ORIGINAL ARTICLE Determinants of Brown Adipocyte Development and Thermogenesis

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International Journal of Obesity (2010) 34, S59–S66 & 2010 Macmillan Publishers Limited All rights reserved 0307-0565/10 www.nature.com/ijo ORIGINAL ARTICLE Determinants of brown adipocyte development and thermogenesis

D Richard1, AC Carpentier2, G Dore´1, V Ouellet1 and F Picard1

1Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Que´bec, et Groupe interdisciplinaire de Recherche sur l’Obe´site´ de l’Universite´ Laval, Que´bec, Canada and 2Centre de recherche clinique E´tienne-Le Bel du Centre hospitalier universitaire de Sherbrooke, Que´bec, Canada

The brown adipocyte is a thermogenic cell. Its thermogenic potential is conferred by uncoupling protein-1, which ‘uncouples’ adenosine triphosphate synthesis from energy substrate oxidation. Brown fat cells in so-called classical brown adipose tissue (BAT) share their origin with myogenic factor-5-expressing myoblasts. The development of myocyte/brown adipocyte progenitor cells into a brown adipocyte lineage is apparently triggered by bone morphogenetic protein-7, which stimulates inducers of brown fat cell differentiation, such as PRD1-BF1-RIZ1 homologous domain-containing-16 and peroxisome proliferator-activated receptor-g co-activator-1-a. The control of brown fat cell development and activity is physiologically ensured by the sympathetic nervous system (SNS), which densely innervates BAT. SNS-mediated thermogenesis is largely governed by hypothalamic and brainstem neurons. With regard to energy balance, the leptin–melanocortin pathway appears to be a major factor in controlling brown adipocyte thermogenesis. The involvement of this homeostatic pathway further supports the role of the brown adipocyte in energy balance regulation. The interest for the brown fat cell and its potential role in energy balance has been further rejuvenated recently by the demonstration that BAT can be present in substantial amounts in humans, in contrast to what has always been thought. Positron emission tomography/computed tomography scanning investigations have indeed revealed the presence in humans of important neck and shoulder cold-activable BAT depots, in particular, in young, lean and female subjects. This short review summarizes recent progress made in the biology of the brown fat cell and focuses on the determinants of the brown adipocyte development and activity. International Journal of Obesity (2010) 34, S59–S66; doi:10.1038/ijo.2010.241

Keywords: brown adipose tissue; thermogenesis; uncoupling protein-1; brown adipocyte; brown adipocyte development

Introduction maintain a normal core temperature.2,3 Studies carried out at the end of the 1970s demonstrated that BAT could Brown adipose tissue (BAT) is a specialized heat-producing contribute to more than 60% of non-shivering thermogen- tissue. Its existence was revealed in the middle of the esis induced by noradrenaline in cold-adapted rats.4 The sixteenth century by the Swiss naturalist Conrad Gesner,1 extraordinary thermogenic protential of the brown adipo- who described BAT as being ‘neither fat nor flesh’ (nec cyte is conferred by uncoupling protein-1 (UCP1). UCP1 is a pinguitudo nec caro). BAT is particularly abundant in rodents, mitochondrial protein uniquely found in brown adipocytes. such as rats, mice, hamsters, and gerbils, in which it is It represents the ultimate phenotypic signature of this cell.5,6 apparent as discrete small depots mostly found in the Once activated, UCP1 disconnects (uncouples) the mito- interscapular, subscapular, axillary, perirenal and periaortic chondrial oxidation of fatty acids from adenosine tripho- regions (the so-called classical BAT depots). BAT is mainly sphate (ATP) synthesis, thereby initiating heat production. recognized for its ability to generate heat. The thermogenic The recent demonstration that BAT can exist in substantial capacity of this tissue is such that it allows small mammals to amount in humans7–12 has rejuvenated the interest for BAT live below their thermoneutral temperature without having and for BAT thermogenesis in energy balance regulation. to rely on muscle-mediated shivering thermogenesis to This renewed appeal for BAT has been further aroused by the discovery that brown fat cells in typical BAT (in contrast to brown fat cells in white adipose tissue (WAT)) do not Correspondence: Dr D Richard, Centre de recherche de l’Institut universitaire originate from white adipocyte precursors but from myocyte ´ de cardiologie et de pneumologie de Quebec, 2725 chemin Sainte-Foy, 13–17 Que´bec, Canada G1 V 4G5. progenitor cells and by the description from transneur- E-mail: [email protected] onal viral retrograde tract tracing studies18–20 of numerous Brown adipocyte development and thermogenesis D Richard et al S60 brain pathways that drive the sympathetic nervous system brown adipocyte genes.28 PPARg is regarded as a master (SNS) outflow to BAT. protein for adipocyte differentiation (be they white or This short review summarizes the recent progress made in brown) from preadipocytes.29–31 Finally, further supporting the biology of the brown adipocyte. The focus is on (i) the the notion that brown adipocytes and myocytes derive from cellular biology of brown (UCP1 expressing) adipocyte a common cell lineage, the studies by Forner et al.32 and in BAT and WAT depots, (ii) the neural control of BAT Walden et al.33 respectively, showed that the proteomics of thermogenesis and (iii) the determinants of BAT prevalence brown fat corresponded more to that of muscle than to that in humans. of white fat, and that the muscle microRNAs (myomiR) miR- 1, miR-133a and miR-206 were expressed in brown, but not white adipocytes. The term ‘adipomyocyte’ has been judi- The cellular biology of the brown fat cell ciously coined by Cannon et al.34 to designate the brown adipocytes in the classical BAT depots. Although white fat cells are round and comprise a single lipid droplet surrounded by a small amount of cytoplasm and few mitochondria, brown adipocytes are polygonal in Brown fat cells in WAT have their own origin appearance and contain numerous small lipid vacuoles, Notably, brown adipocytes can also develop in typical WAT, 35 encircled by a perceptible cytoplasm and abundant and well- where they might contribute to thermogenesis. Within developed mitochondria packed with laminar cristae.6,21,22 WAT, brown fat cells develop on specific stimuli, such as 21,36 Brown adipocytes make up classical BAT depots and can PPARg agonism and the adrenergic activation induced 