Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
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Overnutrition is associated with chronic inflammation in metabolic tissues. Whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Here we show that a mediator of metabolic inflammation, IKKbeta/NF-kappaB, normally remains inactive although enriched in hypothalamic neurons. Overnutrition atypically activates hypothalamic IKKbeta/NF-kappaB at least in part through elevated endoplasmic reticulum stress in the hypothalamus. While forced activation of hypothalamic IKKbeta/NF-kappaB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKbeta either broadly across the brain or locally within the mediobasal hypothalamus, or specifically in hypothalamic AGRP neurons significantly protects against obesity and glucose intolerance. The molecular mechanisms involved include regulation by IKKbeta/NF-kappaB of SOCS3, a core inhibitor of insulin and leptin signaling. Our results show that the hypothalamic IKKbeta/NF-kappaB program is a general neural mechanism for energy imbalance underlying obesity and suggest that suppressing hypothalamic IKKbeta/NF-kappaB may represent a strategy to combat obesity and related diseases.
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SOCS-3 induced via the IKKβ-NFκβ pathway during cellular inflammation can contribute to leptin resistance and has been implicated in the pathogenesis of diet-induced obesity.
“Since SOCS-3 can also be induced via the IKKβ-NFκβ pathway during cellular inflammation, this mechanism can contribute to leptin resistance in this setting (211) and has been implicated in the pathogenesis of diet-induced obesity (DIO) (87, 119, 211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
Increasing SOCS-3 expression in the mediobasal hypothalamus using a lentiviral approach blocked the protection against diet-induced obesity conferred by AgRP-neuron-specific IKKβ knockout.
“increasing SOCS-3 expression in the mediobasal hypothalamus using a lentiviral approach blocked the protection against DIO conferred by AgRP-neuron-specific IKKβ knockout (211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
Interventions that reduce hypothalamic inflammation, either by reducing neuronal IKKβ signaling using gene therapy or by pharmacological administration of an IKKβ inhibitor, reduce food intake and body weight in diet-induced obese animals and maintain central leptin and insulin sensitivity.
“interventions that reduce hypothalamic inflammation, either by reducing neuronal IKKβ signaling using a gene therapy approach (211) or by pharmacological administration of a IKKβ inhibitor, reduce food intake and body weight in DIO animals (148) and maintain central leptin and insulin sensitivity.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
Central administration of an ER stress inhibitor suppressed hypothalamic NF-κB levels in high-fat-fed rats and lowered both food intake and body weight in diet-induced obese animals.
“central administration of an ER stress inhibitor suppressed hypothalamic NF-κB levels in HF-fed rats and lowered both food intake and body weight in DIO animals (211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
Activation of hypothalamic IKKβ/NF-κB signaling using a gene therapy approach promotes hyperphagia and weight gain and reduces leptin and insulin signaling in mice.
“activation of hypothalamic IKKβ/NF-κB signaling using a gene therapy approach promotes hyperphagia and weight gain and reduces leptin and insulin signaling in mice (211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
Rats fed a high-fat diet for 20 weeks exhibit both leptin resistance and hypothalamic inflammation, as measured by elevated mRNA and protein levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 resulting from activation of IKKβ and JNK-1.
“rats fed a HFD for 20-weeks exhibit both leptin resistance and hypothalamic inflammation, as measured by elevated mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) resulting from activation of IKKβ and JNK-1 (45, 148, 211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
Mice with cell-type specific deletion of IKKβ in AgRP neurons are protected against diet-induced obesity and exhibit reduced expression of SOCS-3 in the mediobasal hypothalamus.
“mice with cell-type specific deletion of IKKβ in AgRP neurons, which are protected against DIO and exhibit reduced expression of SOCS-3 in the mediobasal hypothalamus (211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [211]
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Cites
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199 · see citing works
Shared Principles in NF-κB Signaling
Hayden, M. S., & Ghosh, S. (2008) · Cell · doi:10.1016/j.cell.2008.01.020 · Cited by 4,814 · see citing works
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
TLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690 · see citing works
Özcan, U., Yilmaz, E., Özcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O., Görgün, C. Z., & Hotamisligil, G. S. (2006) · Science · doi:10.1126/science.1128294 · Cited by 2,413 · see citing works
Abnormal splicing of the leptin receptor in diabetic mice
Lee, G.-H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., & Friedman, J. M. (1996) · Nature · doi:10.1038/379632a0 · Cited by 2,327 · see citing works
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E. (2005) · Nature Medicine · doi:10.1038/nm1166 · Cited by 2,245 · see citing works
Self-citationRole of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235 · see citing works
Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z.-W., Karin, M., & Shoelson, S. E. (2001) · Science · doi:10.1126/science.1061620 · Cited by 1,884 · see citing works
Self-citationIKK-β links inflammation to obesity-induced insulin resistance
Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z.-W., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J., & Karin, M. (2005) · Nature Medicine · doi:10.1038/nm1185 · Cited by 1,773 · see citing works
Self-citationIKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice
Cai, D., Frantz, J. D., Tawa, N. E., Melendez, P. A., Oh, B.-C., Lidov, H. G. W., Hasselgren, P.-O., Frontera, W. R., Lee, J., Glass, D. J., et al. (2004) · Cell · doi:10.1016/j.cell.2004.09.027 · Cited by 1,367 · see citing works
Self-citationHypothalamic mTOR Signaling Regulates Food Intake
Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., & Seeley, R. J. (2006) · Science · doi:10.1126/science.1124147 · Cited by 1,278 · 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
Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis
Balthasar, N., Coppari, R., McMinn, J., Liu, S. M., Lee, C. E., Tang, V., Kenny, C. D., McGovern, R. A., Chua, S. C., Elmquist, J. K., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.004 · Cited by 935 · see citing works
Diabetes, Obesity, and the Brain
Schwartz, M. W., & Porte, D. (2005) · Science · doi:10.1126/science.1104344 · Cited by 841 · see citing works
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719 · see citing works
Ueki, K., Kondo, T., & Kahn, C. R. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5434-5446.2004 · Cited by 686 · see citing works
Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., Torisu, T., Chien, K. R., Yasukawa, H., & Yoshimura, A. (2004) · Nature Medicine · doi:10.1038/nm1071 · Cited by 651 · see citing works
Neuronal PTP1B regulates body weight, adiposity and leptin action
Bence, K. K., Delibegovic, M., Xue, B., Gorgun, C. Z., Hotamisligil, G. S., Neel, B. G., & Kahn, B. B. (2006) · Nature Medicine · doi:10.1038/nm1435 · Cited by 633 · see citing works
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G. B., et al. (2002) · Nature Neuroscience · doi:10.1038/nn861 · Cited by 572 · see citing works
Molecular 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
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 · see citing works
Hypothalamic sensing of fatty acids
Lam, T. K. T., Schwartz, G. J., & Rossetti, L. (2005) · Nature Neuroscience · doi:10.1038/nn1456 · Cited by 478 · see citing works
IRS-2 pathways integrate female reproduction and energy homeostasis
Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (2000) · Nature · doi:10.1038/35030105 · Cited by 455 · see citing works
Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake
Kitamura, T., Feng, Y., Kitamura, Y., Chua, S. C., Xu, A. W., Barsh, G. S., Rossetti, L., & Accili, D. (2006) · Nature Medicine · doi:10.1038/nm1392 · Cited by 449 · see citing works
PI3K 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 · see citing works
Attenuation of leptin and insulin signaling by SOCS proteins
Howard, J. K., & Flier, J. S. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.09.007 · Cited by 371 · see citing works
Overfeeding Rapidly Induces Leptin and Insulin Resistance
Wang, J., Obici, S., Morgan, K., Barzilai, N., Feng, Z., & Rossetti, L. (2001) · Diabetes · doi:10.2337/diabetes.50.12.2786 · Cited by 355 · see citing works
Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis
Kim, M.-S., Pak, Y. K., Jang, P., NamKoong, C., Choi, Y.-S., Won, J. C., Kim, K., Kim, S., Kim, H.-S., Park, J., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1731 · Cited by 333 · see citing works
Morton, G. J., Gelling, R. W., Niswender, K. D., Morrison, C. D., Rhodes, C. J., & Schwartz, M. W. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.10.009 · Cited by 292 · see citing works
Kievit, P., Howard, J. K., Badman, M. K., Balthasar, N., Coppari, R., Mori, H., Lee, C. E., Elmquist, J. K., Yoshimura, A., & Flier, J. S. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.06.010 · Cited by 242 · see citing works
Everhart, M. B., Han, W., Sherrill, T. P., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.8.4995 · Cited by 232 · see citing works
Consumption of a high-fat diet alters the homeostatic regulation of energy balance
Woods, S. C., D’Alessio, D. A., Tso, P., Rushing, P. A., Clegg, D. J., Benoit, S. C., Gotoh, K., Liu, M., & Seeley, R. J. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.07.026 · Cited by 150 · see citing works
Lehrke, M., & Lazar, M. A. (2004) · Nature Medicine · doi:10.1038/nm0204-126 · Cited by 138 · see citing works
The Fat-Brain Axis Enters a New Dimension
Elmquist, J. K., & Flier, J. S. (2004) · Science · doi:10.1126/science.1096746 · Cited by 111 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Inflammatory Mechanisms in Obesity
Gregor, M. F., & Hotamisligil, G. S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101322 · Cited by 3,754 · see citing works
Type 2 diabetes as an inflammatory disease
Donath, M. Y., & Shoelson, S. E. (2011) · Nature Reviews Immunology · doi:10.1038/nri2925 · Cited by 3,737 · see citing works
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Hotamisligil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.034 · Cited by 2,802 · see citing works
Inflammation, metaflammation and immunometabolic disorders
Hotamisligil, G. S. (2017) · Nature · doi:10.1038/nature21363 · Cited by 2,570 · see citing works
Inflammatory links between obesity and metabolic disease
Lumeng, C. N., & Saltiel, A. R. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57132 · Cited by 2,319 · see citing works
NF-κB, Inflammation, and Metabolic Disease
Baker, R. G., Hayden, M. S., & Ghosh, S. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2010.12.008 · Cited by 1,952 · see citing works
Obesity is associated with hypothalamic injury in rodents and humans.
Thaler, J. P., Yi, C.-X., Schur, E. A., Guyenet, S. J., Hwang, B. H., Dietrich, M. O., Zhao, X., Sarruf, D. A., Izgur, V., Maravilla, K. R., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59660 · Cited by 1,857 · see citing works
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 · see citing works
Adapting to obesity with adipose tissue inflammation
Reilly, S. M., & Saltiel, A. R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.90 · Cited by 1,204 · see citing works
Nutrient sensing and inflammation in metabolic diseases
Hotamisligil, G. S., & Erbay, E. (2008) · Nature Reviews Immunology · doi:10.1038/nri2449 · Cited by 1,040 · see citing works
Endoplasmic Reticulum Stress Plays a Central Role in Development of Leptin Resistance
Ozcan, L., Ergin, A. S., Lu, A., Chung, J., Sarkar, S., Nie, D., Myers, M. G., & Ozcan, U. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.004 · Cited by 875 · see citing works
Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH
Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D. (2013) · Nature · doi:10.1038/nature12143 · Cited by 834 · see citing works
Self-citationPenninx, B. W., Milaneschi, Y., Lamers, F., & Vogelzangs, N. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-129 · Cited by 839 · see citing works
