The cellular and functional complexity of thermogenic fat.
Journal
Nature reviews. Molecular cell biology
ISSN: 1471-0080
Titre abrégé: Nat Rev Mol Cell Biol
Pays: England
ID NLM: 100962782
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
accepted:
08
02
2021
pubmed:
25
3
2021
medline:
23
7
2021
entrez:
24
3
2021
Statut:
ppublish
Résumé
Brown and beige adipocytes are mitochondria-enriched cells capable of dissipating energy in the form of heat. These thermogenic fat cells were originally considered to function solely in heat generation through the action of the mitochondrial protein uncoupling protein 1 (UCP1). In recent years, significant advances have been made in our understanding of the ontogeny, bioenergetics and physiological functions of thermogenic fat. Distinct subtypes of thermogenic adipocytes have been identified with unique developmental origins, which have been increasingly dissected in cellular and molecular detail. Moreover, several UCP1-independent thermogenic mechanisms have been described, expanding the role of these cells in energy homeostasis. Recent studies have also delineated roles for these cells beyond the regulation of thermogenesis, including as dynamic secretory cells and as a metabolic sink. This Review presents our current understanding of thermogenic adipocytes with an emphasis on their development, biological functions and roles in systemic physiology.
Identifiants
pubmed: 33758402
doi: 10.1038/s41580-021-00350-0
pii: 10.1038/s41580-021-00350-0
pmc: PMC8159882
mid: NIHMS1687529
doi:
Substances chimiques
Uncoupling Protein 1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
393-409Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK063720
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120649
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR001271
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK098722
Pays : United States
Organisme : NIDDK NIH HHS
ID : DP1 DK126160
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK127575
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125283
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK020541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK097441
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125281
Pays : United States
Références
Cinti, S.Obesity, Type 2 Diabetes and the Adipose Organ: A Pictorial Atlas from Research to Clinical Applications 1st edn (Springer, 2017).
Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013).
pubmed: 23388824
pmcid: 3576510
doi: 10.1101/gad.211649.112
Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).
pubmed: 24100998
doi: 10.1038/nm.3361
Lidell, M. E. et al. Evidence for two types of brown adipose tissue in humans. Nat. Med. 19, 631–634 (2013).
pubmed: 23603813
doi: 10.1038/nm.3017
Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
pubmed: 22796012
pmcid: 3402601
doi: 10.1016/j.cell.2012.05.016
Shinoda, K. et al. Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat. Med. 21, 389–394 (2015).
pubmed: 25774848
pmcid: 4427356
doi: 10.1038/nm.3819
Cypess, A. M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 19, 635–639 (2013).
pubmed: 23603815
pmcid: 3650129
doi: 10.1038/nm.3112
Ikeda, K., Maretich, P. & Kajimura, S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol. Metab. 29, 191–200 (2018).
pubmed: 29366777
pmcid: 5826798
doi: 10.1016/j.tem.2018.01.001
Lepper, C. & Fan, C. M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010).
pubmed: 20641127
pmcid: 3113517
doi: 10.1002/dvg.20630
Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
pubmed: 18719582
pmcid: 2583329
doi: 10.1038/nature07182
Atit, R. et al. β-Catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006).
pubmed: 16730693
doi: 10.1016/j.ydbio.2006.04.449
Sanchez-Gurmaches, J. & Guertin, D. A. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat. Commun. 5, 4099 (2014).
pubmed: 24942009
doi: 10.1038/ncomms5099
Sebo, Z. L., Jeffery, E., Holtrup, B. & Rodeheffer, M. S. A mesodermal fate map for adipose tissue. Development 145, dev166801 (2018).
pubmed: 30045918
pmcid: 6141776
doi: 10.1242/dev.166801
Wang, W. et al. Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc. Natl Acad. Sci. USA 111, 14466–14471 (2014).
pubmed: 25197048
pmcid: 4209986
doi: 10.1073/pnas.1412685111
Zhang, L. et al. Generation of functional brown adipocytes from human pluripotent stem cells via progression through a paraxial mesoderm state. Cell Stem Cell 27, 784–797.e11 (2020). This study generates human brown adipocytes from pluripotent stem cells by a serum-free directed differentiation strategy.
pubmed: 32783886
doi: 10.1016/j.stem.2020.07.013
Xue, B. et al. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J. Lipid Res. 48, 41–51 (2007).
pubmed: 17041251
doi: 10.1194/jlr.M600287-JLR200
Lee, Y. H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by β-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).
pubmed: 22482730
pmcid: 3322390
doi: 10.1016/j.cmet.2012.03.009
Berry, D. C., Jiang, Y. & Graff, J. M. Mouse strains to study cold-inducible beige progenitors and beige adipocyte formation and function. Nat. Commun. 7, 10184 (2016).
pubmed: 26729601
pmcid: 4728429
doi: 10.1038/ncomms10184
Liu, W. et al. A heterogeneous lineage origin underlies the phenotypic and molecular differences of white and beige adipocytes. J. Cell Sci. 126, 3527–3532 (2013).
pubmed: 23781029
pmcid: 3744022
Oguri, Y. et al. CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling. Cell 182, 563–577.e20 (2020).
pubmed: 32615086
pmcid: 7415677
doi: 10.1016/j.cell.2020.06.021
Long, J. Z. et al. A smooth muscle-like origin for beige adipocytes. Cell Metab. 19, 810–820 (2014).
pubmed: 24709624
pmcid: 4052772
doi: 10.1016/j.cmet.2014.03.025
Vishvanath, L. et al. Pdgfrβ
pubmed: 26626462
doi: 10.1016/j.cmet.2015.10.018
Schulz, T. J. et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc. Natl Acad. Sci. USA 108, 143–148 (2011).
pubmed: 21173238
doi: 10.1073/pnas.1010929108
Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008).
