Brown and Beige Fat: Physiological Roles beyond Heat Generation
2015; Cell Press; Volume: 22; Issue: 4 Linguagem: Inglês
10.1016/j.cmet.2015.09.007
ISSN1932-7420
AutoresShingo Kajimura, Bruce M. Spiegelman, Patrick Seale,
Tópico(s)Lipid metabolism and biosynthesis
ResumoSince brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes. Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes. Brown and beige adipose cells have the capacity to burn glucose and fat to produce heat. This thermogenic function is mediated, in large part, by the action of uncoupling protein 1 (UCP1), a polypeptide that resides in the inner mitochondrial membrane of brown and beige adipocytes. UCP1, when activated, dissipates the proton gradient generated by the electron transport chain. This futile cycle of proton pump and leak reduces mitochondrial membrane potential, which in turn drives high levels of substrate oxidation and results in the generation of heat (Cannon and Nedergaard, 2004Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (2228) Google Scholar, Lowell and Spiegelman, 2000Lowell B.B. Spiegelman B.M. Towards a molecular understanding of adaptive thermogenesis.Nature. 2000; 404: 652-660Crossref PubMed Google Scholar). Brown adipose cells develop in dedicated deposits of brown adipose tissue (BAT). In mice, the large BAT depots, including the interscapular, axillary, and cervical BAT, develop prenatally and provide a source of heat to protect newborns against cold exposure. The sympathetic nervous system (SNS) is intimately involved in regulating both the growth of BAT and its thermogenic function. Brown adipocytes are innervated by sympathetic fibers, which, upon cold exposure, release norepinephrine (NE) to acutely activate thermogenesis (Cannon and Nedergaard, 2004Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (2228) Google Scholar). NE also elicits a signaling cascade via P38 MAPK and PGC-1α to increase the transcription of thermogenic genes in brown adipocytes; this allows for sustained thermogenesis during longer-term cold exposure (Cao et al., 2004Cao W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (241) Google Scholar). Finally, cold exposure stimulates BAT expansion through activating the proliferation and differentiation of brown adipose precursor cells (Bronnikov et al., 1992Bronnikov G. Houstĕk J. Nedergaard J. 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. 1992; 267: 2006-2013Abstract Full Text PDF PubMed Google Scholar, Géloën et al., 1988Géloën A. Collet A.J. Guay G. Bukowiecki L.J. Beta-adrenergic stimulation of brown adipocyte proliferation.Am. J. Physiol. 1988; 254: C175-C182PubMed Google Scholar). Another notable feature of BAT is its dense capillary bed that supplies adipocytes with substrate and oxygen for oxidation and enables the efficient distribution of heat to the rest of the body. Brown-like adipocytes that have a multilocular morphology and express UCP1 can also be found in white adipose tissue (WAT) depots (Cinti, 1999Cinti S. The Adipose Organ. 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Schaart G. et al.Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.Cell. 2012; 150: 366-376Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar). Notably, fully stimulated beige adipocytes express similar UCP1 levels as brown adipocytes and undergo UCP1-mediated uncoupled respiration (Long et al., 2014Long J.Z. Svensson K.J. Tsai L. Zeng X. Roh H.C. Kong X. Rao R.R. Lou J. Lokurkar I. Baur W. et al.A smooth muscle-like origin for beige adipocytes.Cell Metab. 2014; 19: 810-820Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, Okamatsu-Ogura et al., 2013Okamatsu-Ogura Y. Fukano K. Tsubota A. Uozumi A. Terao A. Kimura K. Saito M. Thermogenic ability of uncoupling protein 1 in beige adipocytes in mice.PLoS ONE. 2013; 8: e84229Crossref PubMed Scopus (0) Google Scholar, Shabalina et al., 2013Shabalina I.G. Petrovic N. de Jong J.M. Kalinovich A.V. Cannon B. Nedergaard J. 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PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein.Cell Metab. 2012; 15: 395-404Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, Vitali et al., 2012Vitali A. Murano I. Zingaretti M.C. Frontini A. Ricquier D. Cinti S. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes.J. Lipid Res. 2012; 53: 619-629Crossref PubMed Scopus (98) Google Scholar). There also exists a great deal of variability in the beige-ing response among inbred strains of mice, as first reported by Collins et al. (Collins et al., 1997Collins S. Daniel K.W. Petro A.E. Surwit R.S. Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice.Endocrinology. 