Cited by 593Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

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Leptin in human physiology and pathophysiology

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Mantzoros, Christos S., Magkos, Faidon, Brinkoetter, Mary, Sienkiewicz, Elizabeth, Dardeno, Tina A., Kim, Sang-Yong, Hamnvik, Ole-Petter R., Koniaris, Anastasia·2011·American Journal of Physiology-Endocrinology and Metabolism

DOI 10.1152/ajpendo.00315.2011PMC PMC3191548

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Abstract

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.

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Muoio, D. M., Dohm, G. L., Fiedorek, F. T., Tapscott, E. B., Coleman, R., & Dohn, G. L. (1997) · Diabetes · doi:10.2337/diab.46.8.1360 · Cited by 464
Monogenic Obesity in Humans
Farooqi, I. S., & O’Rahilly, S. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.56.062904.144924 · Cited by 452
Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice
Kim, J. K., Gavrilova, O., Chen, Y., Reitman, M. L., & Shulman, G. I. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8456 · Cited by 443
Insulin Resistance in Morbid Obesity
Greco, A. V., Mingrone, G., Giancaterini, A., Manco, M., Morroni, M., Cinti, S., Granzotto, M., Vettor, R., Camastra, S., & Ferrannini, E. (2002) · Diabetes · doi:10.2337/diabetes.51.1.144 · Cited by 442
Leptin Inhibits Osteoclast Generation
Holloway, W. R., Collier, F., Aitken, C. J., Myers, D. E., Hodge, J. M., Malakellis, M., Gough, T. J., Collier, G., & Nicholson, G. C. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.2.200 · Cited by 440
Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies
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) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706473105 · Cited by 436
Serum Adiponectin Levels Are Inversely Associated with Overall and Central Fat Distribution but Are Not Directly Regulated by Acute Fasting or Leptin Administration in Humans: Cross-Sectional and Interventional Studies
Gavrila, A., Chan, J. L., Yiannakouris, N., Kontogianni, M. D., Miller, L. C., Orlova, C., & Mantzoros, C. S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030214 · Cited by 434
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Body Fat Mass and Macronutrient Intake in Relation to Circulating Soluble Leptin Receptor, Free Leptin Index, Adiponectin, and Resistin Concentrations in Healthy Humans
Yannakoulia, M., Yiannakouris, N., Blüher, S., Matalas, A., Klimis‐Zacas, D. J., & Mantzoros, C. S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021604 · Cited by 429
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The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients
Marchetti, P., Bugliani, M., Lupi, R., Marselli, L., Masini, M., Boggi, U., Filipponi, F., Weir, G. C., Eizirik, D. L., & Cnop, M. (2007) · Diabetologia · doi:10.1007/s00125-007-0816-8 · Cited by 413
Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: Impact on differentiation markers, apoptosis, and osteoclastic signaling
Gordeladze, J. O., Drevon, C. A., Syversen, U., & Reseland, J. E. (2002) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10156 · Cited by 411
Leptin reverses weight loss–induced changes in regional neural activity responses to visual food stimuli
ROSENBAUM, M. S., Sy, M., Pavlovich, K. H., Leibel, R. L., & Joy Hirsch, C. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35055 · Cited by 408
Effect of Lifestyle Modification on Adipokine Levels in Obese Subjects with Insulin Resistance
Monzillo, L. U., Hamdy, O., Horton, E. S., Ledbury, S., Mullooly, C., Jarema, C., Porter, S., Ovalle, K., Moussa, A., & Mantzoros, C. S. (2003) · Obesity Research · doi:10.1038/oby.2003.144 · Cited by 395
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Leptin Indirectly Regulates Gonadotropin-Releasing Hormone Neuronal Function
Quennell, J. H., Mulligan, A. C., Tups, A., Liu, X., Phipps, S. J., Kemp, C. J., Herbison, A. E., Grattan, D. R., & Anderson, G. M. (2009) · Endocrinology · doi:10.1210/en.2008-1693 · Cited by 385
Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa.
