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Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
Abstract
Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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“On the other hand, recent work suggest that BAT of “humanized” mice is notably similar to human BAT (de Jong et al., 2019).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as de Jong et al., 2019
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“There is increasing evidence that studying mice living at temperatures corresponding to their thermoneutral zone is important for obtaining data that can be “translatable” to humans [35-37].”
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“Importantly, BAT from obese mice housed chronically at thermoneutrality, closer resembles human BAT and this model of “physiologically humanized BAT” represents the best choice for modeling BAT physiology (22).”
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“In contrast, a recent study suggests that when mice are physiologically humanized, meaning housed at thermoneutrality, fed a “Western diet,” and examined at 9– 11 months old, their BAT becomes comparable with human supraclavicular BAT (23), although this conclusion has raised some discussion (24).”
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“Despite the claim that human BAT resembles more murine beige cells than murine BAT (Sharp et al., 2012; Shinoda et al., 2015), recent data indicate that human BAT and murine BAT exhibit similar histology and transcriptional patterns when mice are at thermoneutrality (30 C) (de Jong et al., 2019).”
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“As we humans spend most of our time under thermoneutral conditions [59,60], any facultative diet-induced thermogenesis that exists should be manifest in humans.”
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“Since human BAT is a mixture of classical brown and beige adipocytes (Wu et al., 2012; de Jong et al., 2019) and surrounded by white adipocytes in most cases (Saito et al., 2009; Zingaretti et al., 2009), the regulation of adipogenesis through cell–cell interaction may be important.”
BackgroundSkeletal muscle, not adipose tissue, mediates cold-induced metabolic benefits
Townsend, L. K., Wang, D., Wright, D. C., & Blondin, D. P. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00837-4 · Cited by 15
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“This degenerative process can also be mimicked by maintaining mice at ther-moneutrality (~28 – 30 °C) or by chronic high-fat diet feeding 21,25 .”
BackgroundThe obesity‐linked human lncRNA AATBC stimulates mitochondrial function in adipocytes
Giroud, M., Kotschi, S., Kwon, Y., Thuc, O. L., Hoffmann, A., Gil‐Lozano, M., Karbiener, M., Higareda‐Almaraz, J. C., Khani, S., Tews, D., et al. (2023) · EMBO Reports · doi:10.15252/embr.202357600 · Cited by 16
“In mice, thermoneu-trality is ca. 30 ° C (Cannon & Nedergaard, 2011), but humans are thermoneutral at much lower temperatures and, therefore, humans only display limited thermogenic activity (de Jong et al , 2019).”
BackgroundNguyen, V. T.-T., Vu, V. V., & Pham, P. V. (2023) · Adipocyte · doi:10.1080/21623945.2023.2237164 · Cited by 15
Pinto, Y. O., Festuccia, W. T., & Magdalon, J. (2022) · HORMONES · doi:10.1007/s42000-022-00361-2 · Cited by 12
Pani, S., Dey, S., Pati, B., Senapati, U., & Bal, N. C. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac151 · Cited by 12
The Influence of Ambient Temperature on Adipose Tissue Homeostasis, Metabolic Diseases and Cancers
Ginting, R. P., Lee, J.-M., & Lee, M.-W. (2023) · Cells · doi:10.3390/cells12060881 · Cited by 11
Zhuang, Y., Zhang, X., Zhang, S., Sun, Y., Wang, H., Chen, Y., Zhang, H., Zou, P., Feng, Y., Lü, X., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59618-0 · Cited by 11
“Thermoneutral housing in combination with HFD can be used to thermally humanize mice 38 , and BAT from mice housed under such conditions remarkably resembles human BAT 3,38 .”
Du, K., Chen, G.-H., Bai, X., Chen, L., Hu, S., Li, Y., Wang, G., He, J.-W., & Lai, S. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.981661 · Cited by 10
Sympathetic innervation of the supraclavicular brown adipose tissue: A detailed anatomical study
Mori, S., Beyer, R. S., Bernardes‐Souza, B., Sorg, J. M., Hoover, D. B., Sacks, H. S., Fishbein, M. C., Chang, G., Peacock, W. J., John, M. A. S., et al. (2023) · PLoS ONE · doi:10.1371/journal.pone.0290455 · Cited by 10
“This is, in part, because BAT depots in humans are not identical to those in mice, in terms of distribution, molecular and anatomic morphology, and innervation [12].”
In-vivo detection of white adipose tissue browning: a multimodality imaging approach
Holmes, L. R., Garside, J. C., Frank, J., Livingston, E. W., Snyder, J., Khalaf, N., Yuan, H., & Branca, R. T. (2023) · Scientific Reports · doi:10.1038/s41598-023-42537-9 · Cited by 10
Przygodda, F., Lautherbach, N. E. S., Buzelle, S. L., Gonçalves, D. A. P., de Assis, A. P., Paula-Gomes, S., Garófalo, M. A. R., Heck, L. C., Matsuo, F. S., Mota, R. F., et al. (2020) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00065.2019 · Cited by 9
Zhang, H., Wang, D.-S., Wu, S.-H., Huang, G., Chen, D.-H., Ma, H., Zhang, Y.-T., Guo, L.-H., Liu, R.-Q., Gui, Z.-H., et al. (2023) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2023.114258 · Cited by 9
Adipose tissue growth and development: the modulating role of ambient temperature
Symonds, M. E., Pope, M., Bloor, I. D., Law, J., Alagal, R. I., & Budge, H. (2020) · Journal of Endocrinology · doi:10.1530/joe-20-0075 · Cited by 9
“There are increasing indications from animal studies that brown and beige cells could be activated through individual nutrients such as capsaicin analogues (Darre & Domene 2015, Derbenev & Zsombok 2016).”
BackgroundReply to ‘Confounding issues in the ‘humanized’ brown fat of mice’
de Jong, J. M. A., Cannon, B., Nedergaard, J., Wolfrum, C., & Petrovič, N. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0193-x · Cited by 9
Qimuge, N., Lindsund, E., Bokhari, M. H., Pang, W., & Petrovič, N. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.105760 · Cited by 9
Sun, Q., Cui, X., Yin, D., Li, J., Li, J., & Du, L. (2025) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-025-01090-x · Cited by 8
“At thermoneutrality (30 °C), the morphology and gene expression profile of murine classical brown adipose tissue more closely resemble those of human brown adipose tissue, whereas beige adipose tissue significantly dimin - ishes its thermogenic potential under these conditions [142].”
Tóth, B. B., Barta, Z., Barta, Á. B., & Fésüs, L. (2021) · BMC Genomics · doi:10.1186/s12864-021-08126-8 · Cited by 6
Li, M., & Speakman, J. R. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2087-8_15 · Cited by 8
Regulatory networks determining substrate utilization in brown adipocytes
Onogi, Y., & Ussar, S. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.04.001 · Cited by 8
Tóth, B. B., Arianti, R., Shaw, A., Vámos, A., Veréb, Z., Póliska, S., Győry, F., Bacsó, Z., Fésüs, L., & Kristóf, E. (2020) · Cells · doi:10.3390/cells9040987 · Cited by 41
Supraclavicular brown adipocytes originate from Tbx1+ myoprogenitors
Huang, Z., Gu, C., Zhang, Z., Arianti, R., Swaminathan, A., Tran, K., Battist, A., Kristóf, E., & Ruan, H. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002413 · Cited by 9
Lai, M., Zhou, W., Zou, W., Qiu, L., Liang, Z., Chen, W., Wang, Y., Guo, B., Zhao, C., Zhang, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60474-1 · Cited by 7
“Meanwhile, long-term exposure to thermoneutral temperatures leads to BAT remodeling, characterized by loss of function, lipid accumulation, and diminished mitochondrial quality 35,36 .”
Boulet, N., Luijten, I. H. N., Cannon, B., & Nedergaard, J. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00352.2020 · Cited by 7
Beige or brite adipocytes of the adipose organ: Link with white and brown adipocytes
Amri, E. (2024) · Annales d Endocrinologie · doi:10.1016/j.ando.2024.05.002 · Cited by 7
Xiang, X., Liu, Y., Zeng, Z., Zhao, X., Shi, Q., Huang, X., Yang, H., Song, C., Xu, S., & Jin, S. (2025) · Journal of Functional Foods · doi:10.1016/j.jff.2025.106675 · Cited by 7
Innervation of supraclavicular adipose tissue: A human cadaveric study
Sievers, W., Rathner, J. A., Green, R. A., Kettle, C., Irving, H. R., Whelan, D. R., Fernandez, R. G. D., & Zacharias, A. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236286 · Cited by 7
“The comparatively smaller cell size supports the contention that the supraclavicular adipocytes are BATlike [35].”
InfluentialStable Isotope Tracing and Metabolomics to Study In Vivo Brown Adipose Tissue Metabolic Fluxes
Jung, S. M., Le, J., Doxsey, W. G., Haley, J. D., Park, G. S. H., Guertin, D. A., & Jang, C. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2087-8_8 · Cited by 7
Zhao, L., Zhu, Q., Li, M., Yang, H., & Zhao, Y. (2025) · The Journal of Physiology · doi:10.1113/jp289263 · Cited by 6
“In mice exposed to thermoneutral conditions, BAT resembles characteristics of white adipocytes (Cui et al., 2016; de Jong et al., 2019; Fischer et al., 2020; Shi et al., 2021).”
Distinct precursor landscape of subcutaneous and visceral fat in development and aging
Lin, F., & Sul, H. S. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116706 · Cited by 7
“23 It has also been described that diminished adipogenic capacity and thus hypertrophy of VAT may be a dominant mechanism underlying insulin resistance in obesity.”
Isolation and Characterization of Human Brown Adipocytes
Schéele, C., Henriksen, T. I., & Nielsen, S. J. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2087-8_14 · Cited by 5
Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue
Davies, V. S., Lindsund, E., Petrovič, N., Cannon, B., & Nedergaard, J. (2023) · Biochimie · doi:10.1016/j.biochi.2023.01.006 · Cited by 5
Cheng, C., Wu, B., Zhang, L., Wan, Q., Peng, H., Liu, X., Zheng, H., Zhang, H., & Zou, C. (2023) · Magnetic Resonance Materials in Physics Biology and Medicine · doi:10.1007/s10334-023-01133-8 · Cited by 4
“Recent studies have shown that human BAT is pheno-copied by classical BAT in physiologically humanized mice [34].”
Sun, W. (2021) · Science · doi:10.1126/science.abm8138 · Cited by 4
CFTR regulates brown adipocyte thermogenesis via the cAMP/PKA signaling pathway
Choi, K.-M., Cho, S.-H., Kim, J. H., Kim, A.-R. L., Kong, X., & Yoon, J. C. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.08.012 · Cited by 4
“Both humans and mice possess constitutively active and inducible thermogenic fat [48,49], and recent data have highlighted the importance of human BAT in metabolic health [26].”
BackgroundPurinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue
Jaeckstein, M. Y., Fischer, A. W., Rissiek, B., Stähler, T., Heine, M., Behrens, J., Mann, O., Pfeifer, A., Magnus, T., Schlein, C., et al. (2025) · EMBO Reports · doi:10.1038/s44319-025-00642-y · Cited by 3
“…in extensive lipid accumulation, loss of mitochondria and thermogenic proteins such as UCP1, activation of in fl ammatory pathways and a higher abundance of pro-in fl ammatory immune cells including macrophages (de Jong et al, 2019; Fischer et al, 2020b; Kotzbeck et al, 2018; Schlein et al, 2021).”
InfluentialBatokine in Central Nervous System Diseases
Shen, M., Zhang, M., Mao, N., & Lin, Z. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03490-w · Cited by 3
“However, the gene expression profile of BAT in humans is highly similar to classical rodent BAT, and both exert a profound and similar effects on systemic metabolism [2, 12, 13].”
Background
Metadata
- Authors
- 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., Niemi, T., Nuutila, P., Cinti, S., Nielsen, S., Scheele, C., Virtanen, K., Cannon, B., Nedergaard, J., Wolfrum, C., & Petrovic, N.
- Affiliations
- ETH Zurich (CH)
- University of Pavia (IT)
- University of Copenhagen (DK)
- Harvard University (US)
- Stockholm University (SE)
- Turku University Hospital (FI)
- University of Turku (FI)
- Copenhagen University Hospital (DK)
- ORCID
- Venue
- Nature Metabolism
- Published
- 2019-08-19
- Volume
- 1
- Issue
- 8
- Pages
- 830-843
- ISSN
- 2522-5812 (ISSN-L)
- OpenAlex
- W2969227545
- Cited by
- 137
- References
- 74
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 18 · 2023: 18 · 2022: 23 · 2021: 27 · 2020: 25 · 2019: 3
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-09-10)
- Open access
- closed
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- brown adipose tissue, thermoneutrality, high-fat high-sugar diet, thermogenesis, obesity, translational model, adipose tissue gene expression, adipose tissue morphology
- MeSH terms
- Animals, Adipose Tissue, Brown, Humans, Thermogenesis, Mice
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