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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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“Tyr985 also plays an important role in LRb signal attenuation by binding the inhibitory suppressor of cytokine signaling-3 (SOCS3) molecule (11).”
BackgroundInfluentialSelf-citationImpairment of hepatic Stat-3 activation and reduction of PPARα activity in fructose-fed rats
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Self-citationAdipokines as novel modulators of lipid metabolism
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Hypothalamic ERK Mediates the Anorectic and Thermogenic Sympathetic Effects of Leptin
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Endoplasmic Reticulum Stress Induces Leptin Resistance
Hosoi, T., Sasaki, M., Miyahara, T., Hashimoto, C., Matsuo, S., Yoshii, M., & Ozawa, K. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.050070 · Cited by 206
“STAT3 signal, results in marked obesity (Bates et al., 2003).”
BackgroundInfluentialThe role of leptin in leptin resistance and obesity
Enriori, P. J., Evans, A. E., Sinnayah, P., & Cowley, M. A. (2006) · Obesity · Cited by 197
Inflammatory cause of metabolic syndrome via brain stress and NF-κB
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“However, under pathological conditions such as overnutrition-induced intracellular metabolic stresses, neuronal proinflammatory pathways are activated, which in turn impairs leptin and insulin signaling, leading to neuronal dysfunction and central body weight dysregulation [223-230].”
BackgroundPI3K integrates the action of insulin and leptin on hypothalamic neurons
Xu, A. W. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200524301 · Cited by 420
“In addition, work of Myers and colleagues (6) has shown that animals carrying a modified leptin receptor that cannot activate Stat3, Lepr1138Ser, develop a subset of the same phenotypic abnormalities caused by a null Lepr allele; thus, it will be interesting to examine the effects of leptin on PI3K activation and elec…”
BackgroundThe ins and outs of leptin receptor activation
Zabeau, L., Lavens, D., Peelman, F., Eyckerman, S., Vandekerckhove, J. S., & Tavernier, J. H. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00440-x · Cited by 193
The Role of Hypothalamic Mammalian Target of Rapamycin Complex 1 Signaling in Diet-Induced Obesity
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“Several studies have identified the hypothalamic signaling through STAT3 as a critical player for the ability of leptin to regulate energy balance (Bates et al., 2003).”
Leptin signaling and circuits in puberty and fertility
Elias, C. F., & Purohit, D. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1095-1 · Cited by 200
“In these mice, as in db/db and ob/ob mice, the expression of hypothalamic POMC mRNA was reduced and AgRP mRNA was increased compared with control mice, demonstrating that STAT3 is required for the regulation of both mRNAs [23]; but while db/db and ob/ob mice were infertile, s/s mice showed improved fertility indicatin…”
BackgroundInfluentialCritical Role for Hypothalamic mTOR Activity in Energy Balance
Mori, H., Inoki, K., Münzberg, H., Opland, D. M., Faouzi, M., Villanueva, E. C., Ikenoue, T., Kwiatkowski, D. J., MacDougald, O. A., Myers, M. G., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.005 · Cited by 189
“The appropriate control of Agrp expression in the same neurons that display dysregulated Npy expression is consistent with previous findings demonstrating that the expression of Npy and Agrp are controlled by distinct upstream signals (Bates et al., 2003; Kitamura et al., 2006), and it suggests an important role for h…”
BackgroundResultSelf-citationRegulation of the O-Linked β-N-Acetylglucosamine Transferase by Insulin Signaling
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Molecular and neural mediators of leptin action
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AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity
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“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-citationElevated Hypothalamic TCPTP in Obesity Contributes to Cellular Leptin Resistance
Loh, K., Fukushima, A., Zhang, X., Galić, S., Briggs, D. I., Enriori, P. J., Simonds, S. E., Wiede, F., Reichenbach, A., Hauser, C., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.09.011 · Cited by 185
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BackgroundResultInfluentialSelf-citationFunctional relationship between obesity and male reproduction: from humans to animal models
Teerds, K. J., de Rooij, D. G., & Keijer, J. (2011) · Human Reproduction Update · doi:10.1093/humupd/dmr017 · Cited by 190
Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons
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Leptin receptor signaling: pathways to leptin resistance
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“Homologous replacement of tyrosine 1138 with serine (ObR ) or deletion of neuronal STAT3 results in severe hyperphagia and morbid obesity, indicating that the JAK2-STAT3 pathway is indispensable for the hypothalamic anorectic actions of leptin (115-118).”
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“The biological importance of long form LepR through via the JAK/STAT pathway in maintaining body weight and energy homeostasis has been definitively demonstrated (Bates et al., 2003).”
