Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The cellular and functional complexity of thermogenic fat

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Characteristics and anatomical distribution of thermogenic adipocytes.
Fig. 2: Beige fat biogenesis.
Fig. 3: Regulation and heterogeneity of thermogenic fat.
Fig. 4: Thermogenic mechanisms in adipocytes.
Fig. 5: The multifaceted roles of brown and beige fat.
Fig. 6: Harnessing thermogenic fat activity for precision medicine.

References

  1. 1.

    Cinti, S.Obesity, Type 2 Diabetes and the Adipose Organ: A Pictorial Atlas from Research to Clinical Applications 1st edn (Springer, 2017).

  2. 2.

    Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lidell, M. E. et al. Evidence for two types of brown adipose tissue in humans. Nat. Med. 19, 631–634 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Shinoda, K. et al. Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat. Med. 21, 389–394 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Ikeda, K., Maretich, P. & Kajimura, S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol. Metab. 29, 191–200 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Lepper, C. & Fan, C. M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    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).

    CAS  PubMed  Google Scholar 

  12. 12.

    Sanchez-Gurmaches, J. & Guertin, D. A. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat. Commun. 5, 4099 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Sebo, Z. L., Jeffery, E., Holtrup, B. & Rodeheffer, M. S. A mesodermal fate map for adipose tissue. Development 145, dev166801 (2018).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    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).

    CAS  PubMed  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  Google Scholar 

  16. 16.

    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).

    CAS  PubMed  Google Scholar 

  17. 17.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Oguri, Y. et al. CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling. Cell 182, 563–577.e20 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Long, J. Z. et al. A smooth muscle-like origin for beige adipocytes. Cell Metab. 19, 810–820 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Vishvanath, L. et al. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 23, 350–359 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008).

    CAS  Google Scholar 

  25. 25.

    Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Cattaneo, P. et al. Parallel lineage-tracing studies establish fibroblasts as the prevailing in vivo adipocyte progenitor. Cell Rep. 30, 571–582.e2 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Finlin, B. S. et al. Human adipose beiging in response to cold and mirabegron. JCI Insight 3, e121510 (2018).

    Google Scholar 

  29. 29.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Raajendiran, A. et al. Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues. Cell Rep. 27, 1528–1540.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Singh, A. M. et al. Human beige adipocytes for drug discovery and cell therapy in metabolic diseases. Nat. Commun. 11, 2758 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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  PubMed Central  Google Scholar 

  33. 33.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    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).

    CAS  Google Scholar 

  35. 35.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Tajima, K. et al. Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis. Nat. Metab. 1, 886–898 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Rosenwald, M., Perdikari, A., Rulicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Altshuler-Keylin, S. et al. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24, 402–419 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lu, X. et al. Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism. Sci. Signal. 11, eaap8526 (2018).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Roh, H. C. et al. Warming induces significant reprogramming of beige, but not brown, adipocyte cellular identity. Cell Metab. 27, 1121–1137.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Fisher, F. M. et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    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  PubMed Central  Google Scholar 

  49. 49.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    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  PubMed Central  Google Scholar 

  51. 51.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Chen, Y. et al. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature 565, 180–185 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Jun, H. et al. Adrenergic-independent signaling via CHRNA2 regulates beige fat activation. Dev. Cell 54, 106–116.e5 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Song, A. et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J. Clin. Invest. 130, 247–257 (2019).

    Google Scholar 

  59. 59.

    Lee, K. Y. et al. Developmental and functional heterogeneity of white adipocytes within a single fat depot. EMBO J. 38, e99291 (2019).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    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  PubMed Central  Google Scholar 

  65. 65.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    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  PubMed Central  Google Scholar 

  72. 72.

    Gaudry, M. J. et al. Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades. Sci. Adv. 3, e1602878 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).

