Advertisement

Brown Adipose Tissue Development and Metabolism

  • Su Myung Jung
  • Joan Sanchez-GurmachesEmail author
  • David A. GuertinEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 251)

Abstract

Brown adipose tissue is well known to be a thermoregulatory organ particularly important in small rodents and human infants, but it was only recently that its existence and significance to metabolic fitness in adult humans have been widely realized. The ability of active brown fat to expend high amounts of energy has raised interest in stimulating thermogenesis therapeutically to treat metabolic diseases related to obesity and type 2 diabetes. In parallel, there has been a surge of research aimed at understanding the biology of rodent and human brown fat development, its remarkable metabolic properties, and the phenomenon of white fat browning, in which white adipocytes can be converted into brown like adipocytes with similar thermogenic properties. Here, we review the current understanding of the developmental and metabolic pathways involved in forming thermogenic adipocytes, and highlight some of the many unknown functions of brown fat that make its study a rich and exciting area for future research.

Keywords

Adipogenesis Beige adipocyte Brite adipocyte Brown adipose tissue Development Glucose and lipid metabolism Lineage tracing Progenitor cells Thermogenesis Ucp1 

Notes

Acknowledgments

SMJ is supported by a postdoctoral fellowship award from the American Diabetes Association (1-18-PDF-128). JSG is supported by an American Heart Association Career Development award (18CDA34080527). DAG is supported by grants from the NIH (R01DK094004 and R01CA196986) and a Leukemia and Lymphoma Society Career Development Award.

References

  1. Abu-Remaileh M, Wyant GA, Kim C, Laqtom NN, Abbasi M, Chan SH, Freinkman E, Sabatini DM (2017) Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358:807–813PubMedPubMedCentralGoogle Scholar
  2. Acosta JR, Joost S, Karlsson K, Ehrlund A, Li X, Aouadi M, Kasper M, Arner P, Ryden M, Laurencikiene J (2017) Single cell transcriptomics suggest that human adipocyte progenitor cells constitute a homogeneous cell population. Stem Cell Res Ther 8:250PubMedPubMedCentralGoogle Scholar
  3. Ahfeldt T, Schinzel RT, Lee Y-K, Hendrickson D, Kaplan A, Lum DH, Camahort R, Xia F, Shay J, Rhee EP, Clish CB, Deo RC, Shen T, Lau FH, Cowley A, Mowrer G, Al-Siddiqi H, Nahrendorf M, Musunuru K, Gerszten RE, Rinn JL, Cowan CA (2012) Programming human pluripotent stem cells into white and brown adipocytes. Nat Cell Biol 14:209–219PubMedPubMedCentralGoogle Scholar
  4. Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, Woelk L, Fan H, Logan DW, Schurmann A, Saraiva LR, Schulz TJ (2017) Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20:771–784.e6PubMedPubMedCentralGoogle Scholar
  5. Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL, Niswander L, Conlon RA (2006) beta-Catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol 296:164–176PubMedGoogle Scholar
  6. Baglioni S, Francalanci M, Squecco R, Lombardi A, Cantini G, Angeli R, Gelmini S, Guasti D, Benvenuti S, Annunziato F, Bani D, Liotta F, Francini F, Perigli G, Serio M, Luconi M (2009) Characterization of human adult stem-cell populations isolated from visceral and subcutaneous adipose tissue. FASEB J 23:3494–3505PubMedGoogle Scholar
  7. Baglioni S, Cantini G, Poli G, Francalanci M, Squecco R, Di Franco A, Borgogni E, Frontera S, Nesi G, Liotta F, Lucchese M, Perigli G, Francini F, Forti G, Serio M, Luconi M (2012) Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS One 7:e36569PubMedPubMedCentralGoogle Scholar
  8. Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, Cinti S (2010) The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab 298:E1244–E1253PubMedGoogle Scholar
  9. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmuller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J (2011) Brown adipose tissue activity controls triglyceride clearance. Nat Med 17:200–205PubMedGoogle Scholar
  10. Bartelt A, Widenmaier SB, Schlein C, Johann K, Goncalves RLS, Eguchi K, Fischer AW, Parlakgul G, Snyder NA, Nguyen TB, Bruns OT, Franke D, Bawendi MG, Lynes MD, Leiria LO, Tseng YH, Inouye KE, Arruda AP, Hotamisligil GS (2018) Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 24:292–303PubMedPubMedCentralGoogle Scholar
  11. Benador IY, Veliova M, Mahdaviani K, Petcherski A, Wikstrom JD, Assali EA, Acin-Perez R, Shum M, Oliveira MF, Cinti S, Sztalryd C, Barshop WD, Wohlschlegel JA, Corkey BE, Liesa M, Shirihai OS (2018) Mitochondria bound to lipid droplets have unique bioenergetics, composition, and dynamics that support lipid droplet expansion. Cell Metab 27:869–885 e6PubMedGoogle Scholar
  12. Berry R, Rodeheffer MS (2013) Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol 15:302–308PubMedPubMedCentralGoogle Scholar
  13. Berry R, Jeffery E, Rodeheffer MS (2014) Weighing in on adipocyte precursors. Cell Metab 19:8–20PubMedGoogle Scholar
