Fettgewebe, Stammzellen, Adipositas, Metabolismus. Zusammenfassung ... major routes: de novo lipogenesis from non-lipid precursors or uptake of fatty acids ...
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Fettgewebe – was gibt es Neues?
Adipose tissue – What’s new? Max Lafontan Key words Adipocytes, lipolysis, leptin, adiponectin, adipose tissue-derived stromal cells, inflammation
Schlüsselwörter Fettgewebe, Stammzellen, Adipositas, Metabolismus
Summary Adipose tissue excess and dysfunction is a risk factor for the development of type 2 diabetes and cardiovascular diseases. The usual perception of adipose tissue as a storage location for fatty acids has been expanded by the notion that it also produces a large number of hormones and cytokines. Recent findings in adipose tissue metabolism and human adipocyte biology and physiology will be discussed as well as mechanisms involved in the control of free fatty acid uptake and fat deposition and recent advances in the regulation of lipolytic pathways. Growth factors, cytokines, chemokines, vasoactive factors, eicosanoids, proteins of the complement system, acute phase reactants and acute phase proteins, binding proteins and extracellular matrix proteins have been identified in adipose tissue. In obesity, adipose tissue is characterized by an increased production and secretion of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on adipose tissue physiology but also systemic effects on other organs. Obese adipose tissue is infiltrated by macrophages and lymphocytes, which may be a source of some locally-produced pro-inflammatory cytokines. The relative and quantitative contribution of the adipocytes and other cells of the stroma-vascular fraction of the adipose tissue (i.e., macrophages, lymphocytes, microvascular endothelial cells and adipose-derived stromal/stem cells) to the global secretion of the adipose tissue in normal and obese patients still remain unclear. A fully intact pathway of innate immunity exists in the adipocyte. The lipolysaccharide-activated Toll-like receptor (TLR)-4 with its closely related receptor TLR-2 has been identified in the human adipocyte. Lipolysaccharide (LPS) and fatty acids (i.e., particularly saturated fatty acids) are able to activate the TLR-4 /nuclear factor-kappaB pathway and results in the secretion of immunomodulatory molecules in adipose tissue.
Zusammenfassung Über lange Zeit hinweg wurde das Fettgewebe (FG) lediglich als ruhende Energiereserve angesehen. Die hat sich in den letzten Jahren dramatisch geändert, nachdem neue Erkenntnisse zur endokrinen Aktivität von Adipozyten und der Immunfunktion des FG gewonnen wurden. Die Biologie des FG ist ein „weißer Fleck“ auf der dermatologischen Landkarte, obwohl die Nachfrage nach chirurgischen Eingriffen hierbei steigt. FG ist eine reichlich zur Verfügung stehende, leicht erreichbare und wieder auffüllbare Quelle von FG-Stammzellen. Es handelt sich dabei um multipotente, Zellen, die sich zur Adipozyten-, Chondrozyten-, Myozyten- und Osteoblasten-Linien differenzieren können. FG-Stammzellen könnten potenzielle Bedeutung für Reparatur und Regeneration von akut und chronisch geschädigtem Gewebe erlangen. Die Erfordernis nach einem besseren Verständnis der FG-Biologie und -Physiologie in der Dermatologie war nie so dringlich wie heute, um Behandlungen, chirurgische Praktiken und Ergebnisse zu verbessern. Diese Übersicht wird sich auf die neuen Ergebnisse der FG-Forschung für den Adipozyten-Metabolism und die Physiologie konzentrieren.
Introductory comments Adipose tissue (AT) has long been regarded as mainly a resting tissue dedicated to energy storage and release. In recent years, this view has dramatically changed following new insights into the endocrine activity of adipocytes and the immunological functions of AT. The biology of AT is a “black hole” in the field of dermatology although the demand for surgical procedures involving the manipulation of subcutaneous AT is rising every year: surgical removal, liposuction and lipofilling procedures, lysing with hypo-osmotic solutions or phosphatidylcholine/biliary salt mixtures, etc. Dermatologists sucking out AT and placing it elsewhere with rather crude technology must think carefully about the fate of the tissue and cells they manipulate. Those performing techniques aimed at adipocyte rupture
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must question the evolution of the products appearing in AT after lesions promoted by such treatments. Obesity is recognized as having an impact on clinical dermatology but the putative physiological role of subcutaneous AT on skin biology is largely unknown and research is neglected. This situation is probably explained by the fact that AT research has almost exclusively been carried out by non-dermatological scientists. AT is also an abundant, accessible, and replenishable source of adiposederived adult stem cells that can be isolated from liposuction waste tissue by collagenase digestion and various isolation and expansion procedures [1]. These adipose-derived stem cells (ASCs) are multipotent, differentiating along the adipocyte, chondrocyte, myocyte, and osteoblast lineages. ASCs cells could have potential applications for
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the repair and regeneration of acute and chronically damaged tissues. Nevertheless, a number of additional pre-clinical safety and efficacy studies will be needed before the promise of these cells can be fully realized. The need for a better understanding of AT biology and physiology has never been so acute in the field of dermatology to improve treatments, surgical practices and outcomes. This review will focus on the recent findings in human fat cell (adipocyte) metabolism and AT physiology. AT tissue is now recognized as a key endocrine organ with white adipocytes, but also cells of the stroma-vascular fraction of AT, secreting a number of hormones and paracrine factors involved in endocrine and/or local regulation inside the AT. Finally, particular attention will be paid to human fat cell precursors and ATderived stem cells that can be used for regenerative medicine.