1997; 138: 405-413Crossref PubMed Scopus (0) Google Scholar). Kozak and colleagues used classical genetic approaches to study this trait in great detail and identified several loci that affect UCP1 induction in white fat (Guerra et al., 1998Guerra C. Koza R.A. Yamashita H. Walsh K. Kozak L.P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity.J. Clin. Invest. 1998; 102: 412-420Crossref PubMed Google Scholar, Koza et al., 2000Koza R.A. Hohmann S.M. Guerra C. Rossmeisl M. Kozak L.P. Synergistic gene interactions control the induction of the mitochondrial uncoupling protein (Ucp1) gene in white fat tissue.J. Biol. Chem. 2000; 275: 34486-34492Crossref PubMed Scopus (59) Google Scholar, Xue et al., 2007Xue B. Rim J.S. Hogan J.C. Coulter A.A. Koza R.A. Kozak L.P. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat.J. Lipid Res. 2007; 48: 41-51Crossref PubMed Scopus (142) Google Scholar). The genetic variability controlling UCP1 activation was only observed in white fat, providing some of the earliest evidence that beige and brown fat cells may belong to different lineages (see later). Importantly, the induction of UCP1 in white fat (i.e., beige-ing of WAT) is associated with a reduction in obesity in animals treated with the β3-adrenergic agonist, CL 316,243 (Guerra et al., 1998Guerra C. Koza R.A. Yamashita H. Walsh K. Kozak L.P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity.J. Clin. Invest. 1998; 102: 412-420Crossref PubMed Google Scholar). Thus, the capacity for UCP1 induction in white fat is strongly correlated with obesity reduction caused by β3-agonists. Do humans have thermogenic brown and/or beige fat? And if so, do these tissues affect systemic metabolism in a meaningful way? Through the use of 18F-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography computed tomography (18F-FDG-PET) imaging, it is now evident that humans have substantial depots of UCP1+ adipose cells and that these tissues are activated to take up glucose by cold or β-adrenergic agonist treatment (Cypess et al., 2009Cypess A.M. Lehman S. Williams G. Tal I. Rodman D. Goldfine A.B. Kuo F.C. Palmer E.L. Tseng Y.H. Doria A. et al.Identification and importance of brown adipose tissue in adult humans.N. Engl. J. Med. 2009; 360: 1509-1517Crossref PubMed Scopus (1452) Google Scholar, Cypess et al., 2014Cypess A.M. Haft C.R. Laughlin M.R. Hu H.H. Brown fat in humans: consensus points and experimental guidelines.Cell Metab. 2014; 20: 408-415Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Cypess et al., 2015Cypess A.M. Weiner L.S. Roberts-Toler C. Franquet Elía E. Kessler S.H. Kahn P.A. English J. Chatman K. Trauger S.A. Doria A. Kolodny G.M. 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The expression levels of these genes have been used as a way to classify human UCP1+ adipose depots as brown or beige. Human infants have a thin layer of interscapular BAT that shares morphological and molecular features with rodent brown fat (Heaton, 1972Heaton J.M. The distribution of brown adipose tissue in the human.J. Anat. 1972; 112: 35-39PubMed Google Scholar, Lidell et al., 2013aLidell M.E. Betz M.J. Dahlqvist Leinhard O. Heglind M. Elander L. Slawik M. Mussack T. Nilsson D. Romu T. Nuutila P. et al.Evidence for two types of brown adipose tissue in humans.Nat. Med. 2013; 19: 631-634Crossref PubMed Scopus (201) Google Scholar). This infant interscapular BAT expresses genes that are characteristic of classical brown adipocytes (Lidell et al., 2013bLidell M.E. Betz M.J. Dahlqvist Leinhard O. Heglind M. Elander L. Slawik M. Mussack T. Nilsson D. Romu T. Nuutila P. et al.Evidence for two types of brown adipose tissue in humans.Nat. 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Matsushita M. Okamatsu-Ogura Y. Kameya T. Kawai Y. Miyagawa M. Tsujisaki M. Saito M. Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans.Obesity. 2011; 19: 1755-1760Crossref PubMed Scopus (0) Google Scholar). This may be analagous to the reduction in beige fat mass that occurs in aging mice (Rogers et al., 2012Rogers N.H. Landa A. Park S. Smith R.G. Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue.Aging Cell. 2012; 11: 1074-1083Crossref PubMed Scopus (26) Google Scholar). It will now be important to determine how aging suppresses beige and/or brown fat recruitment. The major classical BAT depots in mice, including the interscapular, cervical, and axillary depots, are interspersed in and around deep back (epaxial) muscles and develop before WAT during embryogenesis. Most of the adipocytes in these tissues originate from precursors in the somites that also give rise to skeletal myocytes, dorsal dermis, as well as a subset of white adipocytes in certain depots. The somitic multipotent precursor population is marked by the expression of certain transcription factors, including Pax7, Engrailed-1 (En1), and the myogenic factor, Myf5 (Atit et al., 2006Atit R. Sgaier S.K. Mohamed O.A. Taketo M.M. Dufort D. Joyner A.L. Niswander L. Conlon R.A. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse.Dev. Biol. 2006; 296: 164-176Crossref PubMed Scopus (172) Google Scholar, Lepper and Fan, 2010Lepper C. Fan C.M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells.Genesis. 2010; 48: 424-436Crossref PubMed Scopus (109) Google Scholar, Sanchez-Gurmaches et al., 2012Sanchez-Gurmaches J. Hung C.M. Sparks C.A. Tang Y. Li H. Guertin D.A. 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Through prospective analyses of different Myf5Cre lineage-traced precursor populations, Early B Cell Factor-2 (Ebf2) was identified as a specific marker gene of embryonic brown preadipocytes (Wang et al., 2014bWang W. Kissig M. Rajakumari S. Huang L. Lim H.W. Won K.J. Seale P. Ebf2 is a selective marker of brown and beige adipogenic precursor cells.Proc. Natl. Acad. Sci. USA. 2014; 111: 14466-14471Crossref PubMed Scopus (30) Google Scholar). EBF2 marks cells in the somitic mesoderm that do not express markers of other developmentally related lineages, including muscle or dermis. The activation of Ebf2 is likely to be an early step in brown adipose lineage commitment (Figure 1). Further studies are needed to determine which inductive cues initiate Ebf2 expression and adipogenic commitment. An obvious candidate is BMP7, which has been shown to play a pivotal role in BAT development. Loss of BMP7 or BMP-receptor signaling results in a near-complete absence of BAT development (Schulz et al., 2013Schulz T.J. Huang P. Huang T.L. Xue R. McDougall L.E. Townsend K.L. Cypess A.M. Mishina Y. Gussoni E. Tseng Y.H. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat.Nature. 2013; 495: 379-383Crossref PubMed Scopus (116) Google Scholar, Tseng et al., 2008Tseng Y.H. Kokkotou E. Schulz T.J. Huang T.L. Winnay J.N. Taniguchi C.M. Tran T.T. Suzuki R. Espinoza D.O. Yamamoto Y. et al.New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.Nature. 2008; 454: 1000-1004Crossref PubMed Scopus (474) Google Scholar). The common somitic origin of brown adipocytes and muscle suggested that these lineages may be closely related in development. Consistent with this, brown preadipose cells express many muscle-specific genes, and the mitochondrial proteomes of brown fat and muscle are highly related to one another (Forner et al., 2009Forner F. Kumar C. Luber C.A. Fromme T. Klingenspor M. Mann M. Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions.Cell Metab. 2009; 10: 324-335Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, Timmons et al., 2007Timmons J.A. Wennmalm K. Larsson O. Walden T.B. Lassmann T. Petrovic N. Hamilton D.L. Gimeno R.E. Wahlestedt C. Baar K. et al.Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.Proc. Natl. Acad. Sci. USA. 2007; 104: 4401-4406Crossref PubMed Scopus (336) Google Scholar). Interestingly, several factors influence muscle versus brown fat cell fate, including PRDM16, C/EBP-β, EHMT1, EWS, and ZFP516 (Dempersmier et al., 2015Dempersmier J. Sambeat A. Gulyaeva O. 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Cell. 2013; 26: 393-404Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, Seale et al., 2008Seale P. Bjork B. Yang W. Kajimura S. Chin S. Kuang S. Scimè A. Devarakonda S. Conroe H.M. Erdjument-Bromage H. et al.PRDM16 controls a brown fat/skeletal muscle switch.Nature. 2008; 454: 961-967Crossref PubMed Scopus (881) Google Scholar) (Figure 1). Notably, EHMT1, an important coregulator of PRDM16, is required to suppress the expression of muscle-specific genes in BAT. Similarly, EWS was shown to be required for BAT development, and its deletion causes the ectopic expression of muscle genes in BAT (Park et al., 2013Park J.H. Kang H.J. Kang S.I. Lee J.E. Hur J. Ge K. Mueller E. Li H. Lee B.C. Lee S.B. A multifunctional protein, EWS, is essential for early brown fat lineage determination.Dev. Cell. 2013; 26: 393-404Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). PRDM16, which can potently suppress muscle gene expression, is, however, not required for BAT development in mice, presumably because other related factors can compensate in its absence (Harms et al., 2014Harms M.J. Ishibashi J. Wang W. Lim H.W. Goyama S. Sato T. Kurokawa M. Won K.J. Seale P. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice.Cell Metab. 2014; 19: 593-604Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). The embryonic origin(s) of beige fat cells (and white fat cells) is more complica
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