Confavreux CB, Levine RL, Karsenty G. A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol. 2009;310:21–29
  10. Rosen CJ, Klibanski A. Bone, fat, and body composition: evolving concepts in the pathogenesis of osteoporosis. Am J Med. 2009;122:409–414
  11. Rosen CJ. Leptin's RIGHT turn to the brain stem. Cell Metab. 2009;10:243–244
  12. Reid IR. Relationships between fat and bone. Osteoporos Int. 2008;19:595–606
  13. Nguyen ND, Pongchaiyakul C, Center JR, Eisman JA, Nguyen TV. Identification of high-risk individuals for hip fracture: a 14-year prospective study. J Bone Miner Res. 2005;20:1921–1928Epub 2005 May 31.
  14. Nguyen ND, Pongchaiyakul C, Center JR, Eisman JA, Nguyen TV. Abdominal fat and hip fracture risk in the elderly: the Dubbo Osteoporosis Epidemiology Study. BMC Musculoskelet Disord. 2005;6:11
  15. De Laet C, Kanis JA, Oden A, Johanson H, Johnell O, Delmas P, et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int. 2005;16:1330–1338
  16. Nguyen TV, Sambrook PN, Eisman JA. Bone loss, physical activity, and weight change in elderly women: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res. 1998;13:1458–1467
  17. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. 2009;301:513–521
  18. Nguyen ND, Center JR, Eisman JA, Nguyen TV. Bone loss, weight loss, and weight fluctuation predict mortality risk in elderly men and women. J Bone Miner Res. 2007;22:1147–1154
  19. Belfrage P, Fredrikson G, Olsson H, Stralfors P. Molecular mechanisms for hormonal control of adipose tissue lipolysis. Int J Obes. 1985;9(Suppl 1):129–135
  20. Driessler F, Baldock PA. Hypothalamic regulation of bone. J Mol Endocrinol 45: 175–181.
  21. Zengin A, Zhang L, Herzog H, Baldock PA, Sainsbury A. Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat. Trends Endocrinol Metab 21: 411–418.
  22. Baraban SC. Neuropeptide Y and limbic seizures. Rev Neurosci. 1998;9:117–128
  23. Lin S, Boey D, Herzog H. NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides. 2004;38:189–200
  24. Ekblad E, Edvinsson L, Wahlestedt C, Uddman R, Hakanson R, Sundler F. Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers. Regul Pept. 1984;8:225–235
  25. Baldock PA, Allison SJ, Lundberg P, Lee NJ, Slack K, Lin EJ, et al. Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem. 2007;282:19092–19102
  26. Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med. 2007;13:803–811
  27. Yang K, Guan H, Arany E, Hill DJ, Cao X. Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor. FASEB J. 2008;22:2452–2464
  28. Parker RM, Herzog H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci. 1999;11:1431–1448
  29. Blomqvist AG, Herzog H. Y-receptor subtypes—how many more?. Trends Neurosci. 1997;20:294–298
  30. Naveilhan P, Neveu I, Arenas E, Ernfors P. Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system. Neuroscience. 1998;87:289–302
  31. Lee NJ, Doyle KL, Sainsbury A, Enriquez RF, Hort YJ, Riepler SJ, et al. Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J Bone Miner Res. 2010;25:1736–1747
  32. Lundberg P, Allison SJ, Lee NJ, Baldock PA, Brouard N, Rost S, et al. Greater bone formation of Y2 knockout mice is associated with increased osteoprogenitor numbers and altered Y1 receptor expression. J Biol Chem. 2007;282:19082–19091
  33. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197–207
  34. Allison S, Baldock P, Enriquez R, Lin E, During M, Gardiner E, et al. Critical interplay between neuropeptide Y and sex steroid pathways in bone and adipose tissue homeostasis. J Bone Miner Res. 2008;
  35. Baldock PA, Sainsbury A, Allison S, Lin EJ, Couzens M, Boey D, et al. Hypothalamic control of bone formation: distinct actions of leptin and Y2 receptor pathways. J Bone Miner Res. 2005;20:1851–1857
  36. Baldock PA, Lee NJ, Driessler F, Lin S, Allison S, Stehrer B, et al. Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight. PLoS One. 2009;4:e8415
