STAT3 signalling is required for leptin regulation of energy balance but not reproduction
Abstract
Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recent evidence from transgenic animal models suggests that, in addition to the STAT3 signaling system, a distinct and parallel signal transduction pathway exists that regulates hypothalamic neuropeptide Y (NPY) and controls fertility, most likely through activation of extracellular signal-related kinase (ERK) and PI3K kinase.
“Recent evidence from transgenic animal models suggests that, in addition to the STAT3 signaling system, a distinct and parallel signal transduction pathway exists that regulates hypothalamic neuropeptide Y (NPY) and controls fertility, most likely through activation of extracellular signal-related kinase (ERK) and PI3K kinase (55).”
From The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men (2003) · cites this paper as [55]
Mice with homozygous knock-in substitution of LepRb tyrosine residue Tyr1138 had decreased POMC and increased AgRP mRNA levels in the hypothalamus and displayed hyperphagia and decreased energy expenditure, leading to massive early-onset obesity associated with increased serum leptin levels.
“Mice with homozygous knock-in substitution of LepRb tyrosine residue Tyr1138”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Bates et al., 2003
Mice with LepRb Tyr1138 replaced by serine (s/s) are unable to recruit STAT3 and are characterized by hyperphagia, obesity, and reduced energy expenditure.
“Mice bearing a mutant LepRb gene in which Tyr1138 is replaced by a serine residue (s/s mice) are unable to recruit STAT3 and are characterized by hyperphagia, obesity (14) and reduced energy expenditure (12)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [14]
The Tyr1138→STAT3 pathway plays a crucial role in the regulation of energy homeostasis.
“suggesting that the Tyr1138 →STAT3 pathway plays a crucial role in the regulation of regulation of energy homeostasis (12, 14).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [14]
The phenotype of s/s mice does not completely mimic that of ob/ob or db/db mice with respect to glucose metabolism, immune function, or reproduction, implying that other LepRb signals contribute to leptin action.
“However, the phenotype of these s/s mice does not completely mimic that of either ob/ob or db/db mice with respect to glucose metabolism, immune function or reproduction (13, 14), implying that other LepRb signals must also contribute to leptin action.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [14]
Cites
Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451 · see citing works
Self-citationIdentification 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 · see citing works
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 · see citing works
Self-citationCongenital leptin deficiency is associated with severe early-onset obesity in humans
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., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936 · see citing works
Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdán, M. G., Diano, S., Horvath, T. L., Cone, R. D., & Low, M. J. (2001) · Nature · doi:10.1038/35078085 · Cited by 2,356 · see citing works
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.-M., et al. (1998) · Nature · doi:10.1038/32911 · Cited by 2,346 · see citing works
Abnormal splicing of the leptin receptor in diabetic mice
Lee, G.-H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., & Friedman, J. M. (1996) · Nature · doi:10.1038/379632a0 · Cited by 2,327 · see citing works
Chen, H., Charlat, O., Tartaglia, L. A., Woolf, E. A., Weng, X., Ellis, S. J., Lakey, N. D., Culpepper, J., More, K. J., Breitbart, R. E., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81294-5 · Cited by 2,214 · see citing works
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein
Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., & Barsh, G. S. (1997) · Science · doi:10.1126/science.278.5335.135 · Cited by 1,881 · see citing works
Chehab, F. F., Lim, M. E., & Lu, R. (1996) · Nature Genetics · doi:10.1038/ng0396-318 · Cited by 1,476 · see citing works
Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons
Hahn, T. M., Breininger, J. F., Baskin, D. G., & Schwartz, M. W. (1998) · Nature Neuroscience · doi:10.1038/1082 · Cited by 1,164 · see citing works
Self-citationPhenotypes 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 · see citing works
Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E., & Yancopoulos, G. D. (1995) · Science · doi:10.1126/science.7871433 · Cited by 979 · see citing works
Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area
Elias, C. F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R. S., Bjorbæk, C., Flier, J. S., Saper, C. B., & Elmquist, J. K. (1999) · Neuron · doi:10.1016/s0896-6273(01)80035-0 · Cited by 924 · see citing works
Early onset of reproductive function in normal female mice treated with leptin
Chehab, F. F., Mounzih, K., Lu, R., & Lim, M. E. (1997) · Science · doi:10.1126/science.275.5296.88 · Cited by 822 · see citing works
The 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 810 · see citing works
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 · see citing works
Self-citationAttenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y
Erickson, J. C., Hollopeter, G., & Palmiter, R. D. (1996) · Science · doi:10.1126/science.274.5293.1704 · Cited by 794 · see citing works
Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., & Ashford, M. L. J. (1997) · Nature · doi:10.1038/37379 · Cited by 628 · see citing works
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 · see citing works
Self-citationUnraveling the central nervous system pathways underlying responses to leptin
Elmquist, J. K., Maratos-Flier, E., Saper, C. B., & Flier, J. S. (1998) · Nature Neuroscience · doi:10.1038/2164 · Cited by 520 · see citing works
Self-citationDivergent 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 · see citing works
Self-citationLeptin 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 293 · see citing works
Catzeflis, C., Pierroz, D. D., Rohner‐Jeanrenaud, F., Rivier, J., Sizonenko, P. C., & Aubert, M. L. (1993) · Endocrinology · doi:10.1210/endo.132.1.8380374 · Cited by 206 · see citing works
Leptin Requirement for Conception, Implantation, and Gestation in the Mouse
Malik, N. M., Carter, N. D., Murray, J. F., Scaramuzzi, R. J., Wilson, C. A., & Stock, M. J. (2001) · Endocrinology · doi:10.1210/endo.142.12.8535 · Cited by 130 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
“Thus, our data establish a novel pathway for the regulation of food intake which, in response to leptin, most probably acts in a coordinate manner with the STAT”
BackgroundAdipose tissue as an endocrine organ
Galić, S., Oakhill, J. S., & Steinberg, G. R. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.08.018 · Cited by 1,597 · see citing works
“Tyrosine phosphorylation of ObR-L at Tyr1138 within hypothalamic nuclei, has been found to be critical for the regulation of food intake and energy expenditure (Bates et al., 2003).”
BackgroundHypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D. (2008) · Cell · doi:10.1016/j.cell.2008.07.043 · Cited by 1,350 · see citing works
Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
Vong, L., Ye, C., Yang, Z., Choi, B. J., Chua, S. C., & Lowell, B. B. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.028 · Cited by 1,203 · see citing works
“It has previously been established that leptin’s anti-obesity effects require Tyr1138 of the LEPR, which allows for phosphorylation-dependent docking and activation (via subsequent phosphorylation) of the latent transcription factor, STAT3 (Bates et al., 2003).”
The Human Obesity Gene Map: The 2005 Update
Rankinen, T., Zuberi, A., Chagnon, Y. C., Weisnagel, S. J., Argyropoulos, G., Walts, B., Pérusse, L., & Bouchard, C. (2006) · Obesity · doi:10.1038/oby.2006.71 · Cited by 1,119 · see citing works
“7) Lepr 1p31 LEPR Selective loss of long form of leptin receptor Obesity (448)”
BackgroundLeptin and Obesity: Role and clinical implication.
Obradovic, M., Sudar-Milovanovic, E., Soskic, S., Essack, M., Arya, S., Stewart, A. J., Gojobori, T., & Isenovic, E. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.585887 · Cited by 1,121 · see citing works
Flier, J. S. (2004) · Cell · doi:10.1016/s0092-8674(03)01081-x · Cited by 1,105 · see citing works
Mechanisms of leptin action and leptin resistance.
Myers, M. G., Cowley, M. A., & Münzberg, H. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100707 · Cited by 1,074 · see citing works
Self-citationLeptin receptor signaling in POMC neurons is required for normal body weight homeostasis
Balthasar, N., Coppari, R., McMinn, J., Liu, S. M., Lee, C. E., Tang, V., Kenny, C. D., McGovern, R. A., Chua, S. C., Elmquist, J. K., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.004 · Cited by 935 · see citing works
Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding
Hommel, J. D., Trinko, R., Sears, R. M., Georgescu, D., Liu, Z.-W., Gao, X.-B., Thurmon, J. J., Marinelli, M., & DiLeone, R. J. (2006) · Neuron · doi:10.1016/j.neuron.2006.08.023 · Cited by 902 · see citing works
“This indicates that leptin action on the VTA can also modulate behavioral responses to rewarding or novel food, consistent with proposed roles of the VTA dopamine neurons (Schultz and Dickinson, 2000) and observations of dopamine release in the NAc in response to novel food ( Bassareo and Di Chiara, 1999 ).”