37,38 also develop in relative abundance in WAT upon adrenergic by either cold exposure or by treatment with b3 39 stimulation.23,24 adrenergic receptor agonists. The origin of the brown adipocytes in WAT is still uncertain, as it is not clear whether these cells develop Brown adipocytes in so-called classical BAT depots through the differentiation of specific precursors, the share their origin with myocytes differentiation/transdifferentiation of white preadipocytes Evidence has accumulated in recent years to suggest that or the process of transdifferentiation of already differentiated brown fat cells in classical BAT depots do not share their origin cells.22,24,40,41 According to Cinti,22 white to brown with white adipocytes, butratherwithmyocytes.13–17,25 Atit adipocytes transdifferentiation on adrenergic stimulation et al.,13 using a genetic fate mapping approach, demon- would occur gradually.22 The mature white adipocyte strated that engrailed-1 (En1)-expressing cells of the dermo- would first transform into a multilocular cell, first devoid myotome are the primordia of not only the dermis and of UCP1, which would eventually evolve into an UCP1- muscle but also interscapular BAT. Concomitantly, Timmons positive brown fat cell. In addition to being supported et al.15 reported that brown preadipocytes (from those morphologically, the transdifferentiation hypothesis is also classical BAT depots) exhibit a myogenic transcriptional corroborated by the observation that the total number of profile, whereas Seale et al.,14,17 Tseng et al.16 and Kajimura adipocytes (white plus brown) in a given WAT depot does et al.25 decoded the sequence of events leading to brown fat not change after adrenergic stimulation (cold exposure), differentiation from myogenic factor-5-expressing myo- whereas the proportion of brown adipocytes significantly blasts. Seale et al.14,17 described PRD1-BF1-RIZ1 homologous increases,42 and by the finding that the newly emerging domain-containing-16 (PRDM16) as a major transcription brown adipocytes in WAT following b3-adrenergic stimula- factor in BAT adipogenesis. PRDM16 has a key role in tion are 5-bromo-2-deoxyuridine negative (indicating a triggering brown adipocyte differentiation, mitochondrial low mitotic index).38 However, the transdifferentiation biogenesis and expression of UCP1. Meanwhile, Tseng et al.16 hypothesis is still disputed. Petrovic et al.41 failed to provide demonstrated that bone morphogenetic protein-7 (BMP7) any evidence of the transformation of mature white could trigger the commitment of mesenchymal progenitor adipocytes into UCP1-positive adipocytes. Those authors cells to a brown adipocyte lineage, while inducing early rather proposed that brown adipocytes found in typical WAT regulators of brown fat such as PRDM16 and peroxisome would represent a subset of adipocyes with a developmental proliferator-activated receptor-g (PPARg) co-activator-1-a origin which is different from brown adipocytes found in (PGC1a). Similar to PRDM16, PGC-1a is a PPARg transcrip- classical BAT. WAT brown adipocytes, which would on tional co-activator that confers the brown adipocyte with its adrenergic stimulation convincingly express PGC1a and energy-burning phenotype.26,27 More recently, Kajimura UCP1, apparently express less PRDM16 than BAT brown et al.25 demonstrated that PRDM16 controls brown adipo- adipocytes, even upon stimulation with a PPARg agonist.41 genesis from myoblasts by forming a transcriptional com- In addition, they do not transcribe muscle-specific micro- plex with the active form of CCAAT/enhancer-binding RNAs, such as miR-206, whereas they express Homeobox-C9 protein-b (C/EBPb). Together with C/EBPa and C/EBPd, (Hoxc9), a gene characterizing classic white adipocytes. C/EBPb contributes to the establishment of the brown fat Those cells have been designated as ‘brite adipocytes’ lineage through sustained transactivation of PPARg and (brown-in-white).41

International Journal of Obesity Brown adipocyte development and thermogenesis D Richard et al S61 UCP1 provides the brown adipocyte with its extraordinary with different protein complexes (including PPARs) to thermogenic potential induce Ucp1. Ucp1’s promoter contains many distinct bind- UCPI is a six-domain transmembrane protein that is located ing sites, allowing a wide range of proteins to influence its 2,5 in the inner membrane of the BAT mitochondrion. It is, transcription. These binding sites include cyclic adenosine together with UCP2 and UCP3, a member of the UCP monophosphate, thyroid, PPAR, retinoic acid-response ele- superfamily, within which it is the only thermogenic ments (respectively abbreviated as CRE, TRE, PPRE, RARE). 43 44 protein and likely the only true UCP. Studies conducted Retinoid X receptor-a is a nuclear receptor that acts in the in UCP1-deficient mice have indisputably revealed the brown adipocyte as a partner of, for instance, PPARg and importance of UCP1 in non-shivering thermoregulatory thyroid receptor-b for heterodimers. b-Adrenergic activation 45 thermogenesis, whereas studies conducted in UCP2- and upregulates levels of CRE, PPARg, thyroid receptor-b, which UCP3-ablated mice have proved to be unpersuasive in all contribute to increase Ucp1’s promoter transactiva- 46 revealing a thermogenic function for UCP2 and UCP3. tion.51,52 In addition, BMP7 would stimulate PRDM16 UCP1 uncouples ATP synthesis from mitochondrial sub- expression, which then would activate PGC1a and UCP1, 6,47–49 strate oxidation. Brown adipocyte-derived fatty acids, leading to an increase in thermogenesis. The binding of liver which originate from the breakdown of intracellular trigly- X receptor-a and its co-repressor nuclear receptor interacting cerides in response to b-adrenergic activation, constitute the protein-1 (known as RIP140) to PPARg would block the main energy substrate for BAT heat production. They transcriptional activity of PPARg by dislocating the PPARg/ additionally activate UCP1 by overriding the inhibitory PGC-1a complex off the PPARg-response element53 on the 6,47–49 action of purine nucleotides on UCP1. Fatty acid Ucp1 promoter. oxidation generates nicotinamide adenine dinucleotide and flavin adenine dinucleotide, which furnish electrons that are ultimately transported from one to another protein complex The control of the brown fat cell activity making up the mitochondrial respiratory chain (electron transport chain). This electron transport is coupled with the Brown adipocytes, in BAT depots in particular, are richly pumping of protons from the mitochondrial matrix to the innervated by SNS efferents.54,55 The release by SNS nerves of intermembrane space, which establishes the proton gradient noradrenaline in the vicinity of the adipocytes not only across the inner mitochondrial membrane. In most cells, the enhances thermogenic activity but also increases the mitochondrial electrochemical proton gradient finds its way capacity (synthesis of UCP1, accessory thermogenic proteins, through the proton-conducting unit of the ATP synthase mitochondria) of the brown fat cell to produce heat. SNS assembly, thereby producing the protonmotive force to drive activation is the physiological trigger of brown adipocyte phosphorylation of ADP to ATP. In stimulated brown thermogenesis.6 Conditions such as cold exposure or adipocytes, the proton gradient is dissipated through the overfeeding increase noradrenaline turnover rate in BAT.56 alternative UCP1 proton channel and is prevented from Consistently, those conditions do not produce any thermo- accessing the ATP synthase complex. As a consequence, ATP genic activity in mice lacking b-adrenoreceptors (b-less is barely synthesized and seemingly does not accumulate to mice).57–59 decelerate the activated catabolic cascades through which Clusters of neurons from several brain nuclei are implicated 47 heat is necessarily produced. UCP1 thus serves as a conduit in the thermoregulation control brown adipocyte activity.18 In to dissipate the ATP-generating electrochemical proton addition, most energy-balance regulation centers modulate gradient that builds up across the mitochondrial inner SNS-mediated thermogenesis in brown fat cells.60 The control membrane concomitantly with electron transport during of BAT activity is basically ensured by the ‘autonomic’ brain BAT oxidation of fatty acids. and involves hypothalamic nuclei, such as the median UCP1 expression is physiologically enhanced by adrener- preoptic nucleus, arcuate nucleus (ARC), retrochiasmatic area, gic stimulation (Figure 1). It can also pharmacologically be paraventricular nucleus, lateral hypothalamus, dorsomedial 36 induced by PPARg agonists. The b3-adrenergic receptor, at hypothalamus, and a significant number of brainstem nuclei least in rodents, is regarded as the key adrenergic receptor including the periaqueductal gray, lateral paragigantocellular 50 triggering BAT activity. The b-adrenergic pathway prompts nucleus and raphe nuclei.18,60–62 the production of cyclic adenosine monophosphate, which in turn activates protein kinase-A-dependent phophoryla- tion of p38a mitogen-activated protein kinase (p38a map The leptin–melanocortin pathway is a major controller kinase). p38a map kinase phosphorylates activating-tran- of brown adipocyte thermogenesis scription factor-2 to induce PGC1a transcription, a key node One of the most important brain entities involved in brown in catecholamine-induced thermogenesis. PGC-1a is directly adipocyte thermogenesis, with reference to energy balance, involved in the stimulation of UCP1 expression through its is the melanocortin system.63–66 This system comprises 26 ability to co-activate PPARg. In addition, PGC1a directly proopiomelanocortin (POMC) neurons, which essentially interacts with nuclear respiratory factors 1 and 2 (NRF1and originate from the ARC and which also express cocaine NRF2) to stimulate de novo mitochondrion synthesis, and and amphetamine-regulated transcript (CART). POMC post-

International Journal of Obesity Brown adipocyte development and thermogenesis D Richard et al S62 Catecholamines cold

Adenylyl Cyclase βARs AKAP γ β β RII 2 GEFs J1P2/IB2 α Gα C C MKK3 P38 map JIP4 ? kinase Rac1 P P PP cyclic AMP MKKK

Activated PKA PP

? ?

? BMP7 PRDM16 Thermogenesis Sirt1 ? PP Nucleus Activation of ATF2 ATF2 mitochondrial NRF1 NRF2 PGC1α genes CRE2

PGC1α P P P UCP1 NFE212 CREB CREB RXR PP PPAR RXR

TR α ATF2 ATF2 PGC1

? β α α

γ PRDM16 PRDM16? CRE4 NFE2 TRE/RARE CRE PPRE PPAR T4 T3 UCP1 RXR RIP140 α cAMP γ LXRα PRDM16 ? DIO2 PPRE

Figure 1 Catecholamine-induced thermogenesis in the brown adipocyte. Conditions such as cold exposure or overfeeding stimulates the sympathetic nervous system (SNS), which induces the thermogenic activity and capacity of the brown fat cell. Noradrenaline binds to b-adrenergic receptors present on the outer membrane of the cell, leading to cyclic adenosine monophosphate (cAMP) release. cAMP activates PKA, ultimately triggering phosphorylation of p38a map kinase. p38a map kinase directly phosphorylates ATF2 to induce PGC1a transcription, a key node in the catecholamine-induced thermogenesis. PGC1a directly interact with NRF1 and NRF2 to stimulate de novo mitochondria and with different protein complexes (including PPARs) to induce the transcription of UCP1. The UCP1 promoter contains many distinct binding sites, allowing a wide range of protein to influence its transcription. BMP7 stimulates PRDM16 expression, which then activates the promoter of PGC1a and UCP1, leading to increased thermogenesis. The binding of LXRa and its co-repressor RIP140 to PPARg can inhibit UCP1 production by disrupting PPARg from its complex. See text for more details. ATF, activating transcription factor; bARs, b-adrenergic receptors; BMP7, bone morphogenetic protein- 7; CREB, cAMP-response element-binding protein; NRF, nuclear respiratory factor; p38a map kinase, p38a mitogen-activated protein kinase; PGC1a, Peroxisome proliferator-activated receptor-g co-activator 1-a; PKA, protein kinase A; PPARg, peroxisome proliferator-activated receptor-g; PPRE, PPARg-response element; PRDM16, PRD1-BF1-RIZ1 homologous domain-containing-16; RXRa, retinoid X receptor; RARE, retinoid X receptor-response element; RIP140, nuclear receptor- interacting protein-1; TRb, thyroid receptor-b; TRE, TR-response element.

translational cleavage frees the peptidergic fragment established a connection between the MC4R-containing a-melanocyte-stimulating hormone. a-Melanocyte-stimulat- neurons and BAT or WAT. We even observed in some brain ing hormone is a catabolic peptide binding to the melano- nuclei (paraventricular nucleus, raphe pallidus and lateral cortin-3 and 4 receptors (MC3R and MC4R), the two main paragigantocellular nucleus) that more than 80% of the receptors of the brain metabolic melanocortin system. MC4R neurons projecting to BAT express the MC4R.19 deficiency causes massive and widespread body fat deposi- The activity of the melanocortin system is modulated by tion resulting from not only an increase in energy intake but the adipose-derived hormone leptin.72,73 Leptin is a cata- also a decrease in thermogenesis.66,67 In contrast, MC4R bolic hormone whose action is partly exerted at the levels of agonists, such as Melanotan II (MTIIFa synthetic analog of a- the ARC by the signal transducer and activator of transcrip- melanocyte-stimulating hormone), induce UCP1 in BAT68,69 tion-3 signaling cascade. Leptin modulates the activity of the while enhancing SNS discharge to both adipose tissues.69 melanocortin system through directly reducing the synthesis Song et al.19,70 and Voss-Andreae et al.71 have clearly of POMC and indirectly blunting the synthesis of neuropep-

International Journal of Obesity Brown adipocyte development and thermogenesis D Richard et al S63 tide Y and agouti-related protein, the latter being an iodothyronine deiodinase, PGC1a, PRDM16 and b3-adrener- endogenous MC4R antagonist/inverse agonist.74 gic receptor,10 which are all key factors in BAT thermogen- There is evidence that the leptin receptor long form esis. The cervical/supraclavicular UCP1-positive cells display (LepRb) and MC4R could be part of the same homeostatic the classical morphology of brown fat cells with numerous pathway controlling SNS activity in adipose tissues. Absence cytoplasmic uniform fat vacuoles and abundant mitochon- of the MC4R has been shown to compromise the ability of dria.7,8 They are highly vascularized and densely innervated leptin (be it injected centrally or peripherally) to increase with nerve fibers immunopositive for tyrosine hydroxylase, UCP1 expression in BAT and WAT.75 At least three pathways indicating a rich sympathetic innervation.7 could depend on the MC4R, emphasizing the importance of Positron emission tomography/computed tomography the leptin–melanocortin pathway in brown adipocyte activ- 18F-FDG scanning reveals in humans that the main BAT ity. A first pathway would consist of LepRb/POMC/CART depots are cervical/supraclavicular, paravertebral, mediast- neurons in the ARC that project to the paraventricular inal and perirenal (Figure 2). The cervical/supraclavicular nucleus to form synapses with MC4R-expressing neurons depot appears to be the most prevalent and the one with the that directly descend to the intermediolateral (IML) cell highest 18F-FDG uptake activity following exposure to column in the lateral horn of the spinal cord to synapse with cold.10 The prevalence of 18F-FDG uptake in adipose tissue SNS preganglionic neurons.76 The descending division of the (i) increases with exposure to below thermoneutral tempera- paraventricular nucleus comprises a very high percentage of ture;8,11,88–90 (ii) is higher in women than men;8 (iii) neurons connected to BAT and WAT.19,70 These neurons decreases with age;7,8,88 and (iv) is inversely correlated with could be oxytocin neurons,77 even though this has not been body mass index and body fat content.7,8,88 The prevalence clearly demonstrated. A second pathway would consist of LepRb/POMC/CART neurons in the retrochiasmatic area that project to the IML to form synapses with MC4R-expressing SNS preganglionic neurons.78 The MC4R is indeed expressed at the level of the IML on SNS preganglionic neurons.79 A third pathway would consist of LepRb/POMC/CART neurons in the ARC that project directly or indirectly (through a neuronal relay in the periaqueductal gray) to the raphe pallidus to ultimately form synapses with MC4R-expressing SNS premotor neurons, most likely serotonin (5-HT) neu- rons80 involved in the control of BAT (and possibly WAT) thermogenesis.81 MTII injections in the raphe pallidus increased BAT SNS activity.82 On the other hand, the possibility that leptin can also control brown adipocyte activity independently of the MC4R cannot, of course, be excluded.83 A MC4R-indepen- dent pathway could consist of LepRb/melanin-concentrating hormone/orexin neurons in the lateral hypothalamus that project directly to the IML to control the SNS outflow to BAT and WAT. Melanin-concentrating hormone- and orexin- expressing neurons project to the IML.84,85

Determinants of human BAT thermogenesis

In the last decade, nuclear medicine strongly challenged the belief that adult humans carry only vestiges of BAT.86,87 Indeed, positron emission tomography/computed tomography scanning investigations, using the glucose analog 18F-fluorodeoxyglucose (18F-FDG), revealed symmetrical 18F-FDG uptake by fat depots in the cervical/supraclavicular, paravertebral, mediastinal and perirenal regions of the body. Figure 2 Brown adipose tissue (BAT) in humans demonstrated by positron Those fat depots were a posteriori demonstrated to have 18 7–10 emission tomography (PET) after intravenous injection of F-fluorodeoxyglu- all the histological characteristics of brown fat sites. cose (18F-FDG). Fused PET/computed tomography images reveals cervical/ 18 F-FDG-detected fat expresses UCP1 (mRNA and protein) supraclavicular, paravertebral, mediastinal and perirenal 18F-FDG sites that and mRNAs encoding other proteins, such as type II have been confirmed to be brown fat.

International Journal of Obesity Brown adipocyte development and thermogenesis D Richard et al S64 that regard, transneuronal viral retrograde tract tracing studies18–20 have been particularly instrumental in identifying major thermogenic brain sites. Finally, the conclusive proof from positron emission tomography/computed tomography scanning investigations that BAT can be present in substantial amounts in adult human individuals has emerged as the finding that has contributed the most to the rejuvenated interest in BAT.86 The observations that 18F- FDG uptake by fat tissue is stimulated by below thermoneutral temperatures8,11,88–90 and is blunted by aging, fatness and b-blockers support the prediction of a brown adipocyte involvement in energy balance regulation.91

Conflict of interest

ACC has received lecture fees from Pfizer, grant support from GlaxoSmithKline, Pfizer, Philips, Merck and Co. and Am- sterdam Molecular Therapeutics, and holds two patents Figure 3 Determinants of 18F-FDG uptake in BAT. Acute 18F-FDG uptake in related to this subject area. The remaining authors have BAT necessitates an SNS-mediated BAT activation ( þ ) likely driven by a below declared no conflict of interest. heat-neutral temperature or other potential BAT activators. Factors such as young age or chronic exposure to a cold environment (as it is likely to occur in winter) could enhance BAT capacity for thermogenesis (BAT mass, BAT mitochondria content, BAT UCP1 content). The larger the BAT capacity, the References higher would be the 18F-FDG uptake on a given activation. Low body mass index or absence of diabetes (or other factors associated with those 1 Gesner C. Medici Tigurini Historiae Animalium Liber I de Quad- conditions) could also enhance BAT capacity. Having a higher temperature rupedibusuiuiparis. threshold than men for thermogenesis, women would more readily respond 92 2 Klingenspor M. Cold-induced recruitment of brown adipose to cold. Reproduced from reference Ouellet et al. (with the permission of tissue thermogenesis. Exp Physiol 2003; 88: 141–148. J Clin Endocrinol Metab; Copyright 2010, The Endocrine Society). 3 Himms-Hagen J. Brown adipose tissue thermogenesis: interdisci- plinary studies. FASEB J 1990; 4: 2890–2898. of BAT 18F-FDG uptake is also reduced in diabetic patients8 4 Foster DO, Frydman ML. Tissue distribution of cold-induced and decreases in patients taking b-blockers.8 Figure 3 thermogenesis in conscious warm- or cold-acclimated rats 18 reevaluated from changes in tissue blood flow: the dominant tentatively illustrates the main determinants of F-FDG role of brown adipose tissue in the replacement of shivering by uptake in BAT of adult humans. nonshivering thermogenesis. Can J Physiol Pharmacol 1979; 57: 257–270. 5 Ricquier D. Respiration uncoupling and metabolism in the control of energy expenditure. Proc Nutr Soc 2005; 64: 47–52. Conclusion 6 Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277–359. 7 Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon Several recent investigations have raised interest in the B et al. The presence of UCP1 demonstrates that metabolically brown adipocyte. This thermogenic cell is found in adipose active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009; 23: 3113–3120. tissues and its origin depends on the adipose tissue depot 8 Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB type. The hypothesis that brown fat cells in classical BAT et al. Identification and importance of brown adipose tissue in share their origin with muscle cells has driven many elegant adult humans. N Engl J Med 2009; 360: 1509–1517. series of investigations.13–17,25 Meanwhile, the intriguing 9 van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND et al. Cold-activated origin of the brown fat cell in WAT has also been under 22,24,41 brown adipose tissue in healthy men. N Engl J Med 2009; 360: scrutiny, but there is as yet no clear answer as to 1500–1508. whether the latter emerges through the differentiation of 10 Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, specific precursors, the differentiation/transdifferentiation Niemi T et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518–1525. of white preadipocytes or the process of transdifferentiation 22,24,40,41 11 Cohade C, Mourtzikos KA, Wahl RL. ‘USA-Fat’: prevalence of already differentiated cells. However, it appears is related to ambient outdoor temperature-evaluation with clear that the origin of brown adipocytes in classical WAT is 18F-FDG PET/CT. J Nucl Med 2003; 44: 1267–1270. distinct from that of brown adipocytes in classical BAT. The 12 Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat (00 00 renewed interest for the brown adipocyte has also been USA-Fat ): description on 18F-FDG PET/CT. JNuclMed2003; 44: 170–176. driven by all those studies aimed at disentangling the brain 13 Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL circuits controlling BAT and WAT metabolic activities. In et al. Beta-catenin activation is necessary and sufficient to

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