LRb-STAT3 Signaling Is Required for the Neuroendocrine Regulation of Energy Expenditure by Leptin
Open accessAbstract
Secretion of leptin from adipose tissue communicates body energy status to the neuroendocrine system by activating the long form of the leptin receptor (LRb). Lack of leptin or LRb (as in db/db mice) results in obesity that stems from the combined effects of hyperphagia and decreased energy expenditure. We have previously generated mice in which LRb is replaced with a mutant LRb (LRbS1138) that specifically disrupts LRb→STAT3 (signal transducer and activator of transcription-3) signaling; mice homozygous for this mutant (s/s) display increased feeding and are obese. We have now examined energy expenditure in s/s and db/db mice. Consistent with the increased lean body mass of s/s animals, locomotor activity and acute cold tolerance (partly a measure of shivering thermogenesis) in s/s mice were modestly but significantly improved compared with db/db mice, although they were decreased compared with wild-type mice. Total and resting metabolic rates were similarly depressed in s/s and db/db mice, however. Indeed, s/s and db/db mice display similar reductions in thyroid function and brown adipose tissue expression of uncoupling protein-1, which is regulated by sympathetic nervous system (SNS) tone. Thus, the LRb→STAT3 signal is central to both the control of energy expenditure by leptin and the neuroendocrine regulation of the SNS and the thyroid axis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mice with LepRb Tyr1138 replaced by serine (s/s) are unable to recruit STAT3 and are characterized by hyperphagia, obesity, and reduced energy expenditure.
“Mice bearing a mutant LepRb gene in which Tyr1138 is replaced by a serine residue (s/s mice) are unable to recruit STAT3 and are characterized by hyperphagia, obesity (14) and reduced energy expenditure (12)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [12]
The Tyr1138→STAT3 pathway plays a crucial role in the regulation of energy homeostasis.
“suggesting that the Tyr1138 →STAT3 pathway plays a crucial role in the regulation of regulation of energy homeostasis (12, 14).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [12]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419 · see citing works
Brown Adipose Tissue: Function and Physiological Significance
CANNON, B., & NEDERGAARD, J. (2004) · Physiological Reviews · doi:10.1152/physrev.00015.2003 · Cited by 6,433 · see citing works
Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405 · see citing works
Weight-Reducing Effects of the Plasma Protein Encoded by the <i>obese</i> Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451 · see citing works
Hubert, H. B., Feinleib, M., McNamara, P. M., & Castelli, W. P. (1983) · Circulation · doi:10.1161/01.cir.67.5.968 · Cited by 4,241 · see citing works
Role of leptin in the neuroendocrine response to fasting
Ahima, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996) · Nature · doi:10.1038/382250a0 · Cited by 3,117 · see citing works
Self-citationChen, H., Charlat, O., Tartaglia, L. A., Woolf, E. A., Weng, X., Ellis, S. J., Lakey, N. D., Culpepper, J., More, K. J., Breitbart, R. E., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81294-5 · Cited by 2,214 · see citing works
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S. A., Perna, F., Fontana, S., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15693 · Cited by 1,359 · see citing works
Elmquist, J. K., Elias, C. F., & Saper, C. B. (1999) · Neuron · doi:10.1016/s0896-6273(00)81084-3 · Cited by 1,160 · see citing works
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S. A., Perna, F., Fontana, S., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215693 · Cited by 1,105 · see citing works
Development of obesity in transgenic mice after genetic ablation of brown adipose tissue
Lowell, B. B., S-Susulic, V., Hamann, A., Lawitts, J. A., Himms-Hagen, J., Boyer, B. B., Kozak, L. P., & Flier, J. S. (1993) · Nature · doi:10.1038/366740a0 · Cited by 1,075 · see citing works
Phenotypes of Mouse diabetes and Rat fatty Due to Mutations in the OB (Leptin) Receptor
Chua, S. C., Chung, W. K., Wu-Peng, X. S., Zhang, Y., Liu, S.-M., Tartaglia, L. A., & Leibel, R. L. (1996) · Science · doi:10.1126/science.271.5251.994 · Cited by 1,071 · see citing works
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
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., et al. (2003) · Nature · doi:10.1038/nature01388 · Cited by 1,010 · see citing works
Self-citationJaks and Stats in signaling by the cytokine receptor superfamily.
