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ORIGINAL ARTICLE Determinants of Brown Adipocyte Development and Thermogenesis

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ORIGINAL ARTICLE Determinants of Brown Adipocyte Development and Thermogenesis 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
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