Obesity has created a very serious public health problem, and World Health Organisation has actually warned that there is an urgent need for multinational cooperation to stem the rise of obesity. More than 20 years ago the discovery of Leptin, which is an adipocyte-secreted hormone and primarily acts on the hypothalamic neurons to activate the regulation of energy homeostasis, created much interest in its potential use for the treatment of obesity, but the hope was soon lost after leptin failed to counteract common diet-induced obesity. In recent years some preclinical studies have surprisingly demonstrated that resistance to leptin can be reversed and the effects of leptin therapy can be amplified by several leptin sensitisers. This paper will critically discuss the plausible revival of leptin for obesity therapy with reference to research findings on various influencing factors contributing to the level of expression and secretion of leptin.
Banks, W. A., & Farrell, C. L. (2003). Impaired Transport of Leptin across the Blood-Brain Barrier in Obesity Is Acquired and Reversible. American Journal of Physiology-Endocrinology and Metabolism, 285, E10-E15. https://doi.org/10.1152/ajpendo.00468.2002
Banks, W. A., Davis, S. M., Bates, S. H., & Myers, M. G. (2000). Activation of Downstream Signals by the Long Form of the Leptin Receptor. Journal of Biological Chemistry, 275, 14563-14572. https://doi.org/10.1074/jbc.275.19.14563
Bhavsar, S., Watkins, J., & Young, A. (1998). Synergy between Amylin and Cholecystokinin for Inhibition of Food Intake in Mice. Physiology and Behavior, 64, 557-561. https://doi.org/10.1016/S0031-9384(98)00110-3
Bjorbaek, C. (2009). Central Leptin Receptor Action and Resistance in Obesity. Journal of Investigative Medicine, 57, 789-794. https://doi.org/10.2310/JIM.0b013e3181bb0d49
Bjorbaek, C., Lavery, H. J., Bates, S. H., Olson, R. K., Davis, S. M., Flier, J. S., & Myers Jr., M. G. (2000). SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985. Journal of Biological Chemistry, 275, 40649-40657. https://doi.org/10.1074/jbc.M007577200
Caro, J. F., Kolaczynski, J. W., Nyce, M. R., Ohannesian, J. P., Opentanova, I., Goldman, W. H., Lynn, R. B., Zhang, P. L., Sinha, M. K., & Considine, R. V. (1996). Decreased Cerebrospinal-Fluid/Serum Leptin Ratio in Obesity: A Possible Mechanism for Leptin Resistance. Lancet, 348, 159-161. https://doi.org/10.1016/S0140-6736(96)03173-X
Chopra, M., Siddhu, A., & Tandon, N. (2014). Mechanism of Leptin Action, Resistance and Regulation of Energy Balance: A Review. Asian Journal of Multidisciplinary Studies, 2, 224-234.
Cone, R. D. (2005). Anatomy and Regulation of the Central Melanocortin System. Nature Neuroscience, 8, 571-578. https://doi.org/10.1038/nn1455
Considine, R. V., Sinha, M. K., Heiman, H. L., Kriauciunas, A., Stephens, T. W., Mark, R. N., Ohannesian, J. P., Marco, C. C., McKee, L. J., Bauer, T. L., & Caro, J. F. (1996). Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans. New England Journal of Medicine, 334, 292-295. https://doi.org/10.1056/NEJM199602013340503
Coppari, R., & Bjorbaek, C. (2012). Leptin Revisited: Its Mechanism of Action and Potential for Treating Diabetes. Nature Reviews Drug Discovery, 11, 692-708. https://doi.org/10.1038/nrd3757
Crujeiras, A. B., Carreira, M. C., Cabia, B., Andrade, S., Amil, M., & Casanueva, F. F. (2015). Leptin Resistance in Obesity: An Epigenetic Landscape. Life Sciences, 140, 57-63. https://doi.org/10.1016/j.lfs.2015.05.003
Curioni, C. C., & Lourengo, P. M. (2005). Long-Term Weight Loss after Diet and Exercise: A Systematic Review. International Journal of Obesity, 29, 1168-1174. https://doi.org/10.1038/sj.ijo.0803015
DeLany, J. (2008). Leptin Hormone and Other Biochemical Influences on Systemic Inflammation. Journal of Bodywork & Movement Therapies, 12, 121-132. https://doi.org/10.1016/j.jbmt.2007.11.006
Duntas, L. H., & Biondi, B. (2013). The Interconnections between Obesity, Thyroid Function, and Autoimmunity: The Multifold Role of Leptin. Thyroid, 23, 646-653. https://doi.org/10.1089/thy.2011.0499
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjorbaek, C., & Flier, J. S. (2000). Two Defects Contribute to Hypothalamic Leptin Resistance in Mice with Diet-Induced Obesity. Journal of Clinical Investigation, 105, 1827-1832. https://doi.org/10.1172/JCI9842
Elmquist, J. K., Elias, C. F., & Saper, C. B. (1999). From Lesions to Leptin: Hypothalamic Control of Food Intake and Body Weight. Neuron, 22, 221-232. https://doi.org/10.1016/S0896-6273(00)81084-3
Enriori, P. J., Evans, A. E., Sinnayah, P., & Cowley, M. A. (2006). Leptin Resistance and Obesity. Obesity, 14, 254-258. https://doi.org/10.1038/oby.2006.319
Farooqi, I. S., Jebb, S. A., Langmack, G., Lawrence, E., Cheetham, C. H., Prentice, A. M., Hughes, I. A., McCamish, M. A., & O'Rahilly, S. (1999). Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency. The New England Journal of Medicine, 341, 879-884. https://doi.org/10.1056/NEJM199909163411204
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S. A., Perna, F., Fontana, S., Lechler, R. I., DePaoli, A. M., & O'Rahilly, S. (2002). Beneficial Effects of Leptin on Obesity, T Cell Hyporesponsiveness, and Neuroendocrine/Metabolic Dysfunction of Human Congenital Leptin Deficiency. Journal of Clinical Investigation, 110, 1093-1103. https://doi.org/10.1172/JCI0215693
Friedman, J. M., & Halaas, J. L. (1998). Leptin and the Regulation of Body Weight in Mammals. Nature, 395, 763-770. https://doi.org/10.1038/27376
Gibson, W. T., Farooqi, I. S., Moreau, M., DePaoli, A. M., Lawrence, E., O'Rahilly, S., & Trussell, R. A. (2004). Congenital Leptin Deficiency Due to Homozygosity for the Delta133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy. The Journal of Clinical Endocrinology & Metabolism, 89, 4821-4826. https://doi.org/10.1210/jc.2004-0376
Halaas, J. L., Boozer, C., Blair-West, J., Fidahusein, N., Denton, D. A., & Friedman, J. M. (1997). Physiological Response to Long-Term Peripheral and Central Leptin Infusion in Lean and Obese Mice. Proceedings of the National Academy of Sciences of the United States of America, 94, 8878-8883. https://doi.org/10.1073/pnas.94.16.8878
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995). Weight-Reducing Effects of the Plama Protein Encoded by the Obese Gene. Science, 269, 543-546. https://doi.org/10.1126/science.7624777
Heymsfield, S. B., Greenberg, A. S., Fujioka, K., Dixon, R. M., Kushner, R., Hunt, T., Lubina, J. A., Patane, J., Self, B., Hunt, P., & McCamish, M. (1999). Recombinant Leptin for Weight Loss in Obese and Lean Adults: A Randomized, Controlled, Dose-Escalation Trial. JAMA, 282, 1568-1575. https://doi.org/10.1001/jama.282.16.1568
Hileman, S. M., Pierroz, D. D., Masuzaki, H., Bjorbaek, C., El-Haschimi, K., Banks, W. A., & Flier, J. S. (2002). Characterization of Short Isoforms of the Leptin Receptor in Rat Cerebral Microvessels and of Brain Uptake of Leptin in Mouse Models of Obesity. Endocrinology, 143, 775-783. https://doi.org/10.1210/endo.143.3.8669
Hileman, S. M., Tornoe, J., Flier, J. S., & Bjorbaek, C. (2000). Transcellular Transport of Leptin by Short Leptin Receptor Isoform ObRa in Madin-Darby Canine Kidney Cells. Endocrinology, 141, 1955-1961. https://doi.org/10.1210/endo.141.6.7450
Hubschle, T., Thom, E., Watson, A., Roth, J., Klaus, S., & Meyerhof, W. (2001). Leptin-Induced Nuclear Translocation of STAT3 Immunoreactivity in Hypothalamic Nuclei Involved in Body Weight Regulation. Journal of Neuroscience, 21, 2413-2424.
Ingalls, A. M., Dickie, M. M., & Snell, G. D. (1996). Obese, A New Mutation in the House Mouse. Obesity Research & Clinical Practice, 4, 101. https://doi.org/10.1002/j.1550-8528.1996.tb00519.x
Kaszubska, W., Falls, H. D., Schaefer, V. G., Haasch, D., Frost, L., Hessler, P., Kroeger, P. E., White, D. W., Jirousek, M. R., & Trevillyan, J. M. (2002). Protein Tyrosine Phosphatase 1B Negatively Regulates Leptin Signalling in a Hypothalamic Cell Line. Molecular and Cellular Endocrinology, 195, 109-118.
Kim, Y. W., Kim, J. Y., Park, Y. H., Park, S. Y., Won, K. C., Choi, K. H., Hub, J. Y., & Moon, K. H. (2006). Metformin Restores Leptin Sensitivity in High-Fat-Fed Obese Rats with Leptin Resistance. Diabetes, 55, 716-724. https://doi.org/10.2337/diabetes.55.03.06.db05-0917
Konner, A. C., & Bruning, J. C. (2012). Selective Insulin and Leptin Resistance in Metabolic Disorders. Cell Metabolism, 16, 144-152. https://doi.org/10.1016/j.cmet.2012.07.004
Kramer, F. M., Jeffery, R. W., Forster, J. L., & Snell, M. K. (1989). Long-Term Follow-Up of Behavioral Treatment for Obesity: Patterns of Weight Regain among Men and Women. International Journal of Obesity, 13, 123-136.
Leon-Cabrera, S., Solis-Lozano, L., Suarez-Alvarez, K., Gonzalez-Chavez, A., Bejar, Y. L., Robles-Diaz, G., & Escobedo, G. (2013). Hyperleptinemia Is Associated with Parameters of Low-Grade Systemic Inflammation and Metabolic Dysfunction in Obese Human Beings. Frontiers in Integrative Neuroscience, 7, 62. https://doi.org/10.3389/fnint.2013.00062
Levin, B. E., & Dunn-Meynell, A. A. (2002). Reduced Central Leptin Sensitivity in Rats with Diet-Induced Obesity. American Journal of Physiology Regulatory Integrative & Comparative Physiology, 283, R941-R948. https://doi.org/10.1152/ajpregu.00245.2002
Levin, B. E., Dunn-Meynell, A. A., & Banks, W. A. (2004). Obesity-Prone Rats Have Normal Blood-Brain Barrier Transport but Defective Central Leptin Signaling before Obesity Onset. American Journal of Physiology Regulatory Integrative & Comparative Physiology, 286, 143-150. https://doi.org/10.1152/ajpregu.00393.2003
Licinio, J., Caglayan, S., Ozata, M., Yildiz, B. O., De Miranda, P. B., O'Kirwan, F., Whitby, R., Liang, L., Cohen, P., Bhasin, S., Krauss, R. M., Veldhuis, J. D., Wagner, A. J., DePaoli, A. M., McCann, S. M., & Wong, M. L. (2004). Phenotypic Effects of Leptin Replacement on Morbid Obesity, Diabetes Mellitus, Hypogonadism, and Behavior in Leptin-Deficient Adults. Proceedings of the National Academy of Sciences of the United States of America, 101, 4531-4536. https://doi.org/10.1073/pnas.0308767101
Maffei, M., Halaas, J., Ravussin, E., Pratley, R. E., Lee, G. H., Zhang, Y., Fei, H., Kim, S., Lallone, R., Ranganathan, S., Kern, P. A., & Friedman, J. M. (1995). Leptin Levels in Human and Rodent: Measurement of Plasma Leptin and Ob RNA in Obese and Weight-Reduced Subjects. Nature Medicine, 1, 1155-1161. https://doi.org/10.1038/nm1195-1155
Matthias, B. (2014). Adipokines—Removing Road Blocks to Obesity and Diabetes Therapy. Molecular Metabolism, 3, 230-240. https://doi.org/10.1016/j.molmet.2014.01.005
Milaneschi, Y., Simonsick, E. M., Vogelzangs, N., Strotmeyer, E. S., Yaffe, K., Harris, T. B., Tolea, M. I., Ferrucci, L., & Penninx, B. W. (2012). Leptin, Abdominal Obesity, and Onset of Depression in Older Men and Women. Journal of Clinical Psychiatry, 73, 1205-1211. https://doi.org/10.4088/JCP.11m07552
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., Cheetham, C. H., Earley, A. R., Barnett, A. H., Prins, J. B., & O'Rahilly, S. (1997). Congenital Leptin Deficiency Is Associated with Severe Early-Onset Obesity in Humans. Nature, 387, 903-908.
Moon, B. C., & Friedman, J. M. (1997). The Molecular Basis of the Obese Mutation in ob2j Mice. Genomics, 42, 152-156. https://doi.org/10.1006/geno.1997.4701
Moon, B. C., Chamberland, J. P., Diakopoulos, K. N., Florenza, C. G., Ziemke, F., Schneider, B., & Mantzoros, C. S. (2011). Leptin and Amylin Act in an Additive Manner to Activate Overlapping Signalling Pathways in Peripheral Tissues: In Vitro and ex Vivo Studies in Humans. Diabetes Care, 34, 132-138. https://doi.org/10.2337/dc10-0518
Morris, D. L., & Rui, L. (2009). Recent Advances in Understanding Leptin Signalling and Leptin Resistance. American Journal of Physiology Regulatory Integrative & Comparative Physiology, 297, E1247-E1259.
Morris, D. L., Cho, K. W., & Rui, L. (2010). Critical Role of Src Homology 2 (SH2) Domain of Neuronal SH2B1 in the Regulation of Body Weight and Glucose Homeostasis in Mice. Endocrinology, 151, 3643-3651. https://doi.org/10.1210/en.2010-0254
Morrison, C. D. (2008). Leptin Resistance and the Response to Positive Energy Balance. Physiology & Behavior, 94, 660-663. https://doi.org/10.1016/j.physbeh.2008.04.009
Müller, T. D., Sullivan, L. M., Habegger, K., Yi, C. X., Kabra, D., Grant, E., Ottaway, N., Krishna, R., Holland, J., Hembree, J., Perez-Tilve, D., Pfluger, P. T., DeGuzman, M. J., Siladi, M. E., Kraynov, V. S., Axelrod, D. W., DiMarchi, R., Pinkstaff, J. K., & Tschöp, M.H. (2012). Restoration of Leptin Responsiveness in Diet-Induced Obese Mice Using an Optimized Leptin Analog in Combination with Exendin-4 of FGF21. Journal of Peptide Science, 18, 383-393. https://doi.org/10.1002/psc.2408
Munzberg, H., Bjornholm, M., Bates, S. H., & Myers Jr., M. G. (2005). Leptin Receptor Action and Mechanisms of Leptin Resistance. Cellular and Molecular Life Sciences, 62, 642-652. https://doi.org/10.1007/s00018-004-4432-1
Myers Jr., M. G., Cowley, M. A., & Munzberg, H. (2008). Mechanisms of Leptin Action and Leptin Resistance. Annual Review of Physiology, 70, 537-556. https://doi.org/10.1146/annurev.physiol.70.113006.100707
Myers Jr., M. G., Heymsfield, S. B., Haft, C., Kahn, B. B., Laughlin, M., Leibel, R. L., Tschöp, M. H., & Yanovski, J. A. (2012). Challenges and Opportunities of Defining Clinical Leptin Resistance. Cell Metabolism, 15, 150-156. https://doi.org/10.1016/j.cmet.2012.01.002
Myers Jr., M. G., Leibel, R. L., Seeley, R. J., & Schwartz, M. W. (2010). Obesity and Leptin Resistance: Distinguishing Cause from Effect. Trends in Endocrinology and Metabolism, 21, 643-651. https://doi.org/10.1016/j.tem.2010.08.002
Na, S. Y., & Myung, S. J. (2012). Obesity and Colorectal Cancer. The Korean Journal of Gastroenterology, 59, 16-26. https://doi.org/10.4166/kjg.2012.59.1.16
Ottaway, N., Mahbod, P., Rivero, B., Norman, L. A., Gerler, A., D’Alessio, D. A., & Perez-Tilve, D. (2015). Diet-Induced Obese Mice Retain Endogenous Leptin Action. Cell Metabolism, 21, 877-882. https://doi.org/10.1016/j.cmet.2015.04.015
Pan, H., Guo, J., & Su, Z. (2014). Advances in Understanding the Interrelations between Leptin Resistance and Obesity. Physiology and Behavior, 130, 157-169. https://doi.org/10.1016/j.physbeh.2014.04.003
Panariello, F., Polsinelli, G., Borlido, C., Monda, M., & De Luca, V. (2012). The Role of Leptin in Antipsychotic-Induced Weight Gain: Genetic and Non-Genetic Factors. Journal of Obesity, 2012, Article ID: 572848. https://doi.org/10.1155/2012/572848
Park, H. K., & Ahima, R.S. (2015). Physiology of Leptin: Energy Homeostasis, Neuroendocrine Function and Metabolism. Metabolism: Clinical and Experimental, 64, 24-34. https://doi.org/10.1016/j.metabol.2014.08.004
Paspala, I., Katsiki, N., Kapoukranidou, D., Mikhailidis, D., & Tsiligiroglou-Fachantidou, A. (2012). The Role of Psychological and Neuroendocrine Mechanisms in Appetite Regulation and Obesity. The Open Cardiovascular Medicine Journal, 6, 147-155. https://doi.org/10.2174/1874192401206010147
Pasquali, R., & Gambineri, A. (2006). Metabolic Effects of Obesity on Reproduction. Reproductive Biomedicine Online, 12, 542-551. https://doi.org/10.1016/S1472-6483(10)61179-0
Patel, S. B., Reams, G. P., Spear, R. M., Freeman, R. H., & Villarreal, D. (2008). Leptin: Linking Obesity, the Metabolic Syndrome, and Cardiovascular Disease. Current Hypertension Reports, 10, 131-137. https://doi.org/10.1007/s11906-008-0025-y
Reed, A., Unger, E., Olofsson, L., Piper, M., Myers, M., & Xu, A. (2010). Functional Role of Suppressor of Cytokine Signalling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis. Diabetes, 59, 894-906. https://doi.org/10.2337/db09-1024
Rosen, E. D., & Spiegelman, B. M. (2006). Adipocytes as Regulators of Energy Balance and Glucose Homeostasis. Nature, 444, 847-853. https://doi.org/10.1038/nature05483
Roth, J. D., Roland, B. L., Cole, R. L., Trevaskis, J. L., Weyer, C., Koda, J. E., Anderson, C. M., Parkes, D. G., & Baron, A. D. (2008). Leptin Responsiveness Restored by Amylin agonism in Diet-Induced Obesity: Evidence from Nonclinical and Clinical Studies. Proceedings of the National Academy of Sciences of the United States of America, 105, 7257-7262. https://doi.org/10.1073/pnas.0706473105
Roujeau, C., Jockers, R., & Dam, J. (2014). New Pharmacological Perspectives for the Leptin Receptor in the Treatment of Obesity. Frontier in Endocrinology, 5, 167. https://doi.org/10.3389/fendo.2014.00167
Sáinz, N., Barrenetxe, J., Moreno-Aliaga, M., & Martinez, J.A. (2015). Leptin Resistance and Diet-Induced Obesity: Central and Peripheral Actions of Leptin. Metabolism: Clinical and Experimental, 64, 35-46. https://doi.org/10.1016/j.metabol.2014.10.015
Scarpace, P. J., & Zhang, Y. (2009). Leptin Resistance: A Predisposing Factor for Diet-Induced Obesity. American Journal of Physiology Regulatory Integrative & Comparative Physiology, 296, R493-500. https://doi.org/10.1152/ajpregu.90669.2008
Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J., & Porte, D. J. (1996). Cerebrospinal Fluid Leptin Levels: Relationship to Plasma Levels and to Adiposity in Humans. Nature Medicine, 2, 589-593. https://doi.org/10.1038/nm0596-589
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000). Central Nervous System Control of Food Intake. Nature, 404, 661-671. https://doi.org/10.1038/35007534
Shapiro, A., Turner, N., Gao, Y., Cheng, K. Y., & Scarpace, P. J. (2011). Prevention and Reversal of Diet-Induced Leptin Resistance with a Sugar-Free Diet Despite High Fat Content. British Journal of Nutrition, 106, 390-397. https://doi.org/10.1017/S000711451100033X
St-Pierre, J., & Tremblay, M. L. (2012). Modulation of Leptin Resistance by Protein Tyrosine Phosphatases. Cell Metabolism, 15, 292-297.
Strobel, A., Issad, T., Camoin, L., Ozata, M., & Strosberg, A. D. (1998). A Leptin Missense Mutation Associated with Hypogonadism and Morbid Obesity. Nature Genetics, 18, 213-215. https://doi.org/10.1038/ng0398-213
Szczesna, M., Kirsz, K., Kucharski, M., Szymaszek, P., & Zieba, D. A. (2013). Obesity and Leptin Resistance: The Role of Growth Hormone. Health, 5, 29-39. https://doi.org/10.4236/health.2013.58A3005
Tao, Y., Zhang, H., Gao, B., Guo, J., Hu, Y., & Su, Z. (2011). Water-Soluble Chitosan Nanoparticles Inhibit Hypercholesterolemia Induced by Feeding a High-Fat Diet in Male Sprague-Dawley Rats. Journal of Nanomaterials, 10, 1-5. https://doi.org/10.1155/2011/814606
Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G. J., Campfield, L. A., Clark, F. T., Deeds, J., Muir, C., Sanker, S., Moriarty, A., Moore, K. J., Smutko, J. S., Mays, G. G., Wool, E. A., Monroe, C. A., & Tepper, R. I. (1995). Identification and Expression Cloning of a Leptin Receptor. Leptin Receptor, 83, 1263-1271.