Chan, J. L., & Mantzoros, C. S. (2005) · The Lancet · doi:10.1016/s0140-6736(05)66830-4 · Cited by 382
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Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications
Brennan, A. M., & Mantzoros, C. S. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0196 · Cited by 374
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Hypothalamic pathways linking energy balance and reproduction
Hill, J. W., Elmquist, J. K., & Elias, C. F. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00670.2007 · Cited by 367
Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia
Mancuso, P., Gottschalk, A., Phare, S. M., Peters-Golden, M. L., Lukacs, N. W., & Huffnagle, G. B. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.8.4018 · Cited by 365
Diurnal and Ultradian Dynamics of Serum Adiponectin in Healthy Men: Comparison with Leptin, Circulating Soluble Leptin Receptor, and Cortisol Patterns
Gavrila, A., Peng, C., Chan, J. L., Mietus, J. E., Goldberger, A. L., & Mantzoros, C. S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021721 · Cited by 360
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Expression of Leptin Receptor Isoforms in Rat Brain Microvessels
Bjørbæk, C., Elmquist, J. K., Michl, P., Ahima, R. S., Bueren, A. M. V., McCall, A. L., & Flier, J. S. (1998) · Endocrinology · doi:10.1210/endo.139.8.6154 · Cited by 357
Enhanced Weight Loss With Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy
Ravussin, É., Smith, S. R., Mitchell, J. A., Shringarpure, R., Shan, K., Maier, H., Koda, J. E., & Weyer, C. (2009) · Obesity · doi:10.1038/oby.2009.184 · Cited by 335
Leptin therapy in insulin-deficient type I diabetes
Wang, M.-Y., Chen, L., Clark, G. O., Lee, Y., Stevens, R. D., Ilkayeva, O. R., Wenner, B. R., Bain, J. R., Charron, M. J., Newgard, C. B., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909422107 · Cited by 327
The Stimulatory Effect of Leptin on the Neuroendocrine Reproductive Axis of the Monkey
Finn, P. D., Cunningham, M. J., Pau, K. ‐. F., Spies, H. G., Clifton, D. K., & Steiner, R. A. (1998) · Endocrinology · doi:10.1210/endo.139.11.6297 · Cited by 323
Activation of β3 Adrenergic Receptors Suppresses Leptin Expression and Mediates a Leptin-Independent Inhibition of Food Intake in Mice
Mantzoros, C. S., Frederich, R. C., Flier, J. S., Qu, D., Susulic, V. S., Lowell, B. B., & Maratos–Flier, E. (1996) · Diabetes · doi:10.2337/diab.45.7.909 · Cited by 314
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A Leptin Dose-Response Study in Obese (ob/ob) and Lean (+/?) Mice
Harris, R. B. S., Zhou, J. F., Redmann, S. M., Smagin, G. N., Smith, S. R., Rodgers, E. V., & Zachwieja, J. J. (1998) · Endocrinology · doi:10.1210/endo.139.1.5675 · Cited by 313
AMPK as a mediator of hormonal signalling
Lim, C. T., Kola, B., & Korbonits, M. (2009) · Journal of Molecular Endocrinology · doi:10.1677/jme-09-0063 · Cited by 304
Short Term Effects of Leptin on Hepatic Gluconeogenesis and in Vivo Insulin Action
Rossetti, L., Massillon, D., Barzilai, N., Vuguin, P., Chen, W., Hawkins, M., Wu, J., & Wang, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.27758 · Cited by 304
A Longitudinal Assessment of Hormonal and Physical Alterations during Normal Puberty in Boys. V. Rising Leptin Levels May Signal the Onset of Puberty
Mantzoros, C. S. (1997) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.4.1066 · Cited by 300
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Leptin in human physiology and therapeutics
Dardeno, T. A., Chou, S. H.-H., Moon, H., Chamberland, J. P., Fiorenza, C. G., & Mantzoros, C. S. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.06.002 · Cited by 297
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Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.
