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Diet-Induced Obesity and the Mechanism of Leptin Resistance

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 960)

Abstract

Leptin signaling blockade by chronic overstimulation of the leptin receptor or hypothalamic pro-inflammatory responses due to elevated levels of saturated fatty acid can induce leptin resistance by activating negative feedback pathways. Although, long form leptin receptor (Ob-Rb) initiates leptin signaling through more than seven different signal transduction pathways, excessive suppressor of cytokine signaling-3 (SOCS-3) activity is a potential mechanism for the leptin resistance that characterizes human obesity. Because the leptin-responsive metabolic pathways broadly integrate with other neurons to control energy balance, the methods used to counteract the leptin resistance has extremely limited effect. In this chapter, besides the impairment of central and peripheral leptin signaling pathways, limited access of leptin to central nervous system (CNS) through blood-brain barrier, mismatch between high leptin and the amount of leptin receptor expression, contradictory effects of cellular and circulating molecules on leptin signaling, the connection between leptin signaling and endoplasmic reticulum (ER) stress and self-regulation of leptin signaling has been discussed in terms of leptin resistance.

Keywords

Leptin resistance Leptin receptor Soluble leptin receptor Leptin signaling Suppressor of cytokine signaling 3 (SOCS3) Anorexigenic pro-opiomelanocortin (POMC) neurons Signal transducer and activator of transcription 3 (STAT3) Signal transducer and activator of transcription 5 (STAT5) Phosphodiesterase 3 (PDE3) Endoplasmic reticulum stress 
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References

  1. Balthasar, N., R. Coppari, J. McMinn, S.M. Liu, C.E. Lee, V. Tang, C.D. Kenny, R.A. McGovern, S.C. Chua, J.K. Elmquist, and B.B. Lowell. 2004. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42: 983–991. doi: 10.1016/j.neuron.2004.06.004.PubMedCrossRefGoogle Scholar
  2. Banks, W.A. 2001. Leptin transport across the blood-brain barrier: Implications for the cause and treatment of obesity. Current Pharmaceutical Design 7: 125–133.PubMedCrossRefGoogle Scholar
  3. ———. 2008. The blood-brain barrier as a cause of obesity. Current Pharmaceutical Design 14: 1606–1614.PubMedCrossRefGoogle Scholar
  4. ———. 2012. Role of the blood-brain barrier in the evolution of feeding and cognition. Annals of the New York Academy of Sciences 1264: 13–19. doi: 10.1111/j.1749-6632.2012.06568.x.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Banks, W.A., A.J. Kastin, W. Huang, J.B. Jaspan, and L.M. Maness. 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides 17: 305–311.PubMedCrossRefGoogle Scholar
  6. Banks, W.A., S.A. Farr, and J.E. Morley. 2006. The effects of high fat diets on the blood-brain barrier transport of leptin: Failure or adaptation? Physiology & Behavior 88: 244–248. doi: 10.1016/j.physbeh.2006.05.037.CrossRefGoogle Scholar
  7. Bates, S.H., and M.G. Myers. 2003. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends in Endocrinology and Metabolism 14: 447–452.PubMedCrossRefGoogle Scholar
  8. Bates, S.H., T.A. Dundon, M. Seifert, M. Carlson, E. Maratos-Flier, and M.G. Myers. 2004. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 53: 3067–3073.PubMedCrossRefGoogle Scholar
  9. Belgardt, B.F., A. Husch, E. Rother, M.B. Ernst, F.T. Wunderlich, B. Hampel, T. Klöckener, D. Alessi, P. Kloppenburg, and J.C. Brüning. 2008. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metabolism 7: 291–301. doi: 10.1016/j.cmet.2008.01.006.PubMedCrossRefGoogle Scholar
  10. Bence, K.K., M. Delibegovic, B. Xue, C.Z. Gorgun, G.S. Hotamisligil, B.G. Neel, and B.B. Kahn. 2006. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nature Medicine 12: 917–924. doi: 10.1038/nm1435.PubMedCrossRefGoogle Scholar
  11. Bertolotti, A., Y. Zhang, L.M. Hendershot, H.P. Harding, and D. Ron. 2000. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biology 2: 326–332. doi: 10.1038/35014014.PubMedCrossRefGoogle Scholar
  12. Bjørbaek, C., S. Uotani, B. da Silva, and J.S. Flier. 1997. Divergent signaling capacities of the long and short isoforms of the leptin receptor. The Journal of Biological Chemistry 272: 32686–32695.PubMedCrossRefGoogle Scholar
  13. Bjørbaek, C., J.K. Elmquist, J.D. Frantz, S.E. Shoelson, and J.S. Flier. 1998a. Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell 1: 619–625.PubMedCrossRefGoogle Scholar