Trevaskis, J. L., Coffey, T., Cole, R., Lei, C., Wittmer, C., Walsh, B., Weyer, C., Koda, J., Baron, A. D., Parkes, D. G., & Roth, J. D. (2008). Amylin-Mediated Restoration of Leptin Responsiveness in Diet-Induced Obesity: Magnitude and Mechanisms. Endocrinology, 149, 5679-5687. https://doi.org/10.1210/en.2008-0770
Trevaskis, J. L., Turek, V. F., Griffin, P. S., Wittmer, C., Parkes, D. G., & Roth, J. D. (2010). Multi-Hormonal Weight Loss Combinations in Diet-Induced Obese Rats: Therapeutic Potential of Cholecystockinin? Physiology and Behavior, 100, 187-195. https://doi.org/10.1016/j.physbeh.2010.02.023
Tu, H., Kastin, A. J., Hsuchou, H., & Pan, W. (2008). Soluble Receptor Inhibits Leptintransport. Journal of Cellular Physiology, 214, 301-305.
Unniappan, S., & Keiffler, T.J. (2008) Leptin Extends the Anorectic Effects of Chronic PYY(3-36) Administration in Ad Libitum-Fed Rats. American Journal of Physiology Regulatory Integrative & Comparative Physiology, 295, R51-R58. https://doi.org/10.1152/ajpregu.00234.2007
Wang, L, Barachina, M. D., Martinez, V., Wei, J. Y., & Tache, Y. (2000). Synergistic Interaction between CCK and Leptin to Regulate Food Intake. Regulatory Peptides, 92, 79-85. https://doi.org/10.1016/S0167-0115(00)00153-1
Wauman, J., & Tavernier, J. (2011). Leptin Receptor Signaling Pathways to Leptin Resistance. Frontiers in Bioscience, 16, 2771-2793. https://doi.org/10.2741/3885
Widdowson, P. S., Upton, R., Buckingham, R., Arch, J., & Williams, G. (1997). Inhibition of Food Response to Intracerebroventricular Injection of Leptin Is Attenuated in Rats with Diet-Induced Obesity. Diabetes, 46, 1782-1785. https://doi.org/10.2337/diab.46.11.1782
Wong, I. P., Nguyen, A. D., Khor, E. C., Enriquez, R. F., Eisman, J. A., Sainsbury, A., Herzoq, H., & Baldock, P. A. (2013). Neuropeptide Y Is a Critical Modulator of Leptin’s Regulation of Cortical Bone. Journal of Bone and Mineral Research, 28, 886-898. https://doi.org/10.1002/jbmr.1786
Wooley, S. C., & Garner, D. M. (1994). Dietary Treatments for Obesity Are Ineffective. BMJ: British Medical Journal, 309, 655-656. https://doi.org/10.1136/bmj.309.6955.655
World Health Organisation (2016). Report of the Commission on Ending Childhood Obesity. Available from: www.who.int/end-childhood-obesity/publications/echo-report/en/
World Health Organisation (2017). Fact Sheet on “Obesity and overweight”. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/
Yamada-Goto, N., Katsura, G., Ochi, Y., & Nakao, K. (2012). An Approach toward CNS Dysfunction Associated with Metabolic Syndrome; Implication of Leptin, Which Is a Key Molecule of Obesity, in Depression Associated with Obesity. Nihon Shinkei Seishin Yakurigaku Zasshi, 32, 245-250.
Yan, C., Yang, Y., Saito, K., Zu, P., Wang, C., Hinton Jr., A.O., Yan, X., Wu, Q., Tong, Q., Elmquist, J.K., Fukuda, M., & Xu, Y. (2015). Meta-Chlorophenylpiperazine Enhances Leptin Sensitivity in Diet-Induced Obese Mice. British Journal of Pharmacology, 172, 350-3521. https://doi.org/10.1111/bph.13141
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J.M. (1994). Positional Cloning of the Mouse Obese Gene and Its Human Homologue. Nature, 372, 425-432. https://doi.org/10.1038/372425a0