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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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“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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Items 201–300 of 999
Leptin Signaling Targets the Thyrotropin-Releasing Hormone Gene Promoterin Vivo
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“For example, the s/s mice created by Bates et al. (2003) were developed to investigate the role of individual leptin signals, by introducing a knock-in mutation that disrupted the dominant intracellular signalling pathway through which leptin was believed to have its major action (the STAT3…”
Central nervous control of energy and glucose balance: focus on the central melanocortin system
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“To further confirm that HSP60 is regulated in a leptin-STAT3–dependent manner in vivo, we assessed Hsp60 gene expression in knockin mice expressing a leptin receptor with a mutation at the STAT3 activation site (leprS1138) (32).”
Activation of Stat3 Signaling in AgRP Neurons Promotes Locomotor Activity
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“AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor.”
BackgroundSH2B1 (SH2-B) and JAK2: a multifunctional adaptor protein and kinase made for each other
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Self-citationIntegrative neurobiology of energy homeostasis-neurocircuits, signals and mediators
Sánchez-Lasheras, C., Könner, A. C., & Brüning, J. C. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.08.002 · Cited by 127
“bind STAT3 rapidly develop massive hyperphagia and obesity that resemble very much to that observed in ob/ob or db/db mice [13,62].”
BackgroundA Role for Brain-Specific Homeobox Factor Bsx in the Control of Hyperphagia and Locomotory Behavior
Σάκκου, Μ., Wiedmer, P., Anlag, K., Hamm, A. C., Seuntjens, E., Ettwiller, L. M., Tschöp, M. H., & Treier, M. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.007 · Cited by 117
“In case of Agrp gene regulation , elegant genetic experiments have shown that leptin receptor-dependent Stat3-signaling is modulating Agrp expression (Bates et al., 2003).”
Early-Life Exposure to Testosterone Programs the Hypothalamic Melanocortin System
Nohara, K., Zhang, Y., Waraich, R. S., Laque, A., Tiano, J. P., Tong, J., Münzberg, H., & Mauvais-Jarvis, F. (2011) · Endocrinology · doi:10.1210/en.2010-1288 · Cited by 120
Desai, M., Gayle, D. A., Han, G., & Ross, M. G. (2007) · Reproductive Sciences · doi:10.1177/1933719107303983 · Cited by 120
Leptin Functions in Infectious Diseases
Maurya, R., Bhattacharya, P., Dey, R., & Nakhasi, H. L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02741 · Cited by 118
“STAT3 activates transcription of suppressor of cytokine signaling (SOCS)-3, a protein that inhibits JAK2 and STAT3 signaling during prolonged stimulation of the Leptin receptor long isoform (Lep-Rb) (147, 148).”
BackgroundPleiotropy 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
STAT3 phosphorylation in central leptin resistance
Liu, H., Du, T., Li, C., & Yang, G. (2021) · Nutrition & Metabolism · doi:10.1186/s12986-021-00569-w · Cited by 130
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“However, other explanations are possible as well, given that fertility can be maintained in obese Lep mice without reducing body weight by impairing STAT3 signaling through the leptin receptor (27).”
BackgroundDeletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity
de Lartigue, G., Ronveaux, C. C., & Raybould, H. E. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.06.003 · Cited by 120
“To confirm that the absence of LepR results in the absence of functional responsiveness to leptin in VAN, we measured the ability of an intraperitoneal administration of leptin to induce nuclear translocation of phosphorylated STAT3 (pSTAT3), a known mediator of leptin signaling downstream of LepRb [33,34] (Figure 1D,…”
BackgroundInfluentialObesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
Beutler, L. R., Corpuz, T. V., Ahn, J. S., Kosar, S., Song, W., Chen, Y., & Knight, Z. A. (2020) · eLife · doi:10.7554/elife.55909 · Cited by 113
“It is thought that diet-induced obesity renders AgRP neurons resistant to the effects of leptin, based in part on the fact that exogenous leptin fails to reduce food intake or induce pSTAT3 in obese animals and does not inhibit AgRP neurons in ex vivo preparations from obese animals (Bates et al., 2003; Baver et al.,…”
BackgroundRole of leptin in obesity‐related hypertension
Haynes, W. G. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.031237 · Cited by 117
“This pathway is essential for transduction of the leptin signal, because interruption of the JAK/STAT pathway in mice results in increased food intake and accumulation of adipose tissue (Bates et al. 2003).”
