Dig Dis Sci (2009) 54:1847–1856 DOI 10.1007/s10620-008-0585-3
REVIEW
Adipose Tissue: The New Endocrine Organ? A Review Article Susan E. Wozniak Æ Laura L. Gee Æ Mitchell S. Wachtel Æ Eldo E. Frezza
Received: 20 August 2008 / Accepted: 13 October 2008 / Published online: 4 December 2008 Springer Science+Business Media, LLC 2008
Abstract Fat is either white or brown, the latter being found principally in neonates. White fat, which comprises adipocytes, pre-adipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes, actively participates in hormonal and inflammatory systems. Adipokines include hormones such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidine, chemerin, omentin, and inflammatory cytokines, including tumor necrosis factor alpha (TNF), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator protein (PAI). Multiple roles in metabolic and inflammatory responses have been assigned to adipokines; this review describes the molecular actions and clinical significance of the more important adipokines. The array of adipokines evidences diverse roles for adipose tissue, which looms large in the mediators of inflammation and metabolism. For this reason, treating obesity is more than a reduction of excess fat; it is also the treatment of obesity’s comorbidities, many of which will some day be treated by drugs that counteract derangements induced by adipokine excesses. Keywords Adipose tissue Resistin Adipokines Cytokines Chemokines
S. E. Wozniak L. L. Gee E. E. Frezza Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA M. S. Wachtel Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, USA E. E. Frezza (&) New Life Bariatric, 505 N Lake Shore Drive, Suite 3101, Chicago, IL, USA e-mail:
[email protected]
Introduction The first to suggest a role beyond a repository for lipids for adipose tissue was von Gierke, who in 1905 recognized a role for adipose tissue in glycogen storage [1]. White adipose tissue, the predominant form found in adults (brown fat is principally found in neonates), comprises adipocytes, preadipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes; its multifarious composition renders white fat an important mediator of metabolism and inflammation [2], its general roles being schematized in Fig. 1. Since the first adipokine, leptin, was discovered in 1994, adipose tissue has been granted many vital roles for the host in general, making it an endocrine organ in its own right [3–18]. More specifically we are beginning to better understand the metabolic and inflammatory changes that take place in chronic obesity at the molecular level; the substratum to this discovery is the descriptions of multiple adipokines, including adiponectin, resistin, visfatin, apelin, vaspin, hepcidine, tumor necrosis factor alpha (TNF), chemerin, omentin, MCP-1, and plasminogen activator protein (PAI), many originally described as having originated from other than adipose tissue. Adding to the complexity is heterogeneity with respect to body site: the differing fat depots in the body play distinct roles, secreting different sets of adipokines, [2, 19] as outlined in Fig. 2. This review delineates the molecular description and clinical significance of many of the adipokines.
Hormone-Like Adipokines Leptin Leptin, a 16-kDa nonglycosylated anorexia peptide, hypothalamically modulates body weight, food intake, and fat
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1848 Fig. 1 White adipose tissue effects on metabolism and inflammation. White adipose tissue (WAT) influences metabolism through energy homeostasis, adipocyte differentiation, and insulin sensitivity. WAT affects inflammation through inflammatory control, cardiovascular protection, and vascular inflammation. Figure adapted from Juge-Aubry et al. [2]
Dig Dis Sci (2009) 54:1847–1856 White Adipose Tissue
Metabolism
Energy Homeostasis
-Leptin - IL-6 -IL-1 -IL-1Ra
Fig. 2 Local effects of white adipose tissue secretion. Local subgroups of white adipose tissue (WAT) include visceral, muscle, epicardial, perivascular, and kidney. Visceral WAT controls local and systemic inflammation while epicardial WAT controls local inflammation and chemotaxis. Muscle WAT is mainly involved in insulin resistance and kidney WAT affects intravascular volume hypertension. Perivascular WAT is largely involved with atherosclerosis and hypertension. Figure adapted from Juge-Aubry et al. [2]
Adipocyte Differentiation