Obesity and leptin resistance: distinguishing cause from effect
Myers, M. G., Leibel, R. L., Seeley, R. J., & Schwartz, M. W. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.08.002 · Cited by 906 · see citing works
“of genetic lesions that impair specific leptin-regulated pathways may produce selective leptin resistance, these represent a different case than DIO (39,56).”
Self-citationWang, Z., Aguilar, E. G., Luna, J. I., Dunai, C., Khuat, L. T., Le, C. T., Mirsoian, A., Minnar, C. M., Stoffel, K. M., Sturgill, I. R., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0221-5 · Cited by 865 · see citing works
“…on leptin as a mechanism of obesity induced T cell dysfunction given that STAT3, a major downstream transcription factor of the leptin receptor 44,45 , has known binding sites in the promoter region of PD-1 46,47 and has been implicated in driving expression of PD-1 in human and murine…”
Obesity-Associated Hypertension
Rahmouni, K., Correia, M., Haynes, W. G., & Mark, A. L. (2004) · Hypertension · doi:10.1161/01.hyp.0000151325.83008.b4 · Cited by 780 · see citing works
Intracellular signalling pathways activated by leptin
Frühbeck, G. (. (2006) · Deposito Adademico Digital Universidad De Navarra (University of Navarra) · Cited by 745 · see citing works
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 · see citing works
Adipocytokines in Obesity and Metabolic Disease
Cao, H. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0339 · Cited by 705 · see citing works
Neurogenesis in the Hypothalamus of Adult Mice: Potential Role in Energy Balance
Kokoeva, M. V., Yin, H., & Flier, J. S. (2005) · Science · doi:10.1126/science.1115360 · Cited by 704 · see citing works
Intracellular signalling pathways activated by leptin
Frühbeck, G. (2005) · Biochemical Journal · doi:10.1042/bj20051578 · Cited by 833 · see citing works
The journal of maternal-fetal & neonatal medicine
Societies, O. P. (2002) · Cited by 675 · see citing works
Leptin and the endocrine control of energy balance
Friedman, J. M. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0095-y · Cited by 661 · see citing works
Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism
Park, H. K., & Ahima, R. S. (2014) · Metabolism · doi:10.1016/j.metabol.2014.08.004 · Cited by 675 · see citing works
“Activation JAK2-STAT3 signaling plays a crucial role in leptin's ability to regulate energy homeostasis [16, 17].”
Narrative Review: The Role of Leptin in Human Physiology: Emerging Clinical Applications
Kelesidis, T., Kelesidis, I., Chou, S. H.-H., & Mantzoros, C. S. (2010) · Annals of Internal Medicine · doi:10.7326/0003-4819-152-2-201001190-00008 · Cited by 667 · see citing works
“The binding of leptin to the ObRb receptor activates several signal transduction pathways, including Janus kinase signal transducer and activator of transcription 3 (JAK-STAT3), which is important for regulation of energy homeostasis (15), and phosphatidylinositol 3-kinase (PI3K), which is important for regulation of…”
BackgroundMori, 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 · see citing works
“Stat3 is apparently essential for leptin regulation of energy balanc”
BackgroundThe Brain, Appetite, and Obesity
Berthoud, H., & Morrison, C. D. (2007) · Annual Review of Psychology · doi:10.1146/annurev.psych.59.103006.093551 · Cited by 661 · see citing works
Adipose Tissue as an Endocrine Organ
Ahima, R. S. (2006) · Obesity · doi:10.1038/oby.2006.317 · Cited by 636 · see citing works
“Y1138S (Lepr) mutation disrupted STAT3 activation, resulting in hyperphagia, impairment of thermoregulation, and obesity (35).”
BackgroundInfluentialNeuronal 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 · see citing works
“Leptin-evoked activation of Stat3 suppresses expression of Agrp and stimulates expression of Pomc in the arcuate nucleus; other LRb pathways regulate Np”
BackgroundSelf-citationGuo, S. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0327 · Cited by 627 · see citing works
“…of leptin, an adipocyte-derived hormone that inhibits food intake through CNS leptin receptor neurons activating the Jak2/Stat3 signaling cascade (Bates et al. 2003, Myers & Olson 2012), brain insulin signaling reduced food intake by the activation of PI3K via IRS2 and inactivation of Foxo1,…”
Chan, J. L., Heist, K., DePaoli, A. M., Veldhuis, J. D., & Mantzoros, C. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17490 · Cited by 697 · see citing works
“Recent evidence from transgenic animal models suggests that, in addition to the STAT3 signaling system, a distinct and parallel signal transduction pathway exists that regulates hypothalamic neuropeptide Y (NPY) and controls fertility, most likely through activation of extracellular signal-related kinase (ERK) and PI3…”
BackgroundLeptin Signaling in the Central Nervous System and the Periphery
Bjørbæk, C. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.305 · Cited by 550 · see citing works
“STAT3 activation is likely a crucial component in regulation of body weight by leptin, as specific knockout (KO) of the Y1138 residue of ObRb in mice results in severe obesity (Bates et al., 2003).”