  14. Berry DC, Jiang Y, Graff JM (2016) Mouse strains to study cold-inducible beige progenitors and beige adipocyte formation and function. Nat Commun 7:10184PubMedPubMedCentralGoogle Scholar
  15. Bertholet AM, Kazak L, Chouchani ET, Bogaczynska MG, Paranjpe I, Wainwright GL, Betourne A, Kajimura S, Spiegelman BM, Kirichok Y (2017) Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine cycling. Cell Metab 25:811–822 e4PubMedPubMedCentralGoogle Scholar
  16. Betz MJ, Enerback S (2018) Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nat Rev Endocrinol 14:77–87PubMedGoogle Scholar
  17. Blanchette-Mackie EJ, Scow RO (1983) Movement of lipolytic products to mitochondria in brown adipose tissue of young rats: an electron microscope study. J Lipid Res 24:229–244PubMedGoogle Scholar
  18. Bronnikov G, Houstek J, Nedergaard J (1992) Beta-adrenergic, cAMP-mediated stimulation of proliferation of brown fat cells in primary culture. Mediation via beta 1 but not via beta 3 adrenoceptors. J Biol Chem 267:2006–2013PubMedGoogle Scholar
  19. Bukowiecki L, Collet AJ, Follea N, Guay G, Jahjah L (1982) Brown adipose tissue hyperplasia: a fundamental mechanism of adaptation to cold and hyperphagia. Am J Physiol 242:E353–E359PubMedGoogle Scholar
  20. Bukowiecki LJ, Geloen A, Collet AJ (1986) Proliferation and differentiation of brown adipocytes from interstitial cells during cold acclimation. Am J Physiol 250:C880–C887PubMedGoogle Scholar
  21. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359PubMedGoogle Scholar
  22. Carrer A, Parris JL, Trefely S, Henry RA, Montgomery DC, Torres A, Viola JM, Kuo YM, Blair IA, Meier JL, Andrews AJ, Snyder NW, Wellen KE (2017) Impact of a high-fat diet on tissue acyl-CoA and histone acetylation levels. J Biol Chem 292:3312–3322PubMedPubMedCentralGoogle Scholar
  23. Chabowska-Kita A, Kozak LP (2016) The critical period for brown adipocyte development: genetic and environmental influences. Obesity (Silver Spring) 24:283–290Google Scholar
  24. Chen WW, Freinkman E, Wang T, Birsoy K, Sabatini DM (2016) Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166:1324–1337 e11PubMedPubMedCentralGoogle Scholar
  25. Chi J, Wu Z, Choi CHJ, Nguyen L, Tegegne S, Ackerman SE, Crane A, Marchildon F, Tessier-Lavigne M, Cohen P (2018) Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab 27:226–236.e3PubMedGoogle Scholar
  26. Church CD, Berry R, Rodeheffer MS (2014) Isolation and study of adipocyte precursors. Methods Enzymol 537:31–46PubMedPubMedCentralGoogle Scholar
  27. Cinti S (2002) Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ. J Endocrinol Investig 25:823–835Google Scholar
  28. Cinti S (2005) The adipose organ. Prostaglandins Leukot Essent Fatty Acids 73:9–15PubMedGoogle Scholar
  29. Collins S, Daniel KW, Petro AE, Surwit RS (1997) Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology 138:405–413PubMedGoogle Scholar
  30. Cserjesi P, Lilly B, Bryson L, Wang Y, Sassoon DA, Olson EN (1992) MHox: a mesodermally restricted homeodomain protein that binds an essential site in the muscle creatine kinase enhancer. Development 115:1087–1101PubMedGoogle Scholar
  31. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517PubMedPubMedCentralGoogle Scholar
  32. Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA, Huang TL, Roberts-Toler C, Weiner LS, Sze C, Chacko AT, Deschamps LN, Herder LM, Truchan N, Glasgow AL, Holman AR, Gavrila A, Hasselgren PO, Mori MA, Molla M, Tseng YH (2013) Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 19:635–639PubMedPubMedCentralGoogle Scholar
  33. de Jong JM, Larsson O, Cannon B, Nedergaard J (2015) A stringent validation of mouse adipose tissue identity markers. Am J Physiol Endocrinol Metab 308:E1085–E1105PubMedGoogle Scholar
  34. de Jong JMA, Wouters RTF, Boulet N, Cannon B, Nedergaard J, Petrovic N (2017) The beta3-adrenergic receptor is dispensable for browning of adipose tissues. Am J Physiol Endocrinol Metab 312:E508–e518PubMedGoogle Scholar
  35. Dempersmier J, Sambeat A, Gulyaeva O, Paul SM, Hudak CS, Raposo HF, Kwan HY, Kang C, Wong RH, Sul HS (2015) Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat. Mol Cell 57:235–246PubMedPubMedCentralGoogle Scholar
  36. Du B, Cawthorn WP, Su A, Doucette CR, Yao Y, Hemati N, Kampert S, Mccoin C, Broome DT, Rosen CJ, Yang G, Macdougald OA (2013) The transcription factor paired-related homeobox 1 (Prrx1) inhibits adipogenesis by activating transforming growth factor-beta (TGFbeta) signaling. J Biol Chem 288:3036–3047PubMedGoogle Scholar
  37. Eguchi J, Wang X, Yu S, Kershaw EE, Chiu PC, Dushay J, Estall JL, Klein U, Maratos-Flier E, Rosen ED (2011) Transcriptional control of adipose lipid handling by IRF4. Cell Metab 13:249–259PubMedPubMedCentralGoogle Scholar
  38. Farmer SR (2006) Transcriptional control of adipocyte formation. Cell Metab 4:263–273PubMedPubMedCentralGoogle Scholar
  39. Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400–413PubMedPubMedCentralGoogle Scholar
  40. Friederich-Persson M, Nguyen Dinh Cat A, Persson P, Montezano AC, Touyz RM (2017) Brown adipose tissue regulates small artery function through NADPH oxidase 4-derived hydrogen peroxide and redox-sensitive protein kinase G-1alpha. Arterioscler Thromb Vasc Biol 37:455–465PubMedGoogle Scholar