  14. Bjørbaek, C., J.K. Elmquist, P. Michl, R.S. Ahima, A. van Bueren, A.L. McCall, and J.S. Flier. 1998b. Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139: 3485–3491. doi: 10.1210/endo.139.8.6154.PubMedCrossRefGoogle Scholar
  15. Blouet, C., H. Ono, and G.J. Schwartz. 2008. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metabolism 8: 459–467. doi: 10.1016/j.cmet.2008.10.004.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Briggs, D.I., S.H. Lockie, J. Benzler, Q. Wu, R. Stark, A. Reichenbach, A.J. Hoy, M.B. Lemus, H.A. Coleman, H.C. Parkington, A. Tups, and Z.B. Andrews. 2014. Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice. Endocrinology 155: 2411–2422. doi: 10.1210/en.2013-1861.PubMedCrossRefGoogle Scholar
  17. Broglie, P., K. Matsumoto, S. Akira, D.L. Brautigan, and J. Ninomiya-Tsuji. 2010. Transforming growth factor beta-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway. The Journal of Biological Chemistry 285: 2333–2339. doi: 10.1074/jbc.M109.090522.PubMedCrossRefGoogle Scholar
  18. Bumaschny, V.F., M. Yamashita, R. Casas-Cordero, V. Otero-Corchón, F.S.J. de Souza, M. Rubinstein, and M.J. Low. 2012. Obesity-programmed mice are rescued by early genetic intervention. The Journal of Clinical Investigation 122: 4203–4212. doi: 10.1172/JCI62543.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Burguera, B., M.E. Couce, J. Long, J. Lamsam, K. Laakso, M.D. Jensen, J.E. Parisi, and R.V. Lloyd. 2000. The long form of the leptin receptor (OB-Rb) is widely expressed in the human brain. Neuroendocrinology 71: 187–195. doi:54536.Google Scholar
  20. Cakir, I., M. Perello, O. Lansari, N.J. Messier, C.A. Vaslet, and E.A. Nillni. 2009. Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS One 4: e8322. doi: 10.1371/journal.pone.0008322.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cakir, I., N.E. Cyr, M. Perello, B.P. Litvinov, A. Romero, R.C. Stuart, and E.A. Nillni. 2013. Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing. The Journal of Biological Chemistry 288: 17675–17688. doi: 10.1074/jbc.M113.475343.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Caro, J.F., J.W. Kolaczynski, M.R. Nyce, J.P. Ohannesian, I. Opentanova, W.H. Goldman, R.B. Lynn, P.L. Zhang, M.K. Sinha, and R.V. Considine. 1996. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: A possible mechanism for leptin resistance. Lancet 348: 159–161.PubMedCrossRefGoogle Scholar
  23. Carvalheira, J.B., R.M. Siloto, I. Ignacchitti, S.L. Brenelli, C.R. Carvalho, A. Leite, L.A. Velloso, J.A. Gontijo, and M.J. Saad. 2001. Insulin modulates leptin-induced STAT3 activation in rat hypothalamus. FEBS Letters 500: 119–124.PubMedCrossRefGoogle Scholar
  24. Cesar, H.C., and L.P. Pisani. 2016. Fatty-acid-mediated hypothalamic inflammation and epigenetic programming. The Journal of Nutritional Biochemistry 42: 1–5. doi: 10.1016/j.jnutbio.2016.08.008.PubMedCrossRefGoogle Scholar
  25. Chen, K., F. Li, J. Li, H. Cai, S. Strom, A. Bisello, D.E. Kelley, M. Friedman-Einat, G.A. Skibinski, M.A. McCrory, A.J. Szalai, and A.Z. Zhao. 2006. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nature Medicine 12: 425–432. doi: 10.1038/nm1372.PubMedCrossRefGoogle Scholar
  26. Cheng, A., N. Uetani, P.D. Simoncic, V.P. Chaubey, A. Lee-Loy, C.J. McGlade, B.P. Kennedy, and M.L. Tremblay. 2002. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Developmental Cell 2: 497–503.PubMedCrossRefGoogle Scholar
  27. Cheng, L., Y. Yu, A. Szabo, Y. Wu, H. Wang, D. Camer, and X.-F. Huang. 2015. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice. The Journal of Nutritional Biochemistry 26: 541–548. doi: 10.1016/j.jnutbio.2014.12.011.PubMedCrossRefGoogle Scholar
  28. Chhabra, K.H., J.M. Adams, G.L. Jones, M. Yamashita, M. Schlapschy, A. Skerra, M. Rubinstein, and M.J. Low. 2016. Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity. Molecular Metabolism 5: 869–881. doi: 10.1016/j.molmet.2016.07.012.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cota, D., K. Proulx, K.A.B. Smith, S.C. Kozma, G. Thomas, S.C. Woods, and R.J. Seeley. 2006. Hypothalamic mTOR signaling regulates food intake. Science 312: 927–930. doi: 10.1126/science.1124147.PubMedCrossRefGoogle Scholar
  30. Cota, D., E.K. Matter, S.C. Woods, and R.J. Seeley. 2008. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28: 7202–7208. doi: 10.1523/JNEUROSCI.1389-08.2008.CrossRefGoogle Scholar
  31. Cowley, M.A., J.L. Smart, M. Rubinstein, M.G. Cerdán, S. Diano, T.L. Horvath, R.D. Cone, and M.J. Low. 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411: 480–484. doi: 10.1038/35078085.PubMedCrossRefGoogle Scholar