Ihle, J., & Kerr, I. (1995) · Trends in Genetics · doi:10.1016/s0168-9525(00)89000-9 · Cited by 953 · see citing works
Activation of Downstream Signals by the Long Form of the Leptin Receptor
Banks, A. S., Davis, S. M., Bates, S. H., & Myers, M. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14563 · Cited by 797 · see citing works
Self-citationLeptin Regulation of Neuroendocrine Systems
Ahima, R. S., Saper, C. B., Flier, J. S., & Elmquist, J. K. (2000) · Frontiers in Neuroendocrinology · doi:10.1006/frne.2000.0197 · Cited by 767 · see citing works
Leptin accelerates the onset of puberty in normal female mice.
Ahima, R. S., Dushay, J. R., Flier, S. N., Prabakaran, D., & Flier, J. S. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119172 · Cited by 755 · see citing works
Role of leptin in hypothalamic–pituitary function
Yu, W. H., Kimura, M., Walczewska, A., Karanth, S., & McCann, S. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.3.1023 · Cited by 732 · see citing works
Cytokine signaling through nonreceptor protein tyrosine kinases.
Taniguchi, T. (1995) · Science · doi:10.1126/science.7716517 · Cited by 712 · see citing works
Chan, J. L., Heist, K., DePaoli, A. M., Veldhuis, J. D., & Mantzoros, C. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17490 · Cited by 697 · see citing works
Unraveling the central nervous system pathways underlying responses to leptin
Elmquist, J. K., Maratos-Flier, E., Saper, C. B., & Flier, J. S. (1998) · Nature Neuroscience · doi:10.1038/2164 · Cited by 520 · see citing works
Self-citationLeptin Inhibition of the Hypothalamic-Pituitary-Adrenal Axis in Response to Stress 1
Heiman, M. L., Ahima, R. S., Craft, L. S., Schoner, B. E., Stephens, T. W., & Flier, J. S. (1997) · Endocrinology · doi:10.1210/endo.138.9.5366 · Cited by 454 · see citing works
Rosenbaum, M., Murphy, E. M., Heymsfield, S. B., Matthews, D. E., & Leibel, R. L. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.5.2391 · Cited by 407 · see citing works
A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors
Ste. Marie, L., Miura, G. I., Marsh, D. J., Yagaloff, K., & Palmiter, R. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.220409497 · Cited by 366 · see citing works
Divergent Roles of SHP-2 in ERK Activation by Leptin Receptors
Bjørbæk, C., Buchholz, R. M., Davis, S. M., Bates, S. H., Pierroz, D. D., Gu, H., Neel, B. G., Myers, M. G., & Flier, J. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007439200 · Cited by 364 · see citing works
Self-citationFekete, C., Légrádi, G., Mihály, E., Huang, Q.-H., Tatro, J. B., Rand, W. M., Emerson, C. H., & Lechan, R. M. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-04-01550.2000 · Cited by 308 · see citing works
The Molecular Genetics of Rodent Single Gene Obesities
Leibel, R. L., Chung, W. K., & Chua, S. C. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.51.31937 · Cited by 277 · see citing works
Regulation of Jak Kinases by Intracellular Leptin Receptor Sequences
Kloek, C. E., Haq, A. K., Dunn, S. L., Lavery, H. J., Banks, A. S., & Myers, M. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205148200 · Cited by 233 · see citing works
Self-citationLeptin induction of UCP1 gene expression is dependent on sympathetic innervation
Scarpace, P. J., & Matheny, M. E. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.2.e259 · Cited by 202 · see citing works
Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system
Satoh, N., Ogawa, Y., Katsuura, G., Numata, Y., Masuzaki, H., Yoshimasa, Y., & Nakao, K. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00401-7 · Cited by 189 · see citing works
β-Adrenergic Receptors, Diet-induced Thermogenesis, and Obesity
Lowell, B. B., & Bachman, E. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.r300011200 · Cited by 171 · see citing works
Chua, S. C., Koutras, I. K., Han, L., Liu, S.-M., Kay, J., Young, S. J., Chung, W. K., & Leibel, R. L. (1997) · Genomics · doi:10.1006/geno.1997.4962 · Cited by 156 · see citing works
Légrádi, G., & Lechan, R. M. (1998) · Endocrinology · doi:10.1210/endo.139.7.6113 · Cited by 138 · see citing works
Leptin Signaling Targets the Thyrotropin-Releasing Hormone Gene Promoterin Vivo
Guo, F., Bakal, K., Minokoshi, Y., & Hollenberg, A. N. (2004) · Endocrinology · doi:10.1210/en.2003-1312 · Cited by 135 · see citing works
Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy
Oral, E. A., Ruiz, E., Andewelt, A., Sebring, N., Wagner, A. J., Depaoli, A. M., & Gorden, P. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.7.8591 · Cited by 129 · see citing works
Intracellular Mechanisms Involved in Leptin Regulation of Sympathetic Outflow
Rahmouni, K., Haynes, W. G., Morgan, D. A., & Mark, A. L. (2003) · Hypertension · doi:10.1161/01.hyp.0000048342.54392.40 · Cited by 120 · see citing works
Mihály, E., Fekete, C., Tatro, J. B., Liposits, Z., Stopa, E. G., & Lechan, R. M. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.7.6662 · Cited by 99 · see citing works
The role of leptin-->STAT3 signaling in neuroendocrine function: an integrative perspective
Bates, S. H., & Myers, M. G. (2004) · Journal of Molecular Medicine · doi:10.1007/s00109-003-0494-z · Cited by 81 · see citing works
Self-citationHuo, L., Münzberg, H., Nillni, E. A., & Bjørbæk, C. (2004) · Endocrinology · doi:10.1210/en.2003-1242 · Cited by 79 · see citing works
Obesity research springs a proton leak
Flier, J. S., & Lowell, B. B. (1997) · Nature Genetics · doi:10.1038/ng0397-223 · Cited by 53 · see citing works
Mihaly, E. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.85.7.2596 · Cited by 45 · see citing works
Mitochondrial uncoupling proteins and obesity: Molecular and genetic aspects of UCP1
Kozak, L., & Koza, R. (1999) · International Journal of Obesity · doi:10.1038/sj.ijo.0800941 · Cited by 32 · see citing works
Hisano, S., Fukui, Y., Chikamori‐Aoyama, M., Aizawa, T., & Shibasaki, T. (1993) · Brain Research · doi:10.1016/0006-8993(93)90178-p · Cited by 29 · see citing works
Obesity: prevalence, causes, health risks and treatment
Green, S. M. (1997) · British Journal of Nursing · doi:10.12968/bjon.1997.6.20.1181 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms of leptin action and leptin resistance.
Myers, M. G., Cowley, M. A., & Münzberg, H. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100707 · Cited by 1,074 · see citing works
Self-citationMolecular and anatomical determinants of central leptin resistance
Münzberg, H., & Myers, M. G. (2005) · Nature Neuroscience · doi:10.1038/nn1454 · Cited by 550 · see citing works
Self-citationVarela, L., & Horvath, T. L. (2012) · The EMBO Reports · doi:10.1038/embor.2012.174 · Cited by 426 · see citing works
Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“While leptin-induced activation of STAT3 is critical for normal energy homeostasis (12, 14), selective deletion of STAT3 in either POMC (205) or NPY/AgRP (70) neurons results in a mild-obesity phenotype, as occurs when leptin receptors are selectively deleted from these cells (5, 46, 187).”
