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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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“Both leptin and EPO function is mediated via STAT3 activation and results in decreased food intake (Teng et al., 2011; Bates et al., 2003; Dey et al., 2016).”
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“Additionally, we investigated whether hypothyroidism might also affect the anorectic effect of leptin because the ObRb–STAT3 pathway is a major signalling cascade involved in the satiety effect of leptin (Friedman & Halaas 1998, Elias et al. 1999, Bates et al. 2003).”
Role of leptin in reproduction
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“STAT3 is also involved in leptin signalling, interacting with the long form of the leptin receptor [93].”
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Su, X., Zhang, G., Cheng, Y., & Wang, B. (2021) · Clinica Chimica Acta · doi:10.1016/j.cca.2021.01.013 · Cited by 19
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“Given the importance of hypothalamic STAT3 signaling in the regulation of energy homeostasis [41], potential loss of STAT3 signaling in hypothalamic neurons may contribute to the phenotype exhibited by p-KO mice.”
BackgroundErythropoietin regulates POMC expression via STAT3 and potentiates leptin response
Dey, S., Li, X., Teng, R., Alnaeeli, M., Chen, Z., Rogers, H. M., & Noguchi, C. T. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0171 · Cited by 19
“Leptin stimulation of POMC expression in the hypothalamus is mediated via STAT3 activation (Bates et al. 2003) and we found that Epo-stimulated increase of POMC is also dependent on STAT3 activation.”
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“Furthermore, the importance of Ob-Rb–STAT3 signals from leptin receptors was demonstrated by the replacement of Tyr 1138 in Ob-Rb with a serine residue, which specifically disrupted Ob-Rb–STAT3 signaling in mice, resulting in obesity (5).”
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“Ob-Rb, leptin receptor; SOCS3, suppressor of cytokine signaling 3; NPY, neuropeptide Y; AgRP, agouti-related peptide; POMC, pro-opiomelanocortin; CART; cocaine- and amphetamine-regulated transcript. doi:10.1371/journal.pone.0019913.t002 PLoS ONE | www.plosone.org 8 May 2011 | Volume 6 | Issue 5 | e19913 trition and po…”
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“Tyr705-STAT3 phosphorylation (p-STAT3) is required for homodimerization and translocation of this transcriptional factor to the nucleus, where it regulates leptin-dependent gene expression (Bates et al. 2003; Fig.”
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Bellefontaine, N., & Elias, C. (2014) · Hormones and Behavior · doi:10.1016/j.yhbeh.2014.04.007 · Cited by 15
“Indeed, point mutations in Tyr985 and Tyr1138, which recruit SHP2 and STAT3 respectively, mediate several aspects of energy balance and suppression of the LepRb signaling (Bates et al., 2003; Bjornholm et al., 2007).”
Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice
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“Interestingly, Bates and colleagues also reported dissociation between leptin-regulated control of energy homeostasis and reproductive functions, which could be discriminated at the level of JAK2/STAT3 pathway [13].”
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“Thereafter, phospho-Tyr(705)STAT3 forms homodimers acting as a transcription factor to induce the leptin-dependent gene expression program (3, 5).”
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“STAT3 has a critical role in mediating the anti-obesity effects of leptin (Bates et al., 2003), and the phosphorylation of STAT3 (pSTAT3) after leptin administration has been widely used to assess leptin sensitivity in animals (Munzberg et al., 2003; 2004).”
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“Since intact leptin signaling through STAT3 is also essential for lactation [72], it seems that the responsiveness of the mammary epithelial cells to leptin, IL-6 or other potential paracrine inhibitors is determined by the levels of these factors in the vicinity of the cells, as well as by receptor number and affinit…”
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Self-citationMANF: A New Player in the Control of Energy Homeostasis, and Beyond
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“, 2000), especially the STAT3 transcription factor, which is a key molecule involved in energy balance (Bates et al., 2003).”