Kulkarni, R. N., Wang, Z. L., Wang, R. M., Hurley, J. D., Smith, D. M., Ghatei, M. A., Withers, D. J., Gardiner, J. V., Bailey, C. J., & Bloom, S. R. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119818 · Cited by 296
Leptin is an effective treatment for hypothalamic amenorrhea
Chou, S. H., Chamberland, J. P., Liu, X., Matarese, G., Gao, C., Stefanakis, R., Brinkoetter, M. T., Gong, H., Arampatzi, K., & Mantzoros, C. S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015674108 · Cited by 287
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Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women
Licinio, J., Negrão, A. B., Mantzoros, C., Kaklamani, V., Wong, M.-L., Bongiorno, P. B., Mulla, A., Cearnal, L., Veldhuis, J. D., Flier, J. S., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2541 · Cited by 287
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Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Mellitus1
Seufert, J., Kieffer, T. J., Leech, C. A., Holz, G. G., Moritz, W., Ricordi, C., & Habener, J. F. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.2.5460 · Cited by 278
Endoplasmic Reticulum Stress Markers Are Associated with Obesity in Nondiabetic Subjects
Sharma, N. K., Das, S. K., Mondal, A. K., Hackney, O. G., Chu, W. S., Kern, P. A., Rasouli, N., Spencer, H. J., Yao‐Borengasser, A., & Elbein, S. C. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1001 · Cited by 275
Congenital Leptin Deficiency Due to Homozygosity for the Δ133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy
Gibson, W. T., Farooqi, I. S., Moreau, M., DePaoli, A. M., Lawrence, E., O’Rahilly, S., & Trussell, R. A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0376 · Cited by 275
Characterizaton of Short Isoforms of the Leptin Receptor in Rat Cerebral Microvessels and of Brain Uptake of Leptin in Mouse Models of Obesity
Hileman, S. M., Pierroz, D. D., Masuzaki, H., Bjørbæk, C., El-Haschimi, K., Banks, W. A., & Flier, J. S. (2002) · Endocrinology · doi:10.1210/endo.143.3.8669 · Cited by 274
Leptin Concentrations in Relation to Body Mass Index and the Tumor Necrosis Factor-α System in Humans1
Mantzoros, C. S., Moschos, S. J., Avramopoulos, I., Kaklamani, V., Liolios, A. D., Doulgerakis, D. E., Griveas, I., Katsilambros, N. L., & Flier, J. S. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.10.4323 · Cited by 272
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Leptin Treatment Induces Loss of Bone Marrow Adipocytes and Increases Bone Formation in Leptin-Deficient ob/ob Mice
Hamrick, M. W., Della-Fera, M. A., Choi, Y.-H., Pennington, C., Hartzell, D., & Baile, C. A. (2005) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.050103 · Cited by 268
Energy Homeostasis, Obesity and Eating Disorders: Recent Advances in Endocrinology
Gale, S. M., Castracane, V. D., & Mantzoros, C. S. (2004) · Journal of Nutrition · doi:10.1093/jn/134.2.295 · Cited by 267
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Sleep Loss Reduces Diurnal Rhythm Amplitude of Leptin in Healthy Men
Mullington, J. M., Chan, J. L., Van Dongen, H. P. A., Szuba, M. P., Samaras, J., Price, N. J., Meier‐Ewert, H. K., Dinges, D. F., & Mantzoros, C. S. (2003) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2003.01069.x · Cited by 261
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Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice.
