Divergent responses to thermogenic stimuli in BAT and subcutaneous adipose tissue from interleukin 18 and interleukin 18 receptor 1-deficient mice
Open accessAbstract
Brown and beige adipocytes recruitment in brown (BAT) or white adipose tissue, mainly in the inguinal fat pad (iWAT), meet the need for temperature adaptation in cold-exposure conditions and protect against obesity in face of hypercaloric diets. Using interleukin18 (Il18) and Il18 receptor 1- knockout (Il18r1-KO) mice, this study aimed to investigate the role of IL18 signaling in BAT and iWAT activation and thermogenesis under both stimuli. Il18-KO, extremely dietary obesity-prone as previously described, failed to develop diet-induced thermogenesis as assessed by BAT and iWAT Ucp1 mRNA levels. Overweight when fed standard chow but not HFD, HFD-fed Il18r1-KO mice exhibited increased iWAT Ucp1 gene expression. Energy expenditure was reduced in pre-obese Il18r1-KO mice and restored upon HFD-challenge. Cold exposure lead to similar results; Il18r1-KO mice were protected against acute body temperature drop, displaying a more brown-like structure, alternative macrophage activation and thermogenic gene expression in iWAT than WT controls. Opposite effects were observed in Il18-KO mice. Thus, Il18 and Il18r1 genetic ablation disparate effects on energy homeostasis are likely mediated by divergent BAT responses to thermogenic stimuli as well as iWAT browning. These results suggest that a more complex receptor-signaling system mediates the IL18 adipose-tissue specific effects in energy expenditure.
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Only IL-18r KO mice can increase thermogenesis and white browning in response to HFD or cold.
“If both mouse models are overweight at the basal state but protected against diet-induced obesity, only IL-18r KO mice can increase thermogenesis and white browning in response to HFD or cold [241].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [241]
Mice KO for IL-18r or for IL-18 are both overweight at the basal state but protected against diet-induced obesity.
“If both mouse models are overweight at the basal state but protected against diet-induced obesity, only IL-18r KO mice can increase thermogenesis and white browning in response to HFD or cold [241].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [241]
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Cites
A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81410-5 · Cited by 3,864 · see citing works
Brown adipose tissue activity controls triglyceride clearance
Bartelt, A., Bruns, O. T., Reimer, R., Hohenberg, H., Ittrich, H., Peldschus, K., Kaul, M. G., Tromsdorf, U. I., Weller, H., Waurisch, C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2297 · Cited by 1,608 · see citing works
Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis, R. J., Cross, J. R., Jung, E., Thompson, C. B., Jones, R. G., et al. (2010) · Blood · doi:10.1182/blood-2009-10-249540 · Cited by 1,246 · see citing works
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
Seale, P., Conroe, H. M., Estall, J. L., Kajimura, S., Frontini, A., Ishibashi, J., Cohen, P., Cinti, S., & Spiegelman, B. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci44271 · Cited by 1,241 · see citing works
Adipose tissue browning and metabolic health
Bartelt, A., & Heeren, J. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.204 · Cited by 1,177 · see citing works
Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis
Nguyen, K. D., Qiu, Y., Cui, X., Goh, Y. P. S., Mwangi, J., David, T., Mukundan, L., Brombacher, F., Locksley, R. M., & Chawla, A. (2011) · Nature · doi:10.1038/nature10653 · Cited by 1,038 · see citing works
Rao, R. R., Long, J. Z., White, J. P., Svensson, K. J., Lou, J., Lokurkar, I., Jedrychowski, M. P., Ruas, J. L., Wrann, C. D., Lo, J. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.03.065 · Cited by 973 · see citing works