A diversity of methods to investigate adipocyte biology and adipose tissue physiology AT is a major source of metabolic fuel and the biology of isolated fat cells from human AT, has been extensively studied in vitro. Moreover, fat cell precursors differentiated into adipocytes in vitro have also provided suitable systems to explore fat cell biology and a number of regulatory mechanisms at the cell level. Nevertheless, AT is not the easiest tissue to use for an integrated approach of its biology and physiology. Noticeable progress was made in the 1990’s to improve in vivo studies in humans and reliable techniques are now available. The in situ microdialysis technique has been rapidly expanded and improved by different laboratories (see review [2]). Another useful technique to measure AT metabolism has been introduced by the group of Keith Frayn who described a relatively pure preparation of AT that could be studied by the arterio-venous technique. By cannulating the superficial inferior epigastric vein it is possible to obtain substrate concentrations in samples of blood draining the subcutaneous AT of the anterior abdominal wall from lean and obese subjects [3]. Methods based on the utilization of deuterium- or tritiumlabelled metabolites can also be used to assess triacylglycerol (TAG) storage or mobilization. Finally, nutrigenomics and nutrigenetics, that dominate research in diet-gene and gene-diet responsiveness in the field of personalized nutrition are rapidly expanding. Gene expression profiling studies using rodent obesity models or humans have demonstrated that microarray analysis can successfully differentiate preadipocytes from adipocytes and identify the cellular responses to pharmacological agents and nutritional treatments.
Mechanisms controlling free fatty acid uptake, triacylglycerol synthesis and fat deposition Mature adipocytes have been the major centre of interest for decades. Most energy reserves in the human body are stored in adipocytes as triacylglycerols (TAGs). TAGs may arise in the adipocyte from two major routes: de novo lipogenesis from non-lipid precursors or uptake of fatty acids from the plasma. The major route for TAG deposition in human AT is the uptake of pre-existing fatty acids from circulating TAGs (packed in chylomicrons or very-low-density lipoprotein (VLDL) particles). Lipoprotein lipase (LPL) is the enzyme that hydrolyzes the circulating TAGs. It provides the non-esterified fatty acid (NEFA) substrates for TAG synthesis in fat cells. LPL is synthesized and secreted by the adipocytes and is translocated to the lumen of capillaries via mechanisms that are not fully elucidated.
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It is then bound to the luminal surface of endothelial cells by interaction with cell-surface glycosaminoglycans, especially heparin sulfate proteoglycans (HSPGs). A glycosylphosphatidylinositol-linked (GPIlinked) protein, the GPI-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), located on the luminal face of the capillary endothelium in AT, has recently been identified and seems to play a crucial role in the processing of chylomicrons by LPL [4]. The various steps are summarized in Figure 1. Fatty acids released by LPL action move through the endothelial lining to the adipocytes, where they are taken up; some of them escape adipocyte trapping and are transported by albumin to other tissues. After NEFA uptake, a number of enzymes are involved in TAG accumulation in adipocytes including acyl-coenzyme A:diacylglycerol transferase (DGAT) which catalyses the addition of the third fatty acyl-CoA moiety to diacylglycerol and fatty acid synthase (FAS). Fatty acid trapping (e. g., uptake by adipocytes of NEFAs liberated from plasma TAGs by LPL) represents an important buffering process of normal AT activity [5]. Translocation of long chain fatty acids (LCFA) across the plasma membrane is achieved by a concert of coexisting and complex mechanisms which will not be described in detail here but briefly discussed. LCFA can diffuse passively via a
Fig. 1: Schematic illustration of the binding of lipoprotein lipase (LPL) by heparan sulfate proteoglycans and of a chylomicron particle by GPI-anchored high-density lipoprotein-binding protein 1 (GPIHPB1) on the surface of a capillary microvascular endothelial cell. LPL-dependent lipolysis occupies a central position in lipid and lipoprotein metabolism. LPL is a 448-amino acid glycoprotein synthesized by the adipocyte and transferred to the luminal pole of microvascular endothelial cells. LPL binds to heparan sulfate proteoglycans (HSPGs) on cells, and specifically to the glycosaminoglycan chains of proteoglycans. It is hypothesized that GPIHBP1 might be capable of binding LPL or chylomicrons, or both. Chylomicrons are rapidly metabolized; their residence time in the circulation is only a few minutes. Fatty acid trapping (e. g., uptake by adipocytes of fatty acids liberated from LPL on chylomicron triacylglycerolsTAGs) represents an important buffering process of normal AT activity.The hydrolysis of lipoproteins (chylomicrons and very low density lipoproteins produced by liver) TAGs by LPL provides non esterified fatty acids (NEFA) for storage as TAG in adipocytes. Uptake of NEFAs by adipocytes is enhanced by insulin and acylation stimulating protein. Untrapped NEFAs (i.e., fatty acid leakage) will bind to albumin and flow outside adipose tissue. Fat cell glucose uptake is controlled by the glucose transport protein GLUT-4; it is enhanced by insulin.
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non-saturable system, but transport can also be accelerated by certain membrane proteins as well as by the movement of lipid rafts (i. e., dynamic assemblies of proteins and lipids that float freely within the two dimensional matrix of the membrane bilayer). Amphiphilic LCFAs are hydrophobic molecules, poorly soluble in aqueous solutions, which can flip-flop rapidly across model membranes and diffuse rapidly through the plasma membrane lipid
bilayer (when present in high concentrations) [6]. However, the transport and metabolism of LCFA are now believed to be also carried out by membrane-associated proteins that bind and transport LCFA. Amongst these proteins, a family of membrane-associated proteins termed fatty acid transport proteins (FATP) has been shown to be involved in LCFA uptake. FATP-1 is the most important of the family and its activity is regulated by insulin. Fatty acid translocase FAT/CD36 is involved in regulating the uptake of LCFA into adipocytes and muscle cells. Evidence for a substantial role for facilitated diffusion with fatty acid translocase FAT/CD36 has been provided in the adipocyte. The plasma membrane fatty acid binding protein (FABPpm) and caveolin-1 identified in fat cell membranes also contribute to modulation of LCFA transport although their function is not yet clear. Essential in adipocyte biology, NEFA uptake remains a complex and debated problem. One group has recently concluded that fatty acid transport across the adipocyte plasma membrane is not mediated by either FAT/CD36, FATP-1, FABPpm, caveolin-1 or lipid rafts, but carried out by an as-yet-unidentified membrane protein pump [7].
Recent discoveries in the mechanisms involved in the control of fat mobilization: a new lipase and the lipolytic effect of natriuretic peptides
Fig. 2:The lipolytic pathways in human adipocytes. Signal transduction pathways for catecholamines via beta- and alpha2-adrenergic receptors, for atrial natriuretic peptide via type A receptor (NPR-A) and for insulin are summarized. Intracellular cAMP concentrations are controlled by: i) catecholamines (epinephrine and norepinephrine) via beta-adrenergic receptor-mediated adenylyl cyclase activation, ii) inhibitory receptors (i.e., alpha2-adrenergic receptors, adenosine, prostaglandin, neuropeptideY/ peptideYY and nicotinic acid) via inhibition of adenylyl cyclase activity and iii) insulin via PDE-3B activation. Atrial and B-type natriuretic peptides (ANP and BNP) stimulate NPR-Adependent guanylyl cyclase activity and cGMP production. cAMP and cGMP both contribute to the protein kinase (PKA and PKG (cGK-I))-dependent phosphorylation of HSL and perilipin. Perilipin phosphorylation induces an important physical alteration of lipid droplet surfaces that facilitates the action of ATGL and HSL on TAG hydrolysis. Perilipin phosphorylation releases a co-activator of ATGL which promotes its TAG-hydrolysing activity (not shown). HSL phosphorylation promotes its translocation from the cytosol to the surface of the lipid droplet. PKA and PKG (cGK-I) phosphorylate a number of other substrates (enzymes and transcription factors, not shown in the diagram) and can also influence the secretion of various molecules from adipocytes. Stimulation of insulin receptors counteracts cAMP production via PDE-3B stimulation and is without effect on cGMP production.AC, adenylyl cyclase;A1 adenosine-R,A1 adenosine receptor;ALBP, adipocyte lipid binding protein;AQP-7, aquaporin-7;AR, adrenergic receptor; EP3-PGR: EP3-prostagladin receptor; GC, guanylyl cyclase; Gi, inhibitory GTP-binding protein; Gs, stimulatory GTP-binding protein; HSL, hormone-sensitive lipase; ATGL, adipose triglyceride lipase; MGL, monoacylglycerol lipase; IRS-1, insulin receptor substrate; NEFA, non-esterified fatty acid; NPY-Y1-R, type Y1 neuropeptide receptor PDE-3B, phosphodiesterase-3B; PI3-K, phosphatidylinositol-3-phosphate kinase; PKA, protein kinase A; PKB, protein kinase B/Akt; PKG (cGK-I), protein kinase G; PUMA-G/HM74a-R, nicotinic acid receptor.The products of the complete hydrolysis of triacylglycerols (i.e., NEFAs and glycerol) are released by fat cells. Docking of ALBP to HSL favours the efflux of NEFA while glycerol is channelled by aquaporin-7 (AQP-7), a water-glycerol transporter that is present in the adipocyte plasma membrane.
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To use the AT energy reserves, (during fasting and exercise, for example, AT TAG must first be hydrolysed and the resultant fatty acids (i. e., NEFAs) delivered to the plasma albumin and then to working muscle. This is achieved by a highly active and regulated pathway: lipolysis, whereby TAGs stored in the adipocyte are hydrolysed, and NEFAs delivered to the plasma. Release from AT of the products of lipolysis is pulsatile. In vivo studies based on the use of tracer methodology have clearly shown that lipolytic activity is greater in upper-body subcutaneous AT than in leg AT (per kg of fat) in lean and obese men and women. Fat cell lipid droplets are coated with perilipin, a protein that suppresses lipolysis by blocking access of the lipases to the lipid droplet under basal conditions. Three lipases are involved in the control of TAG hydrolysis. The earliest described and best known, hormonesensitive lipase (HSL), is regulated via its phosphorylation by a protein kinase A (PKA) which is an enzyme activated by cyclic AMP. Another lipase was discovered more recently by three different groups; it is the adipocyte triglyceride lipase (ATGL), also identified as desnutrin and iPLA2ζ TTS-2.2. This lipase possesses an exclusive TAG hydrolase activity. The diacylglycerols produced by ATGL are then hydrolyzed by HSL; the activity of both enzymes is coordinated. Monoacylglycerols are hydrolyzed by the monoacylglycerol lipase (MGL) which is an abundant lipase in adipocytes and is not hormonally regulated. ATGL is activated by a cofactor, comparative gene identification CGI-58, also called ABHD5 (for α/β hydrolase fold domain 5). ABHD5 is a coactivator of ATGL, stimulating TAG hydrolysis by as much as 20-fold. ABHD5 interacts with perilipins on the surface of the lipid droplets and a complex interplay has recently been proposed between ATGL, perilipins and ABHD5 [8]. Fat mobilization is regulated by various mechanisms in humans. It is acutely stimulated by catecholamines (epinephrine and norepinephrine) and natriuretic peptides [9]. Human fat cells express both beta1-2 and alpha2-adrenergic receptors. Acting through binding to beta1-2-adrenoceptors, catecholamines stimulate adenylyl cyclase and promote cAMP production from ATP, PKA activation and lipolysis.
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Conversely, selective stimulation of fat cell alpha2-adrenergic receptors inhibits lipolysis (Figure 2). In fact, the final response to catecholamines is modulated according to the number of both kinds of adrenergic receptors in fat cell membranes, the relative affinity of both receptors for catecholamines, and eventually by post-receptor coupling events [10]. Site-related differences in the in vitro effects of catecholamines have been reported in fat cells from men and women. An enhanced alpha2-adrenergic responsiveness associated with a concomitant decrease in beta-adrenergic responsiveness explains the lower lipolytic effect of catecholamines in gluteal/ femoral fat cells of normal and obese women and abdominal fat cells of obese men [11]. Conversely, visceral adipocytes show the highest beta1-2-adrenergic receptor-mediated lipolytic responsiveness and the weakest alpha2-adrenergic response to catecholamines. Whatever the age and sex, the extent of the fat mass and the level of fat cell hypertrophy strongly affect the functional balance between beta1-2 and alpha2-adrenergic receptors. The hypertrophic subcutaneous fat cells (abdominal, femoral) are known to be the less responsive to the lipolytic action of catecholamines; they have the highest number of alpha2-adrenergic receptors and the lowest number of beta1-2 adrenergic receptors [12]. Physiological confirmation of in vitro results has been obtained using the in situ microdialysis technique. Our laboratory has recently shown that factors secreted by the heart, i.e., atrial- and B-type natriuretic peptides (ANP and BNP respectively) stimulate lipolysis in human fat cells through a pathway independent of cAMP production and PKA activity. Natriuretic peptides act through the type A natriuretic peptide receptor (NPR-A) that possesses an intrinsic guanylyl cyclase activity that generates the second messenger, cyclic guanosine monophosphate (cGMP). The two second messengers, cAMP and cGMP, whose production is activated by the lipolytic hormones, stimulate their corresponding protein kinases (i.e., PKA for cAMP and protein kinase G (PKG) for cGMP), phosphorylate hormone-sensitive lipase (HSL) and perilipin, and activate lipolysis. A number of defects reported at different steps in the lipolytic system of the human fat cell could probably explain why some fat deposits are highly resistant to exercise-induced lipid mobilization [10].
Fat cell precursors and the heterogeneity of the cell types in adipose tissue Mature adipocytes have been the major centre of interest for decades. The other cells present in the stroma-vascular fraction (SVF) of AT have been neglected. AT contains a number of cell types involved in immunological defence, that are embedded in the extracellular matrix of AT consisting of collagen and elastic fibres. The primordial fat pad depot is populated by mesenchymal stem cells and a range of cell phenotypes common to red bone marrow, including preadipocyte and endothelial progenitors, immature monocytes and macrophages, mast cells, fibroblast-like perivascular cells and pericytes. Preadipocyte progenitor cells able to enter the adipocyte lineage are among them. The differentiation program leading to mature adipocytes expressing the enzymes of lipogenesis and lipolysis, hormone receptors and important adipocyte hormones (i.e., adipokines such as leptin and adiponectin) has been extensively studied. In preadipocytes, a network of transcription factors regulates both the adipogenic program as well as all the gene products that characterize the mature
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adipocyte. Extensive studies have been carried out on pluripotent stem cells (such as C3H10T1/2 cells) committed to the adipocyte lineage, or rodent preadipocyte cell lines, most notably the 3T3-L1, 3T3-442A and ob17 cell lines, used as in vitro models for adipocyte differentiation [13]. When implanted subcutaneously into athymic mice, these cells produce fat pads that are histologically and biochemically identical to the host’s AT [14]. It is considered that a great deal about the adipocyte differentiation program and the genes involved in this phase of AT development is known, at least in rodents. However, the “commitment” phase by which pluripotent stem cells are induced to commit to the adipocyte lineage is still unclear and the early markers of the adipoblasts have not been completely identified. Moreover, the epigenetic regulators that control the expression of the transcription program in an in vivo setting remain largely unknown. Proteolytic events, involving the membrane anchored metalloproteinase MT1-MMP, could interfere with AT transcriptional activity and function by remodelling the extracellular matrix barrier as the adipocyte gains its metabolic functions and AT develops. Other metalloproteases such as MMP-2 and MMP-9 are secreted by adipocytes and macrophages and might also interfere with extracellular matrix remodelling in AT [15]. The factors determining fat mass in adults are not fully understood. Increased storage in already mature fat cells is thought to be an important factor in getting fat. Adipocyte number seems to be the major determinant for the fat mass in adults. The number of adipocytes is established during childhood and adolescence and the number of cells stays constant in adulthood in lean and obese individuals with stabilized weight, even after a marked weight loss. Thus the difference in adipocyte number between lean and obese individuals is established during childhood and the number of adipocytes remains constant during adulthood [16]. Kinetic studies on fat mass accretion in humans during the establishment of obesity have shown that a phase of hyperplasia is observed when maximal storage capacity of the adipocytes is reached. Since mature adipocytes are unable to proliferate, the increase in adipocyte number within AT was thought to originate from the proliferation/differentiation of adipocyte precursors, the so-called preadipocytes, present in the SVF. In rodents, high-fat feeding-induced obesity in adults is also characterized by an incremental increase in fat cell size followed by an increase in fat cell number, which could be partly explained by the proliferation of resident preadipocyte progenitors. Indeed, crude cell fractions of human SVF contain fat cell precursors that could proliferate and differentiate into adipocytes in a defined medium [17, 18]. Faced with such results, the traditional belief has been that the new adipocytes appearing with the increase in fat mass arose from a population of resident preadipocyte progenitors in the SVF maintained in a “dormant” state. The physiological and pathological determinants of their recruitment as well as the processes controlling “dormancy” remained poorly defined. Fat cells can also undergo apoptosis or necrosis in vitro and in vivo [19]. It remained unclear for a long time whether adipocytes are generated in vivo and whether adipocytes are replaced during adulthood. A recent study using a method based on the incorporation of 14C from nuclear bomb tests into genomic DNA has allowed an evaluation of the fat cell turnover in humans. Approximately 10 % of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered, suggesting a tight regulation of fat cell number during adulthood [16]. It must be noted that the determinations of the rates of adipocyte turnover performed in this
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study were obtained on subjects with early onset obesity. It could be possible that, as previously mentioned, those gradual and late weight gainers over the years in adulthood may increase their adipocyte size until a threshold point where recruitment of new fat cells from fat cell precursors could occur. Various recent studies have shown a renewed interest in the search and the characterization of the adipocyte precursors in the adult and the mechanisms explaining their presence in fat depots. Similarities exist in cell immunophenotype between AT- and bone marrowderived stroma cells. Furthermore, mesenchymal stem cells are able to differentiate into adipocytes under adipogenic in vitro culture conditions. AT stromal cells in culture exhibit a profile of mesenchymal stem cells markers such as the cell surface marker CD105 and the lack of expression of the cell surface marker CD34 that are restricted in adults to hematopoietic stem and progenitor cells as well as in capillary endothelial cells [20, 21]. A cell population positive for CD34 has been identified in the SVF of human AT by various groups [20, 22, 23]. This stem cell-associated marker CD34 was at peak levels in the SVF cell batches and early passages while reduced levels were observed in serial-passaged adipose-derived stem cells. Recently an approach allowing separation of freshly isolated cell populations present in the SVF from human AT was developed by using magnetic microbeads coupled to antibodies directed against cell surface markers CD34, CD31 (marker for endothelial cells, monocyte macrophage lineage and platelets), and CD14 (marker for the monocyte/ macrophage lineage and the granulocytes). In the case of microvascular bed elements of AT, it was shown that the percentage of CD34+/CD31+ cells (a hallmark of capillary endothelial cells) from the human AT SVF remained constant whatever the BMI. It is suggested that the development of AT in humans is associated with a simultaneous increase of the microcirculatory network. Understanding the role played by AT blood vessels in homing and integrating various circulating lymphocytes, monocytes and bone marrowderived progenitor cells remains a fascinating challenge. Various experiments in mice have shown that disturbing AT vascularization has a major impact on AT development in genetically based and high fat feeding-induced obesity [24]. Among the different subsets of cells freshly isolated from human AT SVF, the CD34+/CD31– cells were the unique cell fraction able to differentiate into adipocytes in adipogenic culture conditions. The ability to differentiate into adipocytes was restricted to cells that did not express the mesenchymal stem cell marker CD105. Moreover, they did not respond to the culture conditions used for hematopoietic colony assays. Thus, in human fat, the adipocyte progenitor cells, (i. e., the preadipocytes) are included in the CD34+/CD31– cell fraction, which displays features distinct from the adult mesenchymal and hematopoietic stem cells [25]. Endothelial progenitor cells have been found in the same subset of the CD34+/CD31– cell population that also differentiate in vitro into endothelial cells, and participate in vivo in the revascularization of the ischemic hindlimb in mice [23]. It remains questionable if adipocytes and endothelial cells share a common precursor as recently proposed [22] or possess different progenitors existing in the CD34+/CD31– cell population; this aspect requires further investigation. A reciprocal relationship exists between the development of blood vessels and adipogenesis. Paracrine regulation of angiogenesis and adipocyte differentiation was demonstrated during in vivo adipogenesis [26] in rodents. It is
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unclear if CD34+/CD31– cells represent the resident “dormant” progenitor pool that has undergone some phenotypic changes when homing in fat depots. It cannot be excluded that they are cells of bone-marrow origin, recruited in AT after docking to microvascular endothelial cells of the AT vasculature. After entering the extra-vascular domain of human AT, they could stay under the control of adipocyte and other SVF cell secretions and gain their specific preadipocyte progenitor phenotype. A recent study in adult mice fed a high-fat diet or receiving thiazolidinedione (i.e., an antidiabetic agent) treatment has revealed a trafficking of bone marrow-derived circulating progenitors to AT [27]. It is a new mechanism for expanding the number of adipocyte progenitors in response to nutritional and pharmacological challenges. Nevertheless, this attractive conclusion is thrown into question by another group that has used a similar experimental design. For these authors, bone-marrow derived circulating progenitor cells failed to transdifferentiate into adipocytes in adult AT in mice. For the authors, bone marrow-derived circulating progenitor cells play a negligible role in expanding the number of adipocytes in the growth of AT in adult rodents [28]. Thus the debate continues and a number of questions remain open concerning the properties of the vascular bed which allows homing and incorporation of circulating progenitor cells to AT. Further studies are required to substantiate if this process occurs (and when) in human AT. It is well known that thiazolidinediones, as described in mice, also promote the appearance of new fat cells in rats. However, it is questionable if such a mechanism contributes to AT expansion and weight gain in humans under thiazolidinedione treatment. Macrophages and endothelial cells, identified by fluorescence-activated cell sorter analysis (FACS), have also been isolated from human AT from various fat depots using antibody-coated microbeads. The number of resident macrophages (i.e., AT macrophages-ATMs) present in human AT was found to correlate positively with BMI [29]. Such a correlation was confirmed by using other approaches in human subcutaneous fat depots [30–32] and has also been observed in various mouse models of obesity [30, 33]. In addition to changes in ATM number, dynamic changes in the ATM phenotype have been shown during the development of high-fat diet-induced obesity in mice. The ATMs shifted from a reparative resident phenotype observed in lean animals to inflammatory newly recruited ATMs in obese mice. In humans, ATMs appear less polarized and possess a proliferative capacity associated with a remodeling proangiogenic phenotype [34, 35]. A significant level of lymphocytes has been identified in the SVF of rodent white AT and an increased accumulation of T cell markers also exists in fat pads in obese patients [36, 37]. It remains to be seen whether changes in the degree of adiposity are associated with a modulation in the number and phenotype of the AT lymphocytes [38]. In addition to the immune cells of the SVF of AT that are the major contributors of cytokine production in AT [39], adipocytes are also capable of producing proinflammatory cytokines such as IL-6 and TNF-α and proteins with a C-terminal complement factor C1q globular domain that has a 3D structure similar to that of TNF-α and that are designated as C1q/tumor necrosis factor-related proteins (CTRPs). These proteins share a similar structure with the adipocyte hormone adiponectin. Adipocytes produce CTRP molecules of the newly described C1q/TNF and C1q-TNF-related proteins that belong to the innate immune system [40]. AT-derived stromal cells, preadipocytes and rodent adipocytes also express a number of Toll-like receptors
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(TLRs) that respond to various stimuli by the production of cytokines [41]. TLRs are a family of innate immune receptors that recognize pathogen-associated molecular patterns [42]. Some of them have been identified in human preadipocytes and adipocytes. TLR-2 and TLR-4 are colocalized with adiponectin in human adipocytes and TLR-4 exhibits the highest expression. TLR-4 is activated by Escherichia coli LPS (lipopolysaccharide) and fatty acids. TLR-2/TLR-4 stimulation was associated with nuclear factor-κB p65 (NF-κB p65) nuclear translocation and proinflammatory cytokine production in human adipocytes [43–45]. Nutritional lipids trigger inflammatory processes and ultimately insulin resistance [44]. Finally, recent studies have clearly enriched our knowledge of the role of AT as a putative immunological organ: thanks to functional TLR expression, adipocytes possess a fully intact pathway of innate immunity and can respond directly to patterns and antigens of microorganisms. The isolation of the various cell types present in the SVF has also opened up major perspectives about the nature and the fate of preadipocyte progenitor cells in human AT. In addition, it is clear that obesity is associated with increased accumulation of both T cells and macrophages in AT, the secretions of which may influence preadipocyte proliferation/differentiation and adipocyte functions.
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An overview of the endocrine factors and cytokines secreted by adipose tissue. The induction of insulin resistance and the appearance of vascular disorder through the altered production and release of numerous bioactive molecules from AT remains an important but still open question. Some recent reviews [46–48] discuss various aspects of the question and we will limit our current contribution to an overview. The factors expressed and/or secreted by AT, as well as their major biological impact is listed in Table 1. Some factors are strictly limited to adipocyte activity; that is the adipokines. A number of other products that are secreted originate mainly from the various cell types of the SVF, although sometimes they may also be weakly secreted by adipocytes [39]. Leptin, adiponectin (Acrp30), retinol binding protein 4 (RBP-4), tumour necrosis factor-α (TNFα), interleukin-6 -8 and-10 (IL-6, IL-8 and IL-10), plasminogen activator inhibitor-1 (PAI-1), resistin, monocyte chemoattractant protein (MCP-1; also known as CCL2), angiotensinogen and angiotensin II, macrophage inflammatory protein-1 (MIP-1β), IL-1 receptor antagonist (IL-1Ra), visfatin, angiopoietin-like peptide 4 (ANGPTL4), vaspin, serum amyloid A (SAA), apelin, omentin and others still poorly studied are new
Tab. 1: Adipose tissue productions. This list of productions/secretions originating from adipocyte and/or various cells of the stromavascular fraction is non exhaustive. The factors are grouped according to their major contribution in the control of major functions. Some productions possess pleiotropic actions and are found in different groups. Lipid and lipoprotein metabolism - lipoprotrein lipase (LPL) - acylation stimulating protein (ASP/C3desARG)) - prostaglandin E2 (PGE2), prostaglandins F-2α (PGF-2α), prostacyclin (PGI2) - autotaxin (lysophospholipase D) and production of lysophosphatidic acid (LPA) - cholesterol ester transport protein (CETP) Food intake and activation of sympathetic nervous system - leptin Metabolism and energy homeostasy - leptin - adiponectin - resistin - interleukin -6 et -8 (IL-6 and IL-8) - retinol binding protein-4 (RBP4) Vessels and angiogenesis - vascular endothelial growth factor (VEGF), thrombopoietin - monobutyrin - leptin, apelin - fasting-induced adipose factor (FIAF) or peroxisome proliferatoractivated receptor γ angiopoietin-related gene) (PGAR) - angiopoietin -2, - angiotensinogen/angiotensin-2, adrenomedullin Metabolism of extracellular matrix - type 6 collagen - plasminogen activator inhibitor-1 (PAI-1) - metalloproteases (gelatinases MMP-2 and MMP-9) - tissue inhibitors of metalloproteases (TIMP -1 toTIMP-3)
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Immune system, acute phase reactants and inflammation - tumor necrosis factor-α (TNF-α) - interleukins 1β, -6, -8, -10 (IL-1β,IL-6,IL-8, IL-10) - interleukin-1 receptor antagonist (IL-1Ra), macrophage inflammatory protein-1β (MIP-1β) - Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) - adipsin, factors C3, B and D of alternate complement system - monocyte chemoattractant protein-1 (MCP-1) - 1-acid glycoprotein - serum amyloïd A 3 (SAA-3) - haptoglobin, pentraxin-3, lipocalin 24p3 - metallothionein - cathepsin S and L Insulin sensitivity of muscle, hepatocyte and adipocyte - leptin - adiponectin - resistin - visfatin - omentin - vaspin - interleukin-6 (IL-6) - adipsin/acylation stimulating protein (ASP) - apelin Growth factors influencing adipose tissue development - Insulin Growth Factor-1 (IGF-1) - Nerve Growth Factor (NGF) - Vascular endothelial growth factor (VEGF) - thrombopoietin
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candidates among the growing number of factors found to be secreted by AT. Leptin and adiponectin are primary adipokines mainly secreted by adipocytes. RBP-4 and apelin are secreted by the adipocytes but they are also secreted by other tissues. TNFα, IL-6, IL-7, IL-8, IL-10, MCP-1, visfatin, PAI-1 are expressed in adipocytes and in activated macrophages and immune cells. Resistin is produced by peripheral mononuclear cells in humans while it is secreted by adipocytes in rodents. A general tendency to overestimate the importance of the adipocyte secretions is linked to a number of original studies that were carried out on AT explants instead of isolated adipocytes. Moreover, the definition of some factors has often been limited to RT-PCR identification of mRNAs without direct identification of the proteins. This field is expanding rapidly, with a recent study reporting changes in six newly identified secretory products of omental AT that were deregulated in obesity: three chemokines (Growth-related oncogene factor; regulated on activation, normal T cell expressed and secreted protein (RANTES); and MIF-1β), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1) and one growth factor (thrombopoietin)[49]. The relative and quantitative contribution of adipocytes and other cells of the SVF fraction (i. e., macrophages, lymphocytes, microvascular endothelial cells and adipose-derived stem cells) as well as mesothelial cells in the omentum to the total secretions of AT still remains unclear. Further studies are needed to clarify this important point. In terms of adipocyte secretions, cell size seems to be an important determinant. Enlarged adipocytes are associated with insulin resistance and are independent predictors of type 2 diabetes. A differential expression of pro- and anti-inflammatory factors was suspected with increasing adipocyte size with a shift towards the dominance of proinflammatory adipokines appearing as a dysregulation of the hypertrophic fat cell.
Conclusions, perspectives and limitations To conclude, as summarized in this review, adipose tissue biology and physiology have seen major developments during the last decade. Initially regarded as a tissue dedicated to energy storage and release of lipids, it is now clear that AT has a number of fascinating functional roles. We must bear in mind that the results of a number of studies on adipocyte biology published in the literature have been obtained using murine preadipose cell lines (i.e. 3T3-L1, 3T3F442A and ob17 cells). In addition, molecular and cellular approaches using knockout and transgenic mice have considerably expanded our knowledge of AT development, adipocyte biology and AT physiology. However, particularly in the field of metabolic regulation, caution must be exercised with respect to the clinical relevance of results obtained with rodent adipocytes and transgenic mice. In this review, we have essentially focused on human AT biology, and we have intentionally neglected brown adipose tissue (BAT). Brown fat cells dissipate chemical energy in the form of heat; their unusual function could be explained by the fact that they possess a common origin with muscle cells [50]. Experimental increases in BAT in mice have been associated with a lean and healthy phenotype while, by contrast, loss of BAT function is linked to obesity and metabolic disease. Until recently, BAT was thought to be metabolically important only in smaller mammals and human infants, while for some authors, BAT may have a much more important role in human metabolism than previously appreciated [51].
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Subcutaneous AT is the “bad guy” for a number of patients and clinicians. Adipocyte genocide seems to be a common practice for a number of dermatologists and cosmetologists, sucking out AT and placing it elsewhere with crude technology. AT merits attention and one might expect that in the near future it will be possible to clarify the coordinated participation of AT with the epidermis and the innate immune system to fight invading pathogens and improve wound healing. The paracrine secretions of subcutaneous AT can no longer be ignored in investigative dermatology. However, the ability of subcutaneous AT to contribute to the immune response could be a double-edged sword. Considering the number of pro-inflammatory and anti-inflammatory cytokines and growth factors that can be produced by AT, they could also and participate in skin diseases and the initiation of some skin cancers. Furthermore, AT tissue is an abundant and accessible source of adult stem cells having the ability to differentiate along multiple lineage pathways. Isolation procedures for AT-derived stem cells and their characterization have recently been reviewed [1]. Many important scientific and medical questions remain on the future of AT-derived stem cells. The mass media have optimistically presented the application of AT-derived stem cells for the treatment of a wide range of diseases. It is therefore very important at the current time that scientists and the medical community clearly distinguish the hope from the hype.
Address of Correspondence Max Lafontan, Ph.D., D.Sc. Research Director Inserm Unit 858, Dept. of Metabolism and Obesity Institute of Molecular Medicine of Rangueil BP 84225 F-31432 Toulouse cedex 4 France
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