Papathanassoglou, E., El-Haschimi, K., Li, X. C., Matarese, G., Strom, T., & Mantzoros, C. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.12.7745 · Cited by 258
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The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin
Kim, M. S., Small, C. J., Stanley, S. A., Morgan, D. G. A., Seal, L. J., Kong, W. M., Edwards, C. M. B., Abusnana, S., Sunter, D., Ghatei, M. A., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8857 · Cited by 256
Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects
Rosenbaum, M., Vandenborne, K., Goldsmith, R., Simoneau, J.-A., Heymsfield, S., Joanisse, D. R., Hirsch, J., Murphy, E., Matthews, D., Segal, K. R., et al. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00474.2002 · Cited by 255
Lipodystrophy: pathophysiology and advances in treatment
Fiorenza, C. G., Chou, S. H.-H., & Mantzoros, C. S. (2010) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.199 · Cited by 255
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Cross-talk between estrogen and leptin signaling in the hypothalamus
Gao, Q., & Horváth, T. L. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00733.2007 · Cited by 251
Identification of Incidental Sequence Polymorphisms and Absence of the db/db Mouse and fa/fa Rat Mutations
Considine, R. V., Caro, J. F., Considine, E. L., Williams, C. J., & Hyde, T. M. (1996) · Diabetes · doi:10.2337/diab.45.7.992 · Cited by 248
In Vivo Administration of Leptin Activates Signal Transduction Directly in Insulin-Sensitive Tissues: Overlapping but Distinct Pathways from Insulin
Kim, Y., Uotani, S., Pierroz, D. D., Flier, J. S., & Kahn, B. B. (2000) · Endocrinology · doi:10.1210/endo.141.7.7536 · Cited by 246
Regulation of Circulating Soluble Leptin Receptor Levels By Gender, Adiposity, Sex Steroids, and Leptin
Chan, J. L., Blüher, S., Yiannakouris, N., Suchard, M. A., Kratzsch, J., & Mantzoros, C. S. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2105 · Cited by 245
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Evidence for Leptin Binding to Proteins in Serum of Rodents and Humans: Modulation With Obesity
Houseknecht, K. L., Mantzoros, C. S., Kuliawat, R., Hadro, E., Flier, J. S., & Kahn, B. B. (1996) · Diabetes · doi:10.2337/diab.45.11.1638 · Cited by 245
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Independent circadian and sleep/wake regulation of adipokines and glucose in humans
Shea, S. A., Hilton, M. F., Orlova, C., Ayers, R. T., & Mantzoros, C. S. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2232 · Cited by 240
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Leptin Induces Insulin-like Signaling That Antagonizes cAMP Elevation by Glucagon in Hepatocytes
Zhao, A. Z., Shinohara, M. M., Huang, D., Shimizu, M., Eldar-Finkelman, H., Krebs, E. G., Beavo, J. A., & Bornfeldt, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.15.11348 · Cited by 237
Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring
Flier, J. S., Harris, M., & Hollenberg, A. N. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9725 · Cited by 230
Synchronicity of Frequently Sampled Thyrotropin (TSH) and Leptin Concentrations in Healthy Adults and Leptin-Deficient Subjects: Evidence for Possible Partial TSH Regulation by Leptin in Humans
Mantzoros, C. S., Ozata, M., Negrao, A. B., Suchard, M. A., Ziotopoulou, M., Caglayan, S., Elashoff, R. M., Cogswell, R. J., Negro, P., Liberty, V., et al. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.7.3284 · Cited by 229
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Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy†
Javor, E. D., Ghany, M. G., Cochran, E. K., Oral, E. A., DePaoli, A. M., Premkumar, A., Kleiner, D. E., & Gorden, P. (2005) · Hepatology · doi:10.1002/hep.20672 · Cited by 228
Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy
Javor, E. D., Cochran, E. K., Musso, C., Young, J. R., DePaoli, A. M., & Gorden, P. (2005) · Diabetes · doi:10.2337/diabetes.54.7.1994 · Cited by 226
Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice
Fujikawa, T., Chuang, J.-C., Sakata, I., Ramadori, G., & Coppari, R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008025107 · Cited by 225
Leptin Regulates Functional Capacities of Polymorphonuclear Neutrophils
Caldefie‐Chezet, F., Poulin, A., & Vasson, M. (2003) · Free Radical Research · doi:10.1080/1071576031000097526 · Cited by 221
Weekly Subcutaneous Pegylated Recombinant Native Human Leptin (PEG-OB) Administration in Obese Men
Hukshorn, C. J., Saris, W. H. M., Westerterp-Plantenga, M. S., Farid, A. R., Smith, F. J., & Campfield, L. A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.11.6955 · Cited by 220
Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats.