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“From the aforementioned data as indicative of common signaling pathway recruited by leptin and LPS in the hypothalamus to modulate food intake reduction, and because STAT3 phosphorylation is not only a marker of leptin signaling but also an indicator of cytokine activation (4, 8, 61), in the present report we intended…”
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Self-citationThe timeline of neuronal and glial alterations in experimental obesity
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“…is also involved in metabolic regulation because when STAT3 signalling is disrupted, as occurs in knock out mice (STAT3 N-/-) or in mice that are transgenic for lepr in which the LRb-STAT3 signal was disrupted, animals become obese (Bates et al., 2003; Gao et al., 2004; Gao and Horvath, 2008b).”
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Oral Vanadium Enhances the Catabolic Effects of Central Leptin in Young Adult Rats
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“Given the critical role of STAT3 signaling with respect to leptin-induced suppression of energy intake and thermogenesis (16), we examined the FIG.”
BackgroundLeptin and Associated Neural Pathways Underlying Obesity‐Induced Hypertension
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“STAT3 deletion selectively in LepRb-expressing cells or in neurons also caused hyperphagia and obesity mimicking the effect of LepRb Y1138 deficiency (Bates et al. 2003; Gao et al. 2004).”
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“The enzymatic cleavage of POMC leads to the formation of α-melanocyte stimulating hormone (α-MSH) which inhibits food intake by stimulating melanocortin-4 receptors (Adan et al., 2006; Bruijnzeel, 2009).”
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“Leptin signaling via JAK/STAT3 pathways activates transcription of several genes that are involved in the regulation of food intake and energy expenditure (4).”
BackgroundKey role of heat shock protein 90 in leptin‐induced STAT3 activation and feeding regulation
Hosoi, T., Kohda, T., Matsuzaki, S., Ishiguchi, M., Kuwamura, A., Akita, T., Tanaka, J., & Ozawa, K. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13520 · Cited by 16
“Following this nuclear import, leptin stimulates the POMC catabolic pathway, resulting in anorexia (Schwartz et al., 2000; Bates et al., 2003).”
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Hyperphagia and Leptin Resistance in Tissue Inhibitor of Metalloproteinase-2 Deficient Mice
Stradecki, H. M., & Jaworski, D. M. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02105.x · Cited by 16
Syed, M., Cozart, M. A., Haney, A. C., Akhter, N., Odle, A. K., Allensworth‐James, M. L., Crane, C., Syed, F. M., & Childs, G. V. (2013) · Endocrinology · doi:10.1210/en.2012-2254 · Cited by 16
Beall, C., Hanna, L., & Ellacott, K. L. J. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160045 · Cited by 16
Ortuño, M. J., Schneeberger, M., Ilanges, A., Marchildon, F., Pellegrino, K., Friedman, J. M., & Ducy, P. (2021) · Journal of Clinical Investigation · doi:10.1172/jci151976 · Cited by 18
“Given that POMC is also expressed in Htr2c-negative neurons of the ARC (36) and that phosphorylated STAT3 (p-STAT3) is a major regulator of its expression (37), we next tested whether Flx affects this transcription factor.”
BackgroundChronic exposure to methylmercury enhances the anorexigenic effects of leptin in C57BL/6J male mice
Ferrer, B., Prince, L. M., Tinkov, A. A., Santamarı́a, A., Farina, M., da Rocha, J. B. T., Bowman, A. B., & Aschner, M. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111924 · Cited by 14
The LEPR Gene Is Associated with Reproductive Seasonality Traits in Rasa Aragonesa Sheep
Lakhssassi, K., Serrano, M., Crespo, B. L., et al. (2020) · Animals · doi:10.3390/ani10122448 · Cited by 15
Grasso, P. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.861350 · Cited by 15
Kisspeptin and leptin in the regulation of fertility
Pankov, Y. A. (2015) · Molecular Biology · doi:10.1134/s0026893315050131 · Cited by 15
Sahu, A. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.05.018 · Cited by 15
Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition
Chun, S., & Jo, Y. (2010) · Journal of Neurophysiology · doi:10.1152/jn.00371.2010 · Cited by 15
“Orexigenic NYP/AgRP neurons also release GABA onto POMC neurons (Cowley et al. 2001; Tong et al. 2008).”