Cohen, P., Levy, J. D., Zhang, Y., Frontini, A., Kolodin, D., Svensson, K. J., Lo, J. C., Zeng, X., Ye, L., Khandekar, M. J., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.021 · Cited by 878 · see citing works
IL-37 is a fundamental inhibitor of innate immunity
Nold, M. F., Nold‐Petry, C. A., Zepp, J. A., Palmer, B. E., Bufler, P., & Dinarello, C. A. (2010) · Nature Immunology · doi:10.1038/ni.1944 · Cited by 850 · see citing works
A Switch from White to Brown Fat Increases Energy Expenditure in Cancer-Associated Cachexia
Petruzzelli, M., Schweiger, M., Schreiber, R., Campos‐Olivas, R., Tsoli, M., Allen, J., Swarbrick, M. M., Rose‐John, S., Rincón, M., Robertson, G. R., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.06.011 · Cited by 752 · see citing works
Barbatelli, G., Murano, I., Madsen, L., Hao, Q., Jimenez, M., Kristiansen, K., Giacobino, J., Matteis, R. D., & Cinti, S. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00600.2009 · Cited by 751 · see citing works
Mauer, J., Chaurasia, B., Goldau, J., Vogt, M. C., Ruud, J., Nguyen, K. D., Theurich, S., Hausen, A. C., Schmitz, J., Brönneke, H. S., et al. (2014) · Nature Immunology · doi:10.1038/ni.2865 · Cited by 727 · see citing works
Stienstra, R., Joosten, L. A. B., Koenen, T. B., van Tits, B. L. J. H., van Diepen, J. A., van den Berg, S. A. A., Rensen, P. C. N., Voshol, P. J., Fantuzzi, G., Hijmans, A., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.011 · Cited by 681 · see citing works
Roberts, L. D., Boström, P., O’Sullivan, J. F., Schinzel, R. T., Lewis, G. D., Dejam, A., Lee, Y.-K., Palma, M. J., Calhoun, S., Georgiadi, A., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.003 · Cited by 643 · see citing works
UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic
Shabalina, I. G., Petrovič, N., de Jong, J. M. A., Kalinovich, A., Cannon, B., & Nedergaard, J. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.044 · Cited by 637 · see citing works
GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK
Beiroa, D., Imbernon, M., Gallego, R., Senra, A., Herranz, D., Villarroya, F., Serrano, M., Fernø, J., Salvador, J., Escalada, J., et al. (2014) · Diabetes · doi:10.2337/db14-0302 · Cited by 602 · see citing works
Orchestration of Metabolism by Macrophages
Biswas, S. K., & Mantovani, A. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.11.013 · Cited by 586 · see citing works
Nold‐Petry, C. A., Lo, C. Y.-W., Rudloff, I., Elgass, K., Li, S., Gantier, M. P., Lotz-Havla, A. S., Gersting, S. W., Cho, S., Lao, J. C., et al. (2015) · Nature Immunology · doi:10.1038/ni.3103 · Cited by 442 · see citing works
Kajimura, S., & Saito, M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170252 · Cited by 428 · see citing works
Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance
Netea, M. G., Joosten, L. A. B., Lewis, E., Jensen, D. R., Voshol, P. J., Kullberg, B. J., Tack, C. J., van Krieken, H., Kim, S.-H., Stalenhoef, A. F., et al. (2006) · Nature Medicine · doi:10.1038/nm1415 · Cited by 424 · see citing works
Versatile functions for IL-6 in metabolism and cancer
Mauer, J., Denson, J. L., & Brüning, J. C. (2015) · Trends in Immunology · doi:10.1016/j.it.2014.12.008 · Cited by 405 · see citing works
IL-37: a new anti-inflammatory cytokine of the IL-1 family
Boraschi, D., Lucchesi, D., Hainzl, S., Leitner, M., Maier, E., Mangelberger, D., Oostingh, G. J., Pfaller, T., Pixner, C., Posselt, G., et al. (2011) · European Cytokine Network · doi:10.1684/ecn.2011.0288 · Cited by 360 · see citing works
Cinti, S. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.009662 · Cited by 350 · see citing works
Hui, X. H., Gu, P., Zhang, J., Nie, T., Pan, Y., Wu, D., Feng, T., Zhong, C., Wang, Y., Lam, K. S. L., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.004 · Cited by 349 · see citing works
