cells Review Towards a Better Understanding of Beige Adipocyte Plasticity Esther Paulo and Biao Wang * Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, CA 94158, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-415-502-2023 Received: 3 November 2019; Accepted: 29 November 2019; Published: 1 December 2019 Abstract: Beige adipocytes are defined as Ucp1+, multilocular adipocytes within white adipose tissue (WAT) that are capable of thermogenesis, the process of heat generation. In both mouse models and humans, the increase of beige adipocyte population, also called WAT browning, is associated with certain metabolic benefits, such as reduced obesity and increased insulin sensitivity. In this review, we summarize the current knowledge regarding WAT browning, with a special focus on the beige adipocyte plasticity, collectively referring to a bidirectional transition between thermogenic active and latent states in response to environmental changes. We further exploit the utility of a unique beige adipocyte ablation system to interrogate anti-obesity effect of beige adipocytes in vivo. Keywords: beige adipocyte; WAT browning; thermogenesis; metabolism 1. Introduction Energy balance requires equivalent energy intake and energy expenditure. When energy intake exceeds energy expenditure, animals store excess energy as fat in adipose. When the adipose tissue is overloaded, excess fat is ectopically deposited in other metabolic tissues. The chronic energy excess can lead to obesity and further metabolic dysfunctions in other organs [1]. Adaptive thermogenesis, the heat production in response to changes of environmental temperature and diet, is a major contributor of total energy expenditure. Adaptative thermogenesis occurs mostly in brown fat [2], which contains specialized mitochondria-rich brown adipocytes whose thermogenic functionality is conferred by the uncoupling protein 1 (Ucp1) [3,4]. Two types of Ucp1+ adipocytes have been distinguished by their localization, developmental origin, and molecular signature in small rodents. The classical brown adipocytes are present in interscapular and perirenal adipose tissues, and they originate from Myf5+/Pax7+ skeletal muscle progenitors [5]. The beige adipocytes (also named brite adipocytes) are formed and clustered within subcutaneous white adipose tissue (WAT) in response to β-adrenergic stimulation [6–8]. The development and function of brown and beige adipocytes have been comprehensively reviewed elsewhere [9–12]. The presence of thermogenic, UCP1+ fat depots in adult humans has been recognized recently by 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) with computer-assisted tomography (CT), due to their increased activity of glucose uptake [13–16]. 18F-FDG positive depots in humans contain both classical brown and beige adipocytes [17–20]. Several studies using anatomical and transcriptome profiling approaches have indicated that interscapular brown fat from human infants and neck brown fat from human adults share features with classical murine brown adipocytes, while supraclavicular fat of adult humans mainly consists of beige adipocytes. Importantly, the Ucp1+ beige adipocytes are steadily observed on humans or mice exposed to cold environment, but their appearances are also negatively correlated with aging and obesity, suggesting a potential role of beige adipocytes in regulating energy homeostasis. Cells 2019, 8, 1552; doi:10.3390/cells8121552 www.mdpi.com/journal/cells Cells 2019, 8, 1552 2 of 16 Cellsenvironment,2019, 8, 1552 but their appearances are also negatively correlated with aging and obesity, suggesting2 of 16 a potential role of beige adipocytes in regulating energy homeostasis. 2. Beige Adipocyte Formation: Different Different Players It has beenbeen wellwell establishedestablished that activity of beigebeige adipocytesadipocytes is dominantlydominantly regulated by the sympathetic nervous system,system, inducedinduced byby thethe coldcold oror justjust thethe feelingfeeling ofof cold (Figure1 1))[ [6–8].6–8]. Chemical denervation withwith 6-hydroxydopamina, 6-hydroxydopamina, prior prior to to 3-week-old 3-week-old age age or prioror prior to cold to cold exposure, exposure, impairs impairs beige adipocytebeige adipocyte formation, formation, indicating indicating the importance the importan ofce sympathetic of sympathetic nerves nerves during during WAT WAT browning browning [21]. Previous[21]. Previous studies studies on anatomical on anatomical positioning positioning of sympathetic of sympathetic nerves nerves in the in subcutaneous the subcutaneous inguinal inguinal white + + adiposewhite adipose tissue (iWAT),tissue (iWAT), for example, for example, by staining by staining the tyrosine the tyrosine hydrolase hydrolase(Th ) sympathetic+ (Th+) sympathetic nerves + innerves fixed in tissues fixed tissues [22,23], [22,23], lack spatial lack spatial and temporal and temporal precision precision [21,24 ,[21,24,25].25]. Th -sympathetic Th+-sympathetic nerves nerves and beigeand beige adipocytes adipocytes are not are distributed not distributed evenly acrossevenly iWAT across [22 ],iWAT suggesting [22], suggesting that anatomic that positioning anatomic ofpositioning sympathetic of sympathetic nerves may nerves also contribute may also tocontri beigebute adipocyte to beige formation.adipocyte formation. However, theHowever, actions the of sympatheticactions of sympathetic nerves, the nerves, engagement the engagement of neurotransmitters, of neurotransmitters, and their and receptors their receptors at the contact at the contact sites of thesites sympathetic of the sympathetic nerve and nerve receiving and receiving cell in live cell mice inare live most mice unknown, are most and unknown, functional and relevance functional of sympatheticrelevance of sympathetic nerve neurotransmission nerve neurotransmission in beige adipocyte in beige plasticity,adipocyte especiallyplasticity, duringespecially the during postnatal the period,postnatal is notperiod, fully is elucidated not fully elucidated yet. yet. Figure 1.1. PlayersPlayers that that are are involved involved in beigein beige adipocyte adipocyt formation.e formation. There There are two are major two routes major to routes generate to + thegenerate Ucp1 +theand Ucp1 multilocular and multilocular beige adipocytes beige adipocytes in white adipose in white tissue adipose (WAT) tissue by various (WAT) physiological by various stimuli,physiological such asstimuli, cold, nutrientsuch as cold, excess, nutrient burn injury,excess, exercise, burn injury, and cancerexercise, cachexia. and cancer The cachexia. first route The is throughfirst route de is novo through beige de adipogenesis novo beige adipogenesis from PDGFR fromα+, or PDGFR PDGFRbα+,+ oror PDGFRb MyoD+ +progenitors or MyoD+ progenitors residing in WAT.residing The in other WAT. route The is other through route transdi is throughfferentiation transdifferentiation from existing whitefrom existing adipocytes. white Although adipocytes. the sympatheticAlthough the nervous sympathetic system nervous (SNS) issystem the major (SNS) driver is the for major beige driver adipocyte for beige formation, adipocyte various formation, types of immunevarious types cells and of immune circulating cells hormones and circulating (thyroid hormone, hormones Natriuretic (thyroid peptides,hormone, FGF21, Natriuretic Irisin, peptides, IL-6) and metabolitesFGF21, Irisin, (succinate, IL-6) and lactate, metabolites and bile (succinate, acid) can lactate, influence and beige bile adipocyteacid) can formationinfluence beige via either adipocyte route. formation via either route. Young et al. first observed the formation of brown-like adipocytes (multilocular in morphology and presenceYoung et ofal. thefirst 32observed kD mitochondrial the formation uncoupling of brown-like protein—Ucp1) adipocytes (multilocular in the parametrial in morphology fat pad, aand traditional presence whiteof the fat 32 pad,kD mitochondrial in female BALB uncoupli/c miceng after protein—Ucp1) cold acclimation in the [26 parametrial]. Numerous fat reportspad, a supporttraditional the white notion fat that pad, these in brown-likefemale BALB/c or “brite” mice adipocytes after cold wereacclimation transdi ff[26].erentiated Numerous from existingreports whitesupport adipocytes the notion [ 27that–31 these]. In brown-like 2012, Wu from or “brite” Spiegelman’s adipocytes group were established transdifferentiated that these from brown-like existing adipocyteswhite adipocytes (re-named [27–31]. as beige In 2012, adipocytes) Wu from represented Spiegelman’s a distinctive group established population that of thermogenic these brown-like active adipocytes (re-named within WAT, as beige in contrast adipocytes) to the classicalrepresente brownd a distinctive adipocytes population from the brownof thermogenic adipose active tissue (BAT) [32]. And importantly, the clonal analysis of this study suggested distinct progenitors that Cells 2019, 8, 1552 3 of 16 can give rise to beige adipocytes, different with the transdifferentiation model. Follow-up studies did reveal that PDGFRα+ progenitors [33] and smooth-muscle lineage/mural progenitors [34–36] can differentiate into beige adipocytes in vitro and in vivo (Figure1). MyoD + progenitors also contribute to beige adipogenesis in the absence of βAR signaling [37], highlighting the heterogeneity of the beige adipocyte population. Notably, these two routes of beige adipocyte formation,