Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold
Abstract
Adaptive nonshivering thermogenesis may have profound effects on energy balance and is therefore therefore is a potential mechanism for counteracting the development of obesity. The molecular basis for adaptive nonshivering thermogenesis has remained a challenge that sparked acute interest with the identification of proteins (UCP2, UCP3, etc.) with high‐sequence similarity to the original uncoupling protein‐1 (UCP1), which is localized only in brown adipose tissue. Using UCP1‐ablated mice, we examined whether any adaptive nonshivering thermogenesis could be recruited by acclimation to cold. Remarkably, by successive acclimation, the UCP1‐ablated mice could be made to subsist for several weeks at 4°C during which they had to constantly produce heat at four times their resting levels. Despite these extreme requirements for adaptive nonshivering thermogenesis, however, no substitution of shivering by any adaptive nonshivering thermogenic process occurred. Thus, although the existence of, for example, muscular mechanisms for adaptive nonshivering thermogenesis has recurrently been implied, we did not find any indication of such thermogenesis. Not even during prolonged and enhanced demand for extra heat production was any endogenous hormone or neurotransmitter able to recruit any UCP1‐independent adaptive nonshivering thermogenic process in muscle or in any other organ, and no proteins other than UCP1—not even UCP2 or UCP3—therefore have the ability to mediate adaptive nonshivering thermogenesis in the cold.
Integrity signals
Registry
Cites
Statistics
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?
UCP1 is unique to BAT and is necessary to mediate BAT thermogenesis.
“UCP1 is unique to BAT and is necessary to mediate BAT thermogenesis 30.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [30]
BAT is not a simple combustion engine, but an exquisitely regulated biological tissue with internal negative feedback pathways.
“Fortunately, BAT is not a simple combustion engine, but an exquisitely regulated biological tissue with internal negative feedback pathways 30,30.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [30]
Cites
Obesity and the regulation of energy balance
Spiegelman, B. M., & Flier, J. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00240-9 · Cited by 2,398 · see citing works
Towards a molecular understanding of adaptive thermogenesis
Lowell, B. B., & Spiegelman, B. M. (2000) · Nature · doi:10.1038/35007527 · Cited by 1,630 · see citing works
Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese
Enerbäck, S., Jacobsson, A., Simpson, E. M., Guerra, C., Yamashita, H., Harper, M.-E., & Kozak, L. P. (1997) · Nature · doi:10.1038/387090a0 · Cited by 1,379 · see citing works
Self-citationArsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., Couplan, E., Alves‐Guerra, M., Goubern, M., Surwit, R. S., et al. (2000) · Nature Genetics · doi:10.1038/82565 · Cited by 1,079 · see citing works
The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP
Ricquier, D., & Bouillaud, F. (2000) · Biochemical Journal · doi:10.1042/bj3450161 · Cited by 806 · see citing works
Energy metabolism in uncoupling protein 3 gene knockout mice
Vidal-Puig, A. J., Grujic, D., Zhang, C.-Y., Hagen, T., Boss, O., Ido, Y., Szczepanik, A., Wade, J., Mootha, V., Cortright, R., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910179199 · Cited by 677 · see citing works
Foster, D. O., & Frydman, M. L. (1979) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y79-039 · Cited by 518 · see citing works
Temperature Regulation in Laboratory Rodents
Gordon, C. J. (1993) · Cambridge University Press eBooks · doi:10.1017/cbo9780511565595 · Cited by 515 · see citing works
Gong, D., Monemdjou, S., Gavrilova, O., Leon, L. R., Marcus‐Samuels, B., Chou, C. J., Everett, C. A., Kozak, L. P., Li, C., Deng, C., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910177199 · Cited by 385 · see citing works
Structure and function of the uncoupling protein from brown adipose tissue
Klingenberg, M., & Huang, S. (1999) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(98)00232-6 · Cited by 359 · see citing works
Thermogenic Responses in Brown Fat Cells Are Fully UCP1-dependent
Matthias, A., Ohlson, K. B. E., Fredriksson, J. M., Jacobsson, A., Nedergaard, J., & Cannon, B. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000547200 · Cited by 342 · see citing works
Self-citationBlock, B. A. (1994) · Annual Review of Physiology · doi:10.1146/annurev.ph.56.030194.002535 · Cited by 281 · see citing works
Wibom, R., Hultman, E., Johansson, M., Matherei, K., Constantin-Teodosiu, D., & Schantz, P. G. (1992) · Journal of Applied Physiology · doi:10.1152/jappl.1992.73.5.2004 · Cited by 208 · see citing works
Oberkofler, H., Dallinger, G., Liu, Y. M., Hell, E., Krempler, F., & Patsch, W. (1997) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37142-x · Cited by 191 · see citing works
Humoral thermogenesis and its role in maintaining energy balance.
Janský, L. (1995) · Physiological Reviews · doi:10.1152/physrev.1995.75.2.237 · Cited by 133 · see citing works
Regional changes in capillary supply in skeletal muscle of high-intensity endurance-trained rats
Gute, D. C., Fraga, C., Laughlin, M. H., & Amann, J. F. (1996) · Journal of Applied Physiology · doi:10.1152/jappl.1996.81.2.619 · Cited by 121 · see citing works
Trayhurn, P., & Nicholls, D. G. (1986) · Edward Arnold eBooks · Cited by 98 · see citing works
Chapter 17 The uncoupling protein thermogenin and mitochondrial thermogenesis
Nedergaard, J., & Cannon, B. (1992) · New comprehensive biochemistry · doi:10.1016/s0167-7306(08)60185-4 · Cited by 70 · see citing works
Self-citationThermal and electromyographic correlates of shivering thermogenesis in the pigeon
Hohtola, E. (1982) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(82)90049-4 · Cited by 68 · see citing works
Self-citationEffects of chronic hypoxia and endurance training on muscle capillarity in rats
Bigard, X. A., Brunet, A., Guézennec, C.-Y., & MONOD, H. (1991) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/bf00371099 · Cited by 58 · see citing works
Behrens, W. A., & Himms‐Hagen, J. (1977) · Journal of Bioenergetics and Biomembranes · doi:10.1007/bf00745042 · Cited by 39 · see citing works
Suzuki, J., Gao, M., Ohinata, H., KUROSHIMA, A., & Koyama, T. (1997) · The Japanese Journal of Physiology · doi:10.2170/jjphysiol.47.513 · Cited by 30 · see citing works
Increased calcium uptake by muscle mitochondria of cold-acclimated rats
Greenway, D. C., & Himms‐Hagen, J. (1978) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1978.234.1.c7 · Cited by 30 · see citing works
Chilibeck, P. D., Bell, G. J., Socha, T. L., & Martin, T. (1998) · Canadian Journal of Applied Physiology · doi:10.1139/h98-005 · Cited by 29 · see citing works
Seasonal changes in enzymes of aerobic heat production in the white-footed mouse
Wickler, S. J. (1981) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1981.240.5.r289 · Cited by 29 · see citing works
Snyder, G. K., Farrelly, C. A., & Coelho, J. R. (1992) · European Journal of Applied Physiology · doi:10.1007/bf00705074 · Cited by 26 · see citing works
Intermittent cold exposure causes a muscle-specific shift in the fiber type composition in rats
Walters, T. J., & Constable, S. H. (1993) · Journal of Applied Physiology · doi:10.1152/jappl.1993.75.1.264 · Cited by 25 · see citing works
Increase in cytochrome oxidase capacity of BAT and other tissues in cold-acclimated gerbils
Bourhim, M., Barré, H., Oufara, S., Minaire, Y., Chatonnet, J., Cohen-Adad, F., & Rouanet, J. L. (1990) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1990.258.5.r1291 · Cited by 20 · see citing works
Cold acclimation-recruited nonshivering thermogenesis: the Syrian hamster is not an exception
Dicker, A., Cannon, B., & Nedergaard, J. (1995) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1995.269.4.r767 · Cited by 18 · see citing works
Self-citationIs there a Life in the Cold without UCP1? Uncoupling Proteins and Thermoregulatory Thermogenesis
Cannon, B., Golozoubova, V., Matthias, A., et al. (2000) · Springer eBooks · doi:10.1007/978-3-662-04162-8_42 · Cited by 13 · see citing works
Self-citationStructural and metabolic changes in skeletal muscle of cold acclimated rats
Soni, A., & Katoch, S. S. (1997) · Journal of Thermal Biology · doi:10.1016/s0306-4565(96)00037-x · Cited by 11 · see citing works
No nonshivering thermogenesis in mice lacking UCP1, despite high UCP2 expression
Cannon, B., Golozoubova, V., Matthias, A., et al. (2000) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/s1095-6433(00)80042-2 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
Self-citationUnexpected evidence for active brown adipose tissue in adult humans
Nedergaard, J., Bengtsson, T., & Cannon, B. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00691.2006 · Cited by 1,824 · see citing works
Self-citationFeldmann, H. M., Golozoubova, V., Cannon, B., & Nedergaard, J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.014 · Cited by 1,318 · see citing works
Self-citationPetrovic, N., Walden, T. B., Shabalina, I. G., Timmons, J. A., Cannon, B., & Nedergaard, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.053942 · Cited by 1,263 · see citing works
Self-citationA Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat
Kazak, L., Chouchani, E. T., Jedrychowski, M. P., Erickson, B. K., Shinoda, K., Cohen, P., Vetrivelan, R., Lu, G. Z., Laznik-Bogoslavski, D., Hasenfuss, S. C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.09.035 · Cited by 787 · see citing works
Thermogenic Mechanisms and Their Hormonal Regulation
Silva, J. E. (2006) · Physiological Reviews · doi:10.1152/physrev.00009.2005 · Cited by 687 · see citing works
Nonshivering thermogenesis and its adequate measurement in metabolic studies
Cannon, B., & Nedergaard, J. (2011) · Journal of Experimental Biology · doi:10.1242/jeb.050989 · Cited by 677 · see citing works
Self-citationCellular bioenergetics as a target for obesity therapy
Tseng, Y.-H., Cypess, A. M., & Kahn, C. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3138 · Cited by 591 · see citing works
Brown fat as a therapy for obesity and diabetes
Cypess, A. M., & Kahn, C. R. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328337a81f · Cited by 376 · see citing works
Sarjeant, K., & Stephens, J. M. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008417 · Cited by 328 · see citing works
Simcox, J., Geoghegan, G., Maschek, J. A., Bensard, C. L., Pasquali, M., Miao, R., Lee, S., Jiang, L., Huck, I., Kershaw, E. E., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.006 · Cited by 277 · see citing works
Lelliott, C. J., Medina-Gomez, G., Petrovic, N., Kis, A., Feldmann, H. M., Bjursell, M., Parker, N., Curtis, K., Campbell, M., Hu, P., et al. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040369 · Cited by 280 · see citing works
“the ability of the mice to maintain some fraction of increased metabolic activity through continued shivering [22–24].”
BackgroundToh, S. Y., Gong, J., Du, G., Li, J. Z., Yang, S., Ye, J., Yao, H., Zhang, Y., Xue, B., Li, Q., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002890 · Cited by 267 · see citing works
Sonoda, J., Mehl, I. R., Chong, L.-W., Nofsinger, R. R., & Evans, R. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611623104 · Cited by 266 · see citing works
UCP1 deficiency increases susceptibility to diet‐induced obesity with age
Kontani, Y., Wang, Y., Kimura, K., Inokuma, K. ‐., Saito, M., Suzuki‐Miura, T., Wang, Z., Sato, Y., Mori, N., & Yamashita, H. (2005) · Aging Cell · doi:10.1111/j.1474-9726.2005.00157.x · Cited by 207 · see citing works
Zhang, C., McFarlane, C., Lokireddy, S., Masuda, S., Ge, X., Gluckman, P. D., Sharma, M., & Kambadur, R. (2012) · Diabetologia · doi:10.1007/s00125-011-2304-4 · Cited by 192 · see citing works
Uncoupling proteins: A role in protection against reactive oxygen species—or not?
Cannon, B., Shabalina, I. G., Kramarova, T. V., Petrovic, N., & Nedergaard, J. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.05.016 · Cited by 182 · see citing works
Self-citationThe regulation of adipose tissue health by estrogens
Steiner, B. M., & Berry, D. C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.889923 · Cited by 171 · see citing works
Mitochondrial uncoupling and lifespan
Mookerjee, S. A., Divakaruni, A. S., Jastroch, M., & Brand, M. D. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.03.010 · Cited by 169 · see citing works
Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints
Speakman, J. R. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071811-150711 · Cited by 163 · see citing works
Golozoubova, V., Gullberg, H., Matthias, A., Cannon, B., Vennström, B., & Nedergaard, J. (2004) · Molecular Endocrinology · doi:10.1210/me.2003-0267 · Cited by 155 · see citing works
Self-citationFibroblast growth factor 21 and browning of white adipose tissue
Cuevas-Ramos, D., Mehta, R., & Aguilar-Salinas, C. A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00037 · Cited by 149 · see citing works
Boucher, J., Mori, M. A., Lee, K. Y., Smyth, G., Liew, C. W., Macotela, Y., Rourk, M., Bluher, M., Russell, S. J., & Kahn, C. R. (2012) · Nature Communications · doi:10.1038/ncomms1905 · Cited by 142 · see citing works
The regulation and turnover of mitochondrial uncoupling proteins
Azzu, V., Jastroch, M., Divakaruni, A. S., & Brand, M. D. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.02.035 · Cited by 146 · see citing works
de Jong, J. M. A., Sun, W., Pires, N. D., Frontini, A., Balaz, M., Jespersen, N. Z., Feizi, A., Petrovic, K., Fischer, A. W., Bokhari, M. H., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0101-4 · Cited by 137 · see citing works
Long-Term Cold Adaptation Does Not Require FGF21 or UCP1
Keipert, S., Kutschke, M., Ost, M., Schwarzmayr, T., van Schothorst, E. M., Lamp, D., Brachthäuser, L., Hamp, I., Mazibuko, S. E., Hartwig, S., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.016 · Cited by 122 · see citing works
Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge
Lu, Y., Fujioka, H., Joshi, D., Li, Q., Sangwung, P., Hsieh, P., Zhu, J., Torio, J., Sweet, D., Wang, L., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-26394-5 · Cited by 76 · see citing works
Paulo, E., Wu, D., Wang, Y., Zhang, Y., Wu, Y., Swaney, D. L., Soucheray, M., Jimenez-Morales, D., Chawla, A., Krogan, N. J., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-29333-6 · Cited by 59 · see citing works
Chen, M. Z., Chang, J. C., Zavala-Solorio, J., Kates, L., Thai, M., Ogasawara, A., Bai, X., Flanagan, S., Nunez, V., Phamluong, K., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.09.003 · Cited by 58 · see citing works
Arruda, A. P., Ketzer, L. A., Nigro, M., Galina, A., Carvalho, D. P., & de Meis, L. (2008) · Endocrinology · doi:10.1210/en.2008-0564 · Cited by 55 · see citing works
Insights into brown adipose tissue evolution and function from non-model organisms
Jastroch, M., Oelkrug, R., & Keipert, S. (2018) · Journal of Experimental Biology · doi:10.1242/jeb.169425 · Cited by 55 · see citing works
Obesity and Exercise: New Insights and Perspectives
James, N. M., & Stanford, K. I. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf017 · Cited by 20 · see citing works
- Authors
- Golozoubova, V., Hohtola, E., Matthias, A., Jacobsson, A., Cannon, B., & Nedergaard, J.
- Affiliations
- Stockholm University (SE)
- University of Oulu (FI)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2001-07-09
- Volume
- 15
- Issue
- 11
- Pages
- 2048-2050
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2115941382
- Cited by
- 503
- References
- 32
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 28 · 2023: 22 · 2022: 18 · 2021: 20 · 2020: 37 · 2019: 26 · 2018: 26 · 2017: 31 · 2016: 27 · 2015: 23 · 2014: 26 · 2013: 20 · 2012: 13
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Physiology › Thermoregulation and physiological responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- UCP1, cold acclimation, brown adipose tissue, UCP2, UCP3, shivering, thermogenesis, energy balance, obesity, muscle thermogenesis
- MeSH terms
- Uncoupling Protein 1, Adaptation, Physiological, Animals, Body Temperature, Body Temperature Regulation, Carrier Proteins, Cold Temperature, Ion Channels, Membrane Proteins, Shivering, Uncoupling Agents, Thermogenesis, Mitochondrial 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