Alboni, S., Cervia, D., Sugama, S., & Conti, B. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-9 · Cited by 301 · see citing works
Wilson, H., Chambers, A. P., Ryan, K. K., Li, B., Sandoval, D. A., Stoffers, D. A., Drucker, D. J., Pérez–Tilve, D., & Seeley, R. J. (2013) · Diabetes · doi:10.2337/db12-1498 · Cited by 292 · see citing works
Pharmacological and nutritional agents promoting browning of white adipose tissue
Bonet, M. L., Oliver, P., & Palou, A. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.12.002 · Cited by 276 · see citing works
UCP1 mRNA does not produce heat
Nedergaard, J., & Cannon, B. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.01.009 · Cited by 264 · see citing works
IL-37 protects against obesity-induced inflammation and insulin resistance
Ballak, D. B., van Diepen, J. A., Moschen, A. R., Jansen, H. J., Hijmans, A., Groenhof, G.-J., Leenders, F., Bufler, P., Boekschoten, M. V., Müller, M. M., et al. (2014) · Nature Communications · doi:10.1038/ncomms5711 · Cited by 221 · see citing works
Bulau, A., Nold, M. F., Li, S., Nold‐Petry, C. A., Fink, M., Mansell, A. S., Schwerd, T., Hong, J., Rubartelli, A., Dinarello, C. A., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1324140111 · Cited by 217 · see citing works
Knudsen, J. G., Murholm, M., Carey, A. L., Biensø, R., Basse, A., Allen, T., Hidalgo, J., Kingwell, B., Febbraio, M., Hansen, J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084910 · Cited by 202 · see citing works
Madsen, L., Pedersen, L. M., Lillefosse, H. H., Fjære, E., Brønstad, I., Hao, Q., Petersen, R. K., Hallenborg, P., Ma, T., Matteis, R. D., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011391 · Cited by 195 · see citing works
Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency
Zorrilla, E. P., Sánchez-Alavez, M., Sugama, S., Brennan, M., Fernandez, R. E., Bartfai, T., & Conti, B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611523104 · Cited by 170 · see citing works
The adipose organ: white‐brown adipocyte plasticity and metabolic inflammation
Smorlesi, A., Frontini, A., Giordano, A., & Cinti, S. (2012) · Obesity Reviews · doi:10.1111/j.1467-789x.2012.01039.x · Cited by 163 · see citing works
Contreras, C., González, F., Fernø, J., Diéguez, C., Rahmouni, K., Nogueiras, R., & López, M. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.919727 · Cited by 163 · see citing works
Self-citationAdaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice
Meyer, C. W., Willershäuser, M., Jastroch, M., Rourke, B. C., Fromme, T., Oelkrug, R., Heldmaier, G., & Klingenspor, M. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00021.2009 · Cited by 162 · see citing works
Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms
Kokkotou, E. G., Jeon, J. Y., Wang, X., Marino, F. E., Carlson, M., Trombly, D. J., & Maratos–Flier, E. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00861.2004 · Cited by 148 · see citing works
The structural basis for receptor recognition of human interleukin-18
Tsutsumi, N., Kimura, T., Arita, K., Ariyoshi, M., Ohnishi, H., Yamamoto, T. S., Zuo, X., Maenaka, K., Park, E. Y., Kondo, N., et al. (2014) · Nature Communications · doi:10.1038/ncomms6340 · Cited by 147 · see citing works
Chandrasekar, B., Boylston, W. H., Venkatachalam, K., Webster, N. J. G., Prabhu, S. D., & Valente, A. J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804236200 · Cited by 143 · see citing works
Interleukin-18 Activates the IRAK-TRAF6 Pathway in Mouse EL-4 Cells
Kojima, H., Takeuchi, M., Ohta, T., Nishida, Y., Arai, N., Ikeda, M., 池上, 伯., & Kurimoto, M. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.8236 · Cited by 137 · see citing works
Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation.