  41. Frontini A, Cinti S (2010) Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab 11:253–256PubMedGoogle Scholar
  42. Garg A (2011) Clinical review#: lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 96:3313–3325PubMedGoogle Scholar
  43. Garretson JT, Szymanski LA, Schwartz GJ, Xue B, Ryu V, Bartness TJ (2016) Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol Metab 5:626–634PubMedPubMedCentralGoogle Scholar
  44. Geloen A, Collet AJ, Bukowiecki LJ (1992) Role of sympathetic innervation in brown adipocyte proliferation. Am J Physiol 263:R1176–R1181PubMedGoogle Scholar
  45. Gensch N, Borchardt T, Schneider A, Riethmacher D, Braun T (2008) Different autonomous myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse embryogenesis. Development 135:1597–1604PubMedGoogle Scholar
  46. Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131:242–256PubMedGoogle Scholar
  47. Griffiths JA, Scialdone A, Marioni JC (2018) Using single-cell genomics to understand developmental processes and cell fate decisions. Mol Syst Biol 14:e8046PubMedPubMedCentralGoogle Scholar
  48. Guastella C, Borsi C, Gibelli S, Della Berta LG (2002) Madelung’s lipomatosis associated with head and neck malignant neoplasia: a study of 2 cases. Otolaryngol Head Neck Surg 126:191–192PubMedGoogle Scholar
  49. Guenantin AC, Briand N, Capel E, Dumont F, Morichon R, Provost C, Stillitano F, Jeziorowska D, Siffroi JP, Hajjar RJ, Feve B, Hulot JS, Collas P, Capeau J, Vigouroux C (2017) Functional human beige adipocytes from induced pluripotent stem cells. Diabetes 66:1470–1478PubMedPubMedCentralGoogle Scholar
  50. Gupta RK, Arany Z, Seale P, Mepani RJ, Ye L, Conroe HM, Roby YA, Kulaga H, Reed RR, Spiegelman BM (2010) Transcriptional control of preadipocyte determination by Zfp423. Nature 464:619–623PubMedPubMedCentralGoogle Scholar
  51. Gupta RK, Mepani RJ, Kleiner S, Lo JC, Khandekar MJ, Cohen P, Frontini A, Bhowmick DC, Ye L, Cinti S, Spiegelman BM (2012) Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15:230–239PubMedPubMedCentralGoogle Scholar
  52. Haldar M, Karan G, Tvrdik P, Capecchi MR (2008) Two cell lineages, myf5 and myf5-independent, participate in mouse skeletal myogenesis. Dev Cell 14:437–445PubMedPubMedCentralGoogle Scholar
  53. Hansen IR, Jansson KM, Cannon B, Nedergaard J (2014) Contrasting effects of cold acclimation versus obesogenic diets on chemerin gene expression in brown and brite adipose tissues. Biochim Biophys Acta 1841:1691–1699PubMedGoogle Scholar
  54. Hanssen MJ, Hoeks J, Brans B, Van Der Lans AA, Schaart G, Van Den Driessche JJ, Jorgensen JA, Boekschoten MV, Hesselink MK, Havekes B, Kersten S, Mottaghy FM, Van Marken Lichtenbelt WD, Schrauwen P (2015) Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med 21:863–865PubMedPubMedCentralGoogle Scholar
  55. Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19:1252–1263PubMedGoogle Scholar
  56. Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, Kurokawa M, Won KJ, Seale P (2014) Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab 19:593–604PubMedPubMedCentralGoogle Scholar
  57. Herbst KL (2012) Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol Sin 33:155–172PubMedPubMedCentralGoogle Scholar
  58. Hu YS, Zhou H, Kartsogiannis V, Eisman JA, Martin TJ, Ng KW (1998) Expression of rat homeobox gene, rHOX, in developing and adult tissues in mice and regulation of its mRNA expression in osteoblasts by bone morphogenetic protein 2 and parathyroid hormone-related protein. Mol Endocrinol 12:1721–1732PubMedGoogle Scholar
  59. Hung CM, Calejman CM, Sanchez-Gurmaches J, Li H, Clish CB, Hettmer S, Wagers AJ, Guertin DA (2014) Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep 8:256–271PubMedPubMedCentralGoogle Scholar
  60. Ikeda K, Maretich P, Kajimura S (2018) The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab 29:191–200PubMedPubMedCentralGoogle Scholar
  61. Jiang Y, Berry DC, Tang W, Graff JM (2014) Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. Cell Rep 9:1007–1022PubMedPubMedCentralGoogle Scholar
  62. Jiang Y, Berry DC, Graff JM (2017) Distinct cellular and molecular mechanisms for beta3 adrenergic receptor-induced beige adipocyte formation. Elife 6:e30329PubMedPubMedCentralGoogle Scholar
  63. Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FM (2010) Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 12:153–163PubMedPubMedCentralGoogle Scholar
  64. Kajimura S, Spiegelman BM, Seale P (2015) Brown and beige fat: physiological roles beyond heat generation. Cell Metab 22:546–559PubMedPubMedCentralGoogle Scholar
  65. Kawate R, Talan MI, Engel BT (1994) Sympathetic nervous activity to brown adipose tissue increases in cold-tolerant mice. Physiol Behav 55:921–925PubMedGoogle Scholar
  66. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, Vetrivelan R, Lu GZ, Laznik-Bogoslavski D, Hasenfuss SC, Kajimura S, Gygi SP, Spiegelman BM (2015) A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163:643–655PubMedPubMedCentralGoogle Scholar
