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A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats

  • Jeong, Jin Kwon (Department of Pharmacology and Physiology, School of Medicine & Health Sciences, The George Washington University) ;
  • Kim, Jae Geun (Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University) ;
  • Kim, Han Rae (Department of Biological Sciences, University of Ulsan) ;
  • Lee, Tae Hwan (Department of Biological Sciences, University of Ulsan) ;
  • Park, Jeong Woo (Department of Biological Sciences, University of Ulsan) ;
  • Lee, Byung Ju (Department of Biological Sciences, University of Ulsan)
  • Received : 2016.11.06
  • Accepted : 2017.03.06
  • Published : 2017.03.31

Abstract

A brain-enriched secreting signal peptide, NELL2, has been suggested to play multiple roles in the development, survival, and activity of neurons in mammal. We investigated here a possible involvement of central NELL2 in regulating feeding behavior and metabolism. In situ hybridization and an immunohistochemical approach were used to determine expression of NELL2 as well as its colocalization with proopiomelanocortin (POMC) and neuropeptide Y (NPY) in the rat hypothalamus. To investigate the effect of NELL2 on feeding behavior, 2 nmole of antisense NELL2 oligodeoxynucleotide was administered into the lateral ventricle of adult male rat brains for 6 consecutive days, and changes in daily body weight, food, and water intake were monitored. Metabolic state-dependent NELL2 expression in the hypothalamus was tested in vivo using a fasting model. NELL2 was noticeably expressed in the hypothalamic nuclei controlling feeding behavior. Furthermore, all arcuatic POMC and NPY positive neurons produced NELL2. The NELL2 gene expression in the hypothalamus was up-regulated by fasting. However, NELL2 did not affect POMC and NPY gene expression in the hypothalamus. A blockade of NELL2 production in the hypothalamus led to a reduction in daily food intake, followed by a loss in body weight without a change in daily water intake in normal diet condition. NELL2 did not affect short-term hunger dependent appetite behavior. Our data suggests that hypothalamic NELL2 is associated with appetite behavior, and thus central NELL2 could be a new therapeutic target for obesity.