Guerra, C. E., Koza, R. A., Walsh, K., Kurtz, D. M., Wood, P. A., & Kozak, L. P. (1998) · Journal of Clinical Investigation · doi:10.1172/jci4532 · Cited by 131 · see citing works
Imbernón, M., Beiroa, D., Vazquez, M. J., Morgan, D. A., Veyrat‐Durebex, C., Porteiro, B., Díaz–Arteaga, A., Senra, A., Busquets, S., Velasquez, D., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.10.051 · Cited by 101 · see citing works
Self-citationDinarello, C. A., & Bufler, P. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.10.004 · Cited by 97 · see citing works
Assessment of brown adipose tissue function
Virtue, S., & Vidal‐Puig, A. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00128 · Cited by 94 · see citing works
Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice
Lindegaard, B., Matthews, V. B., Brandt, C., Højman, P., Allen, T. L., Estévez, E., Watt, M. J., Bruce, C. R., Mortensen, O. H., Syberg, S., et al. (2013) · Diabetes · doi:10.2337/db12-1095 · Cited by 91 · see citing works
Marks, A. R., Vianna, D. M. L., & Carrive, P. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90723.2008 · Cited by 76 · see citing works
Suárez, J., Rivera, P., Arrabal, S., Crespillo, A., Serrano, A., Baixerás, E., Pavón, F. J., Cifuentes, M., Nogueiras, R., Ballesteros, J., et al. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.013110 · Cited by 61 · see citing works
Self-citationMapping of the full length and the truncated interleukin-18 receptor alpha in the mouse brain
Alboni, S., Cervia, D., Ross, B. S., Montanari, C., Gonzalez, A. S., Sánchez-Alavez, M., Marcondes, M. C. G., VRIES, D. D., Sugama, S., Brunello, N., et al. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.06.016 · Cited by 50 · see citing works
Osborn, O., Gram, H., Zorrilla, E., Conti, B., & Bartfai, T. (2008) · Swiss Medical Weekly · doi:10.4414/smw.2008.12276 · Cited by 50 · see citing works
Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells
Alboni, S., Montanari, C., Benatti, C., Sánchez-Alavez, M., Rigillo, G., Blom, J. M. C., Brunello, N., Conti, B., Pariante, C. M., & Tascedda, F. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.02.015 · Cited by 46 · see citing works
Tung, Y. C. L., Rimmington, D., O’Rahilly, S., & Coll, A. P. (2007) · Endocrinology · doi:10.1210/en.2007-0797 · Cited by 46 · see citing works
Alboni, S., Montanari, C., Benatti, C., Blom, J. M. C., Simone, M. L., Brunello, N., Caggia, F., Guidotti, G., Marcondes, M. C. G., Sánchez-Alavez, M., et al. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.11.011 · Cited by 40 · see citing works
Zorrilla, E. P., & Conti, B. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.12.001 · Cited by 40 · see citing works
Pazos, P., Lima, L., Casanueva, F. F., Diéguez, C., & García, M. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072339 · Cited by 28 · see citing works
Self-citationAntisense IRAK-1 oligonucleotide blocks activation of NF-κB and AP-1 induced by IL-18
Guo, F., & Wu, S. (2000) · Immunopharmacology · doi:10.1016/s0162-3109(00)00200-9 · Cited by 18 · see citing works
Booker, C. S., & Grattan, D. R. (2014) · PeerJ · doi:10.7717/peerj.560 · Cited by 7 · see citing works
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Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476 · see citing works
“If both mouse models are overweight at the basal state but protected against dietinduced obesity, only IL-18r KO mice can increase thermogenesis and white browning in response to HFD or cold [241].”
BackgroundBecker, L., Nguyen, L., Gill, J., Kulkarni, S., Pasricha, P. J., & Habtezion, A. (2018) · Gut · doi:10.1136/gutjnl-2016-312940 · Cited by 196 · see citing works
- Authors
- Pazos, P., Lima, L., Tovar, S., González-Touceda, D., Diéguez, C., & García, M. C.
- Affiliations
- Universidade de Santiago de Compostela (ES)
- Venue
- Scientific Reports
- Published
- 2015-12-10
- Volume
- 5
- Issue
- 1
- Pages
- 17977-17977
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4674707
- OpenAlex
- W2286067730
- Cited by
- 33
- References
- 56
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 2
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, cc-by)
- Hispana (submittedVersion, cc-by)
- Repositorio institucional da Universidade de Santiago de Compostela (University of Santiago de Compostela) (submittedVersion, cc-by)
- Funders
- European Commission (245009)
- Ministerio de Economía y Competitividad (GPC2014/030, BFU2007-62683/BFI, CB06/03, PGIDIT06PXIB208067PR)
- Xunta de Galicia (BFU2007-62683/BFI, CB06/03, PGIDIT06PXIB208067PR, GPC2014/030)
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CB06/03)
- Instituto de Salud Carlos III (CB06/03)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- IL-18, brown adipose tissue, subcutaneous adipose tissue, thermogenesis, diet-induced thermogenesis, cold exposure, UCP1, beige adipocytes, adipose tissue browning, energy expenditure, obesity, macrophage activation, energy homeostasis
- MeSH terms
- Animals, Adipose Tissue, Brown, Cold Temperature, Energy Metabolism, Phenotype, Gene Expression, Mice, Knockout, Interleukin-18, Thermogenesis, Subcutaneous Fat, Mice, Receptors, Interleukin-18, Diet, High-Fat
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