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Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
Open accessAbstract
The adipose-derived hormone, leptin, acts via its receptor (LRb) to convey the status of body energy stores to the brain, decreasing feeding and potentiating neuroendocrine energy expenditure. The failure of high levels of leptin in most obese individuals to promote weight loss defines a state of diminished responsiveness to increased leptin, termed leptin resistance. Leptin stimulates the phosphorylation of several tyrosine residues on LRb to mediate leptin action. We homologously replaced LRb in mice with a receptor with a mutation in one of these sites (Tyr985) in order to examine its role in leptin action and signal attenuation in vivo. Mice homozygous for this mutation are neuroendocrinologically normal, but females demonstrate decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat diet-induced obesity, and increased leptin sensitivity in a sex-biased manner. Thus, leptin activates autoinhibitory signals via LRb Tyr985 to attenuate the anti-adiposity effects of leptin, especially in females, potentially contributing to leptin insensitivity in obesity.
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“These results support data from cultured cells (22) suggesting that Tyr985 attenuates leptin action in vivo, presumably by serving as the SOCS-3 binding site (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [24]
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“mutation of Tyr985 in these (l/l) mice resulted in a lean phenotype characterized by reduced food intake and adiposity, and increased leptin sensitivity (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [24]
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“mutation of LRb Tyr985 prevents SOCS-3 action on the leptin receptor and thereby results in mice which display increased leptin sensitivity, are lean and are resistant to DIO (24).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [24]
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Cites
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419
Identification and expression cloning of a leptin receptor, OB-R.
Tartaglia, L. A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G. J., Campfield, L. A., Clark, F. T., Deeds, J., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90151-5 · Cited by 3,496
Role of leptin in the neuroendocrine response to fasting
Ahima, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996) · Nature · doi:10.1038/382250a0 · Cited by 3,117
AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., et al. (2004) · Nature · doi:10.1038/nature02440 · Cited by 1,637
Hypothalamic mTOR Signaling Regulates Food Intake
Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., & Seeley, R. J. (2006) · Science · doi:10.1126/science.1124147 · Cited by 1,278
Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.
Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J. E., Stoffel, M., & Friedman, J. M. (1996) · Nature Genetics · doi:10.1038/ng0996-95 · Cited by 1,086
Phenotypes of Mouse diabetes and Rat fatty Due to Mutations in the OB (Leptin) Receptor
Chua, S. C., Chung, W. K., Wu-Peng, X. S., Zhang, Y., Liu, S.-M., Tartaglia, L. A., & Leibel, R. L. (1996) · Science · doi:10.1126/science.271.5251.994 · Cited by 1,071
Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance
Bjørbæk, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E., & Flier, J. S. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80062-3 · Cited by 1,014
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
Bates, S. H., Stearns, W. H., Dundon, T. A., Schubert, M., Tso, A. W. K., Wang, Y., Banks, A. S., Lavery, H. J., Haq, A. K., Maratos-Flier, E., et al. (2003) · Nature · doi:10.1038/nature01388 · Cited by 1,010 · cited 20×
“Although the effects of Tyr985 and other sensitizers of leptin signaling are most easily and commonly studied by examining the regulation of STAT3 signaling, the increased suppression of AgRP and NPY mRNA expression in the l/l animals also suggests the importance of Tyr985 in attenuating STAT3-independent signals, sin…”
BackgroundMethodInfluentialSelf-citationTwo defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjørbæk, C., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9842 · Cited by 887
Self-citationThe full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors.
Baumann, H., Morella, K. K., White, D. W., Dembski, M., Bailon, P., Kim, H., Lai, C. F., & Tartaglia, L. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8374 · Cited by 827
PTP1B Regulates Leptin Signal Transduction In Vivo
Zabolotny, J. M., Bence, K. K., Stricker‐Krongrad, A., Haj, F. G., Wang, Y., Minokoshi, Y., Kim, Y., Elmquist, J. K., Tartaglia, L. A., Kahn, B. B., et al. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00148-x · Cited by 818
Activation of Downstream Signals by the Long Form of the Leptin Receptor
Banks, A. S., Davis, S. M., Bates, S. H., & Myers, M. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14563 · Cited by 797
Self-citationDhillon, H., Zigman, J. M., Ye, C., Lee, C. E., McGovern, R. A., Tang, V., Kenny, C. D., Christiansen, L. M., White, R. D., Edelstein, E. A., et al. (2006) · Neuron · doi:10.1016/j.neuron.2005.12.021 · Cited by 791
Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice
Münzberg, H., Flier, J. S., & Bjørbæk, C. (2004) · Endocrinology · doi:10.1210/en.2004-0726 · Cited by 737
Self-citationSelective deletion of leptin receptor in neurons leads to obesity
Cohen, P., Zhao, C., Cai, X., Montez, J. M., Rohani, S., Feinstein, P. G., Mombaerts, P., & Friedman, J. M. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13914 · Cited by 664
Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., Torisu, T., Chien, K. R., Yasukawa, H., & Yoshimura, A. (2004) · Nature Medicine · doi:10.1038/nm1071 · Cited by 651
Neuronal PTP1B regulates body weight, adiposity and leptin action
Bence, K. K., Delibegovic, M., Xue, B., Gorgun, C. Z., Hotamisligil, G. S., Neel, B. G., & Kahn, B. B. (2006) · Nature Medicine · doi:10.1038/nm1435 · Cited by 633
Key enzyme in leptin-induced anorexia
Niswender, K. D., Morton, G. J., Stearns, W. H., Rhodes, C. J., Myers, M. G., & Schwartz, M. W. (2001) · Nature · doi:10.1038/35101657 · Cited by 585
Self-citationSelective deletion of leptin receptor in neurons leads to obesity
Cohen, P., Zhao, C., Cai, X., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113914 · Cited by 554
Gonadal Hormones Determine Sensitivity to Central Leptin and Insulin
Clegg, D. J., Brown, L. M., Woods, S. C., & Benoit, S. C. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-1339 · Cited by 552
SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985
Bjørbæk, C., Lavery, H. J., Bates, S. H., Olson, R. K., Davis, S. M., Flier, J. S., & Myers, M. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m007577200 · Cited by 537
Self-citationHoward, J. K., Cave, B. J., Oksanen, L. J., Tzameli, I., Bjørbæk, C., & Flier, J. S. (2004) · Nature Medicine · doi:10.1038/nm1072 · Cited by 490
Leptin Receptor Signaling and the Regulation of Mammalian Physiology
Myers, M. G. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.287 · Cited by 463
Self-citationForkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake
Kitamura, T., Feng, Y., Kitamura, Y., Chua, S. C., Xu, A. W., Barsh, G. S., Rossetti, L., & Accili, D. (2006) · Nature Medicine · doi:10.1038/nm1392 · Cited by 458
Coppari, R., Ichinose, M., Lee, C. E., Pullen, A. E., Kenny, C. D., McGovern, R. A., Tang, V., Liu, S. M., Ludwig, T., Chua, S. C., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.004 · Cited by 457
Gao, Q., Mezei, G., Nie, Y., Rao, Y., Choi, C. S., Bechmann, I., Leranth, C., Toran-Allerand, D., Priest, C. A., Roberts, J. L., et al. (2007) · Nature Medicine · doi:10.1038/nm1525 · Cited by 416
Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis
Elmquist, J. K., Coppari, R., Balthasar, N., Ichinose, M., & Lowell, B. B. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20786 · Cited by 406
Divergent Roles of SHP-2 in ERK Activation by Leptin Receptors
Bjørbæk, C., Buchholz, R. M., Davis, S. M., Bates, S. H., Pierroz, D. D., Gu, H., Neel, B. G., Myers, M. G., & Flier, J. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007439200 · Cited by 364
Self-citationCIS3/SOCS-3 Suppresses Erythropoietin (EPO) Signaling by Binding the EPO Receptor and JAK2
Sasaki, A. T., Yasukawa, H., Shouda, T., Kitamura, T., Đikić, I., & Yoshimura, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003456200 · Cited by 341
Diverse Biochemical Properties of Shp2 Mutants
Keilhack, H., David, F. S., McGregor, M. J., Cantley, L. C., & Neel, B. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504699200 · Cited by 300
Leptin Receptor (OB-R) Signaling
White, D. W., Kuropatwinski, K. K., Devos, R., Baumann, H., & Tartaglia, L. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.7.4065 · Cited by 295
Shp-2 Tyrosine Phosphatase: Signaling One Cell or Many
Feng, G.-S. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4668 · Cited by 285
Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism
Zhang, E. E., Chapeau, E. A., Hagihara, K., & Feng, G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405041101 · Cited by 270
Leptin receptor action and mechanisms of leptin resistance
Münzberg, H., Björnholm, M., Bates, S. H., & Myers, M. G. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4432-1 · Cited by 267
Self-citationThe role of leptin receptor signaling in feeding and neuroendocrine function
Bates, S. H., & Myers, M. G. (2003) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2003.10.003 · Cited by 245
Self-citationSuppressor of Cytokine Signaling 3 Is a Physiological Regulator of Adipocyte Insulin Signaling
Shi, H., Tzameli, I., Bjørbæk, C., & Flier, J. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403886200 · Cited by 223
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
Li, C., & Friedman, J. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.17.9677 · Cited by 176
Monogenic Human Obesity Syndromes
Farooqi, I. S. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.409 · Cited by 170
Dunn, S. L., Björnholm, M., Bates, S. H., Chen, Z., Seifert, M. M., & Myers, M. G. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0353 · Cited by 157
Self-citationBanks, W. A. (2004) · Peptides · doi:10.1016/j.peptides.2004.02.014 · Cited by 153
Transgenic Complementation of Leptin-Receptor Deficiency
Kowalski, T. J., Liu, S.-M., Leibel, R. L., & Chua, S. C. (2001) · Diabetes · doi:10.2337/diabetes.50.2.425 · Cited by 150
Gender Differences in the Control of Energy Homeostasis
Woods, S. C., Gotoh, K., & Clegg, D. J. (2003) · Experimental Biology and Medicine · doi:10.1177/153537020322801012 · Cited by 148
LRb-STAT3 Signaling Is Required for the Neuroendocrine Regulation of Energy Expenditure by Leptin
Bates, S. H., Dundon, T. A., Seifert, M., Carlson, M., Maratos-Flier, E., & Myers, M. G. (2004) · Diabetes · doi:10.2337/diabetes.53.12.3067 · Cited by 139
Self-citationPleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines
Hekerman, P., Zeidler, J., Bamberg‐Lemper, S., Knobelspies, H., Lavens, D., Tavernier, J. H., Joost, H., & Becker, W. B. (2004) · FEBS Journal · doi:10.1111/j.1432-1033.2004.04391.x · Cited by 122
Leptin as a Therapeutic Agent--Trials and Tribulations
Mantzoros, C. S., & Flier, J. S. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.11.7062 · Cited by 117
盛, 裕. (2006) · Medical Entomology and Zoology · Cited by 58
Transcriptional Regulation of Agouti-Related Protein (Agrp) in Transgenic Mice
Kaelin, C. B., Xu, A. W., Lu, X., & Barsh, G. S. (2004) · Endocrinology · doi:10.1210/en.2004-0956 · Cited by 46
Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines
Hekerman, P., Zeidler, J., Bamberg‐Lemper, S., et al. (2004) · FEBS Journal · doi:10.1111/j.1742-4658.2004.04391.x · Cited by 38
Research works printed but not linked: 1
- Mantzoros, 2000, J. Clin. Endocrinol. Metab., 85, 4000
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Metadata
- Authors
- Björnholm, M., Münzberg, H., Leshan, R. L., Villanueva, E. C., Bates, S. H., Louis, G. W., Jones, J. C., Ishida-Takahashi, R., Bjørbaek, C., & Myers, M. G.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Myers, Martin G.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-05-01
- Volume
- 117
- Issue
- 5
- Pages
- 1354-1360
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1838925
- OpenAlex
- W2109717216
- Cited by
- 183
- References
- 48
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 3 · 2021: 3 · 2020: 11 · 2019: 7 · 2018: 8 · 2017: 13 · 2016: 3 · 2015: 8 · 2014: 17 · 2013: 16 · 2012: 17
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Svenska Sällskapet för Medicinsk Forskning
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56731, R37DK056731, DK 57768, R01DK057768, R01DK056731)
- 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 receptor, leptin resistance, obesity, high-fat diet-induced obesity, feeding behavior, orexigenic peptides, sex differences, neuroendocrine regulation, energy homeostasis
- MeSH terms
- Animals, Endocrine System, Female, Male, Mice, Inbred C57BL, Obesity, Receptors, Cell Surface, Sensitivity and Specificity, Sex Factors, Thinness, Tyrosine, Signal Transduction, Amino Acid Substitution, Leptin, Mice, Receptors, Leptin
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