Neurobiology of food intake in health and disease
Morton, G. J., Meek, T. H., & Schwartz, M. W. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3745 · Cited by 748 · see citing works
Adipocytokines in Obesity and Metabolic Disease
Cao, H. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0339 · Cited by 705 · see citing works
Holland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43378 · Cited by 705 · see citing works
Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis
Odegaard, J. I., & Chawla, A. (2013) · Science · doi:10.1126/science.1230721 · Cited by 643 · see citing works
Valdearcos, M., Robblee, M. M., Benjamin, D. I., Nomura, D. K., Xu, A. W., & Koliwad, S. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.018 · Cited by 629 · see citing works
Posey, K. A., Clegg, D. J., Printz, R. L., Byun, J., Morton, G. J., Vivekanandan-Giri, A., Pennathur, S., Baskin, D. G., Heinecke, J. W., Woods, S. C., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90377.2008 · Cited by 586 · see citing works
Hypothalamic stem cells control ageing speed partly through exosomal miRNAs
Zhang, Y., Kim, M. S., Jia, B., Yan, J., Zuniga-Hertz, J. P., Han, C., & Cai, D. (2017) · Nature · doi:10.1038/nature23282 · Cited by 564 · see citing works
Self-citationMitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance
Schneeberger, M., Dietrich, M. O., Sebastián, D., Imbernón, M., Castaño, C., Garcia, A., Esteban, Y., Gonzalez-Franquesa, A., Rodríguez, I. C., Bortolozzi, A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.003 · Cited by 519 · see citing works
Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.013 · Cited by 483 · see citing works
Hypothalamic inflammation in obesity and metabolic disease
Jais, A., & Brüning, J. C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88878 · Cited by 474 · see citing works
Valdearcos, M., Douglass, J. D., Robblee, M. M., Dorfman, M. D., Stifler, D. R., Bennett, M. L., Gerritse, I., Fasnacht, R., Barres, B. A., Thaler, J. P., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.015 · Cited by 477 · see citing works
Tanti, J.-F., & Jager, J. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.07.004 · Cited by 430 · see citing works
Kaltschmidt, B., & Kaltschmidt, C. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001271 · Cited by 392 · see citing works
Common cellular and molecular mechanisms in obesity and drug addiction
Kenny, P. J. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3105 · Cited by 382 · see citing works
Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity
Cintra, D. E., Ropelle, E. R., Moraes, J. C., Pauli, J. R., Morari, J., de Souza, C. T., Grimaldi, R., Stahl, M., Carvalheira, J. B., Saad, M. J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030571 · Cited by 381 · see citing works
JNK1 and IKKβ: molecular links between obesity and metabolic dysfunction
Solinas, G., & Karin, M. (2010) · The FASEB Journal · doi:10.1096/fj.09-151340 · Cited by 347 · see citing works
Self-citationInflammation and the Metabolic Syndrome: The Tissue-Specific Functions of NF-κB
Catrysse, L., & van Loo, G. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.01.006 · Cited by 329 · see citing works
Leptin and the maintenance of elevated body weight
Pan, W. W., & Myers, M. G. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.168 · Cited by 344 · 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
Metabolic disturbances connecting obesity and depression
Hryhorczuk, C., Sharma, S., & Fulton, S. E. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00177 · Cited by 322 · see citing works
Minireview: Inflammation and Obesity Pathogenesis: The Hypothalamus Heats Up
Thaler, J. P., & Schwartz, M. W. (2010) · Endocrinology · doi:10.1210/en.2010-0336 · Cited by 313 · see citing works
Hyperleptinemia Is Required for the Development of Leptin Resistance
Knight, Z. A., Hannan, K. S., Greenberg, M. L., & Friedman, J. M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011376 · Cited by 311 · see citing works
Skipping breakfast is associated with overweight and obesity: A systematic review and meta-analysis
Ma, X., Chen, Q., Pu, Y., Guo, M., Jiang, Z., Huang, W., Long, Y., & Xu, Y. (2020) · Obesity Research & Clinical Practice · doi:10.1016/j.orcp.2019.12.002 · Cited by 293 · see citing works
Food reward, hyperphagia, and obesity
Berthoud, H.-R., Lenard, N. R., & Shin, A. C. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00028.2011 · Cited by 275 · see citing works
Reactive oxygen species and insulin resistance: the good, the bad and the ugly
Tiganis, T. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.11.006 · Cited by 256 · see citing works
Neuroinflammation and neurodegeneration in overnutrition-induced diseases
Cai, D. (2013) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.11.003 · Cited by 256 · see citing works
Self-citationAstrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation
Douglass, J. D., Dorfman, M. D., Fasnacht, R., Shaffer, L. D., & Thaler, J. P. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.01.010 · Cited by 248 · see citing works
Neuronal control of peripheral insulin sensitivity and glucose metabolism
Ruud, J., Steculorum, S. M., & Brüning, J. C. (2017) · Nature Communications · doi:10.1038/ncomms15259 · Cited by 245 · see citing works
Wunderlich, F. T., Ströhle, P., Könner, A. C., Gruber, S., Tovar, S., Brönneke, H. S., Juntti-Berggren, L., Li, L.-S., van Rooijen, N., Libert, C., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.06.011 · Cited by 229 · see citing works
Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models
Zhang, H., Wu, C., Chen, Q., Chen, X., Xu, Z., Wu, J., & Cai, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061477 · Cited by 224 · see citing works
Self-citationDiversity and plasticity of microglial cells in psychiatric and neurological disorders
Nakagawa, Y., & Chiba, K. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.06.010 · Cited by 208 · see citing works
Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB
Purkayastha, S., Zhang, G., & Cai, D. (2011) · Nature Medicine · doi:10.1038/nm.2372 · Cited by 220 · see citing works
Self-citationBuckman, L. B., Hasty, A. H., Flaherty, D. K., Buckman, C. T., Thompson, M. M., Matlock, B. K., Weller, K., & Ellacott, K. L. J. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.06.007 · Cited by 216 · see citing works
Milaneschi, Y., Lamers, F., Bot, M., Drent, M. L., & Penninx, B. W. J. H. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.10.023 · Cited by 209 · see citing works
Zhang, G., Bai, H., Zhang, H., Dean, C., Wu, Q., Li, J., Guariglia, S., Meng, Q., & Cai, D. (2011) · Neuron · doi:10.1016/j.neuron.2010.12.036 · Cited by 208 · see citing works
Self-citationBrain insulin signalling in metabolic homeostasis and disease
Scherer, T., Sakamoto, K., & Buettner, C. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00498-x · Cited by 205 · see citing works
The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction
Sergi, D., Boulestin, H., Campbell, F. M., & Williams, L. M. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900934 · Cited by 194 · see citing works
Luteolin Protects against High Fat Diet-Induced Cognitive Deficits in Obesity Mice
Liu, Y., Fu, X., Lan, N., Li, S., Zhang, J., Wang, S., Li, C., Shang, Y., Huang, T., & Zhang, L. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.02.040 · Cited by 194 · see citing works
Diet impact on mitochondrial bioenergetics and dynamics
Putti, R., Sica, R., Migliaccio, V., & Lionetti, L. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00109 · Cited by 192 · see citing works
Role of Adiposity-Driven Inflammation in Depressive Morbidity
Capuron, L., Lasselin, J., & Castanon, N. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.123 · Cited by 182 · see citing works
Malnutrition in Obesity: Is It Possible?
Kobylińska, M., Antosik, K., Decyk, A., & Kurowska, K. (2022) · Obesity Facts · doi:10.1159/000519503 · Cited by 186 · see citing works
Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation
André, C., Guzman-Quevedo, O., Rey, C., Rémus-Borel, J., Clark, S., Castellanos-Jankiewicz, A., Ladeveze, E., Leste-Lasserre, T., Nadjar, A., Abrous, D. N., et al. (2017) · Diabetes · doi:10.2337/db16-0586 · Cited by 182 · see citing works
Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons
de Lartigue, G., Barbier de la Serre, C., Espero, E., Lee, J., & Raybould, H. E. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00056.2011 · Cited by 179 · see citing works