  32. Cui, Y., L. Huang, F. Elefteriou, G. Yang, J.M. Shelton, J.E. Giles, O.K. Oz, T. Pourbahrami, C.Y.H. Lu, J.A. Richardson, G. Karsenty, and C. Li. 2004. Essential role of STAT3 in body weight and glucose homeostasis. Molecular and Cellular Biology 24: 258–269.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Darnell, J.E., I.M. Kerr, and G.R. Stark. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421.PubMedCrossRefGoogle Scholar
  34. De Souza, C.T., E.P. Araujo, S. Bordin, R. Ashimine, R.L. Zollner, A.C. Boschero, M.J.A. Saad, and L.A. Velloso. 2005. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146: 4192–4199. doi: 10.1210/en.2004-1520.PubMedCrossRefGoogle Scholar
  35. Diaz, B., L. Fuentes-Mera, A. Tovar, T. Montiel, L. Massieu, H.G. Martínez-Rodríguez, and A. Camacho. 2015. Saturated lipids decrease mitofusin 2 leading to endoplasmic reticulum stress activation and insulin resistance in hypothalamic cells. Brain Research 1627: 80–89. doi: 10.1016/j.brainres.2015.09.014.PubMedCrossRefGoogle Scholar
  36. Dietrich, M.O., Z.-W. Liu, and T.L. Horvath. 2013. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155: 188–199. doi: 10.1016/j.cell.2013.09.004.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Dunn, S.L., M. Björnholm, S.H. Bates, Z. Chen, M. Seifert, and M.G. Myers. 2005. Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3. Molecular Endocrinology 19: 925–938. doi: 10.1210/me.2004-0353.PubMedCrossRefGoogle Scholar
  38. Enriori, P.J., A.E. Evans, P. Sinnayah, E.E. Jobst, L. Tonelli-Lemos, S.K. Billes, M.M. Glavas, B.E. Grayson, M. Perello, E.A. Nillni, K.L. Grove, and M.A. Cowley. 2007. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metabolism 5: 181–194. doi: 10.1016/j.cmet.2007.02.004.PubMedCrossRefGoogle Scholar
  39. Frederich, R.C., A. Hamann, S. Anderson, B. Löllmann, B.B. Lowell, and J.S. Flier. 1995. Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nature Medicine 1: 1311–1314.PubMedCrossRefGoogle Scholar
  40. Gamber, K.M., L. Huo, S. Ha, J.E. Hairston, S. Greeley, and C. Bjørbæk. 2012. Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLoS One 7: e30485. doi: 10.1371/journal.pone.0030485.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gao, S., K.P. Kinzig, S. Aja, K.A. Scott, W. Keung, S. Kelly, K. Strynadka, S. Chohnan, W.W. Smith, K.L.K. Tamashiro, E.E. Ladenheim, G.V. Ronnett, Y. Tu, M.J. Birnbaum, G.D. Lopaschuk, and T.H. Moran. 2007. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proceedings of the National Academy of Sciences of the United States of America 104: 17358–17363. doi: 10.1073/pnas.0708385104.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Gong, Y., R. Ishida-Takahashi, E.C. Villanueva, D.C. Fingar, H. Münzberg, and M.G. Myers. 2007. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. The Journal of Biological Chemistry 282: 31019–31027. doi: 10.1074/jbc.M702838200.PubMedCrossRefGoogle Scholar
  43. Gorska, E., K. Popko, A. Stelmaszczyk-Emmel, O. Ciepiela, A. Kucharska, and M. Wasik. 2010. Leptin receptors. European Journal of Medical Research 15(Suppl 2): 50–54.PubMedPubMedCentralGoogle Scholar
  44. Ha, S., S. Baver, L. Huo, A. Gata, J. Hairston, N. Huntoon, W. Li, T. Zhang, E.J. Benecchi, M. Ericsson, S.T. Hentges, and C. Bjørbæk. 2013. Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. PLoS One 8: e77622. doi: 10.1371/journal.pone.0077622.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Harding, H.P., Y. Zhang, A. Bertolotti, H. Zeng, and D. Ron. 2000. Perk is essential for translational regulation and cell survival during the unfolded protein response. Molecular Cell 5: 897–904.PubMedCrossRefGoogle Scholar
  46. Harvey, J., and M.L.J. Ashford. 2003. Leptin in the CNS: Much more than a satiety signal. Neuropharmacology 44: 845–854.PubMedCrossRefGoogle Scholar
  47. Heldsinger, A., G. Grabauskas, X. Wu, S. Zhou, Y. Lu, I. Song, and C. Owyang. 2014. Ghrelin induces leptin resistance by activation of suppressor of cytokine signaling 3 expression in male rats: Implications in satiety regulation. Endocrinology 155: 3956–3969. doi: 10.1210/en.2013-2095.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hosoi, T., and K. Ozawa. 2016. Possible pharmacological approach targeting endoplasmic reticulum stress to ameliorate leptin resistance in obesity. Frontiers in Endocrinology 7: 59. doi: 10.3389/fendo.2016.00059.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Hosoi, T., T. Kawagishi, Y. Okuma, J. Tanaka, and Y. Nomura. 2002. Brain stem is a direct target for leptin’s action in the central nervous system. Endocrinology 143: 3498–3504. doi: 10.1210/en.2002-220077.PubMedCrossRefGoogle Scholar