Burguera, B. G., Couce, M., Curran, G. L., Jensen, M. D., Lloyd, R. V., Cleary, M. P., & Poduslo, J. F. (2000) · Diabetes · doi:10.2337/diabetes.49.7.1219 · Cited by 217
Cerebrospinal Fluid Leptin in Anorexia Nervosa: Correlation with Nutritional Status and Potential Role in Resistance to Weight Gain
Mantzoros, C. S., Flier, J. S., Lesem, M. D., Brewerton, T. D., & Jimerson, D. C. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.6.4006 · Cited by 216
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Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans.
Chan, J. L., Matarese, G., Shetty, G. K., Raciti, P., Kelesidis, I., Aufiero, D., De Rosa, V., Perna, F., Fontana, S., & Mantzoros, C. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505429103 · Cited by 213
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Hereditary Diabetes in Genetically Obese Mice
Mayer, J., Bates, M. W., & Dickie, M. M. (1951) · Science · doi:10.1126/science.113.2948.746 · Cited by 209
Central control of bone remodeling by neuromedin U
Sato, S., Hanada, R., Kimura, A., Abe, T., Μatsumoto, T., Iwasaki, M., Inose, H., Ida, T., Mieda, M., Takeuchi, Y., et al. (2007) · Nature Medicine · doi:10.1038/nm1640 · Cited by 208
Leptin increases FA oxidation in lean but not obese human skeletal muscle: evidence of peripheral leptin resistance
Steinberg, G. R., Parolin, M. L., Heigenhauser, G. J. F., & Dyck, D. J. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00542.2001 · Cited by 207
Leptin stimulates glucose transport and glycogen synthesis in C 2 C 12 myotubes: evidence for a PI3-kinase mediated effect
Berti, L., Kellerer, M., Capp, E., & H�ring, H. U. (1997) · Diabetologia · doi:10.1007/s001250050722 · Cited by 204
Leptin in humans: lessons from translational research
Blüher, S., & Mantzoros, C. S. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26788e · Cited by 203
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Leptin: in search of role(s) in human physiology and pathophysiology
Mantzoros, C. S., & Moschos, S. J. (1998) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1998.00571.x · Cited by 198
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Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways
Kellerer, M., Koch, M., Metzinger, E., Mushack, J., Capp, E., & Häring, H. (1997) · Diabetologia · doi:10.1007/s001250050832 · Cited by 198
Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat.