BackgroundDiet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons
Enriori, P. J., Evans, A. E., Sinnayah, P., Jobst, E. E., Tonelli-Lemos, L., Billes, S. K., Glavas, M. M., Grayson, B. E., Perello, M., Nillni, E. A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.02.004 · Cited by 552 · see citing works
“It is believed to be essential for mediating leptin’s effects on homeostatic energy regulation (Bates et al., 2003).”
BackgroundMolecular and anatomical determinants of central leptin resistance
Münzberg, H., & Myers, M. G. (2005) · Nature Neuroscience · doi:10.1038/nn1454 · Cited by 550 · see citing works
Self-citationLeptin targets in the mouse brain
Scott, M. M., Lachey, J. L., Sternson, S. M., Lee, C. E., Elias, C. F., Friedman, J. M., & Elmquist, J. K. (2009) · Journal of Comparative Neurology · doi:10.1002/cne.22025 · Cited by 484 · see citing works
“It is well established that the CNS is the principal target of leptin action (Schwartz et al., 2000; Spiegelman and Flier, 2001; Niswender and Schwartz, 2003; Benoit et al., 2004).”
BackgroundRecent advances in understanding leptin signaling and leptin resistance
Morris, D. L., & Rui, L. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00274.2009 · Cited by 467 · see citing works
“Mutation of Tyr(1138) abolishes the ability of leptin to activate the STAT3 but not other leptin pathways in both cultured cells and mice (4, 6, 209).”
BackgroundBiology and significance of the JAK/STAT signalling pathways
Kiu, H., & Nicholson, S. E. (2012) · Growth Factors · doi:10.3109/08977194.2012.660936 · Cited by 470 · see citing works
“…cytokines, including the IL-6/gp130 family (Akira et al. 1994; Nakajima et al. 1996; Takeda et al. 1998; Gao et al. 2004; Owaki et al. 2008), IL-10 (Takeda et al. 1999; Blumberg et al. 2001), SG-CSF (Shimozaki et al. 1997), leptin (Bates et al. 2003) and IL-21 (Zhou et al. 2007; Avery et al. 2010).”
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 · see citing works
“Also, in agreement with this, mice lacking leptin-mediated STAT3 activation, which are obese but have normal hypothalamic Npy gene expression, are fertile (Bates et al., 2003).”
BackgroundStructure, production and signaling of leptin
Münzberg, H., & Morrison, C. D. (2014) · Metabolism · doi:10.1016/j.metabol.2014.09.010 · Cited by 455 · see citing works
Forkhead 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 449 · see citing works
“, as well as binding of signal transducer and activator of transcription 3 (Stat3) to Ser1138 of the intracellular domain of the leptin receptor (encoded by Lepr”
From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior
Williams, K. W., & Elmquist, J. K. (2012) · Nature Neuroscience · doi:10.1038/nn.3217 · Cited by 421 · see citing works
The spectrum of T cell metabolism in health and disease
Bantug, G. R., Galluzzi, L., Kroemer, G., & Hess, C. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.99 · Cited by 421 · see citing works
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 · see citing works
“The numbers of synapses were virtually identical between ob/ob and db/db mice, giving further credence to our proposition that it is the long form of the leptin receptor that mediates leptin's effect on POMC synaptology, presumably through STAT3 signalin”
BackgroundMethyl donor supplementation prevents transgenerational amplification of obesity
Waterland, R. A., Travisano, M., Tahiliani, K. G., Rached, M.-T., & Mirza, S. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.100 · Cited by 414 · see citing works
Signaling pathways in obesity: mechanisms and therapeutic interventions
Wen, X., Zhang, B., Wu, B., Xiao, H., Li, Z., Li, R., Xu, X., & Li, T. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01149-x · Cited by 456 · see citing works
Leptin signaling and leptin resistance
Zhou, Y., & Rui, L. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0263-5 · Cited by 417 · see citing works
“Disruption of the STAT3 binding site in LEPRb by replacing Tyr(1138) with Ser or Phe in mice results in hyperphagia and obesity to a similar degree as that in db/db mice [43,44].”