BackgroundInfluentialNonogaki, K., & Kaji, T. (2016) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2016.08.009 · Cited by 15
McCabe, I. C., Fedorko, A., Myers, M. G., Leinninger, G. M., Scheller, E. L., & McCabe, L. R. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27726 · Cited by 15
Self-citationRoles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights
Inamori, K., & Inokuchi, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155349 · Cited by 15
Role of Prolactin in the Metabolic Adaptations to Pregnancy and Lactation
Woodside, B. C., Augustine, R. A., Ladyman, S. R., Naef, L., & Grattan, D. R. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-374285-8.00016-0 · Cited by 16
Differences in metabolomic profiles of male db/db and s/s, leptin receptor mutant mice
Saadat, N., IglayReger, H. B., Myers, M. G., Bodary, P. F., & Gupta, S. V. (2012) · Physiological Genomics · doi:10.1152/physiolgenomics.00081.2011 · Cited by 15
“Activation of STAT3 signaling pathway has been shown to mediate the effects of leptin on melanocortin production and body energy homeostasis (5).”
BackgroundInfluentialSelf-citationTofacitinib and Baricitinib in Type 2 Diabetic Patients with Rheumatoid Arthritis
Martinez-Molina, C., Díaz‐Torné, C., Park, H. S., et al. (2024) · Medicina · doi:10.3390/medicina60030360 · Cited by 14
“Bates SH et al. [15] emphasized the importance of signaling through STAT3 in the regulation of leptin, with its suppression being a cause of obesity.”
BackgroundStat3β mitigates development of atherosclerosis in apolipoprotein E-deficient mice
Lee, J., Baldwin, W. M., Lee, C., & Desiderio, S. V. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1013-5 · Cited by 14
“Several Stat3 activators, including leptin, effect a decrease in weight [38].”
Source of dietary sucrose influences development of leptin resistance in male and female rats
Harris, R. B. S. (2017) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00384.2017 · Cited by 15
Tu, X., Liu, M., Tang, J., Zhang, Y., Shi, Y., Yu, L., & Sun, Z. (2018) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-018-0365-7 · Cited by 13
“Phosphorylation of tyrosine residue 1138 mainly recruits STAT3 and it has been reported that hypothalamic leptin control to reproduction is regulated by signals independent of STAT3 signaling [49].”
BackgroundPhosphatidylinositol‐3 kinase mediates the sweet suppressive effect of leptin in mouse taste cells
Yoshida, R., Margolskee, R. F., & Ninomiya, Y. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15268 · Cited by 15
“…signaling, because the disruption of the STAT3 binding site in Ob- Rb results in hyperphagia and obesity to a similar degree as that in db/db mice (Bates et al., 2003; Jiang et al., 2008) and selective deletion of STAT3 in Ob- Rb expressing neurons leads to profound obesity in mice (Piper et al.,…”
BackgroundIs LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?
Sandin, E. S., Inderhees, J., Müller‐Fielitz, H., Pietrzik, C. U., Herold, E., Willnow, T. E., Pfluger, P. T., Nogueiras, R., Prévot, V., Krey, T., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094998 · Cited by 13
“In the hypothalamus, the primary region regulating appetite and feeding behavior, leptin binds to the long isoform of the LepR (LepRb), which leads foremost to the phosphorylation of signal transducer and activator of transcription 3 (STAT3) [6,7].”