  50. Hosoi, T., M. Sasaki, T. Miyahara, C. Hashimoto, S. Matsuo, M. Yoshii, and K. Ozawa. 2008. Endoplasmic reticulum stress induces leptin resistance. Molecular Pharmacology 74: 1610–1619. doi: 10.1124/mol.108.050070.PubMedCrossRefGoogle Scholar
  51. Hosoi, T., K. Toyoda, K. Nakatsu, and K. Ozawa. 2014a. Caffeine attenuated ER stress-induced leptin resistance in neurons. Neuroscience Letters 569: 23–26. doi: 10.1016/j.neulet.2014.03.053.PubMedCrossRefGoogle Scholar
  52. Hosoi, T., R. Yamaguchi, K. Noji, S. Matsuo, S. Baba, K. Toyoda, T. Suezawa, T. Kayano, S. Tanaka, and K. Ozawa. 2014b. Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress. EMBO Molecular Medicine 6: 335–346. doi: 10.1002/emmm.201303227.PubMedPubMedCentralGoogle Scholar
  53. Howard, J.K., B.J. Cave, L.J. Oksanen, I. Tzameli, C. Bjørbaek, and J.S. Flier. 2004. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nature Medicine 10: 734–738. doi: 10.1038/nm1072.PubMedCrossRefGoogle Scholar
  54. Hribal, M.L., T.V. Fiorentino, and G. Sesti. 2014. Role of C reactive protein (CRP) in leptin resistance. Current Pharmaceutical Design 20: 609–615.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Jéquier, E. 2002. Leptin signaling, adiposity, and energy balance. Annals of the New York Academy of Sciences 967: 379–388.PubMedCrossRefGoogle Scholar
  56. Kahn, B.B., T. Alquier, D. Carling, and D.G. Hardie. 2005. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 1: 15–25. doi: 10.1016/j.cmet.2004.12.003.PubMedCrossRefGoogle Scholar
  57. Karaskov, E., C. Scott, L. Zhang, T. Teodoro, M. Ravazzola, and A. Volchuk. 2006. Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology 147: 3398–3407. doi: 10.1210/en.2005-1494.PubMedCrossRefGoogle Scholar
  58. Kettner, N.M., S.A. Mayo, J. Hua, C. Lee, D.D. Moore, and L. Fu. 2015. Circadian dysfunction induces leptin resistance in mice. Cell Metabolism 22: 448–459. doi: 10.1016/j.cmet.2015.06.005.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kim, M.-S., Y.K. Pak, P.-G. Jang, C. Namkoong, Y.-S. Choi, J.-C. Won, K.-S. Kim, S.-W. Kim, H.-S. Kim, J.-Y. Park, Y.-B. Kim, and K.-U. Lee. 2006. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nature Neuroscience 9: 901–906. doi: 10.1038/nn1731.PubMedCrossRefGoogle Scholar
  60. Kleinridders, A., D. Schenten, A.C. Könner, B.F. Belgardt, J. Mauer, T. Okamura, F.T. Wunderlich, R. Medzhitov, and J.C. Brüning. 2009. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metabolism 10: 249–259. doi: 10.1016/j.cmet.2009.08.013.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Knight, Z.A., K.S. Hannan, M.L. Greenberg, and J.M. Friedman. 2010. Hyperleptinemia is required for the development of leptin resistance. PLoS One 5: e11376. doi: 10.1371/journal.pone.0011376.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Koistinen, H.A., S.L. Karonen, M. Iivanainen, and V.A. Koivisto. 1998. Circulating leptin has saturable transport into intrathecal space in humans. European Journal of Clinical Investigation 28: 894–897.PubMedCrossRefGoogle Scholar
  63. Kwon, O., K.W. Kim, and M.-S. Kim. 2016. Leptin signalling pathways in hypothalamic neurons. Cellular and Molecular Life Sciences: CMLS 73: 1457–1477. doi: 10.1007/s00018-016-2133-1.PubMedCrossRefGoogle Scholar
  64. Labruna, G., F. Pasanisi, C. Nardelli, R. Caso, D.F. Vitale, F. Contaldo, and L. Sacchetti. 2011. High leptin/adiponectin ratio and serum triglycerides are associated with an “at-risk” phenotype in young severely obese patients. Obesity (Silver Spring) 19: 1492–1496. doi: 10.1038/oby.2010.309.CrossRefGoogle Scholar
  65. Lee, Y., M.Y. Wang, T. Kakuma, Z.W. Wang, E. Babcock, K. McCorkle, M. Higa, Y.T. Zhou, and R.H. Unger. 2001a. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. The Journal of Biological Chemistry 276: 5629–5635. doi: 10.1074/jbc.M008553200.PubMedCrossRefGoogle Scholar
  66. Lee, J.Y., K.H. Sohn, S.H. Rhee, and D. Hwang. 2001b. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. The Journal of Biological Chemistry 276: 16683–16689. doi: 10.1074/jbc.M011695200.PubMedCrossRefGoogle Scholar