BackgroundLeptin, from fat to inflammation: old questions and new insights
Otero, M., Lago, R., Lago, F., Casanueva, F. F., Diéguez, C., Gómez-Reino, J. J., & Gualillo, O. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.11.024 · Cited by 407 · see citing works
“in the Y1138S knock-in mouse, so implying a STAT3-independent leptin receptor signaling transduction pathway [51,52].”
BackgroundThe expectant brain: adapting for motherhood
Brunton, P. J., & Russell, J. A. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2280 · Cited by 407 · see citing works
Central nervous system control of metabolism
Myers, M. G., & Olson, D. P. (2012) · Nature · doi:10.1038/nature11705 · Cited by 399 · see citing works
Self-citationIdentifying 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 388 · see citing works
“We and many other groups have systematically examined distributions of mRNA of leptin receptors in the brain by using ISHH (Mercer et al., 1996; Schwartz et al., 1996; Cheung et al., 1997; Fei et al., 1997; Bjorbaek et al., 1998; Elmquist et al., 1998b).”
MethodChan, J. L., & Mantzoros, C. S. (2005) · The Lancet · doi:10.1016/s0140-6736(05)66830-4 · Cited by 382 · see citing works
Gao, Q., Wolfgang, M. J., Neschen, S., Morino, K., Horvath, T. L., Shulman, G. I., & Fu, X.-Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0303992101 · Cited by 385 · see citing works
de Luca, C., Kowalski, T. J., Zhang, Y., Elmquist, J. K., Lee, C., Kilimann, M. W., Ludwig, T. E., Liu, S.-M., & Chua, S. C. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24059 · Cited by 383 · see citing works
“Mice with defective LEPR-B STAT3 signaling are also fertile but unable to lactate, suggesting that leptin mediates its role in the control of lactation via the LEPR-B STAT3–signaling pathway (30).”
BackgroundOverview of Animal Models of Obesity
Lutz, T. A., & Woods, S. C. (2012) · Current Protocols in Pharmacology · doi:10.1002/0471141755.ph0561s58 · Cited by 380 · see citing works
“Analogous to the ob gene mutation, the mutation of the leptin receptor gene is also found in some human families; however, the mutation is very rare. s/s mouse The s/s mouse is a more specific, genetically engineered animal model of leptin receptor deficiency (Bates et al., 2003, 2005).”
BackgroundAdiponectin, Leptin and Cardiovascular Disorders
Zhao, S., Kusminski, C. M., & Scherer, P. E. (2021) · Circulation Research · doi:10.1161/circresaha.120.314458 · Cited by 398 · see citing works
The emerging role of adipokines as mediators of inflammation and immune responses
Lago, F., Diéguez, C., Gómez-Reino, J. J., & Gualillo, O. (2007) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2007.04.007 · Cited by 370 · see citing works
Modern science versus the stigma of obesity
Friedman, J. M. (2004) · Nature Medicine · doi:10.1038/nm0604-563 · Cited by 368 · see citing works
“Evidence from mice carrying point mutations in the gene encoding the leptin receptor indicates that different signaling pathways are probably activated in different neuronal type”
BackgroundDonato, J., Cravo, R. M., Frazão, R., Gautron, L., Scott, M. M., Lachey, J. L., de Castro, I. A., Margatho, L. O., Lee, S., Lee, C., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci45106 · Cited by 356 · see citing works
The Physiology of Obese-Hyperglycemic Mice [ob/obMice]
Lindström, P. (2007) · The Scientific World JOURNAL · doi:10.1100/tsw.2007.117 · Cited by 353 · see citing works
Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance
Sahu, A. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2003.10.001 · Cited by 351 · see citing works
Williams, K. W., Margatho, L. O., Lee, C. E., Choi, M., Lee, S., Scott, M. M., Elias, C. F., & Elmquist, J. K. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3118-09.2010 · Cited by 352 · see citing works
“It is important to note that both insulin and leptin are capable of activating intracellular signaling cascades which regulate gene transcription independent of changes in cellular activity (Bates et al., 2003; Xu et al., 2007; Fukuda et al., 2008; Hill et al., 2008).”
BackgroundAcute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice
Hill, J. W., Williams, K. W., Ye, C., Luo, J., Balthasar, N., Coppari, R., Cowley, M. A., Cantley, L. C., Lowell, B. B., & Elmquist, J. K. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32964 · Cited by 348 · see citing works
“Leptin-induced transactivation of NPY gene promoter mediated by JAK1, JAK2 and STAT3 in the neural cell lines.”
BackgroundInfluentialNeurobiology of Feeding and Energy Expenditure
Gao, Q., & Horvath, T. L. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094324 · Cited by 346 · see citing works
“STAT3 directly activates POMC transcription and inhibits that of NPY, thus exerting an anoretic effect; whereas deficiencies in STAT3 in the brain result in obesity and diabetes (Bates et al. 2003, Gao et al. 2004), a phenotype resembling leptin and leptin receptor mutants.”
BackgroundLeptin and the maintenance of elevated body weight
Pan, W. W., & Myers, M. G. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.168 · Cited by 344 · see citing works
Self-citationLeptin controls adipose tissue lipogenesis via central, STAT3–independent mechanisms
Buettner, C., Muse, E. D., Cheng, A. M., Chen, L., Scherer, T., Pocai, A., Su, K., Cheng, B., Li, X., Harvey-White, J. D., et al. (2008) · Nature Medicine · doi:10.1038/nm1775 · Cited by 342 · see citing works
Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“While leptin-induced activation of STAT3 is critical for normal energy homeostasis (12, 14), selective deletion of STAT3 in either POMC (205) or NPY/AgRP (70) neurons results in a mild-obesity phenotype, as occurs when leptin receptors are selectively deleted from these cells (5, 46, 187).”
BackgroundInfluentialSelf-citationLeptin: Structure, Function and Biology
Zhang, F. P. Y., Chen, Y., Heiman, M. L., & DiMarchi, R. D. (2005) · Vitamins and hormones · doi:10.1016/s0083-6729(05)71012-8 · Cited by 343 · see citing works
“have shown that mice bearing a mutation (Tyr1138Ser) on OBRb are hyperphagic and obese, with measurable deregulation in expression of hypothalamic POMC, NPY, and AgRP genes (Bates et al., 2003).”
BackgroundCentral and Peripheral Regulation of Food Intake and Physical Activity: Pathways and Genes
Lenard, N. R., & Berthoud, H. (2008) · Obesity · doi:10.1038/oby.2008.511 · Cited by 338 · see citing works
Insulin Signaling in the Central Nervous System
Porte, D., Baskin, D. G., & Schwartz, M. W. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1264 · Cited by 334 · see citing works
Self-citationToll-like receptors: linking inflammation to metabolism
Könner, A. C., & Brüning, J. C. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.08.007 · Cited by 327 · see citing works
The Human Obesity Gene Map: The 2004 Update
Përusse, L., Rankinen, T., Zuberi, A. R., Chagnon, Y. C., Weisnagel, S. J., Argyropoulos, G. A., Walts, B., Snyder, E. E., & Bouchard, C. (2005) · Obesity Research · doi:10.1038/oby.2005.50 · Cited by 326 · see citing works
Münzberg, H., Huo, L., Nillni, E. A., Hollenberg, A. N., & Bjørbæk, C. (2003) · Endocrinology · doi:10.1210/en.2002-221037 · Cited by 328 · see citing works
Plum, L. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27123 · Cited by 326 · see citing works
“(D) Representative immunohistochemistry of pStat3 formation in hypothalamic neurons of male ND-fed control and PPKO mice at 12–15 weeks of age.”
BackgroundInfluentialDirect and indirect effects of leptin on adipocyte metabolism
Harris, R. B. S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.009 · Cited by 316 · see citing works
“Similarly, selective removal of ObRb from neural tissue resulted in obesity and diabetes, but did not affect fertility or cold tolerance of mice [122–123].”
BackgroundInfluentialAhima, R. S., & Osei, S. Y. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.02.014 · Cited by 315 · see citing works
“, IL-6, LIF, oncostatin M, ciliary neurotrophic factor, growth hormone and prolactin, the leptin signal is thought to be transmitted mainly by the JAK-STAT pathway [8,14,88,150,203].”