pubmed: 18835024
doi: 10.1016/j.cell.2008.09.036
Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).
pubmed: 23434825
pmcid: 3721064
doi: 10.1038/ncb2696
Cattaneo, P. et al. Parallel lineage-tracing studies establish fibroblasts as the prevailing in vivo adipocyte progenitor. Cell Rep. 30, 571–582.e2 (2020).
pubmed: 31940497
doi: 10.1016/j.celrep.2019.12.046
Finlin, B. S. et al. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J. Clin. Invest. 130, 2319–2331 (2020). This study reports that chronic activation of the β3-AR by mirabegron improves insulin sensitivity and activates beige fat in humans with obesity.
pubmed: 31961829
pmcid: 7190997
doi: 10.1172/JCI134892
Finlin, B. S. et al. Human adipose beiging in response to cold and mirabegron. JCI Insight 3, e121510 (2018).
pmcid: 6129119
doi: 10.1172/jci.insight.121510
Min, S. Y. et al. Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 22, 312–318 (2016).
pubmed: 26808348
pmcid: 4777633
doi: 10.1038/nm.4031
Raajendiran, A. et al. Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues. Cell Rep. 27, 1528–1540.e7 (2019).
pubmed: 31042478
doi: 10.1016/j.celrep.2019.04.010
Singh, A. M. et al. Human beige adipocytes for drug discovery and cell therapy in metabolic diseases. Nat. Commun. 11, 2758 (2020).
pubmed: 32488069
pmcid: 7265435
doi: 10.1038/s41467-020-16340-3
Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013).
pubmed: 23995282
pmcid: 4075943
doi: 10.1038/nm.3324
Himms-Hagen, J. et al. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am. J. Physiol. Cell Physiol. 279, C670–C681 (2000).
pubmed: 10942717
doi: 10.1152/ajpcell.2000.279.3.C670
Barbatelli, G. et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am. J. Physiol. 298, E1244–E1253 (2010).
Shao, M. et al. Cellular origins of beige fat cells revisited. Diabetes 68, 1874–1885 (2019). This study reports the quantitative contribution of beige adipocyte biogenesis via de novo differentiation versus reinstallation of existing adipocytes in vivo.
pubmed: 31540940
pmcid: 6754244
doi: 10.2337/db19-0308
Lee, Y. H., Petkova, A. P., Konkar, A. A. & Granneman, J. G. Cellular origins of cold-induced brown adipocytes in adult mice. FASEB J. 29, 286–299 (2015).
pubmed: 25392270
doi: 10.1096/fj.14-263038
Tajima, K. et al. Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis. Nat. Metab. 1, 886–898 (2019).
pubmed: 32313871
pmcid: 7169975
doi: 10.1038/s42255-019-0106-z
Berry, D. C. et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab. 25, 481 (2017).
pubmed: 28178569
doi: 10.1016/j.cmet.2017.01.011
Rosenwald, M., Perdikari, A., Rulicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).
pubmed: 23624403
doi: 10.1038/ncb2740
Altshuler-Keylin, S. et al. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24, 402–419 (2016).
pubmed: 27568548
pmcid: 5023491
doi: 10.1016/j.cmet.2016.08.002
Lu, X. et al. Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism. Sci. Signal. 11, eaap8526 (2018).
pubmed: 29692364
pmcid: 6410368
doi: 10.1126/scisignal.aap8526
Roh, H. C. et al. Warming induces significant reprogramming of beige, but not brown, adipocyte cellular identity. Cell Metab. 27, 1121–1137.e5 (2018).
pubmed: 29657031
pmcid: 5932137
doi: 10.1016/j.cmet.2018.03.005
Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A
pubmed: 25317558
doi: 10.1038/nature13816
Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).
pubmed: 22307324
pmcid: 3287224
doi: 10.1172/JCI59701
Fisher, F. M. et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).
pubmed: 22302939
pmcid: 3278894
doi: 10.1101/gad.177857.111
Ohno, H., Shinoda, K., Spiegelman, B. M. & Kajimura, S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).
pubmed: 22405074
pmcid: 3410936
doi: 10.1016/j.cmet.2012.01.019
Inagaki, T., Sakai, J. & Kajimura, S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat. Rev. Mol. Cell Biol. 17, 480–495 (2016).
pubmed: 27251423
pmcid: 4956538
doi: 10.1038/nrm.2016.62
Sidossis, L. & Kajimura, S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J. Clin. Invest. 125, 478–486 (2015).
pubmed: 25642708
pmcid: 4319444
doi: 10.1172/JCI78362
Sun, W. et al. Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring. Nat. Med. 24, 1372–1383 (2018).
pubmed: 29988127
doi: 10.1038/s41591-018-0102-y
Jiang, Y., Berry, D. C. & Graff, J. M. Distinct cellular and molecular mechanisms for β3 adrenergic receptor-induced beige adipocyte formation. eLife 6, e30329 (2017).
pubmed: 29019320
pmcid: 5667933
doi: 10.7554/eLife.30329
Bronnikov, G., Houstek, J. & Nedergaard, J. β-Adrenergic, cAMP-mediated stimulation of proliferation of brown fat cells in primary culture. Mediation via β1 but not via β3 adrenoceptors. J. Biol. Chem. 267, 2006–2013 (1992).
pubmed: 1346138
doi: 10.1016/S0021-9258(18)46046-2
McQueen, A. E. et al. The C-terminal fibrinogen-like domain of angiopoietin-like 4 stimulates adipose tissue lipolysis and promotes energy expenditure. J. Biol. Chem. 292, 16122–16134 (2017).
pubmed: 28842503
pmcid: 5625043
doi: 10.1074/jbc.M117.803973
Goh, Y. Y. et al. Angiopoietin-like 4 interacts with integrins β1 and β5 to modulate keratinocyte migration. Am. J. Pathol. 177, 2791–2803 (2010).