-TNFa -MCP-1 -IL-1 -IL-1Ra IL-6
Insulin Sensitivity
Inflammatory Control
-IL-1 -IL-1Ra -IL-6 -TNFa
- IL-1 IL-1Ra -IL-6 -IL-8 -IL-9 -IP-10 -TNFa -MCP-1 -PAI -RANTES
Cardiovascular Protection/ Neo-angiogenesis
-Adiponectin -IL-1 -IL-1Ra -IL-10 -VEGF -Leptin -TNFa
Vascular Inflammation
-IL8 -IL-10 -MCP-1 -RANTES -Resistin
Main Categories of Specialized Functions of Local WAT Deposits
Visceral
Secretion of: IL-8 IP-10 MCP-1 RANTES
Local and Systemic Inflammation
Muscle
Epicardial
Secretion of: IL-6 IL-1b TNFa MCP-1
Secretion of: TNFa Free Fatty Acids IL-6
Insulin Resistance
stores [4, 5]. Leptin levels are proportional to insulin levels and inversely proportional to glucocorticoid concentrations [3–5]. Inflammatory cytokines, including TNF, interleukin-1 (IL-1), and leukemia inhibitory factor, induce leptin production [6]. Testicular steroids decrease and ovarian steroids increase leptin concentrations [7, 8]. Leptin regulates pancreatic islet cells, growth hormone levels, immunology homeostasis, hematopoiesis, angiogenesis, wound healing, osteogenesis, and gastrointestinal function [3, 9]. In the brain leptin has been shown to influence the cortex, hippocampus, and hypothalamus, exerting in the latter local control over appetite and levels of sex steroids, thyroxin, and growth
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Inflammation
Local Inflammation and Chemotaxis
Perivascular
Secretion of: IL-1/IL-1Ra IL-6 IL-8 IP-10 MCP-1 TNFa RANTES
Atherosclerosis and Systolic Hypertension
Kidney
Reabsorption of Na+
Increased Intravascular Volume Hypertension
hormone [10–13]. Leptin administration can regulate puberty in adults and children adults [17]. Decreased leptin signaling or receptor function increased energy intake and lowers energy expenditure [15], with leptin deficiency itself being a known cause of severe early-onset obesity, hypogonadism, hyperinsulinemia, hyperphagia, and impaired Tcell-mediated immunity, treatable with recombinant leptin [16, 17]. High levels of leptin in obese patients do not effect appetite suppression because of resistance to the hormone, which has been posited to be due to leptin receptor signaling defects, downstream blockade in neuronal circuits, and defects in leptin transport across the blood–brain barrier [18].
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Resistin Resistin is a 12-kDa peptide that mostly circulates as a high-molecular-weight hexamer but also has a distinct, more active low-molecular-weight complex [20]. The hormone is expressed in greatest concentration in mononuclear cells, but is also seen in muscle, pancreatic cells, and adipocytes [21]. Resistin encoding messenger RNA (mRNA) displays an even wider range, having been found in white fat, spleen, hypothalamus, adrenal gland, skeletal muscle, gastrointestinal tract, and pancreas [21]. The adipokine stimulates inflammatory cytokines such as IL-1, IL-6, and IL-12 and TNF through a nuclear factor kappa B (NF-j-B)-dependent pathway [22–24] and also reduces endothelial cell production of intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and CC chemokine ligand-2 (CCL-2) [25]. Resistin has been accorded a diabetogenic role in mice, but its function in the pathogenesis of human diabetes remains a matter of debate, with no definite role assigned to it with respect to insulin resistance, its name notwithstanding [26, 27]. Atherosclerotic aneurysmal vessel wall macrophages secrete resistin [28]. Chronic kidney disease increases resistin levels [29]. The hormone accumulates in the synovial lining of rheumatoid arthritis patients [21]. Adiponectin The gene for adiponectin, is located at chromosomal band 3q27, a susceptibility locus for diabetes and cardiovascular disease [30]. Adiponectin has both an adaptor protein, APPL1, as well as two receptors, AdipoR1 and AdipoR2, each comprising seven transmembrane domains [31]. AdipoR1 and AdipoR2 are the main adiponectin receptors with respect to glucose and lipid metabolism [32]. Current experiments also suggest a molecule known as T-cadherin to be an adiponectin receptor [33]. The protein, found in both murine and human blood [34], accounts for 0.01% of human plasma protein; its concentration markedly declines with morbid obesity [35, 36]. Adiponectin induces endothelial VCAM-1, ICAM-1, and pentraxin-3 expression [2]. The hormone, by decreasing reactive oxygen, is an antioxidant [37]. Adiponectin augments endothelial nitrous oxide production, acting to protect the vasculature by reduced platelet aggregation and vasodilation [38, 39]. Adiponectin itself may be antiatherosclerotic, as it acts as an endogenous antithrombotic factor [39, 40] and inhibits macrophage activation and foam cell accumulation, both being critical cytologic elements of atheromas [41]. Stroke, coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers have been associated with decreased adiponectin levels [42]. Hypoadiponectinemia has been correlated with