Keywords

feeding behavior;hypothalamus;metabolic state;NELL2;neural plasticity

Acknowledgement

Supported by : NRF

References

  1. Aihara, K., Kuroda, S., Kanayama, N., Matsuyama, S., Tanizawa, K., and Horie, M. (2003). A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases. Brain Res. Mol. Brain Res. 116, 86-93. https://doi.org/10.1016/S0169-328X(03)00256-0
  2. Baskin, D.G., Breininger, J.F., Bonigut, S., and Miller, M.A. (1999). Leptin binding in the arcuate nucleus is increased during fasting. Brain Res. 828, 154-158. https://doi.org/10.1016/S0006-8993(99)01252-4
  3. Butera, P.C. and Beikirch, R.J. (1989). Central implants of diluted estradiol: independent effects on ingestive and reproductive behaviors of ovariectomized rats. Brain Res. 491, 266-273. https://doi.org/10.1016/0006-8993(89)90062-0
  4. Choi, E.J., Kim, D.H., Kim, J.G., Kim, D.Y., Kim, J.D., Seol, O.J., Jeong, C.S., Park, J.W., Choi, M.Y., Kang, S.G., et al. (2010). Estrogendependent transcription of the NEL-like 2 (NELL2) gene and its role in protection from cell death. J. Biol. Chem. 285, 25074-25084. https://doi.org/10.1074/jbc.M110.100545
  5. Choi, E.J., Ha, C.M., Choi, J., Kang, S.S., Choi, W.S., Park, S.K., Kim, K. and Lee, B.J. (2001). Low-density cDNA array-coupled to PCR differential display identifies new estrogen-responsive genes during the postnatal differentiation of the rat hypothalamus. Brain Res. Mol. Brain Res. 97, 115-128. https://doi.org/10.1016/S0169-328X(01)00302-3
  6. Choi, E.J., Kim, D.H., Kim, H.R., Yun, C.H., Kim, D.Y., Park, J.W., and Lee, B.J. (2014). Neural epidermal growth factor-like like protein 2 (NELL2) promotes aggregation of embryonic carcinoma P19 Cells by inducing N-cadherin expression. PLos One 9, e85898. https://doi.org/10.1371/journal.pone.0085898
  7. Christopherson, K.S., Ullian, E.M., Stokes, C.C., Mullowney, C.E., Hell, J.W., Agah, A., Lawler, J., Mosher, D.F., Bornstein, P., and Barres, B.A. (2005). Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421-433. https://doi.org/10.1016/j.cell.2004.12.020
  8. Czaja, J.A. (1984). Sex differences in the activational effects of gonadal hormones on food intake and body weight. Physiol. Behav. 33, 553-558. https://doi.org/10.1016/0031-9384(84)90370-6
  9. Czaja, J.A., Butera, P.C., and McCaffrey, T.A. (1983). Independent effects of estradiol on water and food intake. Behav. Neurosci. 97, 210-220. https://doi.org/10.1037/0735-7044.97.2.210
  10. Elias, C.F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R.S., Bjorbaek, C., Flier, J.S., Saper, C.B., and Elmquist, J.K. (1999). Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775-786. https://doi.org/10.1016/S0896-6273(01)80035-0
  11. Frago, L.M., and Chowen, J.A. (2015). Hypothalamic leptin and ghrelin signaling as targets for improvement in metabolic control. Curr. Phar. Des. 21, 3596-3605. https://doi.org/10.2174/1381612821666150710145428
  12. Ha, C.H., Choi, J., Choi, E.J., Costa, M.E., Lee, B.J., and Ojeda, S.R. (2008). Nell2, a neuron-specific EGF-like protein, is selectively expressed in glutamatergic neurons and contributes to the glutamatergic control of GnRH neurons at puberty. Neuroendocrinology 88, 199-211. https://doi.org/10.1159/000139579
  13. Hassouna, R., Labarthe, A., and Tolle, V. (2016). Hypothalamic regulation of body growth and appetite by ghrelin-derived peptides during balanced nutrition or undernutrition. Mol. Cell Endocrinol. 438, 42-51. https://doi.org/10.1016/j.mce.2016.09.027
  14. Horvath, T.L. (2005). The hardship of obesity: a soft-wired hypothalamus. Nat. Neurosci. 8, 561-565. https://doi.org/10.1038/nn1453
  15. Horvath, T.L., and Diano, S., (2004). The floating blueprint of hypothalamic feeding circuits. Nat. Rev. Neurosci. 5, 662-667. https://doi.org/10.1038/nrn1479
  16. Horvath, T.L., and Gao, X.B. (2005). Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia. Cell Metab. 1, 279-286. https://doi.org/10.1016/j.cmet.2005.03.003
  17. Hwang, E.M., Kim, D.G., Lee, B.J., Choi, J., Kim, E., Park, N., Kang, D., Han, J., Choi, W.S., Hong, S.G., et al. (2007). Alternative splicing generates a novel non-secretable cytosolic isoform of NELL2. Biochem. Biophys. Res. Commun. 353, 805-811. https://doi.org/10.1016/j.bbrc.2006.12.115
  18. Jaworski, A., Tom, I., Tong, R.K., Gildea, H.K., Koch, A.W., Gonzalez, L.C., and Tessier-Lavigne, M. (2015). Operational reducdancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2. Science 350, 961-965. https://doi.org/10.1126/science.aad2615
  19. Jeong, J.K., Kim, H.R., Hwang, S.M., Park, J.W., and Lee, B.J. (2008a). Region- and neuronal phenotype-specific expression of NELL2 in the adult rat brain. Mol. Cells 26, 186-192.
  20. Jeong, J.K., Ryu, B.J., Choi, J., Kim, D.H., Choi, E.J., Park, J.W., Park, J.J., and Lee, B.J. (2008b). NELL2 participates in formation of the sexually dimorphic nucleus of the preoptic area in rats. J. Neurochem. 106, 1604-1613. https://doi.org/10.1111/j.1471-4159.2008.05505.x