BackgroundHeiss, C. N., Mannerås-Holm, L., Lee, Y. S., Serrano-Lobo, J., Håkansson Gladh, A., Seeley, R. J., Drucker, D. J., Bäckhed, F., & Olofsson, L. E. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109163 · Cited by 114
Ring, L. E., & Zeltser, L. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41985 · Cited by 115
Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes
Gutiérrez-Juárez, R., Obici, S., & Rossetti, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408665200 · Cited by 115
Direct Innervation and Modulation of Orexin Neurons by Lateral Hypothalamic LepRb Neurons
Louis, G. W., Leinninger, G. M., Rhodes, C. J., & Myers, M. G. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1340-10.2010 · Cited by 113
“…converted to cDNA using the SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen). cDNA was analyzed in triplicate via qRT-PCR for Gapdh and neuropeptide gene expression [as previously described (Bates et al., 2003) or as supplied by Applied Biosystems] using an Applied Biosystems 7500.”
MethodSelf-citationPiper, M. L., Unger, E. K., Myers, M. G., & Xu, A. W. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0389 · Cited by 113
Self-citationHormonal induction of leptin resistance during pregnancy
Grattan, D. R., Ladyman, S. R., & Augustine, R. A. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.04.005 · Cited by 114
“Importantly, pSTAT3 is essential for the leptin-induced suppression of food intake [59,60].”
BackgroundCD36-Facilitated Fatty Acid Uptake Inhibits Leptin Production and Signaling in Adipose Tissue
Hajri, T., Hall, A. M., Jensen, D. R., Pietka, T. A., Drover, V. A., Tao, H., Eckel, R., & Abumrad, N. A. (2007) · Diabetes · doi:10.2337/db06-1699 · Cited by 111
“STAT3 phosphorylation (p-STAT3), a sensitive indicator of leptin activity (4,34,35) was 10-fold higher in CD36 / compared with wild-type tissue, whereas total STAT3 content was similar (Fig.”
BackgroundCNS Regulation of Glucose Homeostasis
Lam, C., Chari, M., & Lam, T. K. T. (2009) · Physiology · doi:10.1152/physiol.00003.2009 · Cited by 117
“First, although hepatic insulin resistance is comparable between db/db mice lacking functional leptin receptors and s/s mice with disrupted LRb/STAT3 signaling, s/s mice are less hyperglycemic than db/db mice (9, 19).”
BackgroundHypothalamic leptin regulation of energy homeostasis and glucose metabolism
Morton, G. J. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.135590 · Cited by 114
“This conclusion is further supported by studies of mice (s/s) in which the endogenous leptin receptor gene was replaced with a mutant allele that cannot signal via the Jak-Stat pathway, but otherwise functions normally (Bates et al. 2003, 2005).”
ResultLeptin: At the crossroads of energy balance and systemic inflammation
Steiner, A. A., & Romanovsky, A. A. (2006) · Progress in Lipid Research · doi:10.1016/j.plipres.2006.11.001 · Cited by 112
“LRb has been implicated in most biological effects of leptin [32-34].”
BackgroundLeptin and the Cardiovascular System
Rahmouni, K. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.225 · Cited by 110
“While in vitro studies have shown that leptin receptors signal through different STAT molecules, in vivo studies have demonstrated that, in the hypothalamus, this occurs specifically through activation of STAT3 (Bates et al., 2003).”
BackgroundMonsalve, M., & Olmos, Y. (2011) · Current Drug Targets · doi:10.2174/138945011796150307 · Cited by 113
“[396] Bates SH, Stearns WH, Dundon TA, et al.”
BackgroundRole of AMP‐Activated Protein Kinase in the Control of Appetite
Kola, B. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01745.x · Cited by 117
Hypothalamic control of brown adipose tissue thermogenesis
Labbé, S. M., Caron, A., Lanfray, D., Monge-Roffarello, B., Bartness, T. J., & Richard, D. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00150 · Cited by 112
“Even if signal transducer and activator of transcription 3 (STAT3) signaling plays a major role in leptin’s control of energy metabolism (Bates et al., 2003), recent attention has focused on the implication of the PI3K signaling pathway in mediating hypothalamic leptin actions (Hill et al.”
BackgroundImplications of leptin in neuroendocrine regulation of male reproduction
Landry, D. A., Cloutier, F., & Martin, L. J. (2013) · Reproductive Biology · doi:10.1016/j.repbio.2012.12.001 · Cited by 111
“knock-in mice containing a Y1138S mutation in Ob-Rb [44].”