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increased atherosclerosis-related compounds, including adipocyte fatty-acid-binding protein (A-FABP), lipocalin2, as well as other markers of oxidative stress [43, 44]. The compound has great potential as a marker for atherosclerotic disease, its decrease having been shown to be predictive of acute coronary syndrome, myocardial infarction, coronary artery disease, and ischemic cerebrovascular disease [45, 46]. Apelin Apelin, produced by adipocytes, vascular stromal cells, and the heart, increases with increased insulin levels and also with obesity [47]. Cardiac apelin levels are downregulated by angiotensin II and restored with angiotensin type 1 receptor blocker in animal models with heart failure [48]. Ischemic cardiomyopathy [49] and hypoxia [50] increase apelin levels; atrial fibrillation and chronic heart failure have been associated with decreased apelin levels [51]. Apelin has positive hemodynamic effect, having been shown to be an inotrope in normal and failing rat hearts and in isolated cardiomyocytes [52]. Apelin may regulate insulin resistance by facilitating expression of brown adipose tissue uncoupling proteins and altering adiponectin levels [53]. Visfatin, Hepcidine, Omentin, Vaspin, Adipsin, and Angiopoietin Less well described, but probably equally important, other compounds have been discovered to be products of white fat. Visfatin, also produced by lymphocytes, decreases insulin resistance [54]. Visfatin inhibits apoptosis of activated neutrophils [55], implicating it both as a cause of damage in such conditions as acute lung injury [56] and as a potential therapeutic agent in sepsis [55]. Visfatin administration to mice decreases blood glucose levels; mice lacking one allele have increased plasma glucose [54]. Levels of hepcidine, which was first described as a urinary antimicrobial peptide, increase with obesity and correlate with levels of C-reactive protein and IL-6 [57, 58]. Hepcidine regulates iron homeostasis by inhibiting iron release from macrophages, iron absorption by enterocytes, and iron transport across the placenta. Omentin levels decrease with obesity and insulin resistance and increase as high-density lipoprotein and adiponectin increase [59]. Chemerin levels increase with increases in body mass index (BMI), blood pressure, and triglycerides; chemerin receptor defects impair 3T3-L1 cell differentiation into adipocytes and decrease adiponectin and leptin expression [60]. Vaspin, a serine protease inhibitor, reduces levels of leptin, resistin, and TNF; it improves insulin sensitivity and shows decreased concentrations in the physically fit and increased
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concentrations in obese patients, especially those with impaired glucose tolerance [61, 62]. Adipsin, also known as complement factor D, is mainly produced by monocytes and macrophages resident in fat [63, 64]; it mediates the rate-limiting step in the complement activation alternative pathway and, some say, generates an acylation stimulating protein that increases adipocyte triglyceride production [63]. Serum retinol-binding protein, heretofore limited to the delivery of retinol, has been shown to be increased in diabetic patients and glucose transporter-4 (GLUT-4)-deficient mice, a condition that is reversed by fenretinide, which increases urinary excretion of the protein, yielding, for mice, decreased insulin resistance [65]. Angiopoietin-like peptide-4, induced by peroxisome proliferator-activated receptor (PPAR)-a in the liver and PPAR-c in adipose tissue, shows levels that correlate with lipoprotein [66]; because its injection yields increased triglyceride levels and because other similar proteins are resident in the liver and the gut, the protein may well be part of a signaling pathway that regulates lipid metabolism and storage [66–68].
