脂肪起源

in A 01 Adipocyte progenitor/precursor Lipodystrophy ten ner AT) e) m ests nd lt p from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all ses incl occurs se tissu ly vari bution disorders characterized by regional lipoatrophy with other depots WAT depot and therefore depot names often vary between studies. Biochimica et Biophysica Acta xxx (2013) xxx–xxx BBADIS-63734; No. of pages: 12; 4C: 2, 6, 7, 9 Contents lists available at SciVerse ScienceDirect Biochimica et Bi e ls being spared or even expanding [2,3].With aworldwide obesity epidemic well underway, the study of adipose tissue growth, distribution, and reg- ulation is a major research focus. Yet the developmental origins of fat, the determinants of body fat distribution, and the signalingmechanisms that control fat growth remain poorly defined. 2. Adipose tissue is complex and heterogeneous According to [4],WAT depots in rodents include the anterior subcutane- ous WATs (asWATs) including interscapular and axillary WAT (located in the scapular region), inguinalWAT (ingWAT; attached dorsally along the pelvis to the thigh of the hindlimb), perigonadal WAT (pgWAT; surrounding the uterus and ovaries in females and the epididymis and testes in males), retroperitoneal WAT (rWAT; located within the abdominal cavity along the dorsal wall of the abdomen behind the kid- ney but not attached to the kidney ormixedwith perirenal brown fat), In mammals, fat is typically classified by ance as being either white adipose tissue (W ☆ This article is part of a Special Issue entitled: Modulat and Disease. ⁎ Corresponding author. Tel.: +1 508 856 8064. E-mail address: david.guertin@umassmed.edu (D.A. 0925-4439/$ – see front matter © 2013 Elsevier B.V. All http://dx.doi.org/10.1016/j.bbadis.2013.05.027 Please cite this article as: J. Sanchez-Gurmac http://dx.doi.org/10.1016/j.bbadis.2013.05.0 more favorablemetabolic s also present as fat distri- trunk cavity) or subcutaneous (below the skin). There is not a uni- formly applied system for describing the anatomical location of each and not all fat is equalwith somedepots having properties than others [1]. Some lipodystrophie 1. Introduction: Obesity is a risk factor formanydisea diovascular disease, and cancer. Obesity ceeds energy expenditure causing adipo body fat distribution patterns are high why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte pro- genitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning par- ticularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. © 2013 Elsevier B.V. All rights reserved. uding type2diabetes, car- when energy intake ex- e to overgrow. However, able between individuals tissue (BAT). WAT (the primary site of energy storage) is mostly com- posed of adipocytes containing a large unilocular lipid droplet. WATs are found throughout the body; however, the distribution of mass between each depot varies in the population as a function of genetics, age, and for some depots, sensitivity to hormones and gluco- corticoids. WAT location is often classified as being visceral (in the Brite or beige adipocyte Myf5 w hite adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to White adipose tissue (WAT) Brown adipose tissue (BAT) brown adipocytes originate Adipocyte lineages: Tracing back the orig Joan Sanchez-Gurmaches, David A. Guertin ⁎ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, M a b s t r a c ta r t i c l e i n f o Article history: Received 11 February 2013 Received in revised form 22 May 2013 Accepted 24 May 2013 Available online xxxx Keywords: The obesity epidemic has in opment. Adipose tissue is ge or brown adipose tissue (B adipocytes (brown in whit exist in adult humans sugg combat obesity. To understa adipocytes back to their adu Review j ourna l homepage: www. morphological appear- AT) or brown adipose ion of Adipose Tissue in Health Guertin). rights reserved. hes, D.A. Guertin, Adipocyte li 27 s of fat☆ 605, USA sified efforts to understand the mechanisms controlling adipose tissue devel- ally classified as white adipose tissue (WAT), the major energy storing tissue, , which mediates non-shivering thermogenesis. It is hypothesized that brite ay represent a third adipocyte class. The recent realization that brown fat increasing brown fat energy expenditure could be a therapeutic strategy to adipose tissue development, several groups are tracing the origins of mature recursor and embryonic ancestors. From these studies emerged a model that ophysica Acta evie r .com/ locate /bbad is and mesenteric WAT (mWAT; lining the surface of the intestines) (Fig. 1). Although the primary function of WAT is energy storage, it also functions as an endocrine organ secreting hormones and cyto- kines such as leptin and adiponectin that regulate feeding and metab- olism [5]. Epidemiological studies have found that the accumulation of visceral fat (determined by high waist-to-hip ratio) associates with metabolic disease (i.e. insulin resistance, type 2 diabetes, dyslipidemia, neages: Tracing back the origins of fat, Biochim. Biophys. Acta (2013), 2 J. Sanchez-Gurmaches, D.A. Guertin / Biochimica et Biophysica Acta xxx (2013) xxx–xxx hypertension, atherosclerosis, hepatic steatosis, and cancer) while the accumulation of subcutaneous WAT associates with improved insulin sensitivity and low risk for developing type 2 diabetes [6–14]. Brown adipocytes contain multiple smaller (multilocular) lipid droplets, are rich in mitochondria, and reside in depots that are highly innervated and vascularized. In rodents, BAT is located in discrete depots in interscapular (iBAT), sub-scapular (sBAT), and cervical (cBAT) Fig. 1. The Myf5 lineage contribution to the precursor pool in each fat depot varies with its anatomical location. The contribution of the Myf5 lineage to the adipocyte precursor cell compartment (defined as CD31−CD45−Terr119−CD29+CD34+Sca1+ cells) was recently determined by lineage tracing with Myf5-Cre;R26R-YFP mice. More than 95% of the precursors in brown fat are labeled with Myf5-Cre. In the anterior subcutaneous WATs (including interscapular and axial WATs) nearly 50% of the precursors trace to Myf5+ precursors, and in the rWAT (a visceral WAT), the Myf5 precursors give rise to approximately 70% of the adipocyte precursor cell pool. In contrast, the Myf5 lineage contributes very little to the adipocyte precursor pool in ingWAT and pgWAT, which are 90–95% Myf5neg. The contribution of the Myf5 lineage to the intramuscular adipogenic precursor pool (defined with slightly different cell surface markers) is very low. Dotted line indicates the abdominal cavity. References provided in the text. regions of the upper anterior side of the trunk and neck (Fig. 1) [4]. BAT also grows around parts of the aorta and kidneys [15]. These depots are often called “classical” BAT to distinguish them from brown- adipocyte-like cells, called brite adipocytes, which reside within some WATs (discussed below). In contrast to energy storing white adipocytes, brown adipocytes are specialized to expend energy to generate heat in a process called adaptive thermogenesis [16]. BAT is stimulated by the sympathetic nervous system following exposure to cold temperature and regulates the acute non-shivering thermogenesis response as well as the adaptive cold acclimatization response following chronic cold exposure. Thermogenesis is meditated by uncoupling protein 1 (UCP1), which embeds in the inner mitochondrial membrane, and produces heat by dissipating the proton electrochemical gradient over the inter- mitochondrial membrane space without generating ATP [17]. BAT stores energy for thermogenesis as perilipin coated lipid droplets and glycogen granules [18,19] and upon stimulation rapidly increases glucose and FA uptake to replenish its supplies. The high glucose uptake capacity of BATmakes it readily detectable by 18F-fluorodeoxyglucose positron emis- sion tomography (FDG–PET) [17,20,21]. While long thought to be critical only in rodents and newborn humans, the recent realization that BAT functions in adult humans (made possible by its sensitivity to FDG–PET) [22–26] raises the possibility that therapeutically controlling BAT growth and/or energy expenditure could be a strategy to combat obesity [27–34]. Interest is also growing in a third potential class of adipocyte called a brite adipocyte (also known as a “beige”, “inducible brown”, or “recruitable brown” adipocyte) [19,21,35–41]. This mysterious type of adipocyte exists among classical white adipocytes and is morphologi- cally indistinguishable from its neighboring white adipocytes in the basal or unstimulated state. However, upon stimulation by chronic cold exposure (or other mechanisms that mimic beta-adrenergic Please cite this article as: J. Sanchez-Gurmaches, D.A. Guertin, Adipocyte li http://dx.doi.org/10.1016/j.bbadis.2013.05.027 stimulation) they become multilocular and begin expressing UCP1 [19,21,40,42]. The presence of brite adipocytes in the WAT of mice is not homogeneous. For example, many adipocytes in ingWAT or rWAT becomemultilocular and induce UCP1 following stimulation; however, only a few UCP1+ brite adipocytes arise in pgWAT in the same mice [19,40]. Brite adipocyte content varies between mouse strains and cor- relates with overall strain sensitivity to high fat diet [43–47]. Whether brite adipocytes form by trans-differentiation of existing white adipo- cytes or arise from a unique preadipocyte lineage is under debate (discussed below) [19,40,41,48–51]. Perhaps the biggest unresolved issue pertaining to brite adipocytes is whether these cells actually con- tribute significantly to thermogenesis. For example, while UCP1mRNA is induced in brite adipocytes several hundred-fold relative to white adipocytes (which barely expresses UCP1) [38,52,53], the total UCP1 expression is still an order of magnitude lower than that detected in brown adipose tissue [52]. In fact, the maximum thermogenic capacity of brite fat has been estimated at only ~10% of classical brown fat in mice. A debate is underway as to whether human brown fat is more similar to brite fat or to classical brown fat in mice. Early reports argue that what is currently being called human brown fat is more similar to murine brite fat than to classical murine brown fat [48,49]. However, recent studies that more extensively profile different layers of adipose tissue in newborns and adults reveals that humans have brown fat deposits—particularly in the neck—that have a classic brown fat signa- ture [54,55]. Interestingly, there appears to be a gradient of fat cell types in the neck, with deep neck fat being classical BAT, intermediate cells possibly beingmore brite-like, and themost peripheral adipocytes being classical white adipocytes [55]. These findings are important considering the growing emphasis on developing therapeutic strategies to induce the “browning” of WAT in humans [35,56–59] because they suggest that the studies of classical brown fat in mice could also have important therapeutic implications in humans. The physiological signif- icance and regulatory mechanisms of brown versus brite fat in humans clearly need to be determined. Each individual fat depot is complex, composed not only of mature adipocytes but also of adipocyte precursor cells, fibroblasts, nerves, vascular cells, macrophages, and other cell types (collectively called the stromal vascular fraction or SVF). Adding to their complexity is the fact that adipose tissues are functionally heterogeneous. Although the sharpest functional divergence is clearly between energy storing WAT and energy-expending BAT, functional divergence is also evi- dent between WATs best exemplified by the risk associated with excess visceral fat versus subcutaneous fat. However, such simple distinctions are oversimplifications because differences in lipogenic activity, cell dynamics, proliferative and differentiation capacity, and gene expression even between categorically similar WAT depots have been reported [60–67]. Heterogeneity likely exists even within a single WAT as suggested by studies showing that neighboring adipocytes can respond differently to genetic perturbations or drugs [68–72]. The existence of such heterogeneity within and between fat tissues suggests broad conclusions should not be based on a limited survey of select fat depots, and that each depot should be considered separately. Does adipocyte tissue heterogeneity reflect different developmen- tal origins of adipocytes, variances in the developmental cues a partic- ular adipocyte may experience during differentiation, or extracellular influences on the mature adipocytes unique to the local cell or tissue environment? Answering these questions could lead to new anti- obesity therapies, improve the understanding of lipodystrophies, and increase the prospect of using adipocyte progenitor cells for cell-based therapeutics [17,73,74]. 3. The origin of adipocytes Central to understanding the complexities and heterogeneity of adipose tissue is to understand where the path to becoming an neages: Tracing back the origins of fat, Biochim. Biophys. Acta (2013), Table 1 Summary of recent lineage tracing studies of pre- and mature adipocytes. Genetic approach Promoter location Rationale Reported result References White adipocytes sox10-Cre;R26R-eYFP Transgene Sox10 expresses in pre- and migratory neural crest cells at all rostro-caudal levels Mature adipocytes in the salivary gland labeled positive; pgWAT and ingWAT labeled negative [103,139] PPARγ-tTA;TRE-Cre; R26R-LacZ Knock-in PPARγ is a nuclear receptor expressed in all tissues and is critical for adipogenesis ingWAT and rWAT positive; some positive SVF cells [82] aP2-GFP Transgene aP2 (FABP4) expresses in mature adipocytes and is a target of PPARγ ingWAT positive [82] aP2-Cre;R26R-LacZ Transgene Described above ingWAT and pgWAT positive [82] PDGFRβ-Cre; R26R-LacZ Transgene PDFGRβ is expressed in vascular mural cells ingWAT and rWAT positive [82,140] myf5-Cre;R26R-eYFP Knock-in Myf5 is a muscle differentiation transcription factor that is first expressed in the dermomyotome at E8.0 and expresses in adult satellite cells ingWAT and pgWAT negative [116,117] wnt1-Cre;R26R-eYFP Transgene Restrictive marker of migrating neural crest cells Cephalic WAT positive; pgWAT and ingWAT negative. 70% of adipocyte precursors in cephalic WAT positive; all ingWAT adipocyte precursors negative [104,141] LysM-Cre;R26R-LacZ Knock-in The lysozyme M is exclusively expressed in macrophages and granulocytes 5–20% of pgWAT adipocytes positive [110,111] VE-cadherin-Cre; R26R-LacZ Knock-in VE-cadherin is expressed in endothelial cells, is involved in cell adhesion, and is essential for vascular system development ingWAT and pgWAT positive [96,98] VE-cadherin-Cre; R26R-eGFP Knock-in Described above Subset of mature adipocytes in the pgWAT positive [96,98] VE-cadherin-CreERT2; R26R-LacZ Knock-in VE-cadherin-CreERT2 is a tamoxifen-inducible version of the VE-cadherin-Cre Numerous adipocytes in the ingWAT, pgWAT and BAT positive [97,98] ZFP423-GFP Knock-in Zfp423 is a transcriptional regulator broadly expressed but essential for preadipocyte commitment ingWAT positive [95] pax3-Cre; R26R-mTmG Knock-in Pax3 is a muscle differentiation transcription factor first expressed in dorsal neural crest and somites; it cooperates with Myf5 to drive muscle development 50% of the adipogenic SVF cells from asWAT positive [123,124] myf5-Cre;R26R-LacZ Knock-in Described above Mature adipocytes from asWAT and rWAT positive; few mature adipocytes from ingWAT and pgWAT positive; 50–60% of adipogenic SVF cells from asWAT and rWAT positive; b2% from the ingWAT and pgWAT positive [83,117] myf5-Cre;R26R-eYFP Knock-in Described above 50–70% of the adipocyte precursors from asWAT and rWAT positive; b10% of the adipocyte precursors from pgWAT and ingWAT positive [83,117] vav1-Cre; R26R-mTmG Knock-in Vav1 is a proto-oncogene that expresses in the hematopoietic and lymphoid systems All adipocyte precursors and mature adipocytes from ingWAT, pgWAT, rWAT andmWATnegative [100,112] tie2-Cre;R26R-mTmG Transgene Tie2 is an angiopoietin receptor specific to endothelial cells and some hematopoietic cells All adipocyte precursors and mature adipocytes from ingWAT, pgWAT, rWAT andmWATnegative [100,142] VE-cadherin-Cre; R26R-mTmG Knock-in Described above All adipocyte precursors and mature adipocytes from ingWAT, pgWAT, rWAT andmWATnegative [96,100] PDFGRα-Cre; R26R-mTmG Transgene PDGFRα is expressed in most mesenchymal cells can activate the MAPK, PI3K and PLCγ signaling pathways All adipocyte precursors and mature adipocytes from ingWAT, pgWAT, rWAT and mWAT positive [100,143] Brown adipocytes En1-Cre;R26R-LacZ Knock-in Engrailed 1 is a homeobox transcription factor that expresses in cells of the central dermomyotome BAT positive [114,144] myf5-Cre;R26R-eYFP Knock-in Described above BAT positive [116,117] pax7-CreERT2; R26R-LacZ Knock-in Pax7 is expressed in medial and central cells of the dermomyotome and in adult satellite cells BAT positive [121,122] myf5-Cre;R26R-LacZ Knock-in Described above BAT positive; >99% of adipogenic BAT SVF cells positive [83,117] myf5-Cre;R26R-eYFP Knock-in Described above >95% of BAT adipocyte precursors positive [83,117] VE-cadherin-Cre; R26R-LacZ Knock-in Described above BAT positive [96,98] VE-cadherin-CreERT2; R26R-LacZ Knock-in Described above Many brown adipocytes positive [97,98] Brite adipocytes myf5-Cre;R26R-eYFP Knock-in Described above Brite adipocytes in ingWAT negative [116,117] myf5-Cre;R26R-LacZ Knock-in Described above CL316,243 induced brite adipocytes in asWAT and rWAT positive; brite adipocytes induced in ingWAT negative [83,117] VE-cadherin-CreERT2; R26R-LacZ Knock-in Described above Rosiglitazone induced bright adipocytes in ingWAT positive [97,98] UCP1-CreERT2; R26R-tdRFP Knock-in UCP1 is the most accepted functional marker of brown adipocytes Brite and white adipocytes interconvert in ingWAT depending on the temperature [51] (continued on next page) 3J. Sanchez-Gurmaches, D.A. Guertin / Biochimica et Biophysica Acta xxx (2013) xxx–xxx Please cite this article as: J. Sanchez-Gurmaches, D.A. Guertin, Adipocyte lineages: Tracing back the origins of fat, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbadis.2013.05.027 4 J. Sanchez-Gurmaches, D.A. Guertin / Biochimica et Biophysica Acta xxx (2013) xxx–xxx adipocyte begins. Moreover, strategies targeting nascent adipocytes could be useful in fighting obesity; however the identity of the adipo- cyte progenitor cells is just beginning to be unraveled. As obesity progresses, adipose tissues grow by hypertrophy (increasing the size of their adipocytes) and by hyperplasia (increasing the number of adipocytes) [75–79]. A yearly adipocyte turnover rate for lean and obese humans of 10% has been reported [79], but because mature adipocytes do not divide, a resident adipocyte precursor cell must exist. Undifferentiated adipocyte progenitor cells were long assumed to