  67. Lee, J.-Y., H. Muenzberg, O. Gavrilova, J.A. Reed, D. Berryman, E.C. Villanueva, G.W. Louis, G.M. Leinninger, S. Bertuzzi, R.J. Seeley, G.W. Robinson, M.G. Myers, and L. Hennighausen. 2008. Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity. PLoS One 3: e1639. doi: 10.1371/journal.pone.0001639.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Levin, B.E., A.A. Dunn-Meynell, M.R. Ricci, and D.E. Cummings. 2003. Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats. American Journal of Physiology. Endocrinology and Metabolism 285: E949–E957. doi: 10.1152/ajpendo.00186.2003.PubMedCrossRefGoogle Scholar
  69. Levin, B.E., A.A. Dunn-Meynell, and W.A. Banks. 2004. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 286: R143–R150. doi: 10.1152/ajpregu.00393.2003.PubMedCrossRefGoogle Scholar
  70. Liu, L., S. Chowdhury, X. Fang, J.-L. Liu, and C.B. Srikant. 2014. Attenuation of unfolded protein response and apoptosis by mReg2 induced GRP78 in mouse insulinoma cells. FEBS Letters 588: 2016–2024. doi: 10.1016/j.febslet.2014.04.030.PubMedCrossRefGoogle Scholar
  71. Loh, K., A. Fukushima, X. Zhang, S. Galic, D. Briggs, P.J. Enriori, S. Simonds, F. Wiede, A. Reichenbach, C. Hauser, N.A. Sims, K.K. Bence, S. Zhang, Z.-Y. Zhang, B.B. Kahn, B.G. Neel, Z.B. Andrews, M.A. Cowley, and T. Tiganis. 2011. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metabolism 14: 684–699. doi: 10.1016/j.cmet.2011.09.011.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Lund, I.K., J.A. Hansen, H.S. Andersen, N.P.H. Møller, and N. Billestrup. 2005. Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling. Journal of Molecular Endocrinology 34: 339–351. doi: 10.1677/jme.1.01694.PubMedCrossRefGoogle Scholar
  73. Mantzoros, C.S., A.D. Liolios, N.A. Tritos, V.G. Kaklamani, D.E. Doulgerakis, I. Griveas, A.C. Moses, and J.S. Flier. 1998. Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men. Obesity Research 6: 179–186.PubMedCrossRefGoogle Scholar
  74. Martin, T.L., T. Alquier, K. Asakura, N. Furukawa, F. Preitner, and B.B. Kahn. 2006. Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. The Journal of Biological Chemistry 281: 18933–18941. doi: 10.1074/jbc.M512831200.PubMedCrossRefGoogle Scholar
  75. Metlakunta, A.S., M. Sahu, and A. Sahu. 2008. Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. Endocrinology 149: 1121–1128. doi: 10.1210/en.2007-1307.PubMedCrossRefGoogle Scholar
  76. Milanski, M., G. Degasperi, A. Coope, J. Morari, R. Denis, D.E. Cintra, D.M.L. Tsukumo, G. Anhe, M.E. Amaral, H.K. Takahashi, R. Curi, H.C. Oliveira, J.B.C. Carvalheira, S. Bordin, M.J. Saad, and L.A. Velloso. 2009. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: Implications for the pathogenesis of obesity. Journal of Neuroscience: The Official Journal of the Society for Neuroscience 29: 359–370. doi: 10.1523/JNEUROSCI.2760-08.2009.CrossRefGoogle Scholar
  77. Minokoshi, Y., Y.-B. Kim, O.D. Peroni, L.G.D. Fryer, C. Müller, D. Carling, and B.B. Kahn. 2002. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415: 339–343. doi: 10.1038/415339a.PubMedCrossRefGoogle Scholar
  78. Minokoshi, Y., T. Alquier, N. Furukawa, Y.-B. Kim, A. Lee, B. Xue, J. Mu, F. Foufelle, P. Ferré, M.J. Birnbaum, B.J. Stuck, and B.B. Kahn. 2004. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569–574. doi: 10.1038/nature02440.PubMedCrossRefGoogle Scholar
  79. Morris, D.L., and L. Rui. 2009. Recent advances in understanding leptin signaling and leptin resistance. American Journal of Physiology. Endocrinology and Metabolism 297: E1247–E1259. doi: 10.1152/ajpendo.00274.2009.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Münzberg, H., L. Huo, E.A. Nillni, A.N. Hollenberg, and C. Bjørbaek. 2003. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144: 2121–2131. doi: 10.1210/en.2002-221037.PubMedCrossRefGoogle Scholar
  81. Münzberg, H., M. Björnholm, S.H. Bates, and M.G. Myers. 2005. Leptin receptor action and mechanisms of leptin resistance. Cellular and Molecular Life Sciences: CMLS 62: 642–652. doi: 10.1007/s00018-004-4432-1.PubMedCrossRefGoogle Scholar
  82. Myers, M.G. 2004. Leptin receptor signaling and the regulation of mammalian physiology. Recent Progress in Hormone Research 59: 287–304.PubMedCrossRefGoogle Scholar
  83. Nakazato, M., N. Murakami, Y. Date, M. Kojima, H. Matsuo, K. Kangawa, and S. Matsukura. 2001. A role for ghrelin in the central regulation of feeding. Nature 409: 194–198. doi: 10.1038/35051587.PubMedCrossRefGoogle Scholar
  84. Narin, F., M.E. Atabek, M. Karakukcu, N. Narin, S. Kurtoglu, H. Gumus, B. Coksevim, and R. Erez. 2005. The association of plasma homocysteine levels with serum leptin and apolipoprotein B levels in childhood obesity. Annals of Saudi Medicine 25: 209–214.PubMedGoogle Scholar