growth, immunity, inflammation, apoptosis, and cell division [69]. Their bioactivity is such that only 10% of the receptors need to be engaged to elicit a response [70, 71]. TNF, IL-1, and IL-6, which can initiate both acute and chronic inflammation, are controlled by three classes of proteins: soluble receptors that prevent binding to the cell surface, competitive binding proteins, such as IL-1Ra, and anti-inflammatory cytokines, such as IL-4, IL-10, or TGFb, which decrease inflammatory cytokine production [70]. TNF increases production of itself and of IL-6, nerve growth factor, MCP-1, resistin and visfatin [72, 73], decreases adiponectin and leptin concentrations [72, 73], and facilitates endothelial dysfunction and atherogenesis [74]. PAI increases when insulin resistance develops, encourages thrombosis when local increases are present, particularly atheromas of type II diabetic patients [75], and has been posited to bear a relationship with adiponectin with respect to cardiovascular disease [76]. Adipocyte differentiation is increased with decreased PAI and increased adiponectin and resistin [77]. Chemokines
Inflammatory Cytokines and Anti-Inflammatory Factors Cytokines The more than 100 inflammatory cytokines, divided as shown in Fig. 3 into interferons, interleukins, hematopoietic factors, chemokines, and growth factors, influence
Chemokines, traditionally seen as regulators of chemotaxis of inflammatory cells, are now known to be important mediators of a wide array of phenomena, including lymphoid organ development, rheumatoid arthritis, and atherosclerosis. Chemokines act locally, meaning that one can see chemokine activity in perivascular fat in cardiovascular disease, subcutaneous fat in inflammatory skin
AdipocyteSecreted Factors
Inflammatory Cytokines
Anti-inflammatory Factors
Adipocytokine
Interferons
Interleukins
Growth Factors
Chemokines
Anti-inflammatory
Receptor antagonist:
Soluble Receptors
Adipocytokine
Cytokines Leptin
IFNb
IL-1
Resistin
IFNy
IL-6
TNFa
IL-8 IP-10
IL-4
Visfatin
RANTES
IL-10
sTNFR
Adiponectin
MCP-1
TGFb
sIL-1R
Fig. 3 Inflammatory and anti-inflammatory adipocyte-secreted factors. Inflammatory cytokine subgroups include adipocytokines, interferons, interleukins, growth factors, and chemokines. Antiinflammatory factors include anti-inflammatory cytokines, receptor
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IL-1Ra
IL-1RII
Adiponectin
antagonists, soluble receptors, and adipocytokines. Many of the newly discovered adipose-tissue-secreted factors were not added to this figure due to a lack of research classifying them as inflammatory or anti-inflammatory. Figure adapted from Juge-Aubry et al. [2]
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1851 Adipocytokine
anti-inflammatory
inflammatory
adiponectin leptin
Endothelial adhesion
IL-6 (C68)
TNF (B:35)
Molecules (VCAM1 &
ROS (B70)
ICAM1) B88
TNF (B68, 71)
IL-12 (C86)
Chemotaxis (B70)
IL-6 (C86)
IL-12 (C68)
IL-1β (B86)
molecules (B40)
NK-cell function (B72)
NF-κB (B87)
IL-6 (C42.)
Neutrophil activation
TNF (B86,87)
Phagocytosis (B42) NF-κΒ (B40,41,43) innate
resistin
IFNγ (B42) Endothelial adhesion
visfatin
Apoptosis of neutrophils (B98) IL-8 (C119) IL-6 (C119)
(CD11b) B70
IL-1RA (B42) IL-10 (C42.)
TH2 response (IL-4) B64 T-cell proliferation (B 64)
T-cell responses (B42) B-cell lymphopoiesis adaptive
(B117)
ND
Thymocytesurvival (B73) ND
ND
Lymphopoiesis (B73) TH1 response (IL-2 and IFNγ) B64
Fig. 4 Adipocytokine role in adaptive and innate immunity. This is a more specific version of Fig. 3 focusing on adiponectin, leptin, resistin, and visfatin. Adiponectin primarily has anti-inflammatory properties, which become inflammatory in the presence of lipopolysaccaride. Adiponectin’s anti-inflammatory properties are part of both innate and adaptive immunity. Leptin, resistin, and visfatin are
only known to have inflammatory properties. Leptin’s inflammatory properties are part of both innate and adaptive immunity while resistin’s and visfatin’s inflammatory properties have only been shown to play a part in innate immunity. Figure adapted from Tilg et al. [86]
diseases, and perirenal fat in glomerulonephritis [78]. Chemokines produced by fat, including IL-8, MCP-1, interferon-gamma inducible protein 10 (IP-10), and regulated upon activation normal T-cell express sequence (RANTES) are often regulated by hormone-like adipokines, including leptin [79]. MCP-1, a mediator of Tlymphocyte recruiting and monocyte trafficking, is increased by leptin, obesity, and insulin-resistance-inducing hormones [80]. Epicardial fat produces more MCP-1 than does subcutaneous fat [81]; there exists a MCP-1 polymorphism associated with high coronary atherosclerosis risk [82].
Discussion Adipose tissue plays a major role with respect to metabolism and inflammation, a role whose mediators comprise adipokines, which include hormone-like proteins and inflammatory cytokines. The locations in which adipose tissue reside help determine its role. Whereas visceral adipose tissue can influence both systemic and local inflammatory processes, muscular deposits figure more prominently with respect to insulin resistance, perivascular fat can facilitate the development of atheromas, and perirenal fat can contribute to hypertension via increased
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lean
obese
blood vessel
apoptotic cell
adipose
adipose
tissue
macrophages
tissue
(AT)
(AT) macrophages
adipocytes
adipocytes
Liver insulin resistance Adiponectin
+
Liver Adiponectin
Leptin
+
ΙL-6
Resistin/
TNFα
FIZZ3
+
CRP
Leptin ?
