The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
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.
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In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
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The link between hypothalamic epigenetic modifications and long-term feeding control
Benite‐Ribeiro, S. A., Putt, D. A., Soares-Filho, M. C., & dos Santos, J. M. (2016) · Appetite · doi:10.1016/j.appet.2016.08.111 · Cited by 25
The hypothalamic ventral premammillary nucleus: A key site in leptin's regulation of reproduction
Leshan, R. L., & Pfaff, D. W. (2014) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2014.08.008 · Cited by 25
Cardiovascular and Sympathetic Effects of Disrupting Tyrosine 985 of the Leptin Receptor
Harlan, S. M., Morgan, D. A., Dellsperger, D. J., Myers, M. G., Mark, A. L., & Rahmouni, K. (2011) · Hypertension · doi:10.1161/hypertensionaha.110.166538 · Cited by 24
Self-citationLiu, J., Yang, X., Yu, S., & Zheng, R. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1286-1_7 · Cited by 25
PI 3K signalling in leptin receptor cells: Role in growth and reproduction
García-Galiano, D., Borges, B. C., Allen, S. J., & Elias, C. F. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12685 · Cited by 24
Neuronal primary cilia integrate peripheral signals with metabolic drives
DeMars, K. M., Ross, M. R., Starr, A., & McIntyre, J. C. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1150232 · Cited by 21
“The STAT3 pathway, initiated by phosphorylation of Tyr1138 on LepRb, promotes POMC expression to regulate food intake (Bates et al., 2003; Baldini and Phelan, 2019).”
BackgroundRuiter, M., Duffy, P., Simasko, S. M., & Ritter, R. C. (2010) · Endocrinology · doi:10.1210/en.2009-0854 · Cited by 24
Heinrich, G., Ghosh, S., DeAngelis, A. M., Schroeder, J. M., Patel, P. R., Castañeda, T. R., Jeffers, S., Lee, A. D., Jung, D. Y., Zhang, Z., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.03.056 · Cited by 24
Self-citationZhang, H., Qin, G., Zhang, Y., Li, S., & Lin, Q. (2016) · Biology Open · doi:10.1242/bio.020750 · Cited by 23
“The biological activities of long-form leptin receptor via the JAK/STAT pathway in maintaining body weight and energy homeostasis have been demonstrated in mammals (Bates et al., 2003).”
BackgroundLeucine supplementation improves leptin sensitivity in high-fat diet fed rats
Yuan, X., Han, S.-F., Zhang, J., Xu, J., & Qin, L. (2015) · Food & Nutrition Research · doi:10.3402/fnr.v59.27373 · Cited by 24
“for leptin regulation of energy balance (5, 21).”
BackgroundSahu, A. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.05.083 · Cited by 24
Hyperphagia and Obesity in Female Mice Lacking Tissue Inhibitor of Metalloproteinase-1
Gerin, I., Louis, G. W., Zhang, X., Prestwich, T. C., Kumar, T. R., Myers, M. G., MacDougald, O. A., & Nothnick, W. B. (2008) · Endocrinology · doi:10.1210/en.2008-1409 · Cited by 23
Self-citationMonogenic human obesity syndromes
Farooqi, I. S. (2006) · Progress in brain research · doi:10.1016/s0079-6123(06)53006-7 · Cited by 24
Vauthier, V., Swartz, T. D., Chen, P. B., Roujeau, C., Pagnon, M., Mallet, J. J., Sarkis, C., Jockers, R., & Dam, J. (2014) · Gene Therapy · doi:10.1038/gt.2014.36 · Cited by 22
Characterization of STAT3-expressing cells in the postnatal rat brain
Gautron, L., Smedt, V. D., & Layé, S. (2006) · Brain Research · doi:10.1016/j.brainres.2006.04.115 · Cited by 23
Leptin in Thrombosis and Atherosclerosis
Wang, H., Luo, W., & Eitzman, D. T. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990015 · Cited by 23
“The relevance of these pathways toward energy balance has been established by the analysis of mice in which the leptin receptor gene has been substituted by a mutant leptin receptor (leprS1138) containing a Tyr1138-Ser substitution that is defective in signal transducer and activator of transcription 3 (STAT3) binding…”
BackgroundElectrophysiology of Kisspeptin Neurons
Alreja, M. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-6199-9_16 · Cited by 21
“Caution should be used to interpret results from STAT3 signaling, as it may not be required for leptin’s regulation of reproduction [ 51 ].”