Reed, A. S., Unger, E. K., Olofsson, L. E., Piper, M. L., Myers, M. G., & Xu, A. W. (2010) · Diabetes · doi:10.2337/db09-1024 · Cited by 176 · see citing works
Zhang, G., & Cai, D. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00196.2011 · Cited by 171 · see citing works
Self-citationBrain regulation of energy balance and body weight
Rui, L. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9261-9 · Cited by 168 · see citing works
Hypothalamic innate immune reaction in obesity
Kälin, S., Heppner, F. L., Bechmann, I., Prinz, M., Tschöp, M. H., & Yi, C.-X. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.48 · Cited by 167 · see citing works
Hypothalamic inflammation and obesity: a mechanistic review
Seong, J., Kang, J. Y., Sun, J. S., & Kim, K. W. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01138-9 · Cited by 158 · see citing works
The central role of hypothalamic inflammation in the acute illness response and cachexia
Burfeind, K. G., Michaelis, K. A., & Marks, D. L. (2016) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2015.10.038 · Cited by 156 · see citing works
Won, J. C., Jang, P., Namkoong, C., Koh, E. H., Kim, S. K., Park, J., Lee, K., & Kim, M. (2009) · Obesity · doi:10.1038/oby.2009.194 · Cited by 153 · see citing works
Hypothalamic inflammation and energy homeostasis: Resolving the paradox
Thaler, J. P., Choi, S. J., Schwartz, M. W., & Wisse, B. E. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.10.002 · Cited by 144 · see citing works
Circadian disruption in the pathogenesis of metabolic syndrome
Maury, E., Hong, H. K., & Bass, J. (2014) · Diabetes & Metabolism · doi:10.1016/j.diabet.2013.12.005 · Cited by 132 · see citing works
The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
Fielder, E., von Zglinicki, T., & Jurk, D. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-161221 · Cited by 126 · see citing works
The role of hypothalamic estrogen receptors in metabolic regulation
Frank, A., Brown, L. M., & Clegg, D. J. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.05.002 · Cited by 128 · see citing works
“intake and energy expenditure (Zhang et al., 2008; Grill and Kaplan, 2002; Williams et al., 2001; Xu et al., 2011).”
Fonken, L. K., Lieberman, R. A., Weil, Z. M., & Nelson, R. J. (2013) · Endocrinology · doi:10.1210/en.2013-1121 · Cited by 125 · see citing works
Lage, R., Vázquez, M. J., Varela, L., Saha, A. K., Vidal‐Puig, A., Nogueiras, R., Diéguez, C., & López, M. (2010) · The FASEB Journal · doi:10.1096/fj.09-150672 · Cited by 123 · see citing works
Naznin, F., Sakoda, H., Okada, T., Tsubouchi, H., Waise, T. M. Z., Arakawa, K., & Nakazato, M. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.11.028 · Cited by 114 · see citing works
The pathophysiology of defective proteostasis in the hypothalamus — from obesity to ageing
Cavadas, C., Aveleira, C. A., Souza, G. F. P., & Velloso, L. A. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.107 · Cited by 105 · see citing works
Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition
Kaneko, K., Fu, Y., Lin, H.-Y., Cordonier, E. L., Mo, Q., Gao, Y., Yao, T., Naylor, J., Howard, V., Saito, K., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci126107 · Cited by 106 · see citing works
Morelli, A., Sarchielli, E., Comeglio, P., Filippi, S., Vignozzi, L., Marini, M., Rastrelli, G., Maneschi, E., Cellai, I., Persani, L., et al. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.09.017 · Cited by 107 · see citing works
Neuroprotective effects of dietary restriction: Evidence and mechanisms
Pani, G. (2015) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2015.03.004 · Cited by 103 · see citing works
Hakim, F., Wang, Y., Carreras, A., Hirotsu, C., Zhang, J., Peris, E., & Gozal, D. (2015) · Sleep · doi:10.5665/sleep.4320 · Cited by 90 · see citing works
Obesity: pathophysiology and therapeutic interventions
Kong, Y., Yang, H., Nie, R., Zhang, X., Zuo, F., Zhang, H., & Nian, X. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00264-9 · Cited by 89 · see citing works
Self-citationType I interferons and endoplasmic reticulum stress in health and disease
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.10.004 · Cited by 83 · see citing works
Linoleic acid rescues microglia inflammation triggered by saturated fatty acid
Tu, T. H., Kim, H., Yang, S., Kim, J. K., & Kim, J. G. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.03.047 · Cited by 84 · see citing works
Nucleus accumbens cytoarchitecture predicts weight gain in children
Rapuano, K. M., Laurent, J. S., Hagler, D. J., Hatton, S. N., Thompson, W. K., Jernigan, T. L., Dale, A. M., Casey, B. J., & Watts, R. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007918117 · Cited by 79 · see citing works
Ye, J. (2015) · Frontiers of Medicine · doi:10.1007/s11684-015-0377-z · Cited by 66 · see citing works
de Kloet, A. D., Pioquinto, D. J., Nguyen, D., Wang, L., Smith, J. A., Hiller, H., & Sumners, C. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.01.016 · Cited by 66 · see citing works
Sen, Z. D., Danyeli, L. V., Woelfer, M., Lamers, F., Wagner, G., Sobanski, T., & Walter, M. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.12.020 · Cited by 65 · see citing works
Leptin, neuroinflammation and obesity
Dragano, N. R. V., Haddad-Tovolli, R., & Velloso, L. A. (2017) · Frontiers of hormone research · doi:10.1159/000452908 · Cited by 45 · see citing works
Integration of Circadian and Metabolic Control of Reproductive Function
Evans, M. C., & Anderson, G. M. (2018) · Endocrinology · doi:10.1210/en.2018-00691 · Cited by 41 · see citing works
Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis
Kim, M. S., Yan, J., Wu, W., Zhang, G., Zhang, Y., & Cai, D. (2015) · Nature Immunology · doi:10.1038/ni.3133 · Cited by 40 · see citing works
Self-citationGut hormone GIP induces inflammation and insulin resistance in the hypothalamus
Fu, Y., Kaneko, K., Lin, H.-Y., Mo, Q., Xu, Y., Suganami, T., Ravn, P., & Fukuda, M. (2020) · Endocrinology · doi:10.1210/endocr/bqaa102 · Cited by 38 · see citing works
Fu, Y.-Y., Zhang, M., Turner, N., Zhang, L.-N., Dong, T.-C., Gu, M., Leslie, S. J., Li, J.-Y., Nan, F.-J., & Li, J. (2013) · Diabetologia · doi:10.1007/s00125-013-2987-9 · Cited by 35 · see citing works
Poon, K. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.591559 · Cited by 20 · see citing works
The influence of parental high-fat high-sugar diet on the gut-brain axis in male offspring
César, H., Nascimento Sertorio, M., Santamarina, A., Alves de Souza, E., Valles Mennitti, L., Jamar, G., Jucá, A., Picin Casagrande, B., Estadela, D., & Pellegrini Pisani, L. (2022) · Food Research International · doi:10.1016/j.foodres.2022.111706 · Cited by 10 · see citing works
Liu, Y., & Gong, F. (2025) · Phytotherapy Research · doi:10.1002/ptr.8415 · Cited by 6 · see citing works
- Authors
- Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D.
- Affiliations
- University of Wisconsin–Madison (US)
- University of California San Diego (US)
- Corresponding author
- Cai, Dongsheng
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 135
- Issue
- 1
- Pages
- 61-73
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2586330
- OpenAlex
- W2077033935
- Cited by
- 1,350
- References
- 36
- Citations by year
- 2026: 43 · 2025: 42 · 2024: 66 · 2023: 62 · 2022: 72 · 2021: 77 · 2020: 68 · 2019: 89 · 2018: 86 · 2017: 105 · 2016: 103 · 2015: 92 · 2014: 105 · 2013: 101 · 2012: 76
- FWCI
- 24.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1750 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R56, R01 DK078750, 1-07-JF-09)
- College of Engineering, University of Wisconsin-Madison (R56, R01 DK078750, 1-07-JF-09)
- American Diabetes Association (R56, R01 DK078750, 1-07-JF-09)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- overnutrition, obesity, energy imbalance, hypothalamus, IKKβ, NF-κB, endoplasmic reticulum stress, metabolic inflammation, insulin signaling, leptin signaling, SOCS3, AgRP neurons, impaired glucose tolerance, mediobasal hypothalamus
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Endoplasmic Reticulum, Energy Metabolism, Humans, Hypothalamus, Immunity, Innate, Insulin Resistance, Mice, Inbred C57BL, Neurons, Obesity, Signal Transduction, NF-kappa B, I-kappa B Proteins, Overnutrition, Suppressor of Cytokine Signaling Proteins, Mice, Agouti-Related Protein
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