BackgroundThe Leptin Receptor Complex: Heavier Than Expected?
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“PI3K – a pivotal enzyme in ARC signalling Previous studies have demonstrated that leptin applied in vivo stimulates hypothalamic ObRb to increase phosphorylation of the signalling protein intermediates STAT3 and MAPK and that both leptin and insulin increase Leptin disrupts cortical actin filaments in GT1-7 cellsFigur…”
BackgroundInfluentialGong, Y., Ishida-Takahashi, R., Villanueva, E. C., Fingar, D. C., Münzberg, H., & Myers, M. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702838200 · Cited by 173
Self-citationMinireview: CNS Mechanisms of Leptin Action
Flak, J. N., & Myers, M. G. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1232 · Cited by 179
Self-citationBates, S. H., Kulkarni, R. N., Seifert, M., & Myers, M. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.02.001 · Cited by 173
Self-citationBrain circuits regulating energy homeostasis
Abizaid, A. B., & Horváth, T. L. (2008) · Regulatory Peptides · doi:10.1016/j.regpep.2007.10.006 · Cited by 171
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“STAT3-mediated signaling are involved in leptin ’ s effect on glucose homeostasis [8,11,13].”
BackgroundSpeakman, J. R., Hambly, C., Mitchell, S. E., & Król, E. (2007) · Obesity Reviews · doi:10.1111/j.1467-789x.2007.00319.x · Cited by 179
“way through which leptin was believed to have its major action (the STAT3 pathway) (12).”
BackgroundInterleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency
Zorrilla, E. P., Sánchez-Alavez, M., Sugama, S., Brennan, M., Fernandez, R. E., Bartfai, T., & Conti, B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611523104 · Cited by 170
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Kubota, T., Kubota, N., & Kadowaki, T. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.004 · Cited by 174
“In contrast, in the presence of increased insulin levels, such as after a meal, synthesis of glycogen and lipid occurs tomaintain blood glucose levels within the normal range (Bechmann et al., 2012).”
BackgroundLeshan, R. L., Greenwald-Yarnell, M. L., Patterson, C. M., Gonzalez, I. E., & Myers, M. G. (2012) · Nature Medicine · doi:10.1038/nm.2724 · Cited by 172
Self-citationXu, A. W., Marie, L. S., Kaelin, C. B., & Barsh, G. S. (2006) · Endocrinology · doi:10.1210/en.2006-1119 · Cited by 169
“Moreover, mice carrying a mutated leptin receptor that abolished Stat3 binding are grossly obese with decreased Pomc but not Agrp and neuropeptide Y (Npy) expression (16).”
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“Similarly, although s/s mice are markedly obese and hyperphagic, targeted deletions of STAT3 from arcuate POMC and AgRP/NPY neurons only result in a mild obese phenotype (43,44,87).”
BackgroundSelective leptin resistance revisited
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“Mice with genetically engineered disruption of leptin-STAT3 signaling (lepr s/s mice) are hyperphagic and profoundly obese, comparable to db/db mice that have a loss-of-function mutation in LepR (7).”
Leshan, R. L., Louis, G. W., Jo, Y., Rhodes, C. J., Münzberg, H., & Myers, M. G. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0155-09.2009 · Cited by 162
“Leptin acts via LepRb in the brain to regulate energy balance and reproduction, suggesting that LepRb-expressing neurons link fat mass and reproductive competence (Ahima et al., 1996; Chehab et al., 1996; Bates et al., 2003).”
BackgroundSelf-citationLeptin Signaling in Kiss1 Neurons Arises after Pubertal Development
Cravo, R. M., Frazão, R., Perelló, M., Osborne-Lawrence, S. L., Williams, K. W., Zigman, J. M., Vianna, C., & Elias, C. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058698 · Cited by 168
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Ladyman, S. R., Augustine, R. A., & Grattan, D. R. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02017.x · Cited by 166
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“These phosphorylated tyrosine residues act as docking sites for downstream signaling molecules, representing a Src homology 2 (SH2)-binding motif that recruits specific SH2-containing effector proteins to mediate subsequent intracellular signaling.24 The major signaling pathway recruited by leptin is the signal transd…”
BackgroundInfluentialCentral actions of adipocyte hormones
Ahima, R. S. (2005) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2005.07.010 · Cited by 162
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“This process is dependent on gp130-mediated activation of JAK2/STAT3 signaling, which is known to underlie the induction of POMC mRNA expression by leptin, suggesting that LIF may activate hypothalamic POMC neurons in a similar manner [160,175].”
Early Life Origins of Obesity: Role of Hypothalamic Programming
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Leptin and its metabolic interactions – an update
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Sexual Dimorphism in Body Fat Distribution and Risk for Cardiovascular Diseases
Nedungadi, T. P., & Clegg, D. J. (2009) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-009-9101-1 · Cited by 154
“Leptin activates the Stat3 signaling cascade and deletion of tyrosine 1138 residue with a serine residue, which disrupted in leptin receptor-STAT3 signal, resulted in obesity [ 6 ].”
BackgroundRole of leptin in female reproduction
Pérez‐Pérez, A., Sánchez-Jiménez, F., Maymó, J. L., Dueñas, J. L., Varone, C. L., & Sánchez‐Margalet, V. (2014) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2014-0387 · Cited by 161
“It has been reported that hypothalamic leptin control of reproduction is regulated by signals independent of STAT3 signaling [20].”
BackgroundDunn, 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-citationCentral Leptin Acutely Reverses Diet-Induced Hepatic Insulin Resistance
Pocai, A., Morgan, K., Buettner, C., Gutierrez-Juarez, R., Obici, S., & Rossetti, L. (2005) · Diabetes · doi:10.2337/diabetes.54.11.3182 · Cited by 153
“Because the latter process requires activation of STAT3 by leptin (38,39), we also investigated whether short-term overfeeding alters the stimulatory effect of leptin on the hypothalamic phosphorylation of STAT3.”
BackgroundKurrasch, D. M., Cheung, C. C., Lee, F. Y., Tran, P. V., Hata, K., & Ingraham, H. A. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2858-07.2007 · Cited by 157
“6B), confirming previous results and reflecting the normal hypothalamic response after loss of leptin signaling (Bates et al., 2003).”
ResultObesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis
Rahmouni, K. (2014) · Hypertension · doi:10.1161/hypertensionaha.114.00920 · Cited by 150
Lin, H. V., Plum, L., Ono, H., Juárez, R. G., Shanabrough, M., Borók, E., Horváth, T. L., Rossetti, L., & Accili, D. (2009) · Diabetes · doi:10.2337/db09-1303 · Cited by 162
“But unlike leptin receptor signaling, where it has been possible to dissect pathways regulating food intake from those regulating energy expenditure (12) and reproduction (13), the question of which neurons mediate specific actions of insulin remains largely unsettled.”
BackgroundBrain Adipocytokine Action and Metabolic Regulation
Ahima, R. S., Qi, Y., Singhal, N. S., Jackson, M. B., & Scherer, P. E. (2006) · Diabetes · doi:10.2337/db06-s018 · Cited by 150
The role of leptin in glucose homeostasis
Denroche, H. C., Huynh, F. K., & Kieffer, T. J. (2012) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2012.00203.x · Cited by 153
Resveratrol protects against peripheral deficits in a mouse model of Huntington's disease
Ho, D. J., Calingasan, N. Y., Wille, E. J., Dumont, M., & Beal, M. F. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.05.006 · Cited by 148
Distribution of leptin‐sensitive cells in the postnatal and adult mouse brain
Caron, É., Sachot, C., Prévot, V., & Bouret, S. G. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22219 · Cited by 162
“Consistent with this hypothesis, mice lacking leptin or leptin receptors (Lepob/Lepob and Leprdb/Leprdb mice, respectively) have reduced brain weight and morphological defects (Bereiter and Jeanrenaud, 1979; Bereiter and Jeanrenaud, 1980; Garris, 1989; Ahima et al., 1999; Steppan and Swick, 1999).”
BackgroundMechanisms linking obesity and cancer
Louie, S. M., Roberts, L. S., & Nomura, D. K. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.02.008 · Cited by 152
“STAT3 signaling is required for proper leptin regulation of energy balance [140].”
BackgroundAdipose Tissue Fibrosis: Mechanisms, Models, and Importance
DeBari, M. K., & Abbott, R. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176030 · Cited by 153
Farr, O. M., Tsoukas, M. A., & Mantzoros, C. S. (2014) · Metabolism · doi:10.1016/j.metabol.2014.07.004 · Cited by 153
“[37] Bates SH, Stearns WH, Dundon TA, et al.”
BackgroundAntiapoptotic Effects of Leptin in Human Neuroblastoma Cells
Russo, V. C., Metaxas, S., Kobayashi, K., Harris, M. A., & Werther, G. A. (2004) · Endocrinology · doi:10.1210/en.2003-1767 · Cited by 146
Ladyman, S. R., & Grattan, D. R. (2004) · Endocrinology · doi:10.1210/en.2004-0338 · Cited by 144
Wada, N., Hirako, S., Takenoya, F., Kageyama, H., Okabe, M., & Shioda, S. (2014) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2014.09.002 · Cited by 156
“Replacement of Phe or Ser in Tyr1138 causes disruption of the STAT3 binding site, resulting in hyperphagia and obesity similar to that seen in db/db mice (Bates et al., 2003; Jiang et al., 2008).”