  67. Kishida T, Ejima A, Yamamoto K, Tanaka S, Yamamoto T, Mazda O (2015) Reprogrammed functional brown adipocytes ameliorate insulin resistance and dyslipidemia in diet-induced obesity and type 2 diabetes. Stem Cell Reports 5:569–581PubMedPubMedCentralGoogle Scholar
  68. Kortelainen ML, Pelletier G, Ricquier D, Bukowiecki LJ (1993) Immunohistochemical detection of human brown adipose tissue uncoupling protein in an autopsy series. J Histochem Cytochem 41:759–764PubMedGoogle Scholar
  69. Kozak LP (2011) The genetics of brown adipocyte induction in white fat depots. Front Endocrinol (Lausanne) 2:64Google Scholar
  70. Krueger KC, Costa MJ, Du H, Feldman BJ (2014) Characterization of Cre recombinase activity for in vivo targeting of adipocyte precursor cells. Stem Cell Reports 3:1147–1158PubMedPubMedCentralGoogle Scholar
  71. Kumar P, Tan Y, Cahan P (2017) Understanding development and stem cells using single cell-based analyses of gene expression. Development 144:17–32PubMedPubMedCentralGoogle Scholar
  72. Labbe SM, Caron A, Bakan I, Laplante M, Carpentier AC, Lecomte R, Richard D (2015) In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis. FASEB J 29:2046–2058PubMedGoogle Scholar
  73. Lee YH, Petkova AP, Mottillo EP, Granneman JG (2012) In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab 15:480–491PubMedPubMedCentralGoogle Scholar
  74. Lee YH, Petkova AP, Konkar AA, Granneman JG (2015) Cellular origins of cold-induced brown adipocytes in adult mice. FASEB J 29:286–299PubMedGoogle Scholar
  75. Lee KY, Sharma R, Gase G, Ussar S, Li Y, Welch L, Berryman DE, Kispert A, Bluher M, Kahn CR (2017) Tbx15 defines a glycolytic subpopulation and white adipocyte heterogeneity. Diabetes 66:2822–2829PubMedPubMedCentralGoogle Scholar
  76. Lehr L, Canola K, Asensio C, Jimenez M, Kuehne F, Giacobino JP, Muzzin P (2006) The control of UCP1 is dissociated from that of PGC-1alpha or of mitochondriogenesis as revealed by a study using beta-less mouse brown adipocytes in culture. FEBS Lett 580:4661–4666PubMedGoogle Scholar
  77. Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS, Mcgehee S, Tal I, Dieckmann W, Gupta G, Kolodny GM, Pacak K, Herscovitch P, Cypess AM, Chen KY (2017) Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci U S A 114:8649–8654PubMedPubMedCentralGoogle Scholar
  78. Lepper C, Fan C-M (2010) Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48:424–436PubMedPubMedCentralGoogle Scholar
  79. Lidell ME, Betz MJ, Leinhard OD, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerback S (2013) Evidence for two types of brown adipose tissue in humans. Nat Med 19:631Google Scholar
  80. Liu W, Shan T, Yang X, Liang S, Zhang P, Liu Y, Liu X, Kuang S (2013) A heterogeneous lineage origin underlies the phenotypic and molecular differences of white and beige adipocytes. J Cell Sci 126:3527–3532PubMedPubMedCentralGoogle Scholar
  81. Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ (2002) Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33:77–80PubMedGoogle Scholar
  82. Long JZ, Svensson KJ, Tsai L, Zeng X, Roh HC, Kong X, Rao RR, Lou J, Lokurkar I, Baur W, Castellot JJ Jr, Rosen ED, Spiegelman BM (2014) A smooth muscle-like origin for beige adipocytes. Cell Metab 19:810–820PubMedPubMedCentralGoogle Scholar
  83. Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, Nomura DK, Spiegelman BM (2016) The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166:424–435PubMedPubMedCentralGoogle Scholar
  84. Lu MF, Cheng HT, Kern MJ, Potter SS, Tran B, Diekwisch TG, Martin JF (1999) prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development 126:495–504PubMedGoogle Scholar
  85. Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111–2117PubMedPubMedCentralGoogle Scholar
  86. Mahdaviani K, Chess D, Wu Y, Shirihai O, Aprahamian TR (2016) Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes. Metabolism 65:26–35PubMedGoogle Scholar
  87. McCormack JG, Denton RM (1977) Evidence that fatty acid synthesis in the interscapular brown adipose tissue of cold-adapted rats is increased in vivo by insulin by mechanisms involving parallel activation of pyruvate dehydrogenase and acetyl-coenzyme A carboxylase. Biochem J 166:627–630PubMedPubMedCentralGoogle Scholar
  88. McKenna A, Findlay GM, Gagnon JA, Horwitz MS, Schier AF, Shendure J (2016) Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353:aaf7907PubMedPubMedCentralGoogle Scholar
  89. Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, Kim JK, Cooper MP, Fitzgibbons T, Brehm MA, Corvera S (2016) Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 22:312–318PubMedPubMedCentralGoogle Scholar
  90. Mo Q, Salley J, Roshan T, Baer LA, May FJ, Jaehnig EJ, Lehnig AC, Guo X, Tong Q, Nuotio-Antar AM, Shamsi F, Tseng YH, Stanford KI, Chen MH (2017) Identification and characterization of a supraclavicular brown adipose tissue in mice. JCI Insight 2Google Scholar
  91. Morrison SF, Madden CJ, Tupone D (2012) Central control of brown adipose tissue thermogenesis. Front Endocrinol (Lausanne) 3Google Scholar