Chinookoswong, N., Wang, J. L., & Shi, Z. Q. (1999) · Diabetes · doi:10.2337/diabetes.48.7.1487 · Cited by 197
Leptin Receptor Action in Hepatic Cells
Wang, Y., Kuropatwinski, K. K., White, D. W., Hawley, T. S., Hawley, R. G., Tartaglia, L. A., & Baumann, H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.26.16216 · Cited by 197
Molecular and neural mediators of leptin action
Robertson, S., Leinninger, G. M., & Myers, M. G. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.04.005 · Cited by 195
Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice
Seufert, J., Kieffer, T. J., & Habener, J. F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.2.674 · Cited by 193
OBESE, A NEW MUTATION IN THE HOUSE MOUSE*
Ingalls, A. M., Dickie, M. M., & Snell, G. D. (1996) · Obesity Research · doi:10.1002/j.1550-8528.1996.tb00519.x · Cited by 192
Selective interaction between leptin and insulin signaling pathways in a hepatic cell line
Szántó, I., & Kahn, C. R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050580497 · Cited by 187
Abnormal Germ Cell Development in Cryptorchidism
Huff, D. S., Fenig, D. M., Canning, D. A., Carr, M. C., Zderic, S. A., & Snyder, H. M. (2001) · Hormone Research in Paediatrics · doi:10.1159/000049957 · Cited by 178
Role of Leptin in Reproduction
Mantzoros, C. S. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06228.x · Cited by 177
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Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor
Carpenter, L. R., Farruggella, T. J., Symes, A. J., Karow, M. L., Yancopoulos, G. D., & Stahl, N. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6061 · Cited by 176
Hypothalamic Actions of Neuromedin U
Wren, A., Small, C. J., Abbott, C. R., Jethwa, P. H., Kennedy, A. R., Murphy, K. G., Stanley, S. A., Zollner, A. N., Ghatei, M. A., & Bloom, S. R. (2002) · Endocrinology · doi:10.1210/en.2002-220308 · Cited by 172
Leptin and the Control of Body Weight: A Review of Its Diverse Central Targets, Signaling Mechanisms, and Role in the Pathogenesis of Obesity
Oswal, A., & Yeo, G. S. H. (2009) · Obesity · doi:10.1038/oby.2009.228 · Cited by 170
Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice
Banks, W. A., Clever, C. M., & Farrell, C. L. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.6.e1158 · Cited by 170
Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia
German, J. P., Thaler, J. P., Wisse, B. E., Oh-I, S., Sarruf, D. A., Matsen, M. E., Fischer, J. D., Taborsky, G. J., Schwartz, M. W., & Morton, G. J. (2011) · Endocrinology · doi:10.1210/en.2010-0890 · Cited by 169
Leptin: its role in obesity and beyond
Tritos, N. A., & Mantzoros, C. S. (1997) · Diabetologia · doi:10.1007/s001250050838 · Cited by 167
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Decreased Leptin Levels in Normal Weight Women with Hypothalamic Amenorrhea: The Effects of Body Composition and Nutritional Intake
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Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women
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Authors: Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S.-Y., Hamnvik, O.-P. R., & Koniaris, A.
Affiliations: Beth Israel Deaconess Medical Center (US)
Brigham and Women's Hospital (US)
Corresponding author: Mantzoros, Christos S.
ORCID: Mantzoros, Christos S.
Magkos, Faidon
Kim, Sang-Yong
Hamnvik, Ole-Petter R.
Venue: American Journal of Physiology-Endocrinology and Metabolism
Publisher: American Physiological Society
Published: 2011-10
Volume: 301
Issue: 4
Pages: E567-E584
ISSN: 0193-1849 (ISSN-L)
1522-1555
DOI: 10.1152/ajpendo.00315.2011
PMC: PMC3191548
OpenAlex: W2010072332
Cited by: 593
References: 294
Citations by year: 2026: 18 · 2025: 21 · 2024: 37 · 2023: 30 · 2022: 46 · 2021: 31 · 2020: 42 · 2019: 40 · 2018: 39 · 2017: 40 · 2016: 39 · 2015: 34 · 2014: 64 · 2013: 58 · 2012: 50
FWCI: 5.92
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK079929, DK-081913, R01DK058785, R56DK058785, DK079929, DK 58785, K24DK081913)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords: leptin, leptin deficiency, leptin resistance, hypothalamic amenorrhea, lipoatrophy, HIV-associated lipoatrophy, energy homeostasis, hypothalamic-pituitary axis, bone mineral density, insulin sensitivity, obesity, leptin therapy
MeSH terms: Adipose Tissue, Amenorrhea, Energy Metabolism, Female, Homeostasis, Humans, Hypothalamic Diseases, Hypothalamus, Male, Neurosecretory Systems, Reproduction, Leptin

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