  85. Naznin, F., K. Toshinai, T.M.Z. Waise, C. NamKoong, A.S. Md Moin, H. Sakoda, and M. Nakazato. 2015. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. The Journal of Endocrinology 226: 81–92. doi: 10.1530/JOE-15-0139.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Ozcan, L., A.S. Ergin, A. Lu, J. Chung, S. Sarkar, D. Nie, M.G. Myers, and U. Ozcan. 2009. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metabolism 9: 35–51. doi: 10.1016/j.cmet.2008.12.004.PubMedCrossRefGoogle Scholar
  87. Page-Wilson, G., K. Meece, A. White, M. Rosenbaum, R.L. Leibel, R. Smiley, and S.L. Wardlaw. 2015. Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: Correlations with body weight and adiposity. American Journal of Physiology. Endocrinology and Metabolism 309: E458–E465. doi: 10.1152/ajpendo.00206.2015.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Pan, W., H. Tu, H. Hsuchou, J. Daniel, and A.J. Kastin. 2007. Unexpected amplification of leptin-induced Stat3 signaling by urocortin: Implications for obesity. Journal of Molecular Neuroscience 33: 232–238. doi: 10.1007/s12031-007-0071-y.PubMedCrossRefGoogle Scholar
  89. Paz-Filho, G., C. Mastronardi, T. Delibasi, M.-L. Wong, and J. Licinio. 2010. Congenital leptin deficiency: Diagnosis and effects of leptin replacement therapy. Arquivos Brasileiros de Endocrinologia e Metabologia 54: 690–697.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Piper, M.L., E.K. Unger, M.G. Myers, and A.W. Xu. 2008. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Molecular Endocrinology 22: 751–759. doi: 10.1210/me.2007-0389.PubMedCrossRefGoogle Scholar
  91. Plum, L., X. Ma, B. Hampel, N. Balthasar, R. Coppari, H. Münzberg, M. Shanabrough, D. Burdakov, E. Rother, R. Janoschek, J. Alber, B.F. Belgardt, L. Koch, J. Seibler, F. Schwenk, C. Fekete, A. Suzuki, T.W. Mak, W. Krone, T.L. Horvath, F.M. Ashcroft, and J.C. Brüning. 2006. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. The Journal of Clinical Investigation 116: 1886–1901. doi: 10.1172/JCI27123.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Procopio, C., F. Andreozzi, E. Laratta, A. Cassese, F. Beguinot, F. Arturi, M.L. Hribal, F. Perticone, and G. Sesti. 2009. Leptin-stimulated endothelial nitric-oxide synthase via an adenosine 5′-monophosphate-activated protein kinase/Akt signaling pathway is attenuated by interaction with C-reactive protein. Endocrinology 150: 3584–3593. doi: 10.1210/en.2008-0921.PubMedCrossRefGoogle Scholar
  93. Ramírez, S., and M. Claret. 2015. Hypothalamic ER stress: A bridge between leptin resistance and obesity. FEBS Letters 589: 1678–1687. doi: 10.1016/j.febslet.2015.04.025.PubMedCrossRefGoogle Scholar
  94. Reed, A.S., E.K. Unger, L.E. Olofsson, M.L. Piper, M.G. Myers, and A.W. Xu. 2010. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 59: 894–906. doi: 10.2337/db09-1024.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Sahu, A. 2002. Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones. Journal of Neuroendocrinology 14: 796–804.PubMedCrossRefGoogle Scholar
  96. ———. 2011. Intracellular leptin-signaling pathways in hypothalamic neurons: The emerging role of phosphatidylinositol-3 kinase-phosphodiesterase-3B-cAMP pathway. Neuroendocrinology 93: 201–210. doi: 10.1159/000326785.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Sahu, A., K. Koshinaka, and M. Sahu. 2013. Phosphatidylinositol 3-kinase is an upstream regulator of the phosphodiesterase 3B pathway of leptin signalling that may not involve activation of Akt in the rat hypothalamus. Journal of Neuroendocrinology 25: 168–179. doi: 10.1111/j.1365-2826.2012.02386.x.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Sahu, M., P. Anamthathmakula, and A. Sahu. 2015. Phosphodiesterase-3B-cAMP pathway of leptin signalling in the hypothalamus is impaired during the development of diet-induced obesity in FVB/N mice. Journal of Neuroendocrinology 27: 293–302. doi: 10.1111/jne.12266.PubMedCrossRefGoogle Scholar
  99. Sai, K., S. Morioka, G. Takaesu, N. Muthusamy, H.T. Ghashghaei, H. Hanafusa, K. Matsumoto, and J. Ninomiya-Tsuji. 2016. TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus. Journal of Cell Science 129: 1855–1865. doi: 10.1242/jcs.180505.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Santoro, A., G. Mattace Raso, and R. Meli. 2015. Drug targeting of leptin resistance. Life Sciences 140: 64–74. doi: 10.1016/j.lfs.2015.05.012.PubMedCrossRefGoogle Scholar
  101. Sarvas, J.L., N. Khaper, and S.J. Lees. 2013. The IL-6 paradox: Context dependent interplay of SOCS3 and AMPK. Journal of Diabetes and Metabolism 13. doi: 10.4172/2155-6156.S13-003.
  102. Sasaki, T. 2015. Age-associated weight gain, leptin, and SIRT1: A possible role for hypothalamic SIRT1 in the prevention of weight gain and aging through modulation of leptin sensitivity. Frontiers in Endocrinology 6: 109. doi: 10.3389/fendo.2015.00109.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Sasaki, T., and T. Kitamura. 2010. Roles of FoxO1 and Sirt1 in the central regulation of food intake. Endocrine Journal 57: 939–946.PubMedCrossRefGoogle Scholar
  104. Scarpace, P.J., M. Matheny, N. Tümer, K.Y. Cheng, and Y. Zhang. 2005. Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats. Diabetologia 48: 1075–1083. doi: 10.1007/s00125-005-1763-x.PubMedCrossRefGoogle Scholar
  105. Schaab, M., H. Kausch, J. Klammt, M. Nowicki, U. Anderegg, R. Gebhardt, S. Rose-John, J. Scheller, J. Thiery, and J. Kratzsch. 2012. Novel regulatory mechanisms for generation of the soluble leptin receptor: Implications for leptin action. PLoS One 7: e34787. doi: 10.1371/journal.pone.0034787.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Schneeberger, M., M.O. Dietrich, D. Sebastián, M. Imbernón, C. Castaño, A. Garcia, Y. Esteban, A. Gonzalez-Franquesa, I.C. Rodríguez, A. Bortolozzi, P.M. Garcia-Roves, R. Gomis, R. Nogueiras, T.L. Horvath, A. Zorzano, and M. Claret. 2013. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155: 172–187. doi: 10.1016/j.cell.2013.09.003.PubMedCrossRefGoogle Scholar
  107. Schröder, M., and R.J. Kaufman. 2005. ER stress and the unfolded protein response. Mutation Research 569: 29–63. doi: 10.1016/j.mrfmmm.2004.06.056.PubMedCrossRefGoogle Scholar
  108. Schwartz, M.W., E. Peskind, M. Raskind, E.J. Boyko, and D. Porte. 1996. Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans. Nature Medicine 2: 589–593.PubMedCrossRefGoogle Scholar
  109. Stanley, S., K. Wynne, B. McGowan, and S. Bloom. 2005. Hormonal regulation of food intake. Physiological Reviews 85: 1131–1158. doi: 10.1152/physrev.00015.2004.PubMedCrossRefGoogle Scholar
  110. Steinberg, G.R., M.L. Parolin, G.J.F. Heigenhauser, and D.J. Dyck. 2002. Leptin increases FA oxidation in lean but not obese human skeletal muscle: Evidence of peripheral leptin resistance. American Journal of Physiology. Endocrinology and Metabolism 283: E187–E192. doi: 10.1152/ajpendo.00542.2001.PubMedCrossRefGoogle Scholar
  111. Suzuki, A., S. Okamoto, S. Lee, K. Saito, T. Shiuchi, and Y. Minokoshi. 2007. Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase. Molecular and Cellular Biology 27: 4317–4327. doi: 10.1128/MCB.02222-06.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Thaler, J.P., and M.W. Schwartz. 2010. Minireview: Inflammation and obesity pathogenesis: The hypothalamus heats up. Endocrinology 151: 4109–4115. doi: 10.1210/en.2010-0336.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Thaler, J.P., C.-X. Yi, E.A. Schur, S.J. Guyenet, B.H. Hwang, M.O. Dietrich, X. Zhao, D.A. Sarruf, V. Izgur, K.R. Maravilla, H.T. Nguyen, J.D. Fischer, M.E. Matsen, B.E. Wisse, G.J. Morton, T.L. Horvath, D.G. Baskin, M.H. Tschöp, and M.W. Schwartz. 2012. Obesity is associated with hypothalamic injury in rodents and humans. The Journal of Clinical Investigation 122: 153–162. doi: 10.1172/JCI59660.PubMedCrossRefGoogle Scholar
  114. Thon, M., T. Hosoi, M. Yoshii, and K. Ozawa. 2014. Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells. Scientific Reports 4: 7096. doi: 10.1038/srep07096.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Torres-Andrade, R., R. Moldenhauer, N. Gutierrez-Bertín, J. Soto-Covasich, C. Mancilla-Medina, C. Ehrenfeld, and B. Kerr. 2014. The increase in body weight induced by lack of methyl CpG binding protein-2 is associated with altered leptin signalling in the hypothalamus. Experimental Physiology 99: 1229–1240. doi: 10.1113/expphysiol.2014.079798.PubMedCrossRefGoogle Scholar
  116. van de Woestijne, A.P., H. Monajemi, E. Kalkhoven, and F.L.J. Visseren. 2011. Adipose tissue dysfunction and hypertriglyceridemia: Mechanisms and management. Obesity Reviews 12: 829–840. doi: 10.1111/j.1467-789X.2011.00900.x.PubMedCrossRefGoogle Scholar
  117. Van Heek, M., D.S. Compton, C.F. France, R.P. Tedesco, A.B. Fawzi, M.P. Graziano, E.J. Sybertz, C.D. Strader, and H.R. Davis. 1997. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. The Journal of Clinical Investigation 99: 385–390. doi: 10.1172/JCI119171.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Wang, J., S. Obici, K. Morgan, N. Barzilai, Z. Feng, and L. Rossetti. 2001. Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50: 2786–2791.PubMedCrossRefGoogle Scholar
  119. Wang, X., Z. Lacza, Y.E. Sun, and W. Han. 2014. Leptin resistance and obesity in mice with deletion of methyl-CpG-binding protein 2 (MeCP2) in hypothalamic pro-opiomelanocortin (POMC) neurons. Diabetologia 57: 236–245. doi: 10.1007/s00125-013-3072-0.PubMedCrossRefGoogle Scholar
  120. Wardlaw, S.L. 2011. Hypothalamic proopiomelanocortin processing and the regulation of energy balance. European Journal of Pharmacology 660: 213–219. doi: 10.1016/j.ejphar.2010.10.107.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Wilsey, J., and P.J. Scarpace. 2004. Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: Role of leptin in the regulation of hypothalamic long-form leptin receptor expression. The Journal of Endocrinology 181: 297–306.PubMedCrossRefGoogle Scholar
  122. Won, J.C., P.-G. Jang, C. Namkoong, E.H. Koh, S.K. Kim, J.-Y. Park, K.-U. Lee, and M.-S. Kim. 2009. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity (Silver Spring) 17: 1861–1865. doi: 10.1038/oby.2009.194.CrossRefGoogle Scholar
  123. Xu, A.W., C.B. Kaelin, K. Takeda, S. Akira, M.W. Schwartz, and G.S. Barsh. 2005. PI3K integrates the action of insulin and leptin on hypothalamic neurons. The Journal of Clinical Investigation 115: 951–958. doi: 10.1172/JCI24301.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Yang, Z., M. Hulver, R.P. McMillan, L. Cai, E.E. Kershaw, L. Yu, B. Xue, and H. Shi. 2012. Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3). PLoS One 7: e47493. doi: 10.1371/journal.pone.0047493.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Yudkin, J.S., C.D. Stehouwer, J.J. Emeis, and S.W. Coppack. 1999. C-reactive protein in healthy subjects: Associations with obesity, insulin resistance, and endothelial dysfunction: A potential role for cytokines originating from adipose tissue? Arteriosclerosis, Thrombosis, and Vascular Biology 19: 972–978.PubMedCrossRefGoogle Scholar
  126. Zabolotny, J.M., K.K. Bence-Hanulec, A. Stricker-Krongrad, F. Haj, Y. Wang, Y. Minokoshi, Y.-B. Kim, J.K. Elmquist, L.A. Tartaglia, B.B. Kahn, and B.G. Neel. 2002. PTP1B regulates leptin signal transduction in vivo. Developmental Cell 2: 489–495.PubMedCrossRefGoogle Scholar
  127. Zhang, X., G. Zhang, H. Zhang, M. Karin, H. Bai, and D. Cai. 2008. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135: 61–73. doi: 10.1016/j.cell.2008.07.043.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Zhang, Z.-Y., G.T. Dodd, and T. Tiganis. 2015. Protein tyrosine phosphatases in hypothalamic insulin and leptin signaling. Trends in Pharmacological Sciences 36: 661–674. doi: 10.1016/j.tips.2015.07.003.PubMedCrossRefGoogle Scholar
  129. Zhang, R., J. Jiao, W. Zhang, Z. Zhang, W. Zhang, L.-Q. Qin, and S.-F. Han. 2016. Effects of cereal fiber on leptin resistance and sensitivity in C57BL/6J mice fed a high-fat/cholesterol diet. Food & Nutrition Research 60: 31690.CrossRefGoogle Scholar
  130. Zhao, A.Z., J.-N. Huan, S. Gupta, R. Pal, and A. Sahu. 2002. A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Nature Neuroscience 5: 727–728. doi: 10.1038/nn885.PubMedGoogle Scholar
  131. Zheng, M., Q. Zhang, Y. Joe, S.-K. Kim, M.J. Uddin, H. Rhew, T. Kim, S.W. Ryter, and H.T. Chung. 2013. Carbon monoxide-releasing molecules reverse leptin resistance induced by endoplasmic reticulum stress. American Journal of Physiology. Endocrinology and Metabolism 304: E780–E788. doi: 10.1152/ajpendo.00466.2012.PubMedCrossRefGoogle Scholar
  132. Zhong, Z., Z. Wen, and J.E. Darnell. 1994. Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–98.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Faculty of Medicine, Department of General SurgeryGazi UniversityBesevlerTurkey
  2. 2.CankayaTurkey

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