BackgroundMice lacking inhibitory leptin receptor signals are lean with normal endocrine function
Björnholm, M., Münzberg, H., Leshan, R. L., Villanueva, E. C., Bates, S. H., Louis, G. W., Jones, J. C., Ishida-Takahashi, R., Bjørbaek, C., & Myers, M. G. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30688 · Cited by 183 · see citing works
Self-citationGong, 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 · see citing works
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 · see citing works
Self-citationSelective leptin resistance revisited
Mark, A. L. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00180.2013 · Cited by 162 · see citing works
Activation of Stat3 Signaling in AgRP Neurons Promotes Locomotor Activity
Mesaros, A., Koralov, S. B., Rother, E., Wunderlich, F. T., Ernst, M. B., Barsh, G. S., Rajewsky, K., & Brüning, J. C. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.01.007 · Cited by 128 · see citing works
Vella, K. R., Ramadoss, P., Lam, F. S., Harris, J. C., Ye, F. D., Same, P. D., O'Neill, N. F., Maratos-Flier, E., & Hollenberg, A. N. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.10.009 · Cited by 104 · see citing works
Self-citationLeptin regulates olfactory-mediated behavior in ob/ob mice
Getchell, T. V., Kwong, K., Saunders, C. P., Stromberg, A. J., & Getchell, M. L. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.11.016 · Cited by 96 · see citing works
Ghamari-Langroudi, M., Vella, K. R., Srisai, D., Sugrue, M. L., Hollenberg, A. N., & Cone, R. D. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0203 · Cited by 92 · see citing works
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 · see citing works
Self-citationSuppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models
Rupp, A. C., Tomlinson, A. J., Affinati, A. H., Yacawych, W. T., Duensing, A. M., True, C., Lindsley, S. R., Kirigiti, M. A., MacKenzie, A., Polex-Wolf, J., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci157515 · Cited by 55 · see citing works
“Furthermore, while LepRb-null mice exhibit severely reduced energy expenditure (29), KO Glp1r mice tended to display increased VO 2 and other parameters of energy expenditure compared with lean controls, although these trends were not statistically significant (Figure 3, J and K, and Supplemental…”
Self-citationLRb signals act within a distributed network of leptin‐responsive neurones to mediate leptin action
Leinninger, G. M., & Myers, M. G. (2008) · Acta Physiologica · doi:10.1111/j.1748-1716.2007.01784.x · Cited by 56 · see citing works
Self-citationRobertson, S., Ishida-Takahashi, R., Tawara, I., Hu, J., Patterson, C. M., Jones, J. C., Kulkarni, R. N., & Myers, M. G. (2010) · Diabetes · doi:10.2337/db09-1556 · Cited by 30 · see citing works
Self-citation
- Authors
- Bates, S. H., Dundon, T. A., Seifert, M., Carlson, M., Maratos-Flier, E., & Myers, M. G.
- Affiliations
- Joslin Diabetes Center (US)
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
- ORCID
- Myers, Martin G.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-12-01
- Volume
- 53
- Issue
- 12
- Pages
- 3067-3073
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2167683697
- Cited by
- 139
- References
- 44
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 1 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 7 · 2017: 8 · 2016: 2 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 8
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (1r01dk053978-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56731, DK-53978, DK 57768, R01DK057768)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- leptin receptor, STAT3 signaling, energy expenditure, leptin, obesity, db/db mice, locomotor activity, cold tolerance, shivering thermogenesis, resting metabolic rate, thyroid function, brown adipose tissue, UCP1, sympathetic nervous system, neuroendocrine regulation, hyperphagia
- MeSH terms
- Uncoupling Protein 1, Animals, Basal Metabolism, Body Composition, Body Temperature Regulation, Body Weight, Calorimetry, Indirect, Carrier Proteins, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Energy Metabolism, Ion Channels, Male, Membrane Proteins, Motor Activity, Receptors, Cell Surface, Thyroxine, Signal Transduction, Trans-Activators, Mutagenesis, Leptin, Mitochondrial Proteins, STAT3 Transcription Factor, Mice, Receptors, Leptin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