pubmed: 20952587
pmcid: 2993291
doi: 10.2353/ajpath.2010.100129
Zhu, Y. et al. Connexin 43 mediates white adipose tissue beiging by facilitating the propagation of sympathetic neuronal signals. Cell Metab. 24, 420–433 (2016). This study identifies the role of the gap junction in beige fat biogenesis via propagation of the sympathetically derived cAMP signal to neighbouring adipocytes.
pubmed: 27626200
pmcid: 5024720
doi: 10.1016/j.cmet.2016.08.005
Chen, Y. et al. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature 565, 180–185 (2019).
pubmed: 30568302
doi: 10.1038/s41586-018-0801-z
Jun, H. et al. Adrenergic-independent signaling via CHRNA2 regulates beige fat activation. Dev. Cell 54, 106–116.e5 (2020).
pubmed: 32533922
pmcid: 7343629
doi: 10.1016/j.devcel.2020.05.017
Wu, Y., Kinnebrew, M. A., Kutyavin, V. I. & Chawla, A. Distinct signaling and transcriptional pathways regulate peri-weaning development and cold-induced recruitment of beige adipocytes. Proc. Natl Acad. Sci. USA 117, 6883–6889 (2020).
pubmed: 32139607
pmcid: 7104269
doi: 10.1073/pnas.1920419117
Song, A. et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J. Clin. Invest. 130, 247–257 (2019).
pmcid: 6934193
doi: 10.1172/JCI129167
Lee, K. Y. et al. Developmental and functional heterogeneity of white adipocytes within a single fat depot. EMBO J. 38, e99291 (2019).
pubmed: 30530479
doi: 10.15252/embj.201899291
Min, S. Y. et al. Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells. Proc. Natl Acad. Sci. USA 116, 17970–17979 (2019). This study reports diverse adipocyte progenitors in human adipose tissue that give rise to beige adipocytes.
pubmed: 31420514
pmcid: 6731669
doi: 10.1073/pnas.1906512116
Xue, R. et al. Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes. Nat. Med. 21, 760–768 (2015).
pubmed: 26076036
pmcid: 4496292
doi: 10.1038/nm.3881
Sun, W. et al. Single-nucleus RNA-seq reveals a new type of brown adipocyte regulating thermogenesis. Nature 587, 98–102 (2020). This study employs single-nucleus RNA-sequencing to characterize adipocyte heterogeneity in mice and humans, and identifies a subpopulation of adipocytes that uses acetate to regulate the thermogenic capacity of neighbouring adipocytes.
pubmed: 33116305
doi: 10.1038/s41586-020-2856-x
Schwalie, P. C. et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature 559, 103–108 (2018). This study, by single-cell RNA-sequencing analysis, identifies distinct subpopulations of adipose precursor cells, including adipogenesis-regulatory cells, in mouse adipose tissue.
pubmed: 29925944
doi: 10.1038/s41586-018-0226-8
Hepler, C. et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. eLife 7, e39636 (2018). This study reveals the functional heterogeneity of visceral WAT perivascular cells and identifies fibro-inflammatory progenitors.
pubmed: 30265241
pmcid: 6167054
doi: 10.7554/eLife.39636
Merrick, D. et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364, eaav2501 (2019). This study employs single-cell RNA sequencing to identify mesenchymal progenitor cells that give rise to adipocytes in mice and humans.
pubmed: 31023895
pmcid: 6816238
doi: 10.1126/science.aav2501
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).
pubmed: 17618855
pmcid: 2564846
doi: 10.1016/j.cmet.2007.06.001
Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 22, 1397–1409 (2008).
pubmed: 18483224
pmcid: 2377193
doi: 10.1101/gad.1666108
Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
pubmed: 21123942
doi: 10.1172/JCI44271
Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).
pubmed: 24439384
pmcid: 3922400
doi: 10.1016/j.cell.2013.12.021
Ohno, H., Shinoda, K., Ohyama, K., Sharp, L. Z. & Kajimura, S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504, 163–167 (2013).
pubmed: 24196706
pmcid: 3855638
doi: 10.1038/nature12652
Berg, F., Gustafson, U. & Andersson, L. The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: a genetic explanation for poor thermoregulation in piglets. PLoS Genet. 2, e129 (2006).
pubmed: 16933999
pmcid: 1550502
doi: 10.1371/journal.pgen.0020129
Gaudry, M. J. et al. Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades. Sci. Adv. 3, e1602878 (2017).
pubmed: 28706989
pmcid: 5507634
doi: 10.1126/sciadv.1602878
Ricquier, D. & Kader, J. C. Mitochondrial protein alteration in active brown fat: a sodium dodecyl sulfate-polyacrylamide gel electrophoretic study. Biochem. Biophys. Res. Commun. 73, 577–583 (1976).
pubmed: 1008874
doi: 10.1016/0006-291X(76)90849-4
Nicholls, D. G. Hamster brown-adipose-tissue mitochondria. Purine nucleotide control of the ion conductance of the inner membrane, the nature of the nucleotide binding site. Eur. J. Biochem. 62, 223–228 (1976).
pubmed: 1253787
doi: 10.1111/j.1432-1033.1976.tb10151.x
Aquila, H., Link, T. A. & Klingenberg, M. The uncoupling protein from brown fat mitochondria is related to the mitochondrial ADP/ATP carrier. Analysis of sequence homologies and of folding of the protein in the membrane. EMBO J. 4, 2369–2376 (1985).
pubmed: 3000775
pmcid: 554512
doi: 10.1002/j.1460-2075.1985.tb03941.x
Bouillaud, F., Ricquier, D., Thibault, J. & Weissenbach, J. Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein. Proc. Natl Acad. Sci. USA 82, 445–448 (1985).
pubmed: 3855564
pmcid: 397055
doi: 10.1073/pnas.82.2.445
Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).
pubmed: 9139827
doi: 10.1038/387090a0
Arsenijevic, D. et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435–439 (2000).
pubmed: 11101840
doi: 10.1038/82565
Gong, D. W. et al. Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J. Biol. Chem. 275, 16251–16257 (2000).
pubmed: 10748195
doi: 10.1074/jbc.M910177199
Klingenberg, M. UCP1 — a sophisticated energy valve. Biochimie 134, 19–27 (2017).
pubmed: 27794497
doi: 10.1016/j.biochi.2016.10.012
Ricquier, D. UCP1, the mitochondrial uncoupling protein of brown adipocyte: a personal contribution and a historical perspective. Biochimie 134, 3–8 (2017).
pubmed: 27916641
doi: 10.1016/j.biochi.2016.10.018
Winkler, E. & Klingenberg, M. Effect of fatty acids on H
pubmed: 8300577
doi: 10.1016/S0021-9258(17)41974-0
Jezek, P., Orosz, D. E., Modriansky, M. & Garlid, K. D. Transport of anions and protons by the mitochondrial uncoupling protein and its regulation by nucleotides and fatty acids. A new look at old hypotheses. J. Biol. Chem. 269, 26184–26190 (1994).
pubmed: 7929332
doi: 10.1016/S0021-9258(18)47176-1
Urbankova, E., Voltchenko, A., Pohl, P., Jezek, P. & Pohl, E. E. Transport kinetics of uncoupling proteins. Analysis of UCP1 reconstituted in planar lipid bilayers. J. Biol. Chem. 278, 32497–32500 (2003).
pubmed: 12826670
doi: 10.1074/jbc.M303721200
Schreiber, R. et al. Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab. 26, 753–763.e7 (2017).
pubmed: 28988821
pmcid: 5683855
doi: 10.1016/j.cmet.2017.09.004
Shin, H. et al. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab. 26, 764–777.e5 (2017).
pubmed: 28988822
pmcid: 5905336
doi: 10.1016/j.cmet.2017.09.002
Anderson, C. M. et al. Dependence of brown adipose tissue function on CD36-mediated coenzyme Q uptake. Cell Rep. 10, 505–515 (2015).
pubmed: 25620701
pmcid: 4318762
doi: 10.1016/j.celrep.2014.12.048
Putri, M. et al. CD36 is indispensable for thermogenesis under conditions of fasting and cold stress. Biochem. Biophys. Commun. 457, 520–525 (2015).
doi: 10.1016/j.bbrc.2014.12.124
Simcox, J. et al. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab. 26, 509–522.e6 (2017). This study identifies a mechanism whereby FFAs from adipose tissue promote acylcarnitine production in the liver, which provides fuel for cold-induced thermogenesis.
pubmed: 28877455
pmcid: 5658052
doi: 10.1016/j.cmet.2017.08.006
Chouchani, E. T. et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 532, 112–116 (2016).
pubmed: 27027295
pmcid: 5549630
doi: 10.1038/nature17399
Wang, G. et al. Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation. Mol. Cell 74, 844–857.e7 (2019).
pubmed: 31000437
pmcid: 6525068
doi: 10.1016/j.molcel.2019.03.021
Ukropec, J., Anunciado, R. P., Ravussin, Y., Hulver, M. W. & Kozak, L. P. UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1
pubmed: 16914547
Ikeda, K. et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23, 1454–1465 (2017). This paper provides direct evidence of a UCP1-independent mechanism in beige fat that controls thermogenesis and glucose homeostasis.
pubmed: 29131158
pmcid: 5727902
doi: 10.1038/nm.4429
de Meis, L. Uncoupled ATPase activity and heat production by the sarcoplasmic reticulum Ca
pubmed: 11342561
doi: 10.1074/jbc.M103318200
Bal, N. C. et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat. Med. 18, 1575–1579 (2012).
pubmed: 22961106
pmcid: 3676351
doi: 10.1038/nm.2897
Tajima, K. et al. Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis. Nat. Commun. 11, 1730 (2020).
pubmed: 32265443
pmcid: 7138828
doi: 10.1038/s41467-020-15589-y
Aquilano, K. et al. Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenesis in subcutaneous adipose tissue. Redox Biol. 36, 101633 (2020).
pubmed: 32863211
pmcid: 7358542
doi: 10.1016/j.redox.2020.101633
Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015). This study identifies a UCP1-independent thermogenic mechanism that involves creatine futile cycling.
pubmed: 26496606
pmcid: 4656041
doi: 10.1016/j.cell.2015.09.035
Kazak, L. et al. Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity. Cell Metab. 26, 660–671.e3 (2017).
pubmed: 28844881
pmcid: 5629120
doi: 10.1016/j.cmet.2017.08.009
Kazak, L. et al. Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity. Nat. Metab. 1, 360–370 (2019).
pubmed: 31161155
pmcid: 6544051
doi: 10.1038/s42255-019-0035-x
Guan, H. P. et al. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat. Med. 8, 1122–1128 (2002).
pubmed: 12357248
doi: 10.1038/nm780
Flachs, P. et al. Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype. Int. J. Obes. 41, 372–380 (2017).
doi: 10.1038/ijo.2016.228
Reidy, S. P. & Weber, J. M. Accelerated substrate cycling: a new energy-wasting role for leptin in vivo. Am. J. Physiol. 282, E312–E317 (2002).
