The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice
Abstract
Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“the ability of leptin to activate pSTAT3, a marker of leptin signaling (49), is impaired in rodent models of DIO, specifically in the hypothalamic ARC (56, 124).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [124]
In the citing paper
“Importantly, P-STAT3 was not detected in the ventromedial (VMH), the dorsomedial (DMH), and the premammillary (PMV) nuclei of HA-ObRb/Pomc-Cre/Leprdb/db mice, regions known to express P-STAT3 in leptin-treated wild type mice (Figure 2C)(Munzberg et al., 2004).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Munzberg et al., 2004
In the citing paper
“Indeed, using a high-fat induced model of obesity in mice, leptin resistance measured by STAT-3 activation was shown to be restricted to the arcuate nucleus of the hypothalamus (60, 194), and this correlated with expression of the suppressor of leptin signaling SOCS-3 (248).”
From Cardiac remodeling in obesity (2008) · cites this paper as [248]
In the citing paper
“Despite this, they do not show the expected reduction in food intake and increase in energy expenditure, thus leading to the concept of leptin resistance, probably due to a decrease in JAK2‐STAT3 signaling in pathologic conditions 127.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [127]
Citations
Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585
Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451
Weight-Reducing Effects of the Plasma Protein Encoded by the obese 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
Effects of the obese Gene Product on Body Weight Regulation in ob / ob Mice
Pelleymounter, M. A., Cullen, M. J., Baker, M. B., Hecht, R., Winters, D., Boone, T., & Collins, F. (1995) · Science · doi:10.1126/science.7624776 · Cited by 4,017
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936
Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdán, M. G., Diano, S., Horvath, T. L., Cone, R. D., & Low, M. J. (2001) · Nature · doi:10.1038/35078085 · Cited by 2,356
Heymsfield, S. B., Greenberg, A. S., Fujioka, K., Dixon, R. M., Kushner, R., Hunt, T., Lubina, J. A., Patane, J., Self, B., Hunt, P., et al. (1999) · JAMA · doi:10.1001/jama.282.16.1568 · Cited by 1,422
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 1,374
Caro, J. F., Kolaczynski, J. W., Nyce, M. R., Ohannesian, J. P., Opentanova, I., Goldman, W. H., Lynn, R. B., Zhang, P.-L., Sinha, M. K., & Considine, R. V. (1996) · The Lancet · doi:10.1016/s0140-6736(96)03173-x · Cited by 1,175
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
Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.
Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J. E., Stoffel, M., & Friedman, J. M. (1996) · Nature Genetics · doi:10.1038/ng0996-95 · Cited by 1,086
Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans
Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J., & Porte, D. (1996) · Nature Medicine · doi:10.1038/nm0596-589 · Cited by 1,014
Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance
Bjørbæk, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E., & Flier, J. S. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80062-3 · Cited by 1,014
Self-citationSTAT3 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
Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area
Elias, C. F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R. S., Bjorbæk, C., Flier, J. S., Saper, C. B., & Elmquist, J. K. (1999) · Neuron · doi:10.1016/s0896-6273(01)80035-0 · Cited by 924
Self-citationSOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2
Rui, L., Yuan, M., Frantz, D., Shoelson, S., & White, M. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200444200 · Cited by 904
Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjørbæk, C., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9842 · Cited by 887
Self-citationMercer, J. G., Hoggard, N., Williams, L. M., Lawrence, C. B., Hannah, L. T., & Trayhurn, P. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)00473-5 · Cited by 881
PTP1B Regulates Leptin Signal Transduction In Vivo
Zabolotny, J. M., Bence, K. K., Stricker‐Krongrad, A., Haj, F. G., Wang, Y., Minokoshi, Y., Kim, Y., Elmquist, J. K., Tartaglia, L. A., Kahn, B. B., et al. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00148-x · Cited by 818
Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
van Heek, M., Compton, D. S., France, C. F., Tedesco, R. P., Fawzi, A. B., Graziano, M. P., Sybertz, E. J., Strader, C. D., & Davis, H. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119171 · Cited by 765
The role of SOCS-3 in leptin signaling and leptin resistance
Bjørbæk, C., El-Haschimi, K., Frantz, J. D., & Flier, J. S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30059 · Cited by 639
Self-citationLeptin Signaling in the Central Nervous System and the Periphery
Bjørbæk, C. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.305 · Cited by 559
Self-citationAttenuation of Leptin Action and Regulation of Obesity by Protein Tyrosine Phosphatase 1B
Cheng, A., Uetani, N., Simoncic, P. D., Chaubey, V. P., Lee-Loy, A., McGlade, C. J., Kennedy, B. P., & Tremblay, M. L. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00149-1 · Cited by 545
Broadwell, R. D., & Brightman, M. (1976) · The Journal of Comparative Neurology · doi:10.1002/cne.901660302 · Cited by 519
Howard, J. K., Cave, B. J., Oksanen, L. J., Tzameli, I., Bjørbæk, C., & Flier, J. S. (2004) · Nature Medicine · doi:10.1038/nm1072 · Cited by 490
Self-citationInsulin Activation of Phosphatidylinositol 3-Kinase in the Hypothalamic Arcuate Nucleus
Niswender, K. D., Morrison, C. D., Clegg, D. J., Olson, R., Baskin, D. G., Myers, M. G., Seeley, R. J., & Schwartz, M. W. (2003) · Diabetes · doi:10.2337/diabetes.52.2.227 · Cited by 476
SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling
Emanuelli, B., Peraldi, P., Filloux, C., Sawka‐Verhelle, D., Hilton, D. J., & OBBERGHEN, E. V. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.21.15985 · Cited by 468
Niswender, K. D., & Schwartz, M. W. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/s0091-3022(02)00105-x · Cited by 428
The Catabolic Action of Insulin in the Brain Is Mediated by Melanocortins
Benoit, S. C., Air, E. L., Coolen, L. M., Strauss, R., Jackman, A., Clegg, D. J., Seeley, R. J., & Woods, S. C. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09048.2002 · Cited by 417
Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake
Grill, H. J., Schwartz, M. W., Kaplan, J. M., Foxhall, J. S., Breininger, J., & Baskin, D. G. (2002) · Endocrinology · doi:10.1210/endo.143.1.8589 · Cited by 395
Gao, Q., Wolfgang, M. J., Neschen, S., Morino, K., Horvath, T. L., Shulman, G. I., & Fu, X.-Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0303992101 · Cited by 385
Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance
Sahu, A. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2003.10.001 · Cited by 358
Impaired transport of leptin across the blood-brain barrier in obesity☆
Banks, W. A., DiPalma, C., & Farrell, C. L. (1999) · Peptides · doi:10.1016/s0196-9781(99)00139-4 · Cited by 334
Münzberg, H., Huo, L., Nillni, E. A., Hollenberg, A. N., & Bjørbæk, C. (2003) · Endocrinology · doi:10.1210/en.2002-221037 · Cited by 328
Self-citationHileman, S. M., Pierroz, D. D., Masuzaki, H., Bjørbæk, C., El-Haschimi, K., Banks, W. A., & Flier, J. S. (2002) · Endocrinology · doi:10.1210/endo.143.3.8669 · Cited by 274
Self-citationA second look at the barriers of the medial basal hypothalamus
Peruzzo, B., Pastor, F., Blázquez, J. L., Schoebitz, K., Peláez, B., Amat, P., & Rodríguez, E. M. (2000) · Experimental Brain Research · doi:10.1007/s002219900289 · Cited by 273
Levin, B. E., Dunn-Meynell, A. A., & Banks, W. A. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00393.2003 · Cited by 269
Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin
Sahu, A. (2004) · Endocrinology · doi:10.1210/en.2004-0032 · Cited by 266
Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible
Banks, W. A., & Farrell, C. L. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00468.2002 · Cited by 241
Ziotopoulou, M., Mantzoros, C. S., Hileman, S. M., & Flier, J. S. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.4.e838 · Cited by 230
Self-citationSuppressor of Cytokine Signaling 3 Is a Physiological Regulator of Adipocyte Insulin Signaling
Shi, H., Tzameli, I., Bjørbæk, C., & Flier, J. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403886200 · Cited by 223
Self-citationSatoh, N., Ogawa, Y., Katsuura, G., Numata, Y., Tsuji, T., Hayase, M., Ebihara, K., Masuzaki, H., Hosoda, K., Yoshimasa, Y., et al. (1999) · Diabetes · doi:10.2337/diabetes.48.9.1787 · Cited by 223
The Concept of Selective Leptin Resistance
Correia, M. L. G., Haynes, W. G., Rahmouni, K., Morgan, D. A., Sivitz, W. I., & Mark, A. L. (2002) · Diabetes · doi:10.2337/diabetes.51.2.439 · Cited by 218
Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications
Mark, A. L., Correia, M. L. G., Rahmouni, K., & Haynes, W. G. (2002) · Journal of Hypertension · doi:10.1097/00004872-200207000-00001 · Cited by 215
The arcuate nucleus as a primary site of satiety effect of leptin in rats
Satoh, N., Ogawa, Y., Katsuura, G., Hayase, M., Tsuji, T., Imagawa, K., Yoshimasa, Y., Nishi, S., Hosoda, K., & Nakao, K. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00163-8 · Cited by 213
Brain Stem Is a Direct Target for Leptin’s Action in the Central Nervous System
Hosoi, T., Kawagishi, T., Okuma, Y., Tanaka, J., & Nomura, Y. (2002) · Endocrinology · doi:10.1210/en.2002-220077 · Cited by 204
Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain
Lin, S., Storlien, L. H., & Huang, X. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02580-4 · Cited by 198
Hübschle, T., Thom, E., Watson, A. M. D., Roth, J., Klaus, S., & Meyerhof, W. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-07-02413.2001 · Cited by 191
Morton, G. J., Niswender, K. D., Rhodes, C. J., Myers, M. G., Blevins, J. E., Baskin, D. G., & Schwartz, M. W. (2003) · Endocrinology · doi:10.1210/en.2002-0115 · Cited by 158
Transgenic Complementation of Leptin-Receptor Deficiency
Kowalski, T. J., Liu, S.-M., Leibel, R. L., & Chua, S. C. (2001) · Diabetes · doi:10.2337/diabetes.50.2.425 · Cited by 150
Ladyman, S. R., & Grattan, D. R. (2004) · Endocrinology · doi:10.1210/en.2004-0338 · Cited by 144
The Effect of Leptin Is Enhanced by Microinjection Into the Ventromedial Hypothalamus
Jacob, R. J., Dziura, J. D., Medwick, M. B., Leone, P., Caprio, S., During, M. J., Shulman, G. I., & Sherwin, R. (1997) · Diabetes · doi:10.2337/diab.46.1.150 · Cited by 134
Cunningham, M. J., Scarlett, J. M., & Steiner, R. A. (2002) · Endocrinology · doi:10.1210/endo.143.3.8661 · Cited by 96
Presynaptic NMDA receptor subunit immunoreactivity in GABAergic terminals in rat brain
Paquet, M., & Smith, Y. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20000724)423:2 · Cited by 95
Bergen, H., Mizuno, T. M., Taylor, J., & Mobbs, C. V. (1999) · Brain Research · doi:10.1016/s0006-8993(99)02186-1 · Cited by 95
Leptin Signaling in the Hypothalamus during Chronic Central Leptin Infusion
Pal, R., & Sahu, A. (2003) · Endocrinology · doi:10.1210/en.2002-0148 · Cited by 72
Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity
Wilsey, J. T., Zolotukhin, S., Prima, V., & Scarpace, P. J. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00193.2003 · Cited by 67
Behavioral and endocrinological effects of single injections of monosodium glutamate in the mouse.
Lorden, J. F., & Caudle, A. B. (1987) · PubMed · Cited by 59
Chua, S. C., Liu, S.-M., Li, Q., Sun, A., DeNino, W. F., Heymsfield, S. B., & Guo, X.-D. E. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00349.2003 · Cited by 35
Hypothalamic Leptin Receptor and Signaling Molecule Expressions in Cafeteria Diet-Fed Rats
Plut, C., Ribière, C., Giudicelli, Y., & Dausse, J. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.054726 · Cited by 33
Elmquist (1998) · doi:10.1002/(sici)1096-9861(19980615)395:4
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Central nervous system control of food intake and body weight
Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S., & Schwartz, M. W. (2006) · Nature · doi:10.1038/nature05026 · Cited by 2,503
The cellular and signaling networks linking the immune system and metabolism in disease
Osborn, O., & Olefsky, J. M. (2012) · Nature Medicine · doi:10.1038/nm.2627 · Cited by 1,551
Obesity and the role of adipose tissue in inflammation and metabolism
Greenberg, A. S., & Obin, M. S. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/83.2.461s · Cited by 1,295
Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
Vong, L., Ye, C., Yang, Z., Choi, B. J., Chua, S. C., & Lowell, B. B. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.028 · Cited by 1,237
Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders
Choe, S. S., Huh, J. Y., Hwang, I. J., Kim, J. I., & Kim, J. B. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00030 · Cited by 1,206
Metadata
- Authors
- Münzberg, H., Flier, J. S., & Bjørbæk, C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Bjørbæk, Christian
- ORCID
- Flier, Jeffrey S.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-11-01
- Volume
- 145
- Issue
- 11
- Pages
- 4880-4889
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2045522606
- Cited by
- 737
- References
- 61
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 16 · 2023: 14 · 2022: 23 · 2021: 22 · 2020: 30 · 2019: 46 · 2018: 30 · 2017: 28 · 2016: 34 · 2015: 45 · 2014: 49 · 2013: 56 · 2012: 51
- FWCI
- 13.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060673, R01 DK60673, R37DK028082, R37 DK 28082)
- 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
- leptin resistance, diet-induced obesity, hypothalamus, arcuate nucleus, STAT3 signaling, SOCS3, leptin receptor, high-fat diet, obesity pathogenesis
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Arcuate Nucleus of Hypothalamus, Body Weight, Dietary Fats, Dorsomedial Hypothalamic Nucleus, Eating, Hyperphagia, Male, Mice, Inbred C57BL, Obesity, Repressor Proteins, RNA, Messenger, Transcription Factors, Ventromedial Hypothalamic Nucleus, Signal Transduction, Leptin, Suppressor of Cytokine Signaling Proteins, Mice
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