  92. Mottillo EP, Balasubramanian P, Lee YH, Weng C, Kershaw EE, Granneman JG (2014) Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation. J Lipid Res 55:2276–2286PubMedPubMedCentralGoogle Scholar
  93. Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG, Mottis A, Jovaisaite V, Frochaux MV, Quiros PM, Deplancke B, Houtkooper RH, Auwerx J (2015) Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep 10:1681–1691PubMedPubMedCentralGoogle Scholar
  94. Murano I, Barbatelli G, Giordano A, Cinti S (2009) Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat 214:171–178PubMedGoogle Scholar
  95. Muzik O, Mangner TJ, Leonard WR, Kumar A, Granneman JG (2017) Sympathetic innervation of cold-activated brown and white fat in lean young adults. J Nucl Med 58:799–806PubMedPubMedCentralGoogle Scholar
  96. Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L (2007) A global double-fluorescent Cre reporter mouse. Genesis 45:593–605PubMedPubMedCentralGoogle Scholar
  97. Nedergaard J, Cannon B (2014) The browning of white adipose tissue: some burning issues. Cell Metab 20:396–407PubMedGoogle Scholar
  98. Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444–E452PubMedGoogle Scholar
  99. Nguyen TB, Louie SM, Daniele JR, Tran Q, Dillin A, Zoncu R, Nomura DK, Olzmann JA (2017) DGAT1-dependent lipid droplet biogenesis protects mitochondrial function during starvation-induced autophagy. Dev Cell 42:9–21 e5PubMedPubMedCentralGoogle Scholar
  100. Nguyen NLT, Xue B, Bartness TJ (2018) Sensory denervation of inguinal white fat modifies sympathetic outflow to white and brown fat in Siberian hamsters. Physiol Behav 190:28–33PubMedGoogle Scholar
  101. Nicholls DG (2006) The physiological regulation of uncoupling proteins. Biochim Biophys Acta 1757:459–466PubMedGoogle Scholar
  102. Nisoli E, Clementi E, Tonello C, Sciorati C, Briscini L, Carruba MO (1998) Effects of nitric oxide on proliferation and differentiation of rat brown adipocytes in primary cultures. Br J Pharmacol 125:888–894PubMedPubMedCentralGoogle Scholar
  103. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMedPubMedCentralGoogle Scholar
  104. Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F, Turcotte EE, Richard D, Carpentier AC (2012) Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Investig 122:545–552PubMedGoogle Scholar
  105. Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL, Rahmouni K, Kliewer SA, Mangelsdorf DJ (2014) FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 20:670–677PubMedPubMedCentralGoogle Scholar
  106. Perrini S, Ficarella R, Picardi E, Cignarelli A, Barbaro M, Nigro P, Peschechera A, Palumbo O, Carella M, De Fazio M, Natalicchio A, Laviola L, Pesole G, Giorgino F (2013) Differences in gene expression and cytokine release profiles highlight the heterogeneity of distinct subsets of adipose tissue-derived stem cells in the subcutaneous and visceral adipose tissue in humans. PLoS One 8:e57892PubMedPubMedCentralGoogle Scholar
  107. Peterson RE, Hoffman S, Kern MJ (2005) Opposing roles of two isoforms of the Prx1 homeobox gene in chondrogenesis. Dev Dyn 233:811–821PubMedGoogle Scholar
  108. Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G (2015) Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab 21:805–821PubMedGoogle Scholar
  109. Pisani DF, Djedaini M, Beranger GE, Elabd C, Scheideler M, Ailhaud G, Amri EZ (2011) Differentiation of human adipose-derived stem cells into “brite” (brown-in-white) adipocytes. Front Endocrinol (Lausanne) 2:87Google Scholar
  110. Potter SS (2018) Single-cell RNA sequencing for the study of development, physiology and disease. Nat Rev Nephrol 14:479–492PubMedGoogle Scholar
  111. Rajakumari S, Wu J, Ishibashi J, Lim HW, Giang AH, Won KJ, Reed RR, Seale P (2013) EBF2 determines and maintains brown adipocyte identity. Cell Metab 17:562–574PubMedPubMedCentralGoogle Scholar
  112. Rambold AS, Cohen S, Lippincott-Schwartz J (2015) Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell 32:678–692PubMedPubMedCentralGoogle Scholar
  113. Ramos S, Pinheiro S, Diogo C, Cabral L, Cruzeiro C (2010) Madelung disease: a not-so-rare disorder. Ann Plast Surg 64:122–124PubMedGoogle Scholar
  114. Razzoli M, Emmett MJ, Lazar MA, Bartolomucci A (2018) beta-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity. FASEB J:fj201800452RGoogle Scholar
  115. Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607PubMedPubMedCentralGoogle Scholar
  116. Rehnmark S, Nedergaard J (1989) DNA synthesis in mouse brown adipose tissue is under beta-adrenergic control. Exp Cell Res 180:574–579PubMedGoogle Scholar
  117. Rivera-Gonzalez GC, Shook BA, Andrae J, Holtrup B, Bollag K, Betsholtz C, Rodeheffer MS, Horsley V (2016) Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis. Cell Stem Cell 19:738–751PubMedPubMedCentralGoogle Scholar
  118. Roberts-Toler C, O'neill BT, Cypess AM (2015) Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity (Silver Spring) 23:1765–1770Google Scholar