Silva, J. E. Thermogenic mechanisms and their hormonal regulation. Physiol. Rev. 86, 435–464 (2006).
pubmed: 16601266
doi: 10.1152/physrev.00009.2005
DosSantos, R. A., Alfadda, A., Eto, K., Kadowaki, T. & Silva, J. E. Evidence for a compensated thermogenic defect in transgenic mice lacking the mitochondrial glycerol-3-phosphate dehydrogenase gene. Endocrinology 144, 5469–5479 (2003).
pubmed: 12960027
doi: 10.1210/en.2003-0687
Anunciado-Koza, R., Ukropec, J., Koza, R. A. & Kozak, L. P. Inactivation of UCP1 and the glycerol phosphate cycle synergistically increases energy expenditure to resist diet-induced obesity. J. Biol. Chem. 283, 27688–27697 (2008).
pubmed: 18678870
pmcid: 2562063
doi: 10.1074/jbc.M804268200
Long, J. Z. et al. The secreted enzyme pm20d1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166, 424–435 (2016).
pubmed: 27374330
pmcid: 4947008
doi: 10.1016/j.cell.2016.05.071
Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015).
pubmed: 26445512
pmcid: 4613812
doi: 10.1016/j.cmet.2015.09.007
Cooney, G. J., Caterson, I. D. & Newsholme, E. A. The effect of insulin and noradrenaline on the uptake of 2-[
pubmed: 3896847
doi: 10.1016/0014-5793(85)80383-5
Guerra, C. et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J. Clin. Invest. 108, 1205–1213 (2001).
pubmed: 11602628
pmcid: 209529
doi: 10.1172/JCI13103
Dallner, O. S., Chernogubova, E., Brolinson, K. A. & Bengtsson, T. β3-Adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of glucose transporter 4 translocation. Endocrinology 147, 5730–5739 (2006).
pubmed: 16959848
doi: 10.1210/en.2006-0242
Olsen, J. M. et al. Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation. J. Cell Biol. 207, 365–374 (2014).
pubmed: 25385184
pmcid: 4226734
doi: 10.1083/jcb.201403080
Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993).
pubmed: 8264795
doi: 10.1038/366740a0
Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).
pubmed: 23221344
doi: 10.1172/JCI62308
de Souza, C. J., Hirshman, M. F. & Horton, E. S. CL-316,243, a β3-specific adrenoceptor agonist, enhances insulin-stimulated glucose disposal in nonobese rats. Diabetes 46, 1257–1263 (1997).
pubmed: 9231648
doi: 10.2337/diab.46.8.1257
Roberts-Toler, C., O’Neill, B. T. & Cypess, A. M. Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity 23, 1765–1770 (2015).
pubmed: 26242777
doi: 10.1002/oby.21134
Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).
pubmed: 21258337
doi: 10.1038/nm.2297
Berbee, J. F. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).
pubmed: 25754609
doi: 10.1038/ncomms7356
Bartelt, A. et al. Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat. Commun. 8, 15010 (2017). This study reports a possible atheroprotective role of thermogenic fat via increased cholesterol flux through HDL.
pubmed: 28422089
pmcid: 5399294
doi: 10.1038/ncomms15010
Balaz, M. et al. Inhibition of mevalonate pathway prevents adipocyte browning in mice and men by affecting protein prenylation. Cell Metab. 29, 901–916.e8 (2019).
pubmed: 30581121
doi: 10.1016/j.cmet.2018.11.017
Worthmann, A. et al. Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat. Med. 23, 839–849 (2017).
pubmed: 28604703
doi: 10.1038/nm.4357
Sponton, C. H. et al. The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT–liver communication. EMBO Rep. 21, e49828 (2020).
pubmed: 32672883
pmcid: 7507062
doi: 10.15252/embr.201949828
Neinast, M. D. et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab. 29, 417–429.e4 (2019).
pubmed: 30449684
doi: 10.1016/j.cmet.2018.10.013
Yoneshiro, T. et al. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature 572, 614–619 (2019). This study reports the role of thermogenic fat in BCAA metabolism and identified the first mitochondrial BCAA transporter.
pubmed: 31435015
pmcid: 6715529
doi: 10.1038/s41586-019-1503-x
Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).
pubmed: 19356713
pmcid: 3640280
doi: 10.1016/j.cmet.2009.02.002
Huffman, K. M. et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care 32, 1678–1683 (2009).
pubmed: 19502541
pmcid: 2732163
doi: 10.2337/dc08-2075
Pietilainen, K. H. et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. 5, e51 (2008).
pubmed: 18336063
pmcid: 2265758
doi: 10.1371/journal.pmed.0050051
Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).
pubmed: 21423183
pmcid: 3126616
doi: 10.1038/nm.2307
Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).
pubmed: 22560213
pmcid: 3695706
doi: 10.1016/j.cmet.2012.01.024
Liu, J. et al. Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study. Metabolomics 13, 104 (2017).
pubmed: 28804275
pmcid: 5533833
doi: 10.1007/s11306-017-1239-2
Guasch-Ferre, M. et al. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care 39, 833–846 (2016).
pubmed: 27208380
pmcid: 4839172
doi: 10.2337/dc15-2251
Felig, P., Marliss, E. & Cahill, G. F. Jr. Plasma amino acid levels and insulin secretion in obesity. N. Engl. J. Med. 281, 811–816 (1969).
pubmed: 5809519
doi: 10.1056/NEJM196910092811503
Crown, S. B., Marze, N. & Antoniewicz, M. R. Catabolism of branched chain amino acids contributes significantly to synthesis of odd-chain and even-chain fatty acids in 3T3-L1 adipocytes. PloS ONE 10, e0145850 (2015).
pubmed: 26710334
pmcid: 4692509
doi: 10.1371/journal.pone.0145850
Green, C. R. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15–21 (2016).
pubmed: 26571352
doi: 10.1038/nchembio.1961
Wallace, M. et al. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat. Chem. Biol. 14, 1021–1031 (2018).
pubmed: 30327559
pmcid: 6245668
doi: 10.1038/s41589-018-0132-2
Su, X. et al. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: effects of obesity and weight loss. Obesity 23, 329–334 (2015).
pubmed: 25328153
doi: 10.1002/oby.20923
Gunawardana, S. C. & Piston, D. W. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 61, 674–682 (2012).
pubmed: 22315305
pmcid: 3282804
doi: 10.2337/db11-0510
Ali Khan, A. et al. Comparative secretome analyses of primary murine white and brown adipocytes reveal novel adipokines. Mol. Cell Proteom. 17, 2358–2370 (2018).
doi: 10.1074/mcp.RA118.000704
Villarroya, J., Cereijo, R., Giralt, M. & Villarroya, F. Secretory proteome of brown adipocytes in response to camp-mediated thermogenic activation. Front. Physiol. 10, 67 (2019).
pubmed: 30792664
pmcid: 6374321
doi: 10.3389/fphys.2019.00067
Deshmukh, A. S. et al. Proteomics-based comparative mapping of the secretomes of human brown and white adipocytes reveals EPDR1 as a novel batokine. Cell Metab. 30, 963–975.e7 (2019).
pubmed: 31668873
doi: 10.1016/j.cmet.2019.10.001
Villarroya, J. et al. New insights into the secretory functions of brown adipose tissue. J. Endocrinol. 243, R19–R27 (2019).
pubmed: 31419785
doi: 10.1530/JOE-19-0295
Whittle, A. J. et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012).
pubmed: 22579288
pmcid: 3383997
doi: 10.1016/j.cell.2012.02.066
Svensson, K. J. et al. A secreted slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab. 23, 454–466 (2016).
pubmed: 26876562
pmcid: 4785066
doi: 10.1016/j.cmet.2016.01.008
Kristof, E. et al. Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp. Cell Res. 377, 47–55 (2019).
pubmed: 30794803
doi: 10.1016/j.yexcr.2019.02.015
Sun, K. et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc. Natl Acad. Sci. USA 109, 5874–5879 (2012).
pubmed: 22451920
pmcid: 3326476
doi: 10.1073/pnas.1200447109
Mahdaviani, K., Chess, D., Wu, Y., Shirihai, O. & Aprahamian, T. R. Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes. Metabolism 65, 26–35 (2016).
pubmed: 26683794
doi: 10.1016/j.metabol.2015.09.012
Cereijo, R. et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab. 28, 750–763.e6 (2018).
pubmed: 30122557
doi: 10.1016/j.cmet.2018.07.015
Campderros, L. et al. Brown adipocytes secrete GDF15 in response to thermogenic activation. Obesity 27, 1606–1616 (2019).
pubmed: 31411815
doi: 10.1002/oby.22584
Nisoli, E., Tonello, C., Benarese, M., Liberini, P. & Carruba, M. O. Expression of nerve growth factor in brown adipose tissue: implications for thermogenesis and obesity. Endocrinology 137, 495–503 (1996).
pubmed: 8593794
doi: 10.1210/endo.137.2.8593794
Zeng, X. et al. Innervation of thermogenic adipose tissue via a calsyntenin 3β-S100b axis. Nature 569, 229–235 (2019).
pubmed: 31043739
pmcid: 6589139
doi: 10.1038/s41586-019-1156-9
Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014).
pubmed: 25401691
pmcid: 4257907
doi: 10.1038/nm.3713
Kong, X. et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab. 28, 631–643.e3 (2018).
pubmed: 30078553
pmcid: 6170693
doi: 10.1016/j.cmet.2018.07.004
Ruan, C. C. et al. A
pubmed: 30017353
doi: 10.1016/j.cmet.2018.06.013
Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 23, 631–637 (2017). This study reports a cold-inducible batokine, 12,13-diHOME, that stimulates fatty acid uptake in brown fat.
pubmed: 28346411
pmcid: 5699924
doi: 10.1038/nm.4297
Stanford, K. I. et al. 12,13-DiHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e3 (2018).
pubmed: 29719226
pmcid: 5935136
doi: 10.1016/j.cmet.2018.03.020
Chen, Y. et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat. Commun. 7, 11420 (2016).
pubmed: 27117818
pmcid: 4853423
doi: 10.1038/ncomms11420
Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).
pubmed: 28199304
pmcid: 5330251
doi: 10.1038/nature21365
Sun, K., Tordjman, J., Clement, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).
pubmed: 23954640
pmcid: 3795900
doi: 10.1016/j.cmet.2013.06.016
Lackey, D. E. et al. Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity. Am. J. Physiol. 306, E233–E246 (2014).
Muir, L. A. et al. Adipose tissue fibrosis, hypertrophy, and hyperplasia: correlations with diabetes in human obesity. Obesity 24, 597–605 (2016).
pubmed: 26916240
doi: 10.1002/oby.21377
Divoux, A. et al. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 59, 2817–2825 (2010).
pubmed: 20713683
pmcid: 2963540
doi: 10.2337/db10-0585
Reggio, S. et al. Increased basement membrane components in adipose tissue during obesity: links with TGFβ and metabolic phenotypes. J. Clin. Endocrinol. Metab. 101, 2578–2587 (2016).
pubmed: 27049236
doi: 10.1210/jc.2015-4304
Henegar, C. et al. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol. 9, R14 (2008).
pubmed: 18208606
pmcid: 2395253
doi: 10.1186/gb-2008-9-1-r14
Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).
pubmed: 19114551
doi: 10.1128/MCB.01300-08
Hasegawa, Y. et al. Repression of adipose tissue fibrosis through a PRDM16–GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metab. 27, 180–194.e6 (2018).
pubmed: 29320702
pmcid: 5765755
doi: 10.1016/j.cmet.2017.12.005
Wang, W. et al. A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate. Cell Metab. 30, 174–189.e5 (2019).
pubmed: 31155495
pmcid: 6836679
doi: 10.1016/j.cmet.2019.05.005
Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972).
pubmed: 5086212
pmcid: 1271341
Hany, T. F. et al. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur. J. Nucl. Med. Mol. Imaging 29, 1393–1398 (2002).
pubmed: 12271425
doi: 10.1007/s00259-002-0902-6
Cohade, C., Osman, M., Pannu, H. K. & Wahl, R. L. Uptake in supraclavicular area fat (“USA-Fat”): description on
pubmed: 12571205
van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
pubmed: 19357405
doi: 10.1056/NEJMoa0808718
Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
pubmed: 19357407
doi: 10.1056/NEJMoa0808949
Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).
pubmed: 19401428
pmcid: 2699872
doi: 10.2337/db09-0530
Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
pubmed: 19357406
pmcid: 2859951
doi: 10.1056/NEJMoa0810780
Leitner, B. P. et al. Mapping of human brown adipose tissue in lean and obese young men. Proc. Natl Acad. Sci.USA 114, 8649–8654 (2017). This study maps brown fat in six distinct anatomical depots in young men, comparing lean individuals and individuals with obesity.
pubmed: 28739898
pmcid: 5559032
doi: 10.1073/pnas.1705287114
Chen, K. Y. et al. Brown adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): recommendations for standardized FDG-PET/CT experiments in humans. Cell Metab. 24, 210–222 (2016).
pubmed: 27508870
pmcid: 4981083
doi: 10.1016/j.cmet.2016.07.014
Sharp, L. Z. et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PloS ONE 7, e49452 (2012).
pubmed: 23166672
pmcid: 3500293
doi: 10.1371/journal.pone.0049452
Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).
pubmed: 23867622
pmcid: 3726164
doi: 10.1172/JCI67803
Hanssen, M. J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).
pubmed: 26147760
doi: 10.1038/nm.3891
Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).
pubmed: 25056438
pmcid: 4238005
doi: 10.2337/db14-0746
Lee, P. et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63, 3686–3698 (2014).
pubmed: 24954193
pmcid: 4207391
doi: 10.2337/db14-0513
Hanssen, M. J. et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65, 1179–1189 (2016). This study shows that short-term cold exposure can lead to the recruitment of brown fat in humans with obesity.
pubmed: 26718499
doi: 10.2337/db15-1372
Vijgen, G. H. et al. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J. Clin. Endocrinol. Metab. 97, E1229–E1233 (2012).
pubmed: 22535970
doi: 10.1210/jc.2012-1289
Raiko, J., Orava, J., Savisto, N. & Virtanen, K. A. High brown fat activity correlates with cardiovascular risk factor levels cross-sectionally and subclinical atherosclerosis at 5-year follow-up. Arterioscler. Thromb. Vasc. Biol. 40, 1289–1295 (2020). This study finds that the presence of cold-induced brown fat activity correlates with lower cardiovascular risk factors and decreased carotid intima-media thickness and higher carotid elasticity on 5-year follow-up.
pubmed: 31941384
doi: 10.1161/ATVBAHA.119.313806
Becher, T. et al. Brown adipose tissue is associated with cardiometabolic health. Nat. Med. 27, 58–65 (2021). This study finds that brown fat in humans is associated with protection from cardio-metabolic diseases, particularly in individuals that are overweight and obese.
pubmed: 33398160
pmcid: 8461455
doi: 10.1038/s41591-020-1126-7
Ma, S. et al. Caloric restriction reprograms the single-cell transcriptional landscape of rattus norvegicus aging. Cell 180, 984–1001.e22 (2020).
pubmed: 32109414
doi: 10.1016/j.cell.2020.02.008
Yoneshiro, T. et al. Impact of UCP1 and β3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans. Int. J. Obes. 37, 993–998 (2013).
doi: 10.1038/ijo.2012.161
Bakker, L. E. et al. Brown adipose tissue volume in healthy lean South Asian adults compared with white Caucasians: a prospective, case-controlled observational study. Lancet Diabetes Endocrinol. 2, 210–217 (2014).
pubmed: 24622751
doi: 10.1016/S2213-8587(13)70156-6
Vosselman, M. J., Vijgen, G. H., Kingma, B. R., Brans, B. & van Marken Lichtenbelt, W. D. Frequent extreme cold exposure and brown fat and cold-induced thermogenesis: a study in a monozygotic twin. PloS ONE 9, e101653 (2014).
pubmed: 25014028
pmcid: 4094425
doi: 10.1371/journal.pone.0101653
Riveros-McKay, F. et al. Genetic architecture of human thinness compared to severe obesity. PLoS Genet. 15, e1007603 (2019).
pubmed: 30677029
pmcid: 6345421
doi: 10.1371/journal.pgen.1007603
Zhang, F. et al. An adipose tissue atlas: an image-guided identification of human-like BAT and beige depots in rodents. Cell Metab. 27, 252–262.e3 (2018).
pubmed: 29320705
pmcid: 5764189
doi: 10.1016/j.cmet.2017.12.004
Fitzgibbons, T. P. et al. Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation. Am. J. Physiol. Heart Circ. Physiol. 301, H1425–H1437 (2011).
pubmed: 21765057
pmcid: 3197360
doi: 10.1152/ajpheart.00376.2011
Sacks, H. S. et al. Uncoupling protein-1 and related messenger ribonucleic acids in human epicardial and other adipose tissues: epicardial fat functioning as brown fat. J. Clin. Endocrinol. Metab. 94, 3611–3615 (2009).
pubmed: 19567523
doi: 10.1210/jc.2009-0571
Lynch, C. J. & Adams, S. H. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat. Rev. Endocrinol. 10, 723–736 (2014).
pubmed: 25287287
pmcid: 4424797
doi: 10.1038/nrendo.2014.171
Villarroya, F., Cereijo, R., Villarroya, J., Gavalda-Navarro, A. & Giralt, M. Toward an understanding of how immune cells control brown and beige adipobiology. Cell Metab. 27, 954–961 (2018).
pubmed: 29719233
doi: 10.1016/j.cmet.2018.04.006
Sakamoto, T. et al. Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice. Am. J. Physiol. 310, E676–E687 (2016).