BackgroundInfluentialAdipokines and the Peripheral and Neural Control of Energy Balance
Ahima, R. S., & Lazar, M. A. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0529 · Cited by 314 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…and displayed hyperphagia and decreased energy expenditure, leading to massive early-onset obesity associated with increased serum leptin levels (Bates et al., 2003; Bates and Myers, 2004), which correlated with increased adipose mass in these mice and also indicated resistance to the normal…”
BackgroundTakahashi, K. A., & Cone, R. D. (2005) · Endocrinology · doi:10.1210/en.2004-1397 · Cited by 308 · see citing works
Selective Insulin and Leptin Resistance in Metabolic Disorders
Könner, A. C., & Brüning, J. C. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.07.004 · Cited by 304 · see citing works
Leptin revisited: its mechanism of action and potential for treating diabetes
Coppari, R., & Bjørbæk, C. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3757 · Cited by 295 · see citing works
Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity
Farooqi, I. S., & O’Rahilly, S. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0966 · Cited by 295 · see citing works
Leptin Deficiency and Diet-Induced Obesity Reduce Hypothalamic Kisspeptin Expression in Mice
Quennell, J. H., Howell, C. S., Roa, J., Augustine, R. A., Grattan, D. R., & Anderson, G. M. (2011) · Endocrinology · doi:10.1210/en.2010-1100 · Cited by 291 · see citing works
Interactions between the “cognitive” and “metabolic” brain in the control of food intake
Berthoud, H. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.12.016 · Cited by 289 · see citing works
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 288 · see citing works
“In addition to activating POMC neurons, the JAK2/STAT3 pathway likely also suppresses AgRP/NPY neurons in the ARC, which produce the orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY), but to a lesser degree [14,80].”
InfluentialThe Tyrosine Phosphatase Shp2 in Development and Cancer
(2010) · Advances in Cancer Research · doi:10.1016/s0065-230x(10)06002-1 · Cited by 277 · see citing works
p70S6 Kinase Phosphorylates AMPK on Serine 491 to Mediate Leptin's Effect on Food Intake
Dagon, Y., Hur, E. E., Zheng, B., Wellenstein, K., Cantley, L. C., & Kahn, B. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.010 · Cited by 283 · see citing works
“This signaling network, which is implicated in leptin’s acute effects (Hill et al., 2008; Niswender et al., 2001), is likely to be complementary to the Stat3-mediated more long-term regulation of food intake and body weight (Bates et al., 2003; Myers et al., 2009).”
BackgroundDiet-induced Obesity Alters AMP Kinase Activity in Hypothalamus and Skeletal Muscle
Martin, T. L., Alquier, T., Asakura, K., Furukawa, N., Preitner, F., & Kahn, B. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512831200 · Cited by 283 · see citing works
Leptin signalling pathways in hypothalamic neurons
Kwon, O., Kim, K. W., & Kim, M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2133-1 · Cited by 283 · see citing works
Neuropeptide Y in normal eating and in genetic and dietary-induced obesity
Beck, B. (2006) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2006.1855 · Cited by 281 · see citing works
CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK
Watt, M. J., Dzamko, N. L., Thomas, W. G., Rose‐John, S., Ernst, M., Carling, D., Kemp, B. E., Febbraio, M. A., & Steinberg, G. R. (2006) · Nature Medicine · doi:10.1038/nm1383 · Cited by 275 · see citing works
“The phosphorylation of Tyr1138 within the long form of LRb is crucial for mediating the effects of leptin on body-weight regulation and STAT3 signalin”
BackgroundThe adipocyte as an endocrine organ in the regulation of metabolic homeostasis
Harwood, H. J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.12.010 · Cited by 273 · see citing works
“and a Y1138S mutation that disrupts STAT3 activation, results in hyperphagia, impairment of thermoregulation, and obesity (Bates et al., 2003; Israel and Chua, 2010).”
BackgroundInfluentialThe melanocortin pathway and control of appetite-progress and therapeutic implications
Baldini, G., & Phelan, K. D. (2019) · Journal of Endocrinology · doi:10.1530/joe-18-0596 · Cited by 279 · see citing works
“Leptin signaling by STAT3 is required for leptin regulation of energy balance (Bates et al. 2003).”