BackgroundInfluentialMaratos–Flier, E. (2008) · Nature Medicine · doi:10.1038/nm0608-604 · Cited by 14
Self-citationLeptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus
Desai, B. N., & Harris, R. B. S. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00501.2014 · Cited by 14
“We used pSTAT3 as a marker for nuclei that were activated directly by leptin (2) and FosB as a marker”
BackgroundMethodInfluentialObesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2 − /− mice
Henry, M. D., Costanzo-Garvey, D. L., Klutho, P. J., & Lewis, R. E. (2014) · Physiological Reports · doi:10.14814/phy2.12053 · Cited by 16
“…(Hummel et al. 1966; Zhang et al. 1994; Halaas et al. 1995; Maffei et al. 1995; Tartaglia et al. 1995; Lee et al. 1996), and identifying the JAK/STAT signaling pathway as the major mechanism through which leptin communicates satiety to the hypothalamus (Ghilardi et al. 1996; Bates et al. 2003).”
BackgroundCelastrol as a tool for the study of the biological events of metabolic diseases
Lan, G., Zhang, J., Ye, W., Yang, F., Li, A., He, W., & Zhang, W. (2019) · Science China Chemistry · doi:10.1007/s11426-018-9404-9 · Cited by 15
Leptin Receptor Mediates Bmal1 Regulation of Estrogen Synthesis in Granulosa Cells
Chu, G., Ma, G., Sun, J., et al. (2019) · Animals · doi:10.3390/ani9110899 · Cited by 14
An Overview of Rodent Models of Obesity and Type 2 Diabetes
Lutz, T. A. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0385-7_2 · Cited by 14
Venema, W., Severi, I., Perugini, J., Mercurio, E. D., Mainardi, M., Maffei, M., Cinti, S., & Giordano, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00140 · Cited by 14
“Activation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway in these hypothalamic neurons is essential for leptin to exert its full metabolic effect, as demonstrated by the hyperphagic and obese phenotypes found in mice where LepRb mutations at tyrosine 1138 prevent S…”
BackgroundLuo, W., Bodary, P. F., Shen, Y., Wickenheiser, K. J., Öhman, M. K., Guo, C., Bahrou, K. L., Myers, M. G., & Eitzman, D. T. (2010) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2010.10.009 · Cited by 14
Self-citationControl of Food Intake Through Regulation of cAMP
Zhao, A. Z. (2005) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(05)67006-8 · Cited by 15
Post-translational modifications of Stat3: The state of the art
Chen, J., Mao, C., Han, N., Zhou, Q., Feng, C., Sun, X., & Song, Y. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.112048 · Cited by 14
Heyward, F. D., Liu, N., Jacobs, C. L., Ivison, R., Machado, N., Üner, A. G., Srinivasan, H., Patel, S. J., Gulko, A., Sermersheim, T. J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48885-y · Cited by 13
Hexosamine biosynthetic pathway activity in leptin resistant sucrose-drinking rats
Harris, R. B. S., & Apolzan, J. W. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.09.016 · Cited by 13
“We did not find any effect of sucrose on the other proteins involved in leptin signaling in hypothalamic tissue, which is consistent with STAT3 activation being essential for leptin’s effects on food intake and energy balance [47].”
BackgroundMejia, P., Trevino-Villarreal, J. H., Niz, M. D., Meibalan, E., Longchamp, A., Reynolds, J. S., Turnbull, L. B., Opoka, R. O., Roussilhon, C., Spielmann, T., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe2484 · Cited by 13
Song, N., Lee, A., Yasmeen, R., Shen, Q., Yang, K., Kumar, S. B., Muhanna, D., Arnipalli, S. R., Noria, S. F., NEEDLEMAN, B. J., et al. (2022) · Cells · doi:10.3390/cells11030425 · Cited by 14
“Similarly, canonical downstream targets of LepR [7,8], STAT3 and STAT5, were not activated by EREG within 15 min (Figure 4C).”
BackgroundInfluentialOliveira, L. D. C., Morais, G. P., Ropelle, E. R., de Moura, L. P., Cintra, D. E., Pauli, J. R., de Freitas, E. C., Rorato, R. C., & da Silva, A. S. R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.858320 · Cited by 17
“Therefore, impairments in the central signaling pathways of insulin (18–20) and leptin (21, 22) are associated with energy imbalance and obesity development.”
Background
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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