Goto, T. et al. Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes. Cytokine 77, 107–114 (2016).
pubmed: 26556104
doi: 10.1016/j.cyto.2015.11.001
Valladares, A., Roncero, C., Benito, M. & Porras, A. TNF-α inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK. FEBS Lett. 493, 6–11 (2001).
pubmed: 11277995
doi: 10.1016/S0014-5793(01)02264-5
Chiang, S. H. et al. The protein kinase IKKε regulates energy balance in obese mice. Cell 138, 961–975 (2009).
pubmed: 19737522
pmcid: 2756060
doi: 10.1016/j.cell.2009.06.046
Mowers, J. et al. Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1. eLife 2, e01119 (2013).
pubmed: 24368730
pmcid: 3869376
doi: 10.7554/eLife.01119
Kumari, M. et al. IRF3 promotes adipose inflammation and insulin resistance and represses browning. J. Clin. Invest. 126, 2839–2854 (2016).
pubmed: 27400129
pmcid: 4966307
doi: 10.1172/JCI86080
Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).
pubmed: 21723505
pmcid: 3169298
doi: 10.1016/j.cmet.2011.04.013
Koncarevic, A. et al. A novel therapeutic approach to treating obesity through modulation of TGFβ signaling. Endocrinology 153, 3133–3146 (2012).
pubmed: 22549226
pmcid: 3791434
doi: 10.1210/en.2012-1016
Guo, T. et al. Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity. eLife 3, e03245 (2014).
pubmed: 25161195
pmcid: 4139062
doi: 10.7554/eLife.03245
Rajbhandari, P. et al. Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes. eLife 8, e49501 (2019).
pubmed: 31644425
pmcid: 6837845
doi: 10.7554/eLife.49501
Rajbhandari, P. et al. IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172, 218–233 e217 (2018). This study characterizes adipocytes and stromal cells identifying crosstalk between immune cells and thermogenic adipocytes.
pubmed: 29249357
doi: 10.1016/j.cell.2017.11.019
Wolf, Y. et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat. Immunol. 18, 665–674 (2017).
pubmed: 28459435
pmcid: 5438596
doi: 10.1038/ni.3746
Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).
pubmed: 29035364
pmcid: 7104364
doi: 10.1038/nm.4422
Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).
pubmed: 28953873
pmcid: 5718149
doi: 10.1038/nature24022
Chung, K. J. et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat. Immunol. 18, 654–664 (2017).
pubmed: 28414311
pmcid: 5436941
doi: 10.1038/ni.3728
Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020).
pubmed: 32076265
pmcid: 7055484
doi: 10.1038/s41586-020-2028-z
Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).
pubmed: 25533952
doi: 10.1038/nature14115
Lee, M. W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).
pubmed: 25543153
doi: 10.1016/j.cell.2014.12.011
Zhang, X. et al. Functional inactivation of mast cells enhances subcutaneous adipose tissue browning in mice. Cell Rep. 28, 792–803.e4 (2019).
pubmed: 31315055
pmcid: 6662660
doi: 10.1016/j.celrep.2019.06.044
Finlin, B. S. et al. Mast cells promote seasonal white adipose beiging in humans. Diabetes 66, 1237–1246 (2017).
pubmed: 28250021
pmcid: 5399616
doi: 10.2337/db16-1057
Lynch, L. et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510–519 (2016).
pubmed: 27593966
pmcid: 5061124
doi: 10.1016/j.cmet.2016.08.003
Cypess, A. M. et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc. Natl Acad. Sci. USA 109, 10001–10005 (2012).
pubmed: 22665804
pmcid: 3382513
doi: 10.1073/pnas.1207911109
Cypess, A. M. et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).
pubmed: 25565203
pmcid: 4298351
doi: 10.1016/j.cmet.2014.12.009
O’Mara, A. E. et al. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J. Clin. Invest. 130, 2209–2219 (2020). This study shows that chronic treatment with mirabegron increases human brown fat activity, which is associated with increased HDL and improved insulin sensitivity.
pubmed: 31961826
pmcid: 7190915
doi: 10.1172/JCI131126
Blondin, D. P. et al. Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab. 32, 287–300.e7 (2020).
pubmed: 32755608
doi: 10.1016/j.cmet.2020.07.005
Broeders, E. P. et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 22, 418–426 (2015).
pubmed: 26235421
doi: 10.1016/j.cmet.2015.07.002
Ramage, L. E. et al. Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab. 24, 130–141 (2016).
pubmed: 27411014
pmcid: 4949380
doi: 10.1016/j.cmet.2016.06.011
Yoneshiro, T., Aita, S., Kawai, Y., Iwanaga, T. & Saito, M. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am. J. Clin. Nutr. 95, 845–850 (2012).
pubmed: 22378725
doi: 10.3945/ajcn.111.018606
Ohyama, K. et al. A synergistic antiobesity effect by a combination of capsinoids and cold temperature through promoting beige adipocyte biogenesis. Diabetes 65, 1410–1423 (2016).
pubmed: 26936964
pmcid: 4839206
doi: 10.2337/db15-0662
Wang, S. et al. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way. Biochem. Biophys. Res. Commun. 466, 247–253 (2015).
pubmed: 26362189
doi: 10.1016/j.bbrc.2015.09.018
Jiang, J. et al. Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming. Metabolism 77, 58–64 (2017).
pubmed: 29046261
pmcid: 5685898
doi: 10.1016/j.metabol.2017.08.006