  21. Kim, H., Ha, C.M., Choi, J., Choi, E.J., Jeon, J., Kim, C., Park, S.K., Kang, S.S., Kim, K., and Lee, B.J. (2002). Ontogeny and the possible function of a novel epidermal growth factor-like repeat domaincontaining protein, NELL2, in the rat brain. J. Neurochem. 83, 1389-1400. https://doi.org/10.1046/j.1471-4159.2002.01245.x
  22. Kim, J.G., Nam-Goong, I.S., Yun, C.H., Jeong, J.K., Kim, E.S., Park, J.J., Lee, Y.C., Kim, Y.I., and Lee, B.J. (2006). TTF-1, a homeodomaincontaining transcription factor, regulates feeding behavior in the rat hypothalamus. Biochem. Biophys. Res. Commun. 349, 969-975. https://doi.org/10.1016/j.bbrc.2006.08.147
  23. King, B.M. (2006). The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol. Behav. 87, 221-244. https://doi.org/10.1016/j.physbeh.2005.10.007
  24. Kuroda, S., and Tanizawa, K. (1999). Involvement of epidermal growth factor-like domain of NELL proteins in the novel proteinprotein interaction with protein kinase C. Biochem. Biophys. Res. Commun. 265, 752-757. https://doi.org/10.1006/bbrc.1999.1753
  25. Kuroda, S., Oyasu, M., Kawakami, M., Kanayama, N., Tanizawa, K., Saito, N., Abe, T., Matsuhashi, S., and Ting, K. (1999). Biochemical characterization and expression analysis of neural thrombospondin- 1-like proteins NELL1 and NELL2. Biochem. Biophys. Res. Commun. 265, 79-86. https://doi.org/10.1006/bbrc.1999.1638
  26. Lin, T.N., Kim, G.M., Chen, J.J., Cheung, W.M., He, Y.Y., and Hsu, C.Y. (2003). Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Stroke 34, 177-186. https://doi.org/10.1161/01.STR.0000047100.84604.BA
  27. Matsuhashi, S., Noji, S., Koyama, E., Myokai, F., Ohuchi, H., Taniguchi, S., and Hori, K. (1995). New gene, nel, encoding a M(r) 93 K protein with EGF-like repeats is strongly expressed in neural tissues of early stage chick embryos. Dev. Dyn. 203, 212-222. https://doi.org/10.1002/aja.1002030209
  28. Matsuyama, S., Aihara, K., Nishino, N., Takeda, S., Tanizawa, K., Kuroda, S., and Horie, M. (2004). Enhanced long-term potentiation in vivo in dentate gyrus of NELL2-deficient mice. Neuroreport 15, 417-420. https://doi.org/10.1097/00001756-200403010-00007
  29. Matsuyama, S., Doe, N., Kurihara, N., Tanizawa, K., Kuroda, S., Iso, H., and Horie, M. (2005). Spatial learning of mice lacking a neuronspecific epidermal growth factor family protein, NELL2. J. Pharmacol. Sci. 98, 239-243. https://doi.org/10.1254/jphs.FP0050211
  30. Mello, C.V., Jarvis, E.D., Denisenko, N., and Rivas, M. (1997). Isolation of song-regulated genes in the brain of songbirds. Methods Mol. Biol. 85, 205-217.
  31. Musatov, S., Chen, W., Pfaff, D.W., Mobbs, C.V., Yang, X.J., Clegg, D.J., Kaplitt, M.G., and Ogawa, S. (2007). Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc. Natl. Acad. Sci. USA 104, 2501-2506. https://doi.org/10.1073/pnas.0610787104
  32. Nelson, B.R., Matsuhashi, S., and Lefcort, F. (2002). Restricted neural epidermal growth factor-like like 2 (NELL2) expression during muscle and neuronal differentiation. Mech. Dev. 119 Suppl 1, S11-19. https://doi.org/10.1016/S0925-4773(03)00084-4
  33. Oyasu, M., Kuroda, S., Nakashita, M., Fujimiya, M., Kikkawa, U., and Saito, N. (2000). Immunocytochemical localization of a neuronspecific thrombospondin-1-like protein, NELL2: light and electron microscopic studies in the rat brain. Brain Res. Mol. Brain Res. 76, 151-160. https://doi.org/10.1016/S0169-328X(99)00342-3
  34. Pinto, S., Roseberry, A.G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J.M., and Horvath, T.L. (2004). Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110-115. https://doi.org/10.1126/science.1089459
  35. Roesch, D.M. (2006). Effects of selective estrogen receptor agonists on food intake and body weight gain in rats. Physiol. Behav. 87, 39-44. https://doi.org/10.1016/j.physbeh.2005.08.035
  36. Ruy B.J., Kim H.R., Jeong J.K., and Lee B.J. (2011). Regulation of the female rat estrous cycle by a neural cell-specific epidermal growth factor-like repeat domain containing protein, NELL2. Mol. Cells 32, 203-207. https://doi.org/10.1007/s10059-011-0086-7
  37. Schwartz, M.W., Seeley, R.J., Woods, S.C., Weigle, D.S., Campfield, L.A., Burn, P., and Baskin, D.G. (1997). Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119-2123. https://doi.org/10.2337/diab.46.12.2119
  38. Watanabe, T.K., Katagiri, T., Suzuki, M., Shimizu, F., Fujiwara, T., Kanemoto, N., Nakamura, Y., Hirai, Y., Maekawa, H., and Takahashi, E. (1996). Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. Genomics 38, 273-276. https://doi.org/10.1006/geno.1996.0628
  39. Nelson, B.R., Claes, K., Todd, V., Chaverra, M., and Lefcort, F. (2004). NELL2 promotes motor and sensory neuron differentiation and stimulates mitogenesis in DRG in vivo. Dev. Biol. 270, 322-335. https://doi.org/10.1016/j.ydbio.2004.03.004