    CAS  PubMed  Google Scholar 

  78. 78.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Klingenberg, M. UCP1 — a sophisticated energy valve. Biochimie 134, 19–27 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Ricquier, D. UCP1, the mitochondrial uncoupling protein of brown adipocyte: a personal contribution and a historical perspective. Biochimie 134, 3–8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Winkler, E. & Klingenberg, M. Effect of fatty acids on H+ transport activity of the reconstituted uncoupling protein. J. Biol. Chem. 269, 2508–2515 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Shin, H. et al. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab. 26, 764–777.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Anderson, C. M. et al. Dependence of brown adipose tissue function on CD36-mediated coenzyme Q uptake. Cell Rep. 10, 505–515 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Putri, M. et al. CD36 is indispensable for thermogenesis under conditions of fasting and cold stress. Biochem. Biophys. Commun. 457, 520–525 (2015).

    CAS  Google Scholar 

  89. 89.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Chouchani, E. T. et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 532, 112–116 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Wang, G. et al. Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation. Mol. Cell 74, 844–857.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Ukropec, J., Anunciado, R. P., Ravussin, Y., Hulver, M. W. & Kozak, L. P. UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1–/– mice. J. Biol. Chem. 281, 31894–31908 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    de Meis, L. Uncoupled ATPase activity and heat production by the sarcoplasmic reticulum Ca2+-ATPase. Regulation by ADP. J. Biol. Chem. 276, 25078–25087 (2001).

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Bal, N. C. et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat. Med. 18, 1575–1579 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Tajima, K. et al. Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis. Nat. Commun. 11, 1730 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Kazak, L. et al. Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity. Cell Metab. 26, 660–671.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Kazak, L. et al. Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity. Nat. Metab. 1, 360–370 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Guan, H. P. et al. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat. Med. 8, 1122–1128 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    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).

    CAS  Google Scholar 

  103. 103.

    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).

    CAS  Google Scholar 

  104. 104.

    Silva, J. E. Thermogenic mechanisms and their hormonal regulation. Physiol. Rev. 86, 435–464 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Long, J. Z. et al. The secreted enzyme pm20d1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166, 424–435 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Cooney, G. J., Caterson, I. D. & Newsholme, E. A. The effect of insulin and noradrenaline on the uptake of 2-[1–14C]deoxyglucose in vivo by brown adipose tissue and other glucose-utilising tissues of the mouse. FEBS Lett. 188, 257–261 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Guerra, C. et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J. Clin. Invest. 108, 1205–1213 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    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).

    CAS  PubMed  Google Scholar 

  112. 112.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993).

    CAS  PubMed  Google Scholar 

  114. 114.

    Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).

    CAS  PubMed  Google Scholar 

  115. 115.

    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  Google Scholar 

  116. 116.

    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).

    CAS  PubMed  Google Scholar 

  117. 117.

    Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

    CAS  PubMed  Google Scholar 

  118. 118.

    Berbee, J. F. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    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).

    CAS  PubMed  Google Scholar 

  121. 121.

    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).

    CAS  PubMed  Google Scholar 

  122. 122.

    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).

    CAS  PubMed  Google Scholar 

  123. 123.

    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).

    CAS  PubMed  Google Scholar 

  124. 124.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    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  PubMed Central  Google Scholar 

  128. 128.

    Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Liu, J. et al. Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study. Metabolomics 13, 104 (2017).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Guasch-Ferre, M. et al. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care 39, 833–846 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    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).

    CAS  PubMed  Google Scholar 

  133. 133.

    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  PubMed Central  Google Scholar 

  134. 134.

    Green, C. R. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15–21 (2016).

    CAS  PubMed  Google Scholar 

  135. 135.

    Wallace, M. et al. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat. Chem. Biol. 14, 1021–1031 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    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).

    CAS  PubMed  Google Scholar 

  137. 137.

    Gunawardana, S. C. & Piston, D. W. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 61, 674–682 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    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).

    Google Scholar 

  139. 139.

    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  PubMed Central  Google Scholar 

  140. 140.

    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).