  37. Elefteriou F, Takeda S, Liu X, Armstrong D, Karsenty G. Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass. Endocrinology. 2003;144:3842–3847
  38. Karl T, Duffy L, Herzog H. Behavioural profile of a new mouse model for NPY deficiency. Eur J Neurosci. 2008;28:173–180
  39. Allison SJ, Baldock PA, Herzog H. The control of bone remodeling by neuropeptide Y receptors. Peptides. 2007;28:320–325
  40. Fetissov SO, Byrne LC, Hassani H, Ernfors P, Hokfelt T. Characterization of neuropeptide Y Y2 and Y5 receptor expression in the mouse hypothalamus. J Comp Neurol. 2004;470:256–265
  41. Parker RMC, Herzog H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci. 1999;11:1431–1448
  42. Lin S, Boey D, Couzens M, Lee N, Sainsbury A, Herzog H. Compensatory changes in [125I]-PYY binding in Y receptor knockout mice suggest the potential existence of further Y receptor(s). Neuropeptides. 2005;39:21–28
  43. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology. 1997;66:393–408
  44. King PJ, Williams G, Doods H, Widdowson PS. Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release. Eur J Pharmacol. 2000;396:R1–R3
  45. Shi YC, Lin S, Castillo L, Aljanova A, Enriquez RF, Nguyen AD, et al. Peripheral-specific Y2 receptor knockdown protects mice from high-fat diet-induced obesity. Obesity (Silver Spring). 2011;
  46. Playford RJ, Cox HM. Peptide YY and neuropeptide Y: two peptides intimately involved in electrolyte homeostasis. Trends Pharmacol Scin. 1996;17:436–438
  47. Koda S, Date Y, Murakami N, Shimbara T, Hananda T, Toshinai K, et al. The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology. 2005;23:305–321
  48. Allison SJ, Baldock P, Sainsbury A, Enriquez R, Lee NJ, Lin EJ, et al. Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice. J Biol Chem. 2006;281:23436–23444
  49. Baldock P, Sainsbury A, Couzens M, Enriquez R, Ghomas GP, Gardiner EM, et al. Hypothalamic Y2 receptors regulate bone formation. J Clin Invest. 2002;109:915–921
  50. Shi YC, Lin S, Wong IP, Baldock PA, Aljanova A, Enriquez RF, et al. NPY neuron-specific Y2 receptors regulate adipose tissue and trabecular bone but not cortical bone homeostasis in mice. PLoS One. 2010;5:e11361
  51. Dumont Y, Fournier A, St-Pierre S, Schwartz TW, Quirion R. Differential distribution of neuropeptide Y1 and Y2 receptors in the rat brain. Eur J Pharmacol. 1990;191:501–503
  52. Igwe JC, Jiang X, Paic F, Ma L, Adams DJ, Baldock PA, et al. Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity. J Cell Biochem. 2009;108:621–630
  53. Lundberg JM, Martinsson A, Hemsen A, Theodorsson-Norheim E, Svendenhag J, Ekblom B, et al. Co-release of neuropeptide Y and catecholamines during physical exercise in man. Biochem Biophys Res Commun. 1985;133:30–36
  54. Kempna P, Korner M, Waser B, Hofer G, Nuoffer JM, Reubi JC, et al. Neuropeptide Y modulates steroid production of human adrenal H295R cells through Y1 receptors. Mol Cell Endocrinol. 2010;314:101–109
  55. Morgan DG, Kulkarni RN, Hurley JD, Wang ZL, Wang RM, Ghatei MA, et al. Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells. Diabetologia. 1998;41:1482–1491
  56. Bjurholm A. Neuroendocrine peptides in bone. Int Orthop. 1991;15:325–329
  57. Bjurholm A, Kreicbergs A, Schultzberg M, Lerner UH. Neuroendocrine regulation of cyclic AMP formation in osteoblastic cell lines (UMR-106-01, ROS 17/2.8, MC3T3-E1, and Saos-2) and primary bone cells. J Bone Miner Res. 1992;7:1011–1019
  58. Amano S, Arai M, Goto S, Togari A. Inhibitory effect of NPY on isoprenaline-induced osteoclastogenesis in mouse bone marrow cells. Biochim Biophys Acta. 2007;1770:966–973
  59. Rodriguez EM, Blazquez JL, Guerra M. The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides. 2010;31:757–776