BackgroundObesity: Pathophysiology and Clinical Management
Gurevich-Panigrahi, T., Panigrahi, S., Wiecheć, E., & Łoś, M. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709787315568 · Cited by 111
“This pathway is essential for the regulation of energy homeostasis by leptin but no t for the leptin-dependent control of re productive func tion and glucose hom eostasis [15] .”
Background20 YEARS OF LEPTIN: Role of leptin in human reproductive disorders
Chou, S. H.-H., & Mantzoros, C. S. (2014) · Journal of Endocrinology · doi:10.1530/joe-14-0245 · Cited by 110
Li, Z., Zhou, Y., Carter‐Su, C., Myers, M. G., & Rui, L. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0111 · Cited by 109
Self-citationProlactin/Leptin Interactions in the Control of Food Intake in Rats
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“Pro-opiomelanocortin (POMC) and NPY neurons in the ARC are considered major sites for the action of leptin on food intake (47), and the phosphorylation of STAT3 and subsequent protein synthesis is a critical step in this pathway (48).”
BackgroundThe Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy
Woodall, M. J., Neumann, S., Campbell, K., Pattison, S. T., & Young, S. L. (2020) · Cancers · doi:10.3390/cancers12051230 · Cited by 110
Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling
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Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases
Peelman, F., Waelput, W., Iserentant, H., Lavens, D., Eyckerman, S., Zabeau, L., & Tavernier, J. H. (2004) · Progress in Lipid Research · doi:10.1016/j.plipres.2004.03.001 · Cited by 108
Synaptic Plasticity in Energy Balance Regulation
Horvath, T. L. (2006) · Obesity · doi:10.1038/oby.2006.314 · Cited by 104
From observation to experimentation: leptin action in the mediobasal hypothalamus
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“Aside from the effects of leptin on acute cellular activity and food intake, the effect of leptin was markedly different in this model than was previously described in the POMC Obr null, STAT-3 mutant and the POMC STAT-3 mutant (37, 41, 43, 57).”
BackgroundResultThe floating blueprint of hypothalamic feeding circuits
Horváth, T. L., & Diano, S. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1479 · Cited by 105
Molecular basis of the obesity associated with Bardet–Biedl syndrome
Guo, D., & Rahmouni, K. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.02.009 · Cited by 103
“Given that specific disruption of leptin-induced activation of the STAT3 pathway leads to severe obesity in mice [65], these data demonstrate that leptin resistance in BBS mice is caused by the inability of leptin to activate the downstream intracellular machinery associated with its receptor.”
BackgroundThe Leptin System during Human Endometrial Receptivity and Preimplantation Development
Cerveró, A., Horcajadas, J. A., MartÍn, J., Pellicer, A., & Simón, C. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-032127 · Cited by 104
“energy but is not vital for reproduction (7).”
BackgroundTargeting the CNS to treat type 2 diabetes
Sandoval, D. A., Obici, S., & Seeley, R. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2874 · Cited by 101
“Indeed, mice carrying a mutation in the leptin receptor gene that selectively disrupts leptin and STAT3 signalling are obese and hyperphagic, although not as hyperglycaemic as diabetic db/db mice, in which the leptin receptor gene is delete”
BackgroundLeptin and the skin: a new frontier
Pöeggeler, B., Schulz, C., Pappolla, M. A., Bodó, E., Tiede, S., Lehnert, H., & Paus, R. (2009) · Experimental Dermatology · doi:10.1111/j.1600-0625.2009.00930.x · Cited by 102
Leptin-Signaling Pathways and Leptin Resistance
Münzberg, H. (2009) · Forum of nutrition/Bibliotheca Nutritio et dieta · doi:10.1159/000264400 · Cited by 101
de Souza, F. S. J., Santangelo, A. M., Bumaschny, V. F., Avale, M. E., Smart, J. L., Low, M. J., & Rubinstein, M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.8.3076-3086.2005 · Cited by 98
“gene were as follows: transgene 1 (1), transgene 2 (2), transgene 3 (2), transgene”
InfluentialSteinberg, G. R., Watt, M. J., Fam, B. C., Proietto, J., Andrikopoulos, S., Allen, A. M., Febbraio, M. A., & Kemp, B. E. (2006) · Endocrinology · doi:10.1210/en.2005-1587 · Cited by 103
“Specifically, tyrosine phosphorylation of 1138 of LRb by leptin is central to these regulatory effects (37).”
BackgroundInteractions between adipose tissue and the immune system in health and malnutrition
Wensveen, F. M., Marinović, S., Šestan, M., Wensveen, T. T., & Polić, B. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.10.006 · Cited by 103
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Why is obesity associated with osteoarthritis? Insights from mouse models of obesity
Griffin, T. M., & Guilak, F. (2008) · Biorheology · doi:10.3233/bir-2008-0485 · Cited by 99
“Mice with inactive STAT3, but not those with inactive MyD88 [54], are hyperphagic and develop obesity [4], suggesting that the STAT3 signaling pathway may mediate the integrated metabolic and in-flammatory effects of these cytokines.”
Role of Adipokines Signaling in the Modulation of T Cells Function
Procaccini, C., Rosa, V. D., Galgani, M., Carbone, F., Rocca, C. L., Formisano, L., & Matarese, G. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00332 · Cited by 103
Pinteaux, E., Inoue, W., Schmidt, L., Molina‐Holgado, F., Rothwell, N. J., & Luheshi, G. N. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04559.x · Cited by 99
“Leptin regulates body weight through the activation of STAT3 (Bates et al. 2003), an intracellular signalling molecule activated by Ob-Rb.”
BackgroundTriantafyllou, G. A., Paschou, S. Α., & Mantzoros, C. S. (2016) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2016.04.012 · Cited by 101
Sanchez, V. C., Goldstein, J., Stuart, R. C., Hovanesian, V., Huo, L., Münzberg, H., Friedman, T. C., Bjørbæk, C., & Nillni, E. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21620 · Cited by 97
“This shows that leptin can directly activate both the PC1 and the PC2 promoters in cells that express ObRb and that the STAT3 transcription factor can mediate this activation (50, 53).”
Williams, K. W., Scott, M. M., & Elmquist, J. K. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.11.042 · Cited by 96
“distal tyrosine residue (Y1138) and is then phosphorylated by JAK2 (Banks et al., 2000; Bates et al., 2003; White et al., 1997).”
Leptin resensitisation: a reversion of leptin-resistant states
Andreoli, M. F., Donato, J., Çakır, I., & Perelló, M. (2019) · Journal of Endocrinology · doi:10.1530/joe-18-0606 · Cited by 101
Wilsey, J. T., & Scarpace, P. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1810297 · Cited by 95
“Regardless of the part played by parallel or downstream pathways, signaling through STAT3 appears to be an absolute requirement for leptin’s effects on energy balance (Bates et al. 2003).”
BackgroundThe impact of leptin on perinatal development and psychopathology
Valleau, J. C., & Sullivan, E. L. (2014) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2014.05.001 · Cited by 95
“Since its discovery in 1994 (Zhang et al., 1994), leptin has been associated with metabolism as a critical regulator of both food intake and energy expenditure (Ahima and Osei, 2004; Bates et al., 2003; Halaas et al., 1995; Prieur et al., 2008; Zhang et al., 1994).”
BackgroundLeptin Stimulates Both JAK2-dependent and JAK2-independent Signaling Pathways
Jiang, L., Li, Z., & Rui, L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805545200 · Cited by 98
Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases
Gómez, R., Lago, F., Gómez-Reino, J. J., Diéguez, C., & Gualillo, O. (2009) · Journal of Molecular Endocrinology · doi:10.1677/jme-08-0131 · Cited by 94
“In particular, mutation of the intracellular tyrosine Y1138 of murine Ob-Rb prevents STAT3 activation and results in hyperphagia, obesity and impaired thermoregulation, and replacing Y1138 with a serine residue likewise causes pronounced obesity in knock-in mice.”
BackgroundSchwartz, M. W., & Niswender, K. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0906 · Cited by 93
Self-citationEvans, J. J., & Anderson, G. M. (2012) · Human Reproduction Update · doi:10.1093/humupd/dms004 · Cited by 101
“, 1999) and leptin (Bates et al., 2003; Donato et al., 2011), there are distinct hypothalamic pathways operating for appetite or fertility.”
BackgroundChehab, F. F. (2014) · Journal of Endocrinology · doi:10.1530/joe-14-0413 · Cited by 93
“While STAT3 signaling is not required for reproduction (Bates et al. 2003), only 15% of KNDy neurons in the ARC phosphorylate STAT3 upon leptin exposure (Cravo et al. 2011).”
Placental Regulation of Energy Homeostasis During Human Pregnancy
Armistead, B., Johnson, E., Vanderkamp, R., Kula-Eversole, E., Kadam, L., Drewlo, S., & Kohan‐Ghadr, H. (2020) · Endocrinology · doi:10.1210/endocr/bqaa076 · Cited by 99
A Homozygous Null Mutation Delineates the Role of the Melanocortin-4 Receptor in Humans
Lubrano-Berthelier, C., Stunff, C. L., Bougneres, P. F., & Vaisse, C. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031993 · Cited by 92
High-throughput proteomic profiling of the fish liver following bacterial infection
Causey, D. R., Pohl, M., Stead, D., Martín, S., Secombes, C. J., & Macqueen, D. J. (2018) · BMC Genomics · doi:10.1186/s12864-018-5092-0 · Cited by 92
Liu, Q., Zhang, J., Zerbinatti, C., Zhan, Y., Kolber, B. J., Herz, J., Muglia, L. J., & Bu, G. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1000575 · Cited by 93
“RT-PCR analysis was performed as described previously [14].”
BackgroundMethodInfluentialYang, G., Lim, C.-Y., Li, C., Xiao, X., Radda, G. K., Cai, L., Cao, X., & Han, W. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804965200 · Cited by 95
Shpakov, A. O., Derkach, K. V., & Berstein, L. M. (2015) · Future Science OA · doi:10.4155/fso.15.23 · Cited by 93
60 YEARS OF POMC: Transcriptional and epigenetic regulation of POMC gene expression
Drouin, J. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0289 · Cited by 91
Lee, J.-Y., Muenzberg, H., Gavrilova, O., Reed, J. A., Berryman, D., Villanueva, E. C., Louis, G. W., Leinninger, G. M., Bertuzzi, S., Seeley, R. J., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001639 · Cited by 90
“Since disruption of the STAT3 binding site on the ObRb results in an obesity syndrome different in numerous aspects from that of complete ObRb deficiency [2], it is possible that STAT5 may participate in leptin action, as well.”
BackgroundInfluentialSelf-citationThe ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy
Assumpção, J. A. F., Pasquarelli-do-Nascimento, G., Viegas, M. S., Bonamino, M., & Magalhães, K. G. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00796-0 · Cited by 97
Leptin system in embryo development and implantation: a protein in search of a function
Cerveró, A., Horcajadas, J., Domı́nguez, F., Pellicer, A., & Simón, C. (2005) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)60943-1 · Cited by 90
“In fact, it was reported that STAT3 signalling was required for leptin regulation of energy balance, but not for reproduction (Bates et al. 2003).”
BackgroundMorton, G. J., Blevins, J. E., Kim, F., Matsen, M. E., & Figlewicz, D. P. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90865.2008 · Cited by 92
“A “knock-in” mouse model in which LepRb (a mutant for Tyr(1138)) replaces endogenous lepr to specifically disrupt lepr-STAT signaling is characterized by hyperphagia and obesity (3), whereas leptin’s ability to acutely reduce food intake depends on intact STAT3 signaling (9).”
BackgroundAllaway, H. C. M., Southmayd, E. A., & De Souza, M. J. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2015-0053 · Cited by 89
Mechanisms mediating renal sympathetic activation to leptin in obesity
Morgan, D. A., Thedens, D. R., Weiss, R., & Rahmouni, K. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90324.2008 · Cited by 89
Astroglial CB1 cannabinoid receptors regulate leptin signaling in mouse brain astrocytes
Bosier, B., Bellocchio, L., Metna‐Laurent, M., Gómez, E. S., Matias, I., Hébert-Chatelain, É., Cannich, A., Maître, M., Lesté-Lasserre, T., Cardinal, P., et al. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.08.001 · Cited by 95
“While the essential role of STAT3 in leptin-mediated regulation of energy balance is well known [36,37], the function of leptin-induced STAT5 phosphorylation in this context remains unclear.”
BackgroundVagal control of satiety and hormonal regulation of appetite
Owyang, C., & Heldsinger, A. (2011) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm.2011.17.4.338 · Cited by 87
“receptor phosphorylation sites replace the endogenous Lepr allele.(89,90) Through this approach, it was demonstrated that leptin binding to its receptor activates the associated Janus kinase-2”
BackgroundAMPK‐dependent hormonal regulation of whole‐body energy metabolism
Dzamko, N. L., & Steinberg, G. R. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01969.x · Cited by 90
“Despite the maintenance of STAT3 phosphorylation, which is considered essential for regulating leptin’s effects on appetite (Bates et al. 2003), the ability of leptin to reduce food intake was lost when dominant negative AMPK was overexpressed in the hypothalamus (Minokoshi et al. 2004).”
BackgroundMinireview: The Brain as a Molecular Target for Diabetic Therapy
Prodi, E., & Obici, S. (2006) · Endocrinology · doi:10.1210/en.2006-0143 · Cited by 88
“Additionally, experiments disrupting selectively the LepR interaction with STAT3 suggest that leptin may improve glucose homeostasis via signaling pathways independent of STAT3 activation (28, 29).”
Metlakunta, A. S., Sahu, M., & Sahu, A. (2007) · Endocrinology · doi:10.1210/en.2007-1307 · Cited by 89
“amus and energy homeostasis (49) and brain-specific STAT3”
BackgroundAmylin-Induced Central IL-6 Production Enhances Ventromedial Hypothalamic Leptin Signaling
Foll, C. L., Johnson, M. D., Dunn-Meynell, A. A., Boyle, C. N., Lutz, T. A., & Levin, B. E. (2014) · Diabetes · doi:10.2337/db14-0645 · Cited by 87
“We postulated that amylin interacts with leptin signaling by causing cells within the VMH to produce IL-6, which is known to phosphorylate STAT3, a common downstream mediator of leptin signaling (35,36), via its IL-6R complex.”
BackgroundWu, H., Tang, X.-Q., Mao, X.-F., & Wang, Y. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1799-17.2017 · Cited by 87
“We further showed that treatment with IL-10, but not IL-4, increased the expression of -endorphin markedly in microglia, consistent with a previous study in which the -endorphin expression was stimulated by IL-10 in human promyelocytic cells (Awad et al., 2012), although it was also reported that IL-4 induced POMC exp…”
BackgroundInfluentialSelf-citationArora, G. K., Gupta, A. K. D., Narayanan, S., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121221 · Cited by 87
“Leptin signals proopiomelanocortin (POMC) neurons of the hypothalamus through the STAT3 pathway to regulate appetite (30, 31).”
BackgroundHyperphagia and Central Mechanisms for Leptin Resistance during Pregnancy
Trujillo‐Güiza, M. L., Spuch, C., Carro, E., & Señarís, R. M. (2011) · Endocrinology · doi:10.1210/en.2010-0975 · Cited by 90
Oswal, A., & Yeo, G. S. H. (2007) · Obesity Reviews · doi:10.1111/j.1467-789x.2007.00378.x · Cited by 87
“Transgenic mice lacking a key intracellular tyrosine residue (Y1138) of ObRb, which is essential for STAT 3 activation, are markedly hyperphagic, obese and at the same time display a suppression of hypothalamic melanocortin activity, suggesting that STAT 3 may participate in energy homeostasis by regulating the melano…”
BackgroundBenomar, Y., Roy, A.-F., Aubourg, A., Djiane, J., & Taouis, M. (2005) · Biochemical Journal · doi:10.1042/bj20041621 · Cited by 91
Central Leptin Receptor Action and Resistance in Obesity
Bjørbæk, C. (2009) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e3181bb0d49 · Cited by 88
“Specifically, mice with Tyr1138 mutated into a serine residue exhibit severe hyperphagia and obesity similar to that of Lepr mice.(63) However, in contrast to Lepr mice, Ser1138 mice are fertile, longer, and less hyperglycemic, altogether indicating that STAT3 signaling is critical for leptin’s regulation of energy in…”
BackgroundCentral Regulation of Metabolism by Protein Tyrosine Phosphatases
Tsou, R. C., & Bence, K. K. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00192 · Cited by 87
“Classical PTPs only dephosphorylate phospho-tyrosine residues while dual-specificity phosphatases can also dephosphorylate serine and threonine residues.”
BackgroundSteroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
Yang, Y., van der Klaauw, A. A., Zhu, L., Cacciottolo, T. M., He, Y., Stadler, L. K. J., Wang, C., Xu, P., Saito, K., Hinton, A. O., Jr., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08737-6 · Cited by 85
Münzberg, H., Jobst, E. E., Bates, S. H., Jones, J. C., Villanueva, E. C., Leshan, R. L., Björnholm, M., Elmquist, J. K., Sleeman, M. W., Cowley, M. A., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3168-06.2007 · Cited by 88
“These data are consistent with chronically increased activity of AgRP/ NPY neurons in the absence of LRbmediated repression signals in db/db mice and with the improved repression of AgRP and NPY mRNA expression in s/s compared with db/db mice (Bates et al., 2003).”
InfluentialSelf-citation
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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