Central Nervous System Regulation of Food Intake
Schwartz, M. W. (2006) · Obesity · doi:10.1038/oby.2006.275 · Cited by 150
“(53) sought to determine the physiological role played by leptin signaling through the JAK-STAT pathway in the neuroendocrine control of energy homeostasis.”
BackgroundSelf-citationLeptin action in pubertal development: recent advances and unanswered questions
Elias, C. F. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.09.002 · Cited by 145
“Neural specific deletion of STAT3 (STAT3N−/−) or deletion of leptin receptormediated STAT3 signaling (LRbS1138 s/s) recapitulate the db/db metabolic phenotype, producing hyperphagic obesity and diabetes (82, 83).”
BackgroundBouret, S. G., Bates, S. H., Chen, S. H., Myers, M. G., & Simerly, R. B. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2277-11.2012 · Cited by 142
Self-citationMurine models for pharmacological studies of the metabolic syndrome
Fellmann, L., do Nascimento, A. R., Tibiriçá, E. V., & Bousquet, P. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.11.004 · Cited by 151
Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice
Lloyd, D. J., Bohan, S., & Gekakis, N. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl111 · Cited by 142
Essential Role of STAT3 in Body Weight and Glucose Homeostasis
Cui, Y., Huang, L., Elefteriou, F., Yang, G., Shelton, J. M., Giles, J. E., Öz, O. K., Pourbahrami, T., Lu, C. Y., Richardson, J. A., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.24.1.258-269.2004 · Cited by 144
“That the leptin pathway of STAT3 activation, but not those of other growth factors or cytokines, is impaired in RIP-Cre/STAT3 mice is further supported by the recent finding that mice defective for STAT3 binding to the leptin receptor are also obese (7).”
BackgroundLRb-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-citationCraig, J. A., Zhu, H., Dyce, P. W., Petrik, J., & Li, J. (2004) · Endocrinology · doi:10.1210/en.2004-0783 · Cited by 142
“5360 Endocrinology, November 2004, 145(11):5355–5363 Craig et al.”
BackgroundInfluentialPlum, L., Rother, E., Münzberg, H., Wunderlich, F. T., Morgan, D. A., Hampel, B., Shanabrough, M., Janoschek, R., Könner, A. C., Alber, J., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.012 · Cited by 138
Cleary, M. P., Juneja, S. C., Phillips, F. C., Hu, X., Grande, J. P., & Maihle, N. J. (2004) · Experimental Biology and Medicine · doi:10.1177/153537020422900207 · Cited by 138
Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators
Roa, J., & Tena-Sempere, M. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.09.027 · Cited by 136
“Interestingly, however, specific elimination of STAT3 from neurons expressing LepR did not perturb reproductive organ development and was fully compatible with cyclic ovarian function in mice (Bates et al., 2003).”
From feeding one to feeding many: hormone‐induced changes in bodyweight homeostasis during pregnancy
Augustine, R. A., Ladyman, S. R., & Grattan, D. R. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.146316 · Cited by 136
“Mice that have had Tyr1138 replaced with a serine residue (s/s knock-in mouse), are unable to activate STAT3 and are obese and hyperphagic and have decreased energy expenditure, but have normal reproductive function and increased linear growth (Bates et al. 2003).”
BackgroundInfluentialHigh-Fat Diet and Female Fertility
Hohos, N. M., & Skaznik-Wikiel, M. E. (2017) · Endocrinology · doi:10.1210/en.2017-00371 · Cited by 142
“Data from the leptin deficient or leptin receptor d eficient female mice suggest that it is the leptin resistance, not necessarily the obesity that is involved in the development of infertility in these mice (89-93).”
BackgroundThere and Back Again: Leptin Actions in White Adipose Tissue
Martínez‐Sánchez, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176039 · Cited by 142
Ahima, R. S., & Osei, S. Y. (2008) · Frontiers of hormone research · doi:10.1159/000115365 · Cited by 136
Donato, J., Silva, R. J., Sita, L. V., Lee, S., Lee, C., Lacchini, S., Bittencourt, J. C., Franci, C. R., Canteras, N. S., & Elias, C. F. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0405-09.2009 · Cited by 137
“In agreement with others suggesting a dissociation between the brain pathways or signaling cascades mediating multiple leptin actions (Hohmann et al., 2000; Bates et al., 2003), our findings also indicate a segregation between the hypothalamic nuclei recruited by leptin to control reproduction and energy homeostasis.”
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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