  60. Marks JL, Wait K. Intracerebroventricular neuropeptide Y acutely influences glucose metabolism and insulin sensitivity in the rat. J Neuroendocrinol. 1997;9:99–103
  61. Willesen MG, Kristensen P, Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology. 1999;70:306–316
  62. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci. 1998;1:445–450
  63. Dowell P, Hu Z, Lane M. Monitoring energy balance: metabolites of fatty acid synthesis as hypothalamic sensors. Annu Rev Biochem. 2005;74:515–534
  64. Beck B, Burlet A, Bazin R, Nicholas JP, Burlet C. Elevated neuropeptide Y in the arcuate nucleus of young obese Zucker rats may contribute to the development of their overeating. J Nutr. 1993;123:1168–1172
  65. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci U S A. 1991;88:10931–10935
  66. McKibbon PE, Cotton SJ, McMillan S, Holloway B, Mayers R, McCarthy HD, et al. Altered neuropeptide Y concentrations in specific hypothalamic regions of obese (fa/fa) Zucker rats. Possible relationship to obesity and neuroendocrine disturbances. Diabetes. 1991;40:1423–1429
  67. Williams G, Steel JH, Cardoso H, Ghatei MA, Lee YC, Gill JS, et al. Increased hypothalamic neuropeptide Y concentrations in diabetic rat. Diabetes. 1988;37:763–772
  68. Baldock PA, Sainsbury A, Allison S, Lin EJ, Couzens M, Boey D, et al. Hypothalamic control of bone formation: distinct actions of leptin and Y2 receptor pathways. J Bone Miner Res. 2005;20:1851–1857
  69. Billington CJ, Briggs JE, Harker S, Grace M, Levine AS. Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am J Physiol. 1994;266:R1765–R1770
  70. Pierroz DD, Catzeflis C, Aebi AC, Rivier JE, Aubert ML. Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary–testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats. Endocrinology. 1996;137:3–12
  71. Sainsbury A, Rohner-Jeanrenaud F, Cusin I, Zakrzewska KE, Halban PA, Gaillard RC, et al. Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo–pituitary–adrenal axis, and vagal mediation of hyperinsulinaemia. Diabetologia. 1997;40:1269–1277
  72. Zarjevski N, Cusin I, Vettor R, Rohner-Jeanrenaud F, Jeanrenaud B. Intracerebroventricular administration of neuropeptide Y to normal rats has divergent effects on glucose utilization by adipose tissue and skeletal muscle. Diabetes. 1994;43:764–769
  73. Wahlestedt C, Skagerberg G, Ekman R, Heilig M, Sundler F, Hakanson R. Neuropeptide Y (NPY) in the area of the hypothalamic paraventricular nucleus activates the pituitary–adrenocortical axis in the rat. Brain Res. 1987;417:33–38
  74. Leibowitz SF, Sladek C, Spencer L, Tempel D. Neuropeptide Y, epinephrine and norepinephrine in the paraventricular nucleus: stimulation of feeding and the release of corticosterone, vasopressin and glucose. Brain Res Bull. 1988;21:905–912
  75. Small CJ, Morgan DG, Meeran K, Heath MM, Gunn I, Edwards CM, et al. Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release. Proc Natl Acad Sci U S A. 1997;94:11686–11691
  76. Harfstrand A, Eneroth P, Agnati L, Fuxe K. Further studies on the effects of central administration of neuropeptide Y on neuroendocrine function in the male rat: relationship to hypothalamic catecholamines. Regul Pept. 1987;17:167–179
  77. Catzeflis C, Pierroz DD, Rohner-Jeanrenaud F, Rivier JE, Sizonenko PC, Aubert ML. Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats. Endocrinology. 1993;132:224–234
  78. Pierroz DD, Catzeflis C, Aebi AC, Rivier JE, Aubert ML. Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary–testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats. Endocrinology. 1996;137:3–12
  79. Billington CJ, Briggs JE, Grace M, Levine AS. Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol. 1991;260:R321–R327
  80. Szreder Z, Hori T, Kaizuka Y. Thermoregulatory effect of intracerebral injections of neuropeptide Y in rats at different environmental temperatures. Gen Pharmacol. 1994;25:85–91
  81. Currie PJ, Coscina DV. Dissociated feeding and hypothermic effects of neuropeptide Y in the paraventricular and perifornical hypothalamus. Peptides. 1995;16:599–604
  82. Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature. 1996;381:415–421
  83. Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science. 1996;274:1704–1707
  84. Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M, Nakamura M. Obesity and mild hyperinsulinemia found in neuropeptide Y–Y1 receptor-deficient mice. Proc Natl Acad Sci U S A. 1998;95:15659–15664
  85. Pedrazzini T, Seydoux J, Kunstner P, Aubert JF, Grouzmann E, Beermann F, et al. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat Med. 1998;4:722–726
  86. Naveilhan P, Svensson L, Nystrom S, Ekstrand AJ, Ernfors P. Attenuation of hypercholesterolemia and hyperglycemia in ob/ob mice by NPY Y2 receptor ablation. Peptides. 2002;23:1087–1091
  87. Howell OW, Scharfman HE, Herzog H, Sundstrom LE, Beck-Sickinger A, Gray WP. Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells. J Neurochem. 2003;86:646–659
  88. Kanatani A, Mashiko S, Murai N, Sugimoto N, Ito J, Fukuroda T, et al. Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology. 2000;141:1011–1016
  89. Pralong FP, Gonzales C, Voirol MJ, Palmiter RD, Brunner HR, Gaillard RC, et al. The neuropeptide Y Y1 receptor regulates leptin-mediated control of energy homeostasis and reproductive functions. FASEB J. 2002;16:712–714
  90. Zhang L, Macia L, Turner N, Enriquez RF, Riepler SJ, Nguyen AD, et al. Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion. Int J Obes (Lond). 2010;34:357–373
  91. Sainsbury A, Bergen HT, Boey D, Bamming D, Cooney GJ, Lin S, et al. Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice. Diabetes. 2006;55:19–26
  92. Burcelin R, Brunner H, Seydoux J, Thorens B, Pedrazzini T. Increased insulin concentrations and glucose storage in neuropeptide Y Y1 receptor-deficient mice. Peptides. 2001;22:421–427
  93. Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat Med. 1998;4:718–721
  94. Iyengar S, Li DL, Simmons RM. Characterization of neuropeptide Y-induced feeding in mice: do Y1–Y6 receptor subtypes mediate feeding?. J Pharmacol Exp Ther. 1999;289:1031–1040
  95. Higuchi H, Niki T, Shiiya T. Feeding behavior and gene expression of appetite-related neuropeptides in mice lacking for neuropeptide Y Y5 receptor subclass. World J Gastroenterol. 2008;14:6312–6317
  96. Herzog H, Darby K, Ball H, Hort Y, Beck-Sickinger A, Shine J. Overlapping gene structure of the human neuropeptide Y receptor subtypes Y1 and Y5 suggests coordinate transcriptional regulation. Genomics. 1997;41:315–319
  97. Wolak ML, DeJoseph MR, Cator AD, Mokashi AS, Brownfield MS, Urban JH. Comparative distribution of neuropeptide Y Y1 and Y5 receptors in the rat brain by using immunohistochemistry. J Comp Neurol. 2003;464:285–311
  98. Labelle M, Boulanger Y, Fournier A, St Pierre S, Savard S. Tissue-specific regulation of fat cell lipolysis by NPY in 7-OHDA-treated rats. Peptides. 1997;18:801–808
  99. Serradeil-Le Gal C, Lafontan M, Raufaste D, Marchand J, Pouzet B, Casellas P, et al. Characterization of NPY receptors controlling lipolysis and leptin secretion in human adipocytes. FEBS Lett. 2000;475:150–156
  100. Sainsbury A, Schwarzer C, Couzens M, Herzog H. Y2 receptor deletion attenuates the type 2 diabetic syndrome of ob/ob mice. Diabetes. 2002;51:3420–3427
  101. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197–207
  102. Sipols AJ, Baskin DG, Schwartz MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 1995;44:147–151
  103. Zengin A, Zhang L, Herzog H, Baldock PA, Sainsbury A. Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat. Trends Endocrinol Metab. 2010;21:411–418

PII: S8756-3282(11)01280-4

doi: 10.1016/j.bone.2011.10.001

Bone
Volume 50, Issue 2 , Pages 430-436 , February 2012