  119. Rodeheffer MS, Birsoy K, Friedman JM (2008) Identification of white adipocyte progenitor cells in vivo. Cell 135:240–249PubMedGoogle Scholar
  120. Roh HC, Tsai LT, Lyubetskaya A, Tenen D, Kumari M, Rosen ED (2017) Simultaneous transcriptional and epigenomic profiling from specific cell types within heterogeneous tissues in vivo. Cell Rep 18:1048–1061PubMedPubMedCentralGoogle Scholar
  121. Roh HC, Tsai LTY, Shao M, Tenen D, Shen Y, Kumari M, Lyubetskaya A, Jacobs C, Dawes B, Gupta RK, Rosen ED (2018) Warming induces significant reprogramming of beige, but not brown, adipocyte cellular identity. Cell Metab 27:1121–1137.e5PubMedGoogle Scholar
  122. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM (1999) PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4:611–617PubMedGoogle Scholar
  123. Rosenwald M, Perdikari A, Rulicke T, Wolfrum C (2013) Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol 15:659–667PubMedGoogle Scholar
  124. Rothwell NJ, Stock MJ (1984) Effects of denervating brown adipose tissue on the responses to cold, hyperphagia and noradrenaline treatment in the rat. J Physiol 355:457–463PubMedPubMedCentralGoogle Scholar
  125. Sacks H, Symonds ME (2013) Anatomical locations of human brown adipose tissue: functional relevance and implications in obesity and type 2 diabetes. Diabetes 62:1783–1790PubMedPubMedCentralGoogle Scholar
  126. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531PubMedPubMedCentralGoogle Scholar
  127. Sakaguchi M, Fujisaka S, Cai W, Winnay JN, Konishi M, O'neill BT, Li M, Garcia-Martin R, Takahashi H, Hu J, Kulkarni RN, Kahn CR (2017) Adipocyte dynamics and reversible metabolic syndrome in mice with an inducible adipocyte-specific deletion of the insulin receptor. Cell Metab 25:448–462PubMedPubMedCentralGoogle Scholar
  128. Sambeat A, Gulyaeva O, Dempersmier J, Tharp KM, Stahl A, Paul SM, Sul HS (2016) LSD1 interacts with Zfp516 to promote UCP1 transcription and brown fat program. Cell Rep 15:2536–2549PubMedPubMedCentralGoogle Scholar
  129. Sanchez-Gurmaches J, Guertin DA (2014) Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat Commun 5:4099PubMedPubMedCentralGoogle Scholar
  130. Sanchez-Gurmaches J, Hung CM, Sparks CA, Tang Y, Li H, Guertin DA (2012) PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab 16:348–362PubMedPubMedCentralGoogle Scholar
  131. Sanchez-Gurmaches J, Hsiao WY, Guertin DA (2015) Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre. Stem Cell Reports 4:541–550PubMedPubMedCentralGoogle Scholar
  132. Sanchez-Gurmaches J, Tang Y, Jespersen NZ, Wallace M, Martinez Calejman C, Gujja S, Li H, Edwards YJK, Wolfrum C, Metallo CM, Nielsen S, Scheele C, Guertin DA (2018) Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis. Cell Metab 27:195–209.e6PubMedGoogle Scholar
  133. Schreiber R, Diwoky C, Schoiswohl G, Feiler U, Wongsiriroj N, Abdellatif M, Kolb D, Hoeks J, Kershaw EE, Sedej S, Schrauwen P, Haemmerle G, Zechner R (2017) Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab 26:753–763.e7PubMedPubMedCentralGoogle Scholar
  134. Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, Cypess AM, Mishina Y, Gussoni E, Tseng YH (2013) Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495:379–383PubMedPubMedCentralGoogle Scholar
  135. Schwalie PC, Dong H, Zachara M, Russeil J, Alpern D, Akchiche N, Caprara C, Sun W, Schlaudraff K-U, Soldati G, Wolfrum C, Deplancke B (2018) A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature 559:103–108PubMedGoogle Scholar
  136. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6:38–54PubMedPubMedCentralGoogle Scholar
  137. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454:961–967PubMedPubMedCentralGoogle Scholar
  138. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM (2011) Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 121:96–105PubMedGoogle Scholar
  139. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J (2013) UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 5:1196–1203PubMedGoogle Scholar
  140. Shan T, Liang X, Bi P, Zhang P, Liu W, Kuang S (2013) Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues. J Lipid Res 54:2214–2224PubMedPubMedCentralGoogle Scholar
  141. Shao M, Gupta RK (2018) Transcriptional brakes on the road to adipocyte thermogenesis. Biochim Biophys Acta Mol Cell Biol Lipids.  https://doi.org/10.1016/j.bbalip.2018.05.010
  142. Shao M, Ishibashi J, Kusminski CM, Wang QA, Hepler C, Vishvanath L, Macpherson KA, Spurgin SB, Sun K, Holland WL, Seale P, Gupta RK (2016) Zfp423 maintains white adipocyte identity through suppression of the beige cell thermogenic gene program. Cell Metab 23:1167–1184PubMedPubMedCentralGoogle Scholar
  143. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S (2012) Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 7:e49452PubMedPubMedCentralGoogle Scholar
  144. Shimazu T, Takahashi A (1980) Stimulation of hypothalamic nuclei has differential effects on lipid synthesis in brown and white adipose tissue. Nature 284:62–63PubMedGoogle Scholar
  145. Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, Maruyama S, Walsh K (2014) Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest 124:2099–2112PubMedPubMedCentralGoogle Scholar
  146. Shin H, Ma Y, Chanturiya T, Cao Q, Wang Y, Kadegowda AKG, Jackson R, Rumore D, Xue B, Shi H, Gavrilova O, Yu L (2017) Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab 26:764–777.e5PubMedPubMedCentralGoogle Scholar
  147. Shinoda K, Luijten IH, Hasegawa Y, Hong H, Sonne SB, Kim M, Xue R, Chondronikola M, Cypess AM, Tseng YH, Nedergaard J, Sidossis LS, Kajimura S (2015) Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat Med 21:389–394PubMedPubMedCentralGoogle Scholar
  148. Silva JE, Larsen PR (1983) Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 305:712–713PubMedGoogle Scholar
  149. Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M, Miao R, Lee S, Jiang L, Huck I, Kershaw EE, Donato AJ, Apte U, Longo N, Rutter J, Schreiber R, Zechner R, Cox J, Villanueva CJ (2017) Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab 26:509–522 e6PubMedPubMedCentralGoogle Scholar
  150. Singh AM, Dalton S (2018) What can ‘brown-ing’ do for you? Trends Endocrinol Metab 29:349–359PubMedGoogle Scholar
  151. Sluse FE, Jarmuszkiewicz W, Navet R, Douette P, Mathy G, Sluse-Goffart CM (2006) Mitochondrial UCPs: new insights into regulation and impact. Biochim Biophys Acta 1757:480–485PubMedGoogle Scholar
  152. Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD, Kostense PJ, Yudkin JS, Heine RJ, Nijpels G, Seidell JC (2003) Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn study. Am J Clin Nutr 77:1192–1197PubMedGoogle Scholar
  153. Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD, Yudkin JS, Heine RJ, Nijpels G, Seidell JC, Hoorn S (2004) Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels: the Hoorn study. Diabetes Care 27:372–377PubMedGoogle Scholar
  154. Stine RR, Shapira SN, Lim HW, Ishibashi J, Harms M, Won KJ, Seale P (2016) EBF2 promotes the recruitment of beige adipocytes in white adipose tissue. Mol Metab 5:57–65PubMedGoogle Scholar
  155. Stone SJ, Levin MC, Zhou P, Han J, Walther TC, Farese RV Jr (2009) The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria. J Biol Chem 284:5352–5361PubMedPubMedCentralGoogle Scholar
  156. Sun K, Kusminski CM, Luby-Phelps K, Spurgin SB, An YA, Wang QA, Holland WL, Scherer PE (2014) Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol Metab 3:474–483PubMedPubMedCentralGoogle Scholar
  157. Sun C, Berry WL, Olson LE (2017) PDGFRalpha controls the balance of stromal and adipogenic cells during adipose tissue organogenesis. Development 144:83–94PubMedPubMedCentralGoogle Scholar
  158. Svensson KJ, Long JZ, Jedrychowski MP, Cohen P, Lo JC, Serag S, Kir S, Shinoda K, Tartaglia JA, Rao RR, Chedotal A, Kajimura S, Gygi SP, Spiegelman BM (2016) A secreted Slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab 23:454–466PubMedPubMedCentralGoogle Scholar
  159. Takahashi A, Shimazu T, Maruyama Y (1992) Importance of sympathetic nerves for the stimulatory effect of cold exposure on glucose utilization in brown adipose tissue. Jpn J Physiol 42:653–664PubMedGoogle Scholar
  160. Tallquist MD, Weismann KE, Hellstrom M, Soriano P (2000) Early myotome specification regulates PDGFA expression and axial skeleton development. Development 127:5059–5070PubMedGoogle Scholar
  161. ten Berge D, Brouwer A, Korving J, Martin JF, Meijlink F (1998) Prx1 and Prx2 in skeletogenesis: roles in the craniofacial region, inner ear and limbs. Development 125:3831–3842PubMedGoogle Scholar
  162. Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia-Martin R, Grinspoon SK, Gorden P, Kahn CR (2017) Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–455PubMedPubMedCentralGoogle Scholar
  163. Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156PubMedGoogle Scholar
  164. Townsend KL, Tseng YH (2015) Of mice and men: novel insights regarding constitutive and recruitable brown adipocytes. Int J Obes Suppl 5:S15–S20PubMedPubMedCentralGoogle Scholar
  165. Trayhurn P (1979) Fatty acid synthesis in vivo in brown adipose tissue, liver and white adipose tissue of the cold-acclimated rat. FEBS Lett 104:13–16PubMedGoogle Scholar
  166. Ussar S, Lee KY, Dankel SN, Boucher J, Haering MF, Kleinridders A, Thomou T, Xue R, Macotela Y, Cypess AM, Tseng YH, Mellgren G, Kahn CR (2014) ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med 6:247ra103PubMedPubMedCentralGoogle Scholar
  167. van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jorgensen JA, Wu J, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD (2013) Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest 123:3395–3403PubMedPubMedCentralGoogle Scholar
  168. van Harmelen V, Skurk T, Hauner H (2005) Primary culture and differentiation of human adipocyte precursor cells. Methods Mol Med 107:125–135PubMedGoogle Scholar
  169. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508PubMedPubMedCentralGoogle Scholar
  170. Van Pelt RE, Jankowski CM, Gozansky WS, Schwartz RS, Kohrt WM (2005) Lower-body adiposity and metabolic protection in postmenopausal women. J Clin Endocrinol Metab 90:4573–4578PubMedPubMedCentralGoogle Scholar
  171. Veniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, Moyer C, Lloyd DJ (2015) Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 21:731–738PubMedGoogle Scholar
  172. Villarroya F, Giralt M (2015) The beneficial effects of brown fat transplantation: further evidence of an endocrine role of brown adipose tissue. Endocrinology 156:2368–2370PubMedGoogle Scholar
  173. Villarroya J, Cereijo R, Villarroya F (2013) An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab 305:E567–E572PubMedGoogle Scholar
  174. Villarroya F, Cereijo R, Villarroya J, Gavalda-Navarro A, Giralt M (2018) Toward an understanding of how immune cells control brown and beige adipobiology. Cell Metab 27:954–961PubMedGoogle Scholar
  175. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525PubMedPubMedCentralGoogle Scholar
  176. Vishvanath L, Macpherson KA, Hepler C, Wang QA, Shao M, Spurgin SB, Wang MY, Kusminski CM, Morley TS, Gupta RK (2016) Pdgfrbeta+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab 23:350–359PubMedGoogle Scholar
  177. Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J (2012) Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab 302:E19–E31PubMedGoogle Scholar
  178. Wang H, Sreenivasan U, Hu H, Saladino A, Polster BM, Lund LM, Gong DW, Stanley WC, Sztalryd C (2011) Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. J Lipid Res 52:2159–2168PubMedPubMedCentralGoogle Scholar
  179. Wang F, Mullican SE, Dispirito JR, Peed LC, Lazar MA (2013a) Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARgamma. Proc Natl Acad Sci U S A 110:18656–18661PubMedPubMedCentralGoogle Scholar
  180. Wang QA, Tao C, Gupta RK, Scherer PE (2013b) Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 19:1338–1344PubMedPubMedCentralGoogle Scholar
  181. Wang GX, Zhao XY, Meng ZX, Kern M, Dietrich A, Chen Z, Cozacov Z, Zhou D, Okunade AL, Su X, Li S, Bluher M, Lin JD (2014a) The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med 20:1436–1443PubMedPubMedCentralGoogle Scholar
  182. Wang W, Kissig M, Rajakumari S, Huang L, Lim HW, Won KJ, Seale P (2014b) Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc Natl Acad Sci U S A 111:14466–14471PubMedPubMedCentralGoogle Scholar
  183. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–376PubMedPubMedCentralGoogle Scholar
  184. Xue Y, Petrovic N, Cao R, Larsson O, Lim S, Chen S, Feldmann HM, Liang Z, Zhu Z, Nedergaard J, Cannon B, Cao Y (2009) Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab 9:99–109PubMedGoogle Scholar
  185. Xue R, Lynes MD, Dreyfuss JM, Shamsi F, Schulz TJ, Zhang H, Huang TL, Townsend KL, Li Y, Takahashi H, Weiner LS, White AP, Lynes MS, Rubin LL, Goodyear LJ, Cypess AM, Tseng YH (2015) Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes. Nat Med 21:760–768PubMedPubMedCentralGoogle Scholar
  186. Ye R, Wang QA, Tao C, Vishvanath L, Shao M, McDonald JG, Gupta RK, Scherer PE (2015) Impact of tamoxifen on adipocyte lineage tracing: inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase. Mol Metab 4:771–778PubMedPubMedCentralGoogle Scholar
  187. Yoneshiro T, Aita S, Mastushita M, Ogawa T, Okamatsu-Ogura Y, Kawai Y, Saito M (2011a) Age-related decrease in brown adipose tissue and obesity in humans. Obesity 19:S79–S79Google Scholar
  188. Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M (2011b) Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity 19:13–16PubMedGoogle Scholar
  189. Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, Miyagawa M, Tsujisaki M, Saito M (2011c) Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity (Silver Spring) 19:1755–1760Google Scholar
  190. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M (2013) Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123:3404–3408PubMedPubMedCentralGoogle Scholar
  191. Yu XX, Lewin DA, Forrest W, Adams SH (2002) Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo. FASEB J 16:155–168PubMedGoogle Scholar
  192. Zhang F, Hao G, Shao M, Nham K, An Y, Wang Q, Zhu Y, Kusminski CM, Hassan G, Gupta RK, Zhai Q, Sun X, Scherer PE, Oz OK (2018) An adipose tissue atlas: an image-guided identification of human-like BAT and beige depots in rodents. Cell Metab 27:252–262.e3PubMedPubMedCentralGoogle Scholar
  193. Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, Carrer A, Sengupta A, Campbell SL, Kuo YM, Frey AJ, Meurs N, Viola JM, Blair IA, Weljie AM, Metallo CM, Snyder NW, Andrews AJ, Wellen KE (2016) ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep 17:1037–1052PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Program in Molecular MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Division of Endocrinology, Division of Developmental BiologyCincinnati Children’s Hospital Research FoundationCincinnatiUSA
  3. 3.Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiUSA
  4. 4.Molecular, Cell and Cancer Biology ProgramUniversity of Massachusetts Medical SchoolWorcesterUSA
  5. 5.Lei Weibo Institute for Rare DiseasesUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations