Abstract
Brown and its related beige adipose tissue (BAT) play a definitive role in maintaining body temperature by producing heat through uncoupling protein 1 (UCP1), which acts by dissociating oxidative phosphorylation from ATP production, resulting in the release of heat. Therefore, in order to maintain high thermogenic capacity, BAT must act as a metabolic sink by taking up vast amounts of circulating glucose and lipids for oxidation. This, along with the rediscovery of BAT in adult humans, has fueled the study of BAT as a putative therapeutic approach to manage the growing rates of obesity and metabolic syndromes. Notably, many of the beneficial consequences of BAT activity overlap with metabolic biomarkers of extended lifespan and healthspan. In this review, we provide background about BAT including the thermogenic program, BAT’s role as a secretory organ, and differences between BAT in mice and humans. We also provide details on BAT during aging, and perspectives on the potential of targeting BAT to promote lifespan and healthspan.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abe Y, Rozqie R, Matsumura Y, Kawamura T, Nakaki R, Tsurutani Y, Tanimura-Inagaki K, Shiono A, Magoori K, Nakamura K, Ogi S, Kajimura S, Kimura H, Tanaka T, Fukami K, Osborne TF, Kodama T, Aburatani H, Inagaki T, Sakai J (2015) JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis. Nat Commun 6:7052. https://doi.org/10.1038/ncomms8052
Alvarez R, de Andrés J, Yubero P, Viñas O, Mampel T, Iglesias R, Giralt M, Villarroya F (1995) A novel regulatory pathway of brown fat thermogenesis. Retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene. J Biol Chem 270:5666–5673
Asano A, Kimura K, Saito M (1999) Cold-induced mRNA expression of angiogenic factors in rat brown adipose tissue. J Vet Med Sci 61:403–409
Austad SN (2016) The geroscience hypothesis: is it possible to change the rate of aging? In: Sierra F (ed) Advances in Geroscience. Springer
Barja G (2007) Mitochondrial oxygen consumption and reactive oxygen species production are independently modulated: implications for aging studies. Rejuvenation Res 10:215–224. https://doi.org/10.1089/rej.2006.0516
Barros MH, Bandy B, Tahara EB, Kowaltowski AJ (2004) Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem 279:49883–49888. https://doi.org/10.1074/jbc.M408918200
Bartke A (2003) Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 78:210–216. https://doi.org/10.1159/000073704
Bartke A, Darcy J (2017) GH and ageing: pitfalls and new insights. Best Pract Res Clin Endocrinol Metab 31:113–125. https://doi.org/10.1016/j.beem.2017.02.005
Bartke A, Sun LY, Longo V (2013) Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev 93:571–598. https://doi.org/10.1152/physrev.00006.2012
Bartness TJ, Wade GN (1984) Effects of interscapular brown adipose tissue denervation on body weight and energy metabolism in ovariectomized and estradiol-treated rats. Behav Neurosci 98:674–685
Bertholet AM, Kazak L, Chouchani ET, Bogaczyńska MG, Paranjpe I, Wainwright GL, Bétourné 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. https://doi.org/10.1016/j.cmet.2017.03.002
Brand MD (2000) Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35:811–820
Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33. https://doi.org/10.1038/384033a0
Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359. https://doi.org/10.1152/physrev.00015.2003
Cannon B, Nedergaard J (2011) Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214:242–253. https://doi.org/10.1242/jeb.050989
Cao W, Medvedev AV, Daniel KW, Collins S (2001) Beta-adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J Biol Chem 276:27077–27082. https://doi.org/10.1074/jbc.M101049200
Carpentier AC, Blondin DP, Virtanen KA, Richard D, Haman F, Turcotte EE (2018) Brown adipose tissue energy metabolism in humans. Front Endocrinol (Lausanne) 9:447. https://doi.org/10.3389/fendo.2018.00447
Cassard-Doulcier AM, Larose M, Matamala JC, Champigny O, Bouillaud F, Ricquier D (1994) In vitro interactions between nuclear proteins and uncoupling protein gene promoter reveal several putative transactivating factors including Ets1, retinoid X receptor, thyroid hormone receptor, and a CACCC box-binding protein. J Biol Chem 269:24335–24342
Cereijo R, Gavaldà-Navarro A, Cairó M, Quesada-López T, Villarroya J, Morón-Ros S, Sánchez-Infantes D, Peyrou M, Iglesias R, Mampel T, Turatsinze JV, Eizirik DL, Giralt M, Villarroya F (2018) CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab 28:750–763.e6. https://doi.org/10.1016/j.cmet.2018.07.015
Chaudhry A, Granneman JG (1999) Differential regulation of functional responses by beta-adrenergic receptor subtypes in brown adipocytes. Am J Phys 277:R147–R153
Chen Y, Buyel JJ, Hanssen MJW, Siegel F, Pan R, Naumann J, Schell M, van der Lans A, Schlein C, Froehlich H, Heeren J, Virtanen KA, van Marken Lichtenbelt W, Pfeifer A (2016) Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat Commun 7:11420. https://doi.org/10.1038/ncomms11420
Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, Lo JC, Zeng X, Ye L, Khandekar MJ, Wu J, Gunawardana SC, Banks AS, Camporez JPG, Jurczak MJ, Kajimura S, Piston DW, Mathis D, Cinti S, Shulman GI, Seale P, Spiegelman BM (2014) Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156:304–316. https://doi.org/10.1016/j.cell.2013.12.021
Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141:2608–2613. https://doi.org/10.1210/endo.141.7.7586
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 360:1509–1517. https://doi.org/10.1056/NEJMoa0810780
Cypess AM, Haft CR, Laughlin MR, Hu HH (2014) Brown fat in humans: consensus points and experimental guidelines. Cell Metab 20:408–415. https://doi.org/10.1016/j.cmet.2014.07.025
Cypess AM, Weiner LS, Roberts-Toler C, Elía EF, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM (2015) Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab 21:33–38. https://doi.org/10.1016/j.cmet.2014.12.009
Darcy J, McFadden S, Fang Y, Huber JA, Zhang C, Sun LY, Bartke A (2016) Brown adipose tissue function is enhanced in long-lived, male Ames dwarf mice. Endocrinology 157:4744–4753. https://doi.org/10.1210/en.2016-1593
Darcy J, McFadden S, Fang Y, Berryman DE, List EO, Milcik N, Bartke A (2018) Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice. Aging (Albany NY) 10:2709–2722. https://doi.org/10.18632/aging.101582
Emmett MJ, Lim HW, Jager J, Richter HJ, Adlanmerini M, Peed LC, Briggs ER, Steger DJ, Ma T, Sims CA, Baur JA, Pei L, Won KJ, Seale P, Gerhart-Hines Z, Lazar MA (2017) Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Nature 546:544–548. https://doi.org/10.1038/nature22819
Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, Kozak LP (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387:90–94. https://doi.org/10.1038/387090a0
Farmer SR (2006) Transcriptional control of adipocyte formation. Cell Metab 4:263–273. https://doi.org/10.1016/j.cmet.2006.07.001
Farmer KJ, Sohal RS (1987) Effects of ambient temperature on free radical generation, antioxidant defenses and life span in the adult housefly, Musca domestica. Exp Gerontol 22:59–65
Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400–413. https://doi.org/10.1016/j.cell.2012.09.010
Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9:203–209. https://doi.org/10.1016/j.cmet.2008.12.014
Florez-Duquet M, Horwitz BA, McDonald RB (1998) Cellular proliferation and UCP content in brown adipose tissue of cold-exposed aging Fischer 344 rats. Am J Phys 274:R196–R203
Goldman DP, Cutler D, Rowe JW, Michaud PC, Sullivan J, Peneva D, Olshansky SJ (2013) Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff (Millwood) 32:1698–1705. https://doi.org/10.1377/hlthaff.2013.0052
Golozoubova V, Gullberg H, Matthias A, Cannon B, Vennstrom B, Nedergaard J (2004) Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors. Mol Endocrinol 18:384–401. https://doi.org/10.1210/me.2003-0267
Goncalves LF, Machado TQ, Castro-Pinheiro C, de Souza NG, Oliveira KJ, Fernandes-Santos C (2017) Ageing is associated with brown adipose tissue remodelling and loss of white fat browning in female C57BL/6 mice. Int J Exp Pathol 98:100–108. https://doi.org/10.1111/iep.12228
Granneman JG (1988) Norepinephrine infusions increase adenylate cyclase responsiveness in brown adipose tissue. J Pharmacol Exp Ther 245:1075–1080
Granneman JG, Moore HP, Granneman RL, Greenberg AS, Obin MS, Zhu Z (2007) Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem 282:5726–5735. https://doi.org/10.1074/jbc.M610580200
Granneman JG, Moore HP, Krishnamoorthy R, Rathod M (2009) Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). J Biol Chem 284:34538–34544. https://doi.org/10.1074/jbc.M109.068478
Guarente L (2008) Mitochondria--a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176. https://doi.org/10.1016/j.cell.2008.01.007
Gunawardana SC, Piston DW (2012) Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 61:674–682. https://doi.org/10.2337/db11-0510
Gunawardana SC, Piston DW (2015) Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 308:E1043–E1055. https://doi.org/10.1152/ajpendo.00570.2014
Hallgren P, Sjostrom L, Hedlund H, Lundell L, Olbe L (1989) Influence of age, fat cell weight, and obesity on O2 consumption of human adipose tissue. Am J Phys 256:E467–E474. https://doi.org/10.1152/ajpendo.1989.256.4.E467
Hanssen MJ et al (2015) Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med 21:863–865. https://doi.org/10.1038/nm.3891
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300
Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F (2011) Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 286:12983–12990. https://doi.org/10.1074/jbc.M110.215889
Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, Shinoda K, Chen Y, Lu X, Maretich P, Tajima K, Ajuwon KM, Soga T, Kajimura S (2017) UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 23:1454–1465. https://doi.org/10.1038/nm.4429
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 163:643–655. https://doi.org/10.1016/j.cell.2015.09.035
Kazak L, Chouchani ET, Lu GZ, Jedrychowski MP, Bare CJ, Mina AI, Kumari M, Zhang S, Vuckovic I, Laznik-Bogoslavski D, Dzeja P, Banks AS, Rosen ED, Spiegelman BM (2017) Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity. Cell Metab 26:660–671 e663. https://doi.org/10.1016/j.cmet.2017.08.009
Kirkland JL (2016) Translating the science of aging into therapeutic interventions. Cold Spring Harb Perspect Med 6:a025908. https://doi.org/10.1101/cshperspect.a025908
Kopchick JJ, List EO, Kelder B, Gosney ES, Berryman DE (2014) Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical. Mol Cell Endocrinol 386:34–45. https://doi.org/10.1016/j.mce.2013.09.004
Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J 368:545–553. https://doi.org/10.1042/BJ20021121
Lepper C, Fan CM (2010) Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48:424–436. https://doi.org/10.1002/dvg.20630
Li Y, Knapp JR, Kopchick JJ (2003) Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice. Exp Biol Med (Maywood) 228:207–215
Liu X, Zheng Z, Zhu X, Meng M, Li L, Shen Y, Chi Q, Wang D, Zhang Z, Li C, Li Y, Xue Y, Speakman JR, Jin W (2013) Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res 23:851–854. https://doi.org/10.1038/cr.2013.64
Liu X, Wang S, You Y, Meng M, Zheng Z, Dong M, Lin J, Zhao Q, Zhang C, Yuan X, Hu T, Liu L, Huang Y, Zhang L, Wang D, Zhan J, Jong Lee H, Speakman JR, Jin W (2015) Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology 156:2461–2469. https://doi.org/10.1210/en.2014-1598
Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro VE, Dhawan S, Abu-Amer W, Izadmehr S, Zhou B, Shin AC, Latif R, Thangeswaran P, Gupta A, Li J, Shnayder V, Robinson ST, Yu YE, Zhang X, Yang F, Lu P, Zhou Y, Zhu LL, Oberlin DJ, Davies TF, Reagan MR, Brown A, Kumar TR, Epstein S, Iqbal J, Avadhani NG, New MI, Molina H, van Klinken JB, Guo EX, Buettner C, Haider S, Bian Z, Sun L, Rosen CJ, Zaidi M (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546:107–112. https://doi.org/10.1038/nature22342
Lynes MD, Tseng YH (2015) The thermogenic circuit: regulators of thermogenic competency and differentiation. Genes Dis 2:164–172. https://doi.org/10.1016/j.gendis.2015.03.001
Lynes MD, Tseng YH (2018) Deciphering adipose tissue heterogeneity. Ann N Y Acad Sci 1411:5–20. https://doi.org/10.1111/nyas.13398
Lynes MD, Leiria LO, Lundh M, Bartelt A, Shamsi F, Huang TL, Takahashi H, Hirshman MF, Schlein C, Lee A, Baer LA, May FJ, Gao F, Narain NR, Chen EY, Kiebish MA, Cypess AM, Blüher M, Goodyear LJ, Hotamisligil GS, Stanford KI, Tseng YH (2017) The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 23:631–637. https://doi.org/10.1038/nm.4297
Ma X, Xu L, Gavrilova O, Mueller E (2014) Role of forkhead box protein A3 in age-associated metabolic decline. Proc Natl Acad Sci U S A 111:14289–14294. https://doi.org/10.1073/pnas.1407640111
Marette A, Bukowiecki LJ (1991) Noradrenaline stimulates glucose transport in rat brown adipocytes by activating thermogenesis. Evidence that fatty acid activation of mitochondrial respiration enhances glucose transport. Biochem J 277 (Pt 1:119–124
Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, Mohammadi M, Potthoff MJ (2014) Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63:4057–4063. https://doi.org/10.2337/db14-0595
van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508. https://doi.org/10.1056/NEJMoa0808718
Martyniak K, Masternak MM (2017) Changes in adipose tissue cellular composition during obesity and aging as a cause of metabolic dysregulation. Exp Gerontol 94:59–63. https://doi.org/10.1016/j.exger.2016.12.007
Mennes E, Dungan CM, Frendo-Cumbo S, Williamson DL, Wright DC (2014) Aging-associated reductions in lipolytic and mitochondrial proteins in mouse adipose tissue are not rescued by metformin treatment. J Gerontol A Biol Sci Med Sci 69:1060–1068. https://doi.org/10.1093/gerona/glt156
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 2. https://doi.org/10.1172/jci.insight.93166
Nechad M, Ruka E, Thibault J (1994) Production of nerve growth factor by brown fat in culture: relation with the in vivo developmental stage of the tissue. Comp Biochem Physiol Comp Physiol 107:381–388
Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444–E452. https://doi.org/10.1152/ajpendo.00691.2006
Nisoli E, Tonello C, Benarese M, Liberini P, Carruba MO (1996) Expression of nerve growth factor in brown adipose tissue: implications for thermogenesis and obesity. Endocrinology 137:495–503. https://doi.org/10.1210/endo.137.2.8593794
Nisoli E, Tonello C, Briscini L, Carruba MO (1997) Inducible nitric oxide synthase in rat brown adipocytes: implications for blood flow to brown adipose tissue. Endocrinology 138:676–682. https://doi.org/10.1210/endo.138.2.4956
Ohno H, Shinoda K, Ohyama K, Sharp LZ, Kajimura S (2013) EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504:163–167. https://doi.org/10.1038/nature12652
Oliverio M, Schmidt E, Mauer J, Baitzel C, Hansmeier N, Khani S, Konieczka S, Pradas-Juni M, Brodesser S, van TM, Bartsch D, Brönneke HS, Heine M, Hilpert H, Tarcitano E, Garinis GA, Frommolt P, Heeren J, Mori MA, Brüning JC, Kornfeld JW (2016) Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. Nat Cell Biol 18:328–336. https://doi.org/10.1038/ncb3316
Ortega-Molina A, Efeyan A, Lopez-Guadamillas E, Muñoz-Martin M, Gómez-López G, Cañamero M, Mulero F, Pastor J, Martinez S, Romanos E, Mar Gonzalez-Barroso M, Rial E, Valverde AM, Bischoff JR, Serrano M (2012) Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab 15:382–394. https://doi.org/10.1016/j.cmet.2012.02.001
Pal M, Febbraio MA, Whitham M (2014) From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol 92:331–339. https://doi.org/10.1038/icb.2014.16
Pamplona R, Barja G (2007) Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. Ageing Res Rev 6:189–210. https://doi.org/10.1016/j.arr.2007.06.002
Pedersen SB, Bruun JM, Kristensen K, Richelsen B (2001) Regulation of UCP1, UCP2, and UCP3 mRNA expression in brown adipose tissue, white adipose tissue, and skeletal muscle in rats by estrogen. Biochem Biophys Res Commun 288:191–197. https://doi.org/10.1006/bbrc.2001.5763
Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sánchez NM, Mahú I, Mendes R, Gres V, Kubasova N, Morris I, Arús BA, Larabee CM, Vasques M, Tortosa F, Sousa AL, Anandan S, Tranfield E, Hahn MK, Iannacone M, Spann NJ, Glass CK, Domingos AI (2017) Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med 23:1309–1318. https://doi.org/10.1038/nm.4422
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839
Rahman S, Lu Y, Czernik PJ, Rosen CJ, Enerback S, Lecka-Czernik B (2013) Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton. Endocrinology 154:2687–2701. https://doi.org/10.1210/en.2012-2162
Ravussin E, Galgani JE (2011) The implication of brown adipose tissue for humans. Annu Rev Nutr 31:33–47. https://doi.org/10.1146/annurev-nutr-072610-145209
Rose G, Crocco P, D'Aquila P, Montesanto A, Bellizzi D, Passarino G (2011a) Two variants located in the upstream enhancer region of human UCP1 gene affect gene expression and are correlated with human longevity. Exp Gerontol 46:897–904. https://doi.org/10.1016/j.exger.2011.07.011
Rose G, Crocco P, De Rango F, Montesanto A, Passarino G (2011b) Further support to the uncoupling-to-survive theory: the genetic variation of human UCP genes is associated with longevity. PLoS One 6:e29650. https://doi.org/10.1371/journal.pone.0029650
Sacks H, Symonds ME (2013) Anatomical locations of human brown adipose tissue: functional relevance and implications in obesity and type 2 diabetes. Diabetes 62:1783–1790. https://doi.org/10.2337/db12-1430
Sambeat A, Gulyaeva O, Dempersmier J, Sul HS (2017) Epigenetic regulation of the thermogenic adipose program. Trends Endocrinol Metab 28:19–31. https://doi.org/10.1016/j.tem.2016.09.003
Schosserer M, Grillari J, Wolfrum C, Scheideler M (2018) Age-induced changes in white, brite, and brown adipose depots: a mini-review. Gerontology 64:229–236. https://doi.org/10.1159/000485183
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 6:38–54. https://doi.org/10.1016/j.cmet.2007.06.001
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scimè 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 454:961–967. https://doi.org/10.1038/nature07182
Sears IB, MacGinnitie MA, Kovacs LG, Graves RA (1996) Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor gamma. Mol Cell Biol 16:3410–3419
Shabalina IG, Jacobsson A, Cannon B, Nedergaard J (2004) Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 279:38236–38248. https://doi.org/10.1074/jbc.M402375200
Shabalina IG, Vyssokikh MY, Gibanova N, Csikasz RI, Edgar D, Hallden-Waldemarson A, Rozhdestvenskaya Z, Bakeeva LE, Vays VB, Pustovidko AV, Skulachev MV, Cannon B, Skulachev VP, Nedergaard J (2017) Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging (Albany NY) 9:315–339. https://doi.org/10.18632/aging.101174
Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P, Krol E, Jackson DM, Johnson MS, Brand MD (2004) Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3:87–95. https://doi.org/10.1111/j.1474-9728.2004.00097.x
Stanford KI, Middelbeek RJW, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, Goodyear LJ (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123:215–223. https://doi.org/10.1172/JCI62308
Stanford KI et al (2018) 12, 13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab 27:1111–1120 e1113. https://doi.org/10.1016/j.cmet.2018.03.020
Stier A, Bize P, Roussel D, Schull Q, Massemin S, Criscuolo F (2014) Mitochondrial uncoupling as a regulator of life-history trajectories in birds: an experimental study in the zebra finch. J Exp Biol 217:3579–3589. https://doi.org/10.1242/jeb.103945
Stout MB, Tchkonia T, Pirtskhalava T, Palmer AK, List EO, Berryman DE, Lubbers ER, Escande C, Spong A, Masternak MM, Oberg AL, LeBrasseur NK, Miller RA, Kopchick JJ, Bartke A, Kirkland JL (2014) Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY) 6:575–586. https://doi.org/10.18632/aging.100681
Stout MB, Swindell WR, Zhi X, Rohde K, List EO, Berryman DE, Kopchick JJ, Gesing A, Fang Y, Masternak MM (2015) Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. Oncotarget 6:26702–26715. https://doi.org/10.18632/oncotarget.5760
Stout MB, Justice JN, Nicklas BJ, Kirkland JL (2017) Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology (Bethesda) 32:9–19. https://doi.org/10.1152/physiol.00012.2016
Takano T, Honma T, Motohashi Y, Kobayashi Y (1987) Streptozotocin diabetes in rats after acclimation to cold environment. Prev Med 16:63–69
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 542:450–455. https://doi.org/10.1038/nature21365
Thonberg H, Lindgren EM, Nedergaard J, Cannon B (2001) As the proliferation promoter noradrenaline induces expression of ICER (induced cAMP early repressor) in proliferative brown adipocytes, ICER may not be a universal tumour suppressor. Biochem J 354:169–177
Vatner DE, Zhang J, Oydanich M, Guers J, Katsyuba E, Yan L, Sinclair D, Auwerx J, Vatner SF (2018) Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Aging Cell 17:e12751. https://doi.org/10.1111/acel.12751
Villarroya F, Cereijo R, Villarroya J, Giralt M (2017a) Brown adipose tissue as a secretory organ. Nat Rev Endocrinol 13:26–35. https://doi.org/10.1038/nrendo.2016.136
Villarroya F, Peyrou M, Giralt M (2017b) Transcriptional regulation of the uncoupling protein-1 gene. Biochimie 134:86–92. https://doi.org/10.1016/j.biochi.2016.09.017
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525. https://doi.org/10.1056/NEJMoa0808949
Wade GN, Gray JM (1978) Cytoplasmic 17 beta-[3H]estradiol binding in rat adipose tissues. Endocrinology 103:1695–1701. https://doi.org/10.1210/endo-103-5-1695
Wang Z, Xu X, Liu Y, Gao Y, Kang F, Liu B, Wang J (2018) Assessment of the aging of the brown adipose tissue by (1)(8)F-FDG PET/CT imaging in the progeria mouse model Lmna. Contrast Media Mol Imaging 2018:8327089. https://doi.org/10.1155/2018/8327089
Westbrook R, Bonkowski MS, Strader AD, Bartke A (2009) Alterations in oxygen consumption, respiratory quotient, and heat production in long-lived GHRKO and Ames dwarf mice, and short-lived bGH transgenic mice. J Gerontol A Biol Sci Med Sci 64:443–451. https://doi.org/10.1093/gerona/gln075
Yamashita H, Sato Y, Kizaki T, Oh S, Nagasawa J, Ohno H (1994) Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch 428:352–356
Yuan X, Hu T, Zhao H, Huang Y, Ye R, Lin J, Zhang C, Zhang H, Wei G, Zhou H, Dong M, Zhao J, Wang H, Liu Q, Lee HJ, Jin W, Chen ZJ (2016) Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Proc Natl Acad Sci U S A 113:2708–2713. https://doi.org/10.1073/pnas.1523236113
Zhu Z, Spicer EG, Gavini CK, Goudjo-Ako AJ, Novak CM, Shi H (2014) Enhanced sympathetic activity in mice with brown adipose tissue transplantation (transBATation). Physiol Behav 125:21–29. https://doi.org/10.1016/j.physbeh.2013.11.008
Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306:1383–1386. https://doi.org/10.1126/science.1100747
Funding
This work was supported in part by US National Institutes of Health (NIH) grants R01DK077097 and R01DK102898 (to Y.-H.T.), and P30DK036836 (to Joslin Diabetes Center’s Diabetes Research Center) from the National Institute of Diabetes and Digestive and Kidney Diseases, and by US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). J.D was supported by institutional research training grant T32DK007260 from NIH. We apologize to those whose work we did not reference due to space limitations.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Darcy, J., Tseng, YH. ComBATing aging—does increased brown adipose tissue activity confer longevity?. GeroScience 41, 285–296 (2019). https://doi.org/10.1007/s11357-019-00076-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-019-00076-0