    CAS  PubMed  Google Scholar 

  141. 141.

    Villarroya, J. et al. New insights into the secretory functions of brown adipose tissue. J. Endocrinol. 243, R19–R27 (2019).

    CAS  PubMed  Google Scholar 

  142. 142.

    Whittle, A. J. et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Svensson, K. J. et al. A secreted slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab. 23, 454–466 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Kristof, E. et al. Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp. Cell Res. 377, 47–55 (2019).

    CAS  PubMed  Google Scholar 

  145. 145.

    Sun, K. et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc. Natl Acad. Sci. USA 109, 5874–5879 (2012).

    CAS  PubMed  Google Scholar 

  146. 146.

    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).

    CAS  PubMed  Google Scholar 

  147. 147.

    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).

    CAS  PubMed  Google Scholar 

  148. 148.

    Campderros, L. et al. Brown adipocytes secrete GDF15 in response to thermogenic activation. Obesity 27, 1606–1616 (2019).

    CAS  PubMed  Google Scholar 

  149. 149.

    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).

    CAS  PubMed  Google Scholar 

  150. 150.

    Zeng, X. et al. Innervation of thermogenic adipose tissue via a calsyntenin 3β-S100b axis. Nature 569, 229–235 (2019).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Kong, X. et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab. 28, 631–643.e3 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Ruan, C. C. et al. A2A receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab. 28, 476–489.e5 (2018).

    CAS  PubMed  Google Scholar 

  154. 154.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Chen, Y. et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat. Commun. 7, 11420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Sun, K., Tordjman, J., Clement, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    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).

    CAS  Google Scholar 

  160. 160.

    Muir, L. A. et al. Adipose tissue fibrosis, hypertrophy, and hyperplasia: correlations with diabetes in human obesity. Obesity 24, 597–605 (2016).

    CAS  PubMed  Google Scholar 

  161. 161.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    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).

    CAS  PubMed  Google Scholar 

  163. 163.

    Henegar, C. et al. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol. 9, R14 (2008).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

    CAS  PubMed  Google Scholar 

  165. 165.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Wang, W. et al. A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate. Cell Metab. 30, 174–189.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    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  Google Scholar 

  169. 169.

    Cohade, C., Osman, M., Pannu, H. K. & Wahl, R. L. Uptake in supraclavicular area fat (“USA-Fat”): description on 18F-FDG PET/CT. J. Nucl. Med. 44, 170–176 (2003).

    CAS  PubMed  Google Scholar 

  170. 170.

    van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    PubMed  Google Scholar 

  171. 171.

    Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).

    CAS  PubMed  Google Scholar 

  172. 172.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    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.

    CAS  PubMed  Google Scholar 

  175. 175.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Sharp, L. Z. et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PloS ONE 7, e49452 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Lee, P. et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63, 3686–3698 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Ma, S. et al. Caloric restriction reprograms the single-cell transcriptional landscape of rattus norvegicus aging. Cell 180, 984–1001.e22 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    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).

    CAS  Google Scholar 

  187. 187.

    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  PubMed Central  Google Scholar 

  188. 188.

    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  PubMed Central  Google Scholar 

  189. 189.

    Riveros-McKay, F. et al. Genetic architecture of human thinness compared to severe obesity. PLoS Genet. 15, e1007603 (2019).

    PubMed  PubMed Central  Google Scholar 

  190. 190.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Lynch, C. J. & Adams, S. H. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat. Rev. Endocrinol. 10, 723–736 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    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).

    Google Scholar 

  196. 196.

    Goto, T. et al. Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes. Cytokine 77, 107–114 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Chiang, S. H. et al. The protein kinase IKKε regulates energy balance in obese mice. Cell 138, 961–975 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    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  PubMed Central  Google Scholar 

  200. 200.

    Kumari, M. et al. IRF3 promotes adipose inflammation and insulin resistance and represses browning. J. Clin. Invest. 126, 2839–2854 (2016).

    PubMed  PubMed Central  Google Scholar 

  201. 201.

    Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Koncarevic, A. et al. A novel therapeutic approach to treating obesity through modulation of TGFβ signaling. Endocrinology 153, 3133–3146 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Guo, T. et al. Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity. eLife 3, e03245 (2014).

    PubMed  PubMed Central  Google Scholar 

  204. 204.

    Rajbhandari, P. et al. Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes. eLife 8, e49501 (2019).

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Wolf, Y. et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat. Immunol. 18, 665–674 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Chung, K. J. et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat. Immunol. 18, 654–664 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210.

    Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

    CAS  PubMed  Google Scholar 

  212. 212.

    Lee, M. W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).

    CAS  PubMed  Google Scholar 

  213. 213.

    Zhang, X. et al. Functional inactivation of mast cells enhances subcutaneous adipose tissue browning in mice. Cell Rep. 28, 792–803.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214.

    Finlin, B. S. et al. Mast cells promote seasonal white adipose beiging in humans. Diabetes 66, 1237–1246 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216.

    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).

    CAS  PubMed  Google Scholar 

  217. 217.

    Cypess, A. M. et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218.

    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  PubMed Central  Google Scholar 

  219. 219.

    Blondin, D. P. et al. Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab. 32, 287–300.e7 (2020).

    CAS  PubMed  Google Scholar 

  220. 220.

    Broeders, E. P. et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 22, 418–426 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Wang, S. et al. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way. Biochem. Biophys. Res. Commun. 466, 247–253 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225.

    Jiang, J. et al. Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming. Metabolism 77, 58–64 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize for being unable to cite large numbers of important contributions to the field due to space limitations. This work was supported by the American Diabetes Association Pathway Program (1-17-ACE-17) to P.C., and by the National Institutes of Health (NIH) (DK097441, DK125281, DK126160, DK127575, DK125283) and the Edward Mallinckrodt, Jr. Foundation to S.K.

Author information

Affiliations

Authors

Contributions

Both authors contributed equally to this work.

Corresponding authors

Correspondence to Paul Cohen or Shingo Kajimura.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks M. Saito, F. Villarroya and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Cristae

Folds in the inner membrane of a mitochondrion where active electron transport takes place.

Catecholamines

Monoamine neurotransmitters that mediate cold-induced thermogenesis.

Thiazolidinediones

(Also known as glitazones). Synthetic ligands of PPARγ typically used in the treatment of type 2 diabetes. They also increase thermogenesis and have been shown to promote recruitment of beige thermogenic adipocytes.

Dermomyotome

Epithelial tissue present during development that combines a dermatome (giving rise to the epidermis) and a myotome (giving rise to skeletal muscle) before they separate in embryogenesis.

Retroperitoneal WAT

White adipose tissue (WAT) in the area between the posterior portion of the parietal peritoneum and the posterior abdominal wall muscles.

β3-Adrenergic signalling

Signalling potently stimulated by cold that is mediated by catecholamines that bind to β3-adrenergic receptors (β3-ARs), G protein-coupled receptors that activate adenylate cyclase to produce a second messenger cAMP.

Inguinal WAT

Subcutaneous adipose tissue located at the juncture of the lower portion of the anterior abdominal wall and legs. Inguinal white adipose tissue (WAT) contains high levels of beige adipocytes.

Insulin resistance

Insulin acts on the insulin receptor on the plasma membrane of target organs and triggers insulin signalling to stimulate anabolic reactions. Insulin action is impaired under insulin resistance conditions, which can eventually lead to type 2 diabetes.

Mitophagy

A selective mechanism to degrade defective mitochondria by autophagy.

Natriuretic peptides

Peptide hormones that induce sodium excretion by the kidney, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and dendroaspis natriuretic peptide (DNP).

Myokine

A secretory molecule released from skeletal muscle. Examples include IL-6 and irisin, both of which are known to activate thermogenic fat biogenesis.