Inflammation
? TNFα IL-6
+
Arteries Anti-
Muscle
Liver
atherogenic
Insulin
responsiveness
responsiveness
?
Resistin/FIZZ3
+
(Atherosclerosis)
? Muscle insulin resistance
Fig. 5 Adipokine expression in lean and obese individuals. On the left side of the figure the lean individual has regular-sized adipocytes and healthy levels of macrophages in their adipose tissue (AT), while on the right side the obese individual has enlarged adipocytes, with many more undergoing apoptosis and large amounts of macrophages engulfing these apoptotic cells. In the lean individual high levels of
adiponectin and low levels of leptin and resistin maintain a healthy homeostatic equilibrium with antiatherogenic properties, and muscle and liver responsiveness. In contrast, in the obese individual on the right, adiponectin levels are low and resistin and visfatin levels are high. This difference furthers atherosclerosis and muscle and liver insulin resistance. Figure adapted from Bastard et al. [87]
intravascular volume. The same adipokine, moreover, can have diverse effects: on a local basis, IL-6 both disrupts insulin signaling in hepatocytes and fat cells and regulates intramyocardial lipid accumulation to the degree that it serves as a cardioprotective agent; systemically it has been assigned a role in the pathogenesis of diabetes mellitus [80, 83–87]. Although the factors have been divided for convenience into hormone-like and inflammatory cytokine adipokines,
the latter being divided into inflammatory and antiinflammatory (Fig. 3), it should be clear that the boundary between the two categories is quite porous, with inflammatory cytokines influencing hormone-like proteins and vice versa. As the interaction of leptin and resistin with IL-6 and TNF shows (Fig. 5), the presence of obesity alters the relationship of the adipokines. The left side of Fig. 5, from a lean patient, shows adipose tissue with normal-sized
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adipocytes and only occasional macrophages. In lean patients, adiponectin concentrations are high and resistin concentrations are low; high levels of adiponectin exert antiatherogenic properties and increase insulin responsiveness, unimpeded by high resistin levels. The right side, from an obese patient, shows large adipocytes, more macrophages, and more apoptotic adipocytes; the cell necrosis induces inflammation and has been related to insulin resistance. Obese persons have high levels of leptin and resistin, yielding increased TNF and IL-6, which have been related to atherosclerosis via C-reactive protein. In contrast the obese patient on the right side of Fig. 5 has high leptin and resistin levels and low adiponectin levels. The high leptin and resistin levels increase insulin resistance and augment production of TNF and IL-6 whereby they can cause atherosclerosis through liver C-reactive protein. The low level of adiponectin in obese persons signifies the deprivation of a compound that counteracts the negative effects of high leptin and resistin. One of the issues still in question is if diabetes type II and other metabolic syndrome pathology are secondary to an inflammatory reaction. Some suggestions can be hypothesized: 1.
2. 3.
Lipid elevation and accumulation in nonadipose tissues (from chronic overnutrition and/or leptin deficiency or resistance) Insulin resistance Uncertainties: • • •
Cardiovascular disease (CVD) risk factors cluster but may not be a syndrome Insulin resistance as unifying etiology not proven Macrophages may play major role
The issues of macrophage and inflammatory factors creating an insulin resistance (IR) environment can be summarized in the following points: 1. 2.
3.
IR present in chronic pro-inflammatory state Inflammatory factors are present in target organs and appear to be increased in adipose tissue of obese humans Increased insulin sensitivity in macrophage-specific IKKb knock-out mouse
From our review, it appears that not only is there a correlation between metabolic and anti-inflammatory factors and type II diabetes, but also that most of the inflammatory factors are not produced in the ‘‘far distance’’ area of the body but in situ by the ‘‘fat cell.’’ This has opened a new door in research to understand the reaction and metabolic response of the adipocytes, which can open the possibility of understanding different disease and not
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just type II diabetes. This research will open the door to the neuroendocrine inflammatory theory of the diabetic.
Conclusion Knowledge of this relationship has generated research, delineated herein, into clinical manipulations with respect to adiponectin that might benefit the obese. Although exponentially increasing knowledge of adipokines promises much with respect to therapy, it markedly diminishes the possibility of summarizing adipokine function in a single review. Future reviews on adipocyte literature will likely focus on specific roles of adipose tissue, perhaps even being limited to specific roles of a few adipokines in specific adipose tissue deposits.
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