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Diet-Induced Obesity and the Mechanism of Leptin Resistance

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Obesity and Lipotoxicity

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • ———. 2008. The blood-brain barrier as a cause of obesity. Current Pharmaceutical Design 14: 1606–1614.

    Article  CAS  PubMed  Google Scholar 

  • ———. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Harvey, J., and M.L.J. Ashford. 2003. Leptin in the CNS: Much more than a satiety signal. Neuropharmacology 44: 845–854.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jéquier, E. 2002. Leptin signaling, adiposity, and energy balance. Annals of the New York Academy of Sciences 967: 379–388.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Myers, M.G. 2004. Leptin receptor signaling and the regulation of mammalian physiology. Recent Progress in Hormone Research 59: 287–304.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • ———. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sasaki, T., and T. Kitamura. 2010. Roles of FoxO1 and Sirt1 in the central regulation of food intake. Endocrine Journal 57: 939–946.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

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    Atilla Engin M.D., Ph.D.

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    Atilla Engin M.D., Ph.D.

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    Ayse Basak Engin

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    Atilla Engin

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Engin, A. (2017). Diet-Induced Obesity and the Mechanism of Leptin Resistance. In: Engin, A., Engin, A. (eds) Obesity and Lipotoxicity. Advances in Experimental Medicine and Biology, vol 960. Springer, Cham. https://doi.org/10.1007/978-3-319-48382-5_16

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