Circadian dysfunction induces leptin resistance in mice
Kettner, N. M., Mayo, S. A., Hua, J., Lee, C., Moore, D. D., & Fu, L. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.005 · Cited by 260 · see citing works
“We found that STAT3 phosphorylation (pSTAT3) in POMC neurons, which is a direct consequence of LEPR-B-mediated JAK2 signaling and is required for LEPR-B-controlled POMC activation (Bates et al., 2003), peaked at ZT2.”
BackgroundNeuronal 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 263 · see citing works
Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin
Sahu, A. (2004) · Endocrinology · doi:10.1210/en.2004-0032 · Cited by 265 · see citing works
“(82) suggests that leptin’s effect on NPY neurons may not be dependent on STAT3 activation.”
BackgroundRecinella, L., Orlando, G., Ferrante, C., Chiavaroli, A., Brunetti, L., & Leone, S. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.578966 · Cited by 261 · see citing works
“In particular, the activation of JAK2/STAT3 signaling was found to be critically involved in modulatory effects of leptin on energy homeostasis (Bates et al., 2003; Dardeno et al., 2010).”
BackgroundRole of Notch and its oncogenic signaling crosstalk in breast cancer
Guo, S., Liu, M., & Gonzalez-Perez, R. R. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.12.002 · Cited by 260 · see citing works
Leptin's Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals
Moon, H., Dalamaga, Μ., Kim, S. Y., Pοlyzos, S. A., Hamnvik, O. R., Magkos, F., Paruthi, J., & Mantzoros, C. S. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1053 · Cited by 257 · see citing works
“Although the ObRb/JAK2/STAT3 pathway is important for leptin-mediated reduction of appetite and body weight, it plays a minor role in leptin’s ability to improve euglycemia (285).”
BackgroundThe role of leptin in leptin resistance and obesity
Zhang, Y., & Scarpace, P. J. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.05.038 · Cited by 253 · see citing works
“The JAK2/STAT3 pathway is believed to be essential for mediating leptin's effects on homeostatic energy regulation [23].”
BackgroundInsulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis
Niswender, K. D., Baskin, D. G., & Schwartz, M. W. (2004) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2004.07.009 · Cited by 262 · see citing works
Self-citationMetabolic control of puberty: Roles of leptin and kisspeptins
Sanchez-Garrido, M. A., & Tena‐Sempere, M. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.01.014 · Cited by 250 · see citing works
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 244 · see citing works
“In the first two of these, it was noted that mutation of the STAT3 binding site on LRb promoted dramatic obesity, with only modest impairment of fertility (6).”
BackgroundAdvances in understanding the interrelations between leptin resistance and obesity
Pan, H., Guo, J., & Su, Z. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.04.003 · Cited by 249 · see citing works
“The process that Y1138 recruits the transcription factor STAT3, together with its phosphorylation by JAK2, dimerization and translocation into the arcuate nucleus, regulates the expression and metabolism of POMC, SOCS3, NPY and AgRP.”
BackgroundInfluential
- Authors
- 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., Neel, B. G., Schwartz, M. W., & Myers, M. G.
- Affiliations
- Joslin Diabetes Center (US)
- Beth Israel Deaconess Medical Center (US)
- University of Washington (US)
- Corresponding author
- Myers, Martin G.
- ORCID
- Venue
- Nature
- Published
- 2003-02
- Volume
- 421
- Issue
- 6925
- Pages
- 856-859
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2103270369
- Semantic Scholar
- 25ab9d73ec0d0c8fc3c6ec167cccbfe002d52c52
- Cited by
- 1,010
- References
- 25
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 19 · 2023: 21 · 2022: 34 · 2021: 35 · 2020: 50 · 2019: 32 · 2018: 46 · 2017: 35 · 2016: 48 · 2015: 52 · 2014: 66 · 2013: 67 · 2012: 54
- FWCI
- 20.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- STAT3 signaling, leptin, leptin receptor, energy homeostasis, obesity, fertility, neuropeptide Y, melanocortin system, hypothalamus, glucose homeostasis, db/db mice, hyperphagia, insulin resistance
- MeSH terms
- Alleles, alpha-MSH, Animals, Blood Glucose, Body Weight, Cell Line, Diabetes Mellitus, DNA-Binding Proteins, Energy Metabolism, Female, Homeostasis, Humans, Infertility, Male, Neuropeptide Y, Obesity, Phenotype, Receptors, Cell Surface, Reproduction, RNA, Messenger, Signal Transduction, Trans-Activators, Leptin, Estrous Cycle, STAT3 Transcription Factor, Mice, Receptors, Leptin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