BackgroundHan, C., Wu, W., Alé, A., Kim, M. S., & Cai, D. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.730408 · Cited by 23
IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons
Larsen, L., Foll, C. L., Dunn-Meynell, A. A., & Levin, B. E. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00258.2016 · Cited by 23
“LepE 67 1(41) 42 6 (35) 76 4 (37) 74 2(32) LepI 9 1(5) 19 4 (16) 9 1 (4) 9 1(4) LepB 6 1(4) 12 3 (11) 4 1 (2) 5 1(2) NLep 18 1(15) 27 3 (32) 11 3 (6) 14 2(6)”
BackgroundFlees, J. J., Greene, E., Ganguly, B., & Dridi, S. (2020) · Neuropeptides · doi:10.1016/j.npep.2020.102005 · Cited by 23
Leptin Sensitivity in the Developing Rat Hypothalamus
Carlo, A.-S., Pyrski, M. M., Loudes, C., Faivre‐Bauman, A., Epelbaum, J., Williams, L. M., & Meyerhof, W. (2007) · Endocrinology · doi:10.1210/en.2007-0822 · Cited by 23
Pitman, R. T., Fong, J., Billman, P., & Puri, N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038444 · Cited by 23
“The observed decrease in NPY mRNA may be modulated by both a decrease in pAMPk [16], previously shown to activate NPY neurons through Ca2+ influx [34], and an observed increase in pSTAT3 [14,22] (Fig 4).”
BackgroundInfluentialMotta, M., Accornero, P., & Baratta, M. (2004) · Regulatory Peptides · doi:10.1016/j.regpep.2004.05.002 · Cited by 23
Wu, Y., Luo, H., Liu, J., Kang, D., McNeilly, A. S., & Cui, S. (2010) · Endocrinology · doi:10.1210/en.2010-0208 · Cited by 23
The Interplay of Genetic Predisposition, Circadian Misalignment, and Metabolic Regulation in Obesity
Halder, S. K., & Melkani, G. C. (2025) · Current Obesity Reports · doi:10.1007/s13679-025-00613-3 · Cited by 24
“S/S mice were utilized to investigate leptin signaling pathways beyond the conventional STAT3 pathway, contributing to overweight and hyperphagia [151, 152].”
Amigó-Correig, M., Barceló-Batllori, S., Piquer, S., Soty, M., Pujadas, G., Gasa, R., Bortolozzi, A. A., Carmona, M. C., & Gomis, R. (2010) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2010.01339.x · Cited by 22
“Although modulated through ERK1/2 [39] in some cell types, other kinases reported to regulate NPY gene expression cannot be excluded, such as PI3K/AKT (protein kinase B) [8,37], protein kinase C [41] or AMP-activated protein kinase [42].”
BackgroundLi, Y., Ye, L., Jia, G., Chen, H., Yu, L., & Wu, D. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2019.12.039 · Cited by 21
XIONG, R.-B., Li, Q., Wan, W.-R., et al. (2014) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2014.1777 · Cited by 22
“Once leptin is combined with a leptin receptor, the corresponding molecules are activated and transported to the cell nucleus, which promotes the transcription of the target genes p‑STAT1 and p‑STAT3 (7).”
Alcazar, M. A. A., Boehler, E., Rother, E., Amann, K., Vohlen, C., von Hörsten, S., Plank, C., & Dötsch, J. (2012) · Endocrinology · doi:10.1210/en.2011-1670 · Cited by 24
Yoshino, S., Satoh, T., Yamada, M., Hashimoto, K., Tomaru, T., Katano-Toki, A., Kakizaki, S., Okada, S., Shimizu, H., Ozawa, A., et al. (2014) · Endocrinology · doi:10.1210/en.2013-2160 · Cited by 22
“Leptin activates STAT3 as a downstream signal in the hypothalamus (35).”
BackgroundDiagnostic value of serum leptin and a promising novel diagnostic model for sepsis
Chen, M., Wang, B., Xu, Y., et al. (2014) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2014.1506 · Cited by 22
“The hormone leptin (molecular weight of 16-kDa) is mainly generated by adipocytes and contributes to the regulation of energy balance by informing the brain of the volume of adipose tissue in the body, thereby regulating food intake and energy expenditure (15-17).”
2-Aminopurine inhibits leptin receptor signal transduction
Hosoi, T., Matsunami, N., Nagahama, T., Okuma, Y., Ozawa, K., Takizawa, T., & Nomura, Y. (2006) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2006.09.044 · Cited by 22
“Recent in vivo data indicate the physiological importance of Tyr 1138-induced STAT3 signaling for mediating energy balance (Bates et al., 2003).”
Hypothalamic stearoyl-CoA desaturase-2 (SCD2) controls whole-body energy expenditure
de Moura, R. F., do Nascimento, L. F. E., Ignácio-Souza, L. M., Morari, J., Razolli, D. S., Solon, C., de Souza, G. F. P., Festuccia, W. T., & Velloso, L. A. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.188 · Cited by 22
Metadata
- 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 › Endocrinology, Diabetes and Metabolism › 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
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