Adiponectin

A fat-selective secretory protein hormone (adipokine) that is involved in regulating glucose and lipid homeostasis. In general, adiponectin levels are positively correlated with metabolic health.

Ancillary/niche cells

Supporting cells releasing paracrine factors.

Epididymal WAT

Visceral adipose tissue attached to the epididymis. Epididymal white adipose tissue (WAT) is known to have lower beiging propensity relative to inguinal WAT of mice.

γδ T cells

A subset of T cells that express a distinctive set (γ and δ-chains) of T cell receptor (TCR) on their surface, distinct from that of conventional T cells (αβ T cells).

Group 2 innate lymphoid cells

(ILC2s). A subset of innate lymphoid cells that produce type 2 cytokines, such as IL-5 and IL-13.

Methionine-enkephalin

(MetEnk). An endogenous opioid peptide that acts on δ-opioid receptor and μ-opioid receptor to a lesser extent.

Mast cells

Immune cells that release histamine and other substances during inflammatory and allergic reactions.

Invariant natural killer T cells

(iNKT cells). Specialized T cells that recognize lipid antigens.

α-Galactosylceramide

(α-GalCer). A synthetic glycolipid that stimulates invariant natural killer T cells.

Liraglutide

A glucagon-like peptide 1 receptor (GLP1R) agonist that acts as an incretin mimetic and increases insulin secretion.

Respiratory chain

(Also known as electron transport chain). Multiple protein complexes that transfer electrons from electron donors, such as NADH, to electron acceptors, thereby generating a proton (H+) gradient across the mitochondrial inner membrane.

Oxidative phosphorylation

A metabolic process in which cells use series of enzymes to oxidize glucose, fatty acids and other metabolites to produce ATP.

Acylcarnitine

A metabolite derived from carnitine and acyl-coenzyme A (acyl-CoA). Generation of acylcarnitine allows the transport of fatty acids into the mitochondrial matrix for oxidation.

Sulfenylation

A post-translational protein modification involving the addition of a sulfenyl group to cysteine residues.

Succinylation

A post-translational modification in which a succinyl group is added to proteins at lysine residues.

Sirtuin

A protein with NAD-dependent deacetylase activity that plays key roles in cellular homeostasis, including ageing, transcription, stress response, inflammation and apoptosis.

5′ AMP-activated protein kinase

(AMPK). A heterotrimeric enzyme complex that is activated in response to low cellular ATP, including low glucose and hypoxia, and stimulates glucose and fatty acid catabolism and autophagy.

Leptin

An adipocyte-derived hormone that regulates food intake and energy expenditure.

N-Acyl amino acids

Lipids that contain a fatty-acid tail covalently conjugated to an amino acid head group.

Triglyceride-rich lipoproteins

Lipoproteins that transport triglycerides and cholesterol; these include very low-density lipoprotein (VLDL) and chylomicrons.

Reverse cholesterol transport

A process in which cholesterol from peripheral organs is returned to the liver via the circulation.

Mevalonate pathway

A metabolic pathway for the synthesis of sterols and isoprenoids.

Bariatric surgery

A surgical procedure that promotes weight loss. These procedures include the Roux-en-Y gastric bypass, sleeve gastrectomy, adjustable gastric band and biliopancreatic diversion with duodenal switch.

Oxylipin

An oxygenated lipid derived from polyunsaturated fatty acid.

β-Hydroxybutyrate

(BHB). A major form of ketone bodies that is generated through fatty acid oxidation or leucine oxidation.

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography

(FDG-PET/CT). An imaging-based technique that measures the uptake of a radioactive glucose analogue.

Chenodeoxycholic acid

A primary bile acid synthesized in the liver.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cohen, P., Kajimura, S. The cellular and functional complexity of thermogenic fat. Nat Rev Mol Cell Biol 22, 393–409 (2021). https://doi.org/10.1038/s41580-021-00350-0

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing