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Adipose Tissue-Derived Factors: Impact on Health and Disease

Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461

Correspondence: Address all correspondence and requests for reprints to: Philipp E. Scherer, Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: scherer{at}aecom.yu.edu

	Abstract

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
The endocrine functions of the adipose organ are widely studied at this stage. The adipose organ, and in particular adipocytes, communicate with almost all other organs. Although some adipose tissue pads assume the functions as distinct "miniorgans," adipocytes can also be present in smaller numbers interspersed with other cell types. Although fat pads have the potential to have a significant systemic impact, adipocytes may also affect neighboring tissues through paracrine interactions. These local or systemic effects are mediated through lipid and protein factors. The protein factors are commonly referred to as adipokines. Their expression and posttranslational modifications can undergo dramatic changes under different metabolic conditions.

Due to the fact that none of the mutations that affect adipose tissue trigger embryonic lethality, the study of adipose tissue physiology lends itself to genetic analysis in mice. In fact, life in the complete absence of adipose tissue is possible in a laboratory setting, making even the most extreme adipose tissue phenotypes genetically amenable to be analyzed by disruption of specific genes or overexpression of others.

Here, we briefly discuss some basic aspects of adipocyte physiology and the systemic impact of adipocyte-derived factors on energy homeostasis.

I. Introduction

II. Complexity of the Adipose Organ

A. Cellular composition

B. Adipose tissue depots

C. Gender differences in adipose organ function

III. Adipocytes and the Regulation of Energy Storage

A. Lipid deposition

B. Adipogenesis

C. Lipid mobilization and utilization

IV. Endocrine Function of the Adipose Organ

A. Adiponectin

B. Resistin

C. Additional adipokines

V. Adipose Tissue: Paracrine Effects

A. TNF

B. IL-6

C. Adipose tissue and the immune system

D. Acute phase reactants

E. Hyperglycemia-induced inflammatory response

F. Toll-like receptors

G. The FAT-ATTAC mouse: a novel mouse model for the study of adipose tissue physiology

VI. Concluding Remarks

	I. Introduction

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
THE ADIPOCYTE IS unique among cells in that one organelle, the lipid droplet, encompasses greater than 95% of the entire cell body. This lipid droplet serves as a storage vessel for triglycerides that can be released through lipolysis and added to by the process of triglyceride synthesis. Because the lipid droplet can assume such a large portion of the entire adipocyte, increases in lipid storage result in increased fat cell size. In fact, the capacity for triglyceride storage by the adipocyte is quite impressive because fat cells range from 25–200 µm in diameter. Hence, the adipocyte is traditionally viewed as a cell that is primarily involved in energy storage. However, it is now clear that the adipocyte has additional roles with the remaining 5% of its cellular mass. It has an exceptionally active secretory pathway whose function is not only to release products of conventional housekeeping genes, but also to release many endocrine and paracrine factors commonly referred to as adipokines. The endocrine functions allow the adipocyte to regulate processes in peripheral tissues such as the liver and the central nervous system such as the hypothalamus. The paracrine effects of adipokines have an impact on neighboring adipocytes as well as other local cell types within adipose tissue.

	II. Complexity of the Adipose Organ

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
A. Cellular composition
Adipose tissue is comprised of adipocytes as well as many additional cell types. Although these additional cells account for a significant proportion of the total cell number in adipose tissue, they are not highly visible in histological sections. Conventionally, these "stromal vascular cells" are being isolated using protocols that have been established many years ago in pioneering studies by Rodbell (1) and colleagues. This involves collagenase digestion followed by flotation of the adipocyte fraction using a low G-force (1). The resultant pellet of this cell suspension contains nonadipocytes. This fraction includes cell types such as preadipocytes, endothelial cells, pericytes, monocytes, macrophages, and others. These cells exert a number of important functions for adipose tissue homeostasis. For example, pericytes and endothelial cells make up the vasculature of tissues and enable processes such as adipose tissue growth and development. Secretion of proangiogenic factors by adipocytes such as vascular endothelial growth factor growth (2), contributes to ongoing angiogenesis within adipose tissue at all times. In fact, blocking vascular endothelial growth factor or angiogenesis has a significant impact on adipose tissue homeostasis (3, 4), suggesting that this process is crucial to sustain normal adipose tissue function and for the support of its metabolic and endocrine functions. Additional cell types including the monocytes and macrophages are present in adipose tissues and are thought to aid in the clearance of necrotic adipocytes, a role that appears to be of importance in adipose tissue in obesity (5). Lastly, adipose tissue is a reservoir of pluripotent stem cells (6). These cells, although poorly defined, may contribute to the pool of differentiated stromal vascular cell types as well as to the adipocyte pool. Whether a particular grouping of cells within the stromal vascular fraction is designated for adipocyte differentiation, such as a preadipocyte, in vivo is not known.

The composition of the stromal vascular fraction of adipose tissue can differ with depot and physiological/pathological state (7, 8). Although the relevance of these differences is poorly understood, potential paracrine effects of stromal vascular cells have long been appreciated (9). Many of the differences in gene expression in adipose tissue depot include changes in genes typically expressed by the stromal vascular cells (10). Recent studies of obese adipose tissue have revealed that increases in inflammatory cytokine expression by adipose tissue parallel increases in adipose tissue macrophage content (11, 12, 13). Because increased inflammatory tone has been shown to have dramatic impact on metabolic and endocrine function of the adipose organ, increased focus has been placed on cellular composition of adipose tissue depots and the factors influencing changes in adipose tissue composition in pathological states.

B. Adipose tissue depots
Unlike other organs, adipose tissue is distributed throughout the body in a variety of locations (14). Different fat pads show relatively minor differences in gene expression at the global level, and very few depot-specific markers have been identified. These include the brown adipose tissue-specific uncoupling protein 1 (15) and the more recently identified visfatin (16) and omentin (17). However, neither omentin nor visfatin is specifically expressed by adipose tissue, and the visceral depot-specific expression of visfatin has recently been questioned as well (18). Interestingly, two recent independent studies by the Kirkland and Kahn laboratories report evidence for intrinsic depot differences in expression of developmental genes that are maintained after differentiation and long-term culture (19, 20). Together, these reports suggest that adipocytes from different depots are distinct and that the heritability of depot differences in developmental genes may contribute to the type of obesity, body fat distribution, and/or development of metabolic disorders.

Nevertheless, despite subtle differences in gene expression, adipose tissue depots vary across all aspects of adipose tissue structure, composition, and impact upon neighboring organs. Adipose tissue depots could be considered "mini-organs" serving functions unique to their location as well as functions universal to the tissue type (21). An example of a physiologically important interaction between an adipose tissue depot and a neighboring organ is the unique relationship between the mammary fat pad and the ductal epithelium of the mammary gland. The mammary fat pad is required for normal growth and development of the mammary gland (22, 23, 24). Mammary adipocytes can influence ductal epithelial cells through secretion of paracrine factors (25). Many different factors contribute to these interactions. These paracrine interactions become particularly relevant in the context of mammary carcinogenesis, when transformed ductal epithelial cells critically depend on the surrounding adipocytes for survival. Our laboratory has embarked on a systemic analysis of specific adipocyte-derived factors with an impact on early lesion growth in breast cancer models, such as the MMTV-PyMT mouse. We have identified several adipocyte-derived factors with a profound impact on tumor growth. We have published our observations related to the adipocyte-derived collagen VI3 chain (26) and seen that collagen VI3 is dramatically up-regulated in adipocytes isolated from tumor specimens in mice and humans. Lack of collagen VI leads to reduced tumor growth. During cancer progression, the adipocyte-derived collagen VI is cleaved near its C-terminal C5 domain and released into the stromal fraction, where it binds to a proteoglycan receptor on the surface of cancer cells, activating the canonical ß-catenin pathway. Unquestionably, additional adipocyte-derived factors play a role in this process. Several in vitro studies support a role for adipose tissue in the regulation of normal and malignant growth (27, 28). Employing specific genetic manipulations to affect the metabolic state of the "stromal" adipocyte will hopefully enable us to identify the critical adipocyte-derived factors that are dysregulated in the obese and insulin-resistant state, thereby identifying candidate factors that are mediating the well-established link between obesity and increased breast cancer incidence (29).

Histologically, two fundamentally different adipose tissue types can be differentiated: white adipose tissue, and brown adipose tissue (BAT). White adipocytes are found in white adipose tissue and contain unilocular lipid droplets suggesting an enhanced capacity for lipid storage. In contrast, brown adipocytes in BAT depots contain multilocular lipid droplets and primarily function in nonshivering thermogenesis. The expression of uncoupling protein 1 in addition to increased presence of mitochondria in adipocytes are the distinguishing features of brown adipocytes and hence BAT. Although the relevance of BAT for adult rodents is widely appreciated, we now also know that substantial amounts of brown adipocytes exist throughout life in human adipose tissue (30). Whether the presence of brown adipocytes in white adipose tissue depots stems from transdifferentiation of white to brown adipocytes or is the result of de novo differentiation of brown adipocytes within traditionally white adipocyte depots is unclear (31).

Most other known depot differences in adipocyte function relate to the variable effects of extrinsic factors on adipose tissue depots. For example, the effects of insulin on metabolism and endocrine function of the adipose organ tend to be greater in sc compared with visceral adipose tissue depots. In contrast, the effects of catecholamines and glucocorticoids tend to be greater in visceral vs. sc adipose tissue depots (32). The reasons for these differences across depots may lie in differences in receptor number, as has been postulated for catecholamines and glucocorticoids (33, 34), or, as in the case of insulin, may involve desensitization via local paracrine factors within visceral adipose tissue depots (35). Given that many of these effects persist after long-term culture of adipose tissue (36), it is unlikely that depot differences in the effects of extrinsic factors on adipose tissue function are entirely dependent on the systemic hormonal milieu in vivo. Instead, depot differences in adipocyte function may derive from differences observed in preadipocytes from varying depots (37), from the influence of factors produced by the stromal vascular compartment, or from factors secreted by neighboring organs.

C. Gender differences in adipose organ function
Gender exerts profound effects on metabolism and endocrine function of the adipose organ. Women have a higher percentage of body fat than men and tend to store adipose tissue preferentially in the gluteal-femoral region as opposed to the classic male pattern obesity concentrated in the visceral and abdominal depots (38). The increased gluteal-femoral adiposity in women is associated with larger fat cell size, increased stimulated lipolysis, and increased triglyceride synthesis in these depots (39). In contrast, increases in abdominal adipose tissue in men are associated with decreased stimulated lipolysis, decreased triglyceride synthesis, and increased lipoprotein lipase (LPL) activity in these depots (39, 40). Interestingly, the differences in visceral adipocyte metabolism between genders disappears with menopause and may be the cause of weight gain in the abdominal region with menopause (41). Together, these findings suggest that female sex hormones play a significant role in these gender depot differences, leading to differences in adipocyte metabolism. Estrogen is an obvious candidate and may mediate several of these differences in adipocyte metabolism. Early studies in rats demonstrated that ovariectomy (OVX) increases LPL activity, whereas supplying exogenous estrogen decreases LPL (42, 43). In agreement with these studies, estrogen decreases lipogenic gene expression in OVX mice and leads to a decrease in body weight independent of food intake (44). Data on the effects of estrogen on lipolysis are less clear. Estrogen increases lipolysis in vivo and increases ß-adrenergic-stimulated lipolysis ex vivo (44, 45). However, estrogen also increases adipocyte expression of perilipin and 2A-adrenergic receptors, two proteins with antilipolytic properties (44, 46). Therefore, estrogen may mediate the gender differences in depot-specific LPL activity leading to increases in adipose tissue deposition in the gluteal-femoral region of females. This remains a very attractive hypothesis, because tissue-specific overexpression of LPL effectively partitions lipid into either muscle or liver (47), although such effects were not seen upon adipose tissue overexpression of LPL (48). However, estrogen may regulate additional aspects of adipose tissue metabolism.

Endocrine function of the adipose organ also exhibits sexual dimorphism. Serum levels of adiponectin, an adipocyte-derived hormone (for more details, see Section IV.A.), are similar in newborn mice at 1wk of age. Yet after sexual maturation, circulating levels of adiponectin are twice as high in female mice compared with male mice (49). The lower level of adiponectin observed in males is likely due to neonatal imprinting in males because castration of neonates but not adult males resulted in increases in serum adiponectin to levels comparable to those seen in females. In females, adiponectin levels are high and remain so even after OVX (pre- and postsexual maturation) until the prolonged absence of estrogen triggers an increase in fat mass that leads to a secondary down-regulation of adiponectin. Estrogen treatment results in decreased adiponectin levels both in vivo and in vitro. The sexual dimorphism also relates to a different distribution of adiponectin complexes in circulation (50). Testosterone selectively reduces the release of the high molecular weight (HMW) form of adiponectin (51). Many of these effects of sex steroids appear to be mediated indirectly via posttranscriptional mechanisms, because there is no difference in adiponectin mRNA levels between male and female fat pads (49). Nevertheless, both male and female sex steroids play a distinct role in the regulation of adiponectin levels in circulation and may therefore account at least in part for the generally improved insulin sensitivity in females through the effects of estrogen on adiponectin levels.

The adipocyte-derived hormone leptin exhibits a similar sexual dimorphism (52). This dimorphism also presents upon sexual maturation and is influenced by sex hormones (53). However, it is important to note that gender differences in adipose tissue-derived hormones are not universal because there is no reported gender difference in circulating levels of the adipokine resistin (54).

	III. Adipocytes and the Regulation of Energy Storage

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
A. Lipid deposition
Lipid levels in an adipocyte are the net result of several different processes, including lipoprotein hydrolysis, fatty acid uptake/de novo fatty acid synthesis, and fatty acid esterification. A dysregulation of these processes leading to increases in serum triglyceride and free fatty acid (FFA) levels combined with the deposition of triglycerides in nonadipose tissues leads to dyslipidemia and lipotoxicity and contributes greatly to the development of the metabolic syndrome. The ability to redirect lipids away from ectopic deposition in cells other than adipocytes toward the adipocyte may be the cause of reversal of many of the metabolic complications associated with diseases such as obesity and diabetes.

Although the control of lipid partitioning to adipocytes is complex, several aspects of this process have been elucidated through the study of thiazolidinediones (TZDs), a class of antidiabetic drugs originally known for their role in improving insulin sensitivity in part through their role as peroxisome proliferator-activated receptor (PPAR)- agonists. In adipose tissue, TZDs increase expression of genes that promote energy storage in the adipocyte including LPL, fatty acid transporter protein, adipocyte fatty acid binding protein, malic enzyme, glucokinase, and the GLUT4 glucose transporter (reviewed in Ref. 55). TZDs also up-regulate fatty acyl-CoA synthase (a gene responsible for de novo lipogenesis; Ref. 56) and increase triglyceride reesterification through the enhanced expression of phosphoenolpyruvate carboxykinase in adipocytes (57, 58). Together, changes in adipocyte gene expression with thiazolidinedione (TZD) treatment result in lipogenesis and repartitioning of triglycerides toward adipose tissue, ultimately leading to improvements in metabolic complications in nonadipose tissues (59).

Glyceroneogenesis is a key process for lipogenesis in the adipocyte. Adipocytes normally lack glycerol kinase and therefore cannot utilize glycerol as a substrate for gluconeogenesis, a process that provides a key component for the triglyceride backbone, glycerol. Deficiencies in the local glyceroneogenic pathway in adipocytes cannot be fully compensated for by increased import of glycerol from circulation. Therefore, the lack of a key enzyme in the glyceroneogenic cascade, such as phosphoenolpyruvate carboxykinase-C, leads to a lean phenotype. We have identified an additional protein, a mitochondrial transporter that plays an integral role in this cascade, the mitochondrial dicarboxylate carrier (mDIC). In fact, this carrier protein is enriched in adipocytes and may be involved in the processes of both lipogenesis and fatty acid reesterification. mDIC functions to shuttle metabolites such as malonate, malate, and succinate into the cytosol in exchange for phosphate, sulfate, and thiosulfate, thereby providing cytosolic machinery with critical metabolites for lipogenesis and glyceroneogenesis. mDIC expression is decreased with cold exposure, a state associated with decreased lipogenesis, and induced by treatment with FFA, further underlining its role in anabolic pathways (60). However, the role of mDIC in TZD-mediated changes on lipid partitioning/deposition is not known. Furthermore, other than increases in mDIC during hyperglycemia, little is known of the regulation of mDIC in metabolic complications associated with obesity and diabetes. Future efforts are under way to elucidate the role of mDIC in energy storage in the adipocyte and its potential as a therapeutic target in disease states.

B. Adipogenesis
As we gain weight, adipose tissue expansion is a two-step process. In an initial phase, we accumulate increased levels of triglycerides in our adipocytes, thereby increasing the average adipocyte size. At later stages, increasing the storage capacity of adipose tissue requires the recruitment and differentiation of preadipocytes from the stromal vascular compartment of adipose tissue. Although the signal dictating the need for preadipocyte recruitment and initiation of differentiation is not known, TZD treatment leads to an increase in fat cell number, putting its target receptor, PPAR, center stage for adipogenesis. PPAR is therefore often referred to as the master regulator of the adipogenic program.

Most of the information regarding the adipogenesis has been obtained in the 3T3-L1 preadipocyte cell line. This cell line was originally isolated for its ability to undergo adipocyte conversion (61, 62) and is now the predominant model for the study of adipogenesis in vitro. Unfortunately, use of primary preadipocytes is hampered by the difficulty in preemptively separating this population from the other cell types in the stromal vascular fraction of adipose tissue and the difficulties in studying the terminal differentiation process of the adipocyte in vivo. Yet the study of adipogenesis in the 3T3-L1 preadipocyte cell line continues to provide insight into this complex process. However, there are many aspects of the adipogenic program that are poorly understood.

In vitro, several studies have demonstrated the importance of p38 MAPK in adipogenesis. p38 Activation occurs early on in the adipogenic program whereby p38 phosphorylates CEBPß, a transcription factor that induces the expression of PPAR (63). Inhibition of p38 during the first few days after the start of adipogenic program results in the inhibition of adipogenesis. The timing of p38 inhibition appears to be critical because inhibition at later time points has no effect on adipogenesis. The effect of p38 activation is potent because constitutive activation of p38 via upstream kinases (MKK6) triggers spontaneous 3T3-L1 cell adipogenesis (64). Interestingly, constitutive p38 activation after full differentiation (d8) results in adipocyte apoptosis (64). This is an unusual phenomenon, because adipocytes are generally very resistant to apoptosis. Future models enabling the study of the role of p38 in adipogenesis in vivo will have to be developed to fully appreciate the role of p38 in adipogenesis vs. apoptosis of the adipocyte.

C. Lipid mobilization and utilization
Lipid mobilization and utilization are two processes intimately intertwined. Lipid mobilization from adipose tissue depots results in the release of FFAs into the blood where they can be transported and taken up by tissues for energy. Lipid utilization requires the uptake of FFAs into the cell where they can be oxidized via the mitochondria through the process of ß-oxidation. The adipocyte plays important roles in both lipid mobilization and utilization. Although several mouse models highlight the importance of adipocyte involvement, our efforts have focused on the regulation of these processes by caveolar/raft structures in the plasma membrane and employ the study of the caveolin-1 null mice.

Caveolin-1 is a member of a family of integral membrane proteins that are frequently a fundamental component of specialized plasma membrane domains called rafts due to their unique lipid composition. A subset of these raft structures are referred to as caveolae. They are cholesterol-rich vesicular invaginations in the cell membrane rich in receptors and downstream signaling effectors (65). Although a lot remains to be clarified regarding the precise function of caveolae, they have an important role in the processes of transcytosis, potocytosis, and cell signaling. In the context of adipocytes, caveolae are particularly interesting because caveolae are a highly abundant component of the plasma membrane of adipocytes, and caveolin-1 is most highly expressed on the adipocyte (66). Over the past 12 yr, the precise role of these caveolar raft structures has been intensely debated, but there is little doubt at this stage that these plasma membrane subdomains have an impact on cellular homeostasis in the adipocyte with respect to insulin signaling, glucose transport, and FFA uptake (67).

Genetic deletion of caveolin-1 in the mouse results in adipocyte abnormalities including defects in lipolysis and thermogenesis (68, 69, 71). In the caveolin-1 null mouse, there is no elevation in circulating FFAs in response to starvation. In addition, there is a lack of response to ß3 adrenergic-stimulated lipolysis in vivo and in vitro. This lack of response accompanied by an inability of protein kinase A (PKA) to phosphorylate perilipin, a lipid droplet protein whose phosphorylation is critical for the lipolytic response to ß-adrenergic stimulation. Coimmunoprecipitation studies suggest that caveolin-1 forms a scaffold between the PKA and perilipin that is instrumental in the phosphorylation of perilipin by PKA. This defect compounds the inability of the caveolin-1 null mouse to maintain core temperature in response to starvation/cold exposure (72). Although the underlying mechanism of this defect is likely dependent on the failure to respond to lipolytic stimulation, there may also be defects in mitochondrial function as suggested by transmission electron microscopy of BAT and in the inability to down-regulate the mitochondrial dicarboxylate carrier mDIC in response to cold exposure in the caveolin-1 null mouse. Together, these studies highlight the importance of caveolar structures in maintaining normal physiological functions of the adipocyte.

	IV. Endocrine Function of the Adipose Organ

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
Studies in the late 1980s have demonstrated that adipocytes can secrete a number of factors and that the secretion of some of these factors is affected by metabolic dysregulation (73, 74). However, the concept describing the adipocyte as an endocrine cell did not gain general acceptance until several additional factors were identified in which expression was highly enriched in adipocytes, such as leptin and Acrp30/adiponectin (75, 76). For the past 10 yr, endocrine aspects of adipose tissue function have become an extremely active area of research, and several additional hormones have been discovered (77). Generally, these adipose tissue-derived factors are referred to as adipokines. These adipokines influence a number of important systemic phenomena (Fig. 1) and interact in the process with a large number of different organ systems (Fig. 2). Although the expression of a number of these secreted products is enriched in adipocytes, expression of only a few of these factors is consistently restricted to adipocytes in rodents and humans. Of these, adiponectin shows the most restricted expression pattern, with very few credible reports for expression in cells other than adipocytes except under conditions of severe hepatic steatosis during which the entire adipogenic program is induced in hepatocytes (78). Other adipocyte-derived hormones such as leptin and adipsin exhibit expression patterns that are less adipocyte specific (73, 79). In fact, several adipose tissue-derived hormones such as resistin, omentin, and visfatin (also known as pre-B-cell colony-enhancing factor) are produced by several other tissues as well (17, 18, 80).

View larger version (45K): [in this window] [in a new window]   FIG. 1. Major disease areas that are affected by adipocyte-derived factors.

View larger version (58K): [in this window] [in a new window]   FIG. 2. Major organ systems that are affected by adipocyte-derived factors.

1. Structure.
Adiponectin is composed of an N-terminal signal sequence, a hypervariable domain, 15 collagenous repeats, and a C-terminal globular domain (84). Circulating adiponectin forms several different complexes in the adipocyte before being secreted into the serum (50). The most basic form of adiponectin secreted by the adipocyte is the trimer. The specific function of these trimers is not well defined. Aside from forming free trimers, adiponectin also forms two higher-ordered structures through the noncovalent binding of two trimers (hexamers) and six trimers (18mers). These higher-ordered complexes are described as low molecular weight (LMW, hexamers) and HMW (18mers) forms of adiponectin. Of these higher-ordered structures, only the HMW form has bioactivity; the function of the LMW form is not yet known. Adiponectin undergoes extensive posttranslational modifications that include several carbohydrate modifications (85), and some of these carbohydrate modifications are essential for its bioactivity (86). Several glycoproteins have been reported to be associated with adiponectin (87), but the relevance of this association is not yet clear.

We have reported the structure of the globular trimeric form at high resolution (88). Surprisingly, although there is no apparent similarity between adiponectin and TNF, a structural comparison reveals a very close relationship between the two molecules. In fact, the availability of the adiponectin structure highlighted the very close structural relationship between members of the C1q superfamily and the TNF superfamily for the first time. This remains an intriguing relationship and may be the underlying explanation for the potent antiinflammatory properties reported for adiponectin, although to date there is no evidence suggesting that adiponectin can directly interact with any member of the TNF receptor superfamily.

2. Function.
Initial studies designed to examine the function of adiponectin employed various forms of recombinant adiponectin. Some of these studies produced recombinant adiponectin through bacterial expression systems. These systems produce a full-length or globular (a proteolytic cleavage product) form of adiponectin. Administration of these bacterially produced forms of adiponectin resulted in decreases in glucose, FFAs, and triglycerides in vivo and increased glucose uptake and fatty acid oxidation in muscles in vitro (89, 90, 91). However, the bacterially produced forms of adiponectin lack the ability to form higher-order structures and are devoid of any relevant posttranslational modifications (88). Therefore, to date it is not clear whether the effects attributed to the globular form are merely an interesting pharmacological observation or whether they have a relevant physiological counterpart. Adiponectin produced by mammalian expression systems is more likely reflecting the structure and function of endogenous adiponectin circulating in plasma. In the liver, administration of adiponectin results in glucose lowering due to decreased hepatic glucose output and suppression of gluconeogenic genes (92, 93). Similar observations can be made in mice endogenously overexpressing adiponectin from adipocytes (94). In support of these findings, mice lacking adiponectin have reduced insulin sensitivity primarily at the level of the liver (95). In the brain, intracerebroventricular administration of adiponectin results in decreased body weight and fat mass (96). These changes were due to increases in energy expenditure and not through effects on food intake. In the heart, adiponectin exerts potent cardioprotective effects and decreases myocardial infarct size in a cardiac ischemic reperfusion model (97, 98, 99, 100). Adenoviral-mediated overexpression of adiponectin accelerates repair in a model of ischemic hind limb by increasing angiogenesis (101).

Adiponectin is present in microgram quantities in the serum and has a rapid turn over (50). Therefore, the use of adiponectin as a protein therapeutic is likely to be quite limited, except for defined acute applications such as in the context of myocardial infarctions. Nevertheless, it is clear that increasing adiponectin levels has many beneficial effects on insulin sensitivity, inflammation, and lipid profiles (102, 103). Early findings demonstrating serum adiponectin levels are inversely correlated with obesity initiated intense investigation of the relationship between adiponectin and all symptoms of the metabolic syndrome (81, 104). Of these studies, strong evidence suggests that hypoadiponectinemia is highly correlated with cardiovascular disease (105, 106). Adiponectin is inversely correlated with cardiovascular risk factors such as dyslipidemia (107), and high serum adiponectin levels decrease the risk of myocardial infarction (108). Future studies examining the mechanisms mediating the chronic effects of adiponectin on the heart and vasculature in disease models will greatly facilitate our understanding of the role of adiponectin in cardiovascular disease.

Hypoadiponectinemia is also associated with insulin resistance and diabetes (109). Studies in rodents suggest that the antidiabetic effects of adiponectin are likely due to decreased hepatic glucose output. In support of this hypothesis, studies in humans show that adiponectin levels correlate with basal and insulin-suppressed endogenous glucose production and not with ß-oxidation (110, 111). The relationship between adiponectin and insulin resistance are present in several different diabetic populations, several of which exhibit this relationship independent of obesity (112, 113, 114, 115). In further support of these findings, studies in monkeys and humans show that adiponectin levels drop before the decrease in whole-body insulin sensitivity (116, 117). Therefore, therapeutic treatments that increase adiponectin levels have great potential to enhance insulin sensitivity as well as exert cardioprotective effects.

One of the most potent insulin-sensitizing classes of therapeutics includes the TZDs (59). TZD treatment results in improvements in insulin sensitivity and improvements in the serum lipid profile. Several lines of evidence suggest that adiponectin mediates several of these beneficial effects. First, TZD treatment increases serum adiponectin (118). More specifically, the improvements in insulin sensitivity with TZD treatment correlate best with the levels of the HMW form of adiponectin (119), suggesting that different forms of adiponectin possess different bioactivities and/or target organs. Beyond these merely correlative observations, we have recently reported that TZD treatment is not as effective in mouse models lacking adiponectin (95). These observations have been confirmed and added value to the very elegant studies by Kadowaki and colleagues (120). Finally, overexpression of adiponectin by adipocytes exerts TZD-like effects on lipid metabolism and insulin sensitivity. Increases in circulating adiponectin in these mice are coupled with improved lipid clearance and insulin sensitivity (94). When crossed to ob/ob mice, adiponectin overexpression confers dramatic metabolic improvements (J.-Y. Kim and P. Scherer, manuscript under review). These improvements include decreased serum triglycerides, decreased fat cell size, increased fat cell number, and improved glucose tolerance. Taken together, these data suggest that adiponectin may mediate several of the beneficial effects of TZDs on metabolism.

How does adiponectin exert its beneficial effects on lipid metabolism? Although a number of different mechanisms may be contributing, we observe in many of our in vivo systems of adiponectin overexpression that there is a significant increase in adipose tissue LPL activity. Similarly, TZD treatment also increases adipose tissue LPL activity in vivo and in vitro (121). It is not clear whether this is an indirect effect exerted through increases in PPAR activity or a reflection of a direct protein/protein interaction between adiponectin and LPL. However, the strong correlation between adiponectin levels and LPL activity can also be seen clinically (122, 123).

TZD exposure primarily leads to an increase in the HMW form (119), highlighting the potential importance of the HMW (124, 125, 126, 127, 128, 129, 130, 131, 132). While measurements of the HMW forms are clearly more informative under some circumstances, other circumstances suggest that the measurements of the HMW form and total adiponectin are comparable correlations. We will have to await the use of recently developed high throughput assays for the measurement of HMW forms in large epidemiological studies to better gauge the appropriate settings under which the HMW measurements will provide added value to the measurement of total levels.

In addition to its antidiabetic effects, several lines of evidence suggest that adiponectin is also antiatherogenic. Clinical and epidemiological studies show a strong positive correlation between hypoadiponectinemia and cardiovascular risk factors such as inflammation and dyslipidemia (108, 133, 134, 135, 136, 137). In fact, several studies have demonstrated that the correlation between hypoadiponectinemia and cardiovascular disease persists even after adjustment for cardiovascular risk factors such as body mass index, diabetes, dyslipidemia, and hypertension (105, 106). A large case-control study demonstrated that high levels of circulating adiponectin were associated with decreased risk of myocardial infarction (108). However, the mechanistic basis for the association between hypoadiponectinemia and cardiovascular disease in humans remains to be established.

Several recent in vivo studies in mice have suggested that adiponectin is beneficial and may protect against cardiovascular disease. Adiponectin knockout mice exhibit increased neointimal hyperplasia, increased smooth muscle cell hyperplasia, and impaired neovascularization after acute vascular injury (99, 138, 139); apolipoprotein E knockout mice expressing high levels of the globular form of adiponectin (transgenically or adenovirally mediated) demonstrated decreases in atherosclerotic lesion formation (140, 141). Together, these data suggest more thoroughly that hypoadiponectinemia may increase risk of cardiovascular disease and that adiponectin may have therapeutic potential in its ability to protect against cardiovascular disease.

Evidence from in vitro studies further supports the notion that adiponectin works against the development of cardiovascular disease. Adiponectin has been shown to play a role as an antiinflammatory factor by decreasing inflammatory cytokine expression and blocking nuclear factor B (NFB) activation (142, 143). Adiponectin-mediated inhibition of NFB in endothelial cells results in decreased expression of vascular adhesion molecules such as vascular cell adhesion molecule 1, E-selectin, and intracellular adhesion molecule 1, suggesting that adiponectin may prevent monocyte extravasations (144). Furthermore, adiponectin may inhibit plaque formation through its ability to inhibit foam cell formation (145) and stimulate smooth muscle cell proliferation (146). Thus, the in vitro data support findings from in vivo studies in mice and humans providing strong evidence that adiponectin may be protective against the development of atherosclerosis and cardiovascular disease.

In summary, adiponectin is an important adipokine that has the potential to be an important mediator of many physiologically relevant processes. Modulation of adiponectin levels has a profound impact, particularly in pathological settings, such as in diabetes, cardiovascular disease, as well as in the context of cancer (not discussed further here) (Fig. 3).

View larger version (57K): [in this window] [in a new window]   FIG. 3. Involvement of adiponectin in the pathological sequelae of various disease areas.

In addition to the adiponectin receptors AdipoR1 and -2, T-cadherin is also a candidate adiponectin receptor (149). T-cadherin is a glycosylphosphatidylinositol-anchored extracellular protein that is expressed in endothelial and smooth muscle cells. T-cadherin was identified as a protein that binds adiponectin in its LMW and HMW forms. However, it does not bind to globular or trimeric forms. At present, T-cadherin has no known signaling capabilities. However, involvement of T-cadherin in formation of adiponectin-dependent signaling complexes is a plausible hypothesis.

Although the adiponectin receptors remain somewhat controversial due to their unusual structures (AdipoR1 and 2), unknown signaling mechanisms (T-cadherin). Several adiponectin-dependent postreceptor signaling events have been revealed. Important to note is the fact that these signaling studies employ the use of bacterially produced full-length or globular adiponectin and examine outcomes that are achieved only by using the bacterially produced or globular form of adiponectin, not adiponectin produced in eukaryotic systems. Regardless of the debate over the pharmacological vs. physiological relevance of the adiponectin used, the elucidation of these pathways will reveal much about the regulation of metabolism and cardiovascular disease.

Several in vitro studies in C2C12 cells demonstrated that adiponectin activates AMPK and p38 MAPK (91). The adiponectin-stimulated activation of AMPK has since been linked to several biological effects. For example, AMPK mediates adiponectin-stimulated increases in glucose uptake and fatty acid oxidation in muscle (91). Another example of AMPK mediation of adiponectin effects is evidenced by several loss-of-function studies in mice where the lack of either adiponectin or AMPK leads to increased apoptosis and cardiac dysfunction in ischemic-reperfusion injury (100). However, further studies testing for gain of function are required before these studies can fully attribute the effects of adiponectin to mediation by AMPK.

Cyclooxygenase-2 (COX-2) has also been shown to mediate some of the effects of adiponectin. Adiponectin activates COX-2 in cardiac cells, resulting in an increase in prostaglandin (E)2 production (100). In a model of ischemia-reperfusion injury, administration of adiponectin decreased infarct size, myocardial apoptosis, and TNF. Inhibition of COX-2 resulted in increased TNF and partially reversed the protective effects of adiponectin on infarct size. COX-2 inhibition had no effect on AMPK activity and vice versa. Thus, in this model of ischemia-reperfusion injury, COX-2 mediates the effect of adiponectin on inflammation, whereas AMPK mediates the effects of adiponectin on apoptosis, together contributing to the cardioprotective effects of adiponectin.

B. Resistin
Resistin (150, 151, 152, 153) is a member of the resistin-like molecule ("RELM") hormone family. Initial findings demonstrated that resistin expression is reduced by TZD treatment and increased in obesity. The physiological role of resistin has proven to be more challenging to figure out than originally anticipated. mRNA levels and protein levels do not correlate very well and in many instances show an inverse relationship (54). Other issues include the differential expression of resistin between rodents (which express resistin predominantly in adipocytes) and humans (where the primary sources are the stromal vascular cells in adipose tissue); this causes some to question whether resistin is truly an adipokine or merely a cytokine produced by immune cells within the stromal vascular fraction. Although the clinical relevance of resistin is still under investigation, it represents a fascinating cytokine at every possible level (154).

1. Structure.
Similar to adiponectin, resistin may be secreted in two distinguishable multimeric forms. Each form is composed of two domains: a carboxy-terminal disulfide-rich ß-sandwich domain and an amino-terminal -helical segment. These protomers combine to form trimers via three-stranded coiled coils within the -helical segments. Two trimers likely bind via tail-to-tail interchain disulfide bonds to form hexamers (155). Whether there is indeed a measurable pool of reduced resistin lacking intact disulfide bonds at the trimer interface in serum remains to be shown. Current efforts in our laboratory are directed toward addressing this issue genetically. A close relative of resistin, RELMß, which is expressed primarily in the colon, shows a very similar overall structure as well and may in fact have partially overlapping functions (155).

2. Function.
Several studies using mouse models have determined that resistin antagonizes insulin action in the liver. During a hyperinsulinemic-euglycemic clamp, administration of mammalian-produced resistin results in severe hepatic but not peripheral insulin resistance, demonstrating that acute resistin treatment blunts hepatic insulin action (80). In addition, comparable experiments performed with recombinant RELMß resulted in insulin resistance in hepatocytes. Similar to acute effects of resistin administration, transgenic overexpression of resistin results in increased fasting glucose and decreased glucose tolerance, suggesting insulin resistance (156). The reciprocal of these findings was found in resistin knockout mice such that there were decreased fasting glucose levels, hepatic glucose production, and gluconeogenic enzymes in the liver (157). Together, these studies suggest that resistin may counterbalance the insulin-sensitizing effects of adiponectin in the liver. Whether these effects are a result of direct interaction of resistin with cell surface receptors on hepatocytes is not yet known, because the resistin and RELMß receptors have not yet been identified.

C. Additional adipokines
In the race to identify and characterize new adipokines, many find the task a daunting one. Advancements in proteomics and microarray technologies have proven to be useful screening tools that provide a multitude of potential new adipokine molecules. However, characterization of putative adipokines is a slow and arduous process often taking 3–5 yr of focused effort. A very exciting recent example of adipokine discovery is the production of retinol binding protein 4 (Rbp4) by adipocytes (158, 159, 160). This suggests the existence of additional adipose tissue-derived adipokines.

One such phenomenon suggestive of the existence of additional adipokines is the stimulation of the adipoinsular axis by ß3 adrenergic receptor agonists in mice (161). Administration of ß3 adrenergic agonists to mice results in a 10- to 100-fold increase in insulin secretion (161). This effect requires the expression of ß3 adrenergic receptors by adipocytes in white adipose tissue (162). Indeed, mice that acutely lose functional adipocytes (163) are nonresponsive to ß3 adrenergic stimulation with respect to insulin release. This is consistent with a model suggesting that adipocytes produce a factor that potently stimulates insulin secretion. Interestingly, this extremely rapid effect does not require elevations in serum glucose or FFAs (our unpublished observations). Thus, given the appropriate readouts, there remains a lot of potential for the discovery of new adipocyte-derived factors.

	V. Adipose Tissue: Paracrine Effects

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
Before the appreciation of adipose tissue as an endocrine tissue, several paracrine factors were identified. These paracrine factors are predominantly produced by the cells of the stromal vascular fraction of adipose tissue and exert potent effects on adipose tissue function. Two important adipokines that have proven paracrine effects on adipocyte metabolism and endocrine function are TNF and IL-6. Certainly additional adipokines may soon be added to this list including IL-1 (164, 165), IL-8 (166, 167), IL-18 (168), and IL-10 (169).

A. TNF
TNF expression is elevated in obese adipose tissue and is associated with whole-body insulin resistance (35, 170). The effects of TNF on adipocytes include increased lipolysis, increased leptin secretion (171), decreased adiponectin secretion (142), decreased glucose transporter 4 expression, impaired insulin signaling, and antagonism of TZDs/PPAR (reviewed in Ref. 172). These events are well described at the molecular level, and findings are consistent from rodent to humans. Further highlighting the importance of TNF in the development of obesity/diabetes, mice lacking TNF or TNF receptors are resistant to the development of diabetes (173, 174), and neutralization of TNF in rodents reduces the severity of insulin resistance (175). Interestingly, several attempts to neutralize TNF in humans have had no effect on insulin sensitivity. One study tested the effect of a TNF-neutralizing antibody on glucose homeostasis in obese non-insulin dependent diabetes mellitus patients (176), whereas the other tested the effects of infliximab, a chimeric monoclonal, high-affinity antibody against the soluble and transmembrane TNF, on insulin resistance in patients with Crohn’s disease (177). However, a recent study demonstrated that treatment with infliximab led to a significant improvement in insulin sensitivity in the most insulin-resistant patients with rheumatoid arthritis and ankylosing spondylitis (178). Thus, it is possible that the limited effects of TNF neutralization on insulin sensitization seen in some human studies may be due to limited accessibility of TNF locally in adipose tissue. Further investigations of the effectiveness of infliximab on type II diabetes in humans are warranted, as is the development of alternative strategies to reduce TNF expression or antagonize its effects in obese/diabetic adipose tissue.

B. IL-6
Unlike TNF, which is likely to act locally, IL-6 is secreted by adipose tissue and enters the circulation (179). Similar to TNF, IL-6 is overexpressed in adipose tissue of obesity and type II diabetics (10). In adipose tissue, IL-6 is produced predominantly by the stromal vascular cells, where it can exert paracrine effects directly on adipocytes. Culturing of human adipose tissue in the presence of IL-6 increases leptin and lipolysis and decreases LPL activity (180). These in vitro findings are supported by an in vivo report where administration of IL-6 in vivo increases FFA levels (181). Together, these data suggest that increased production of IL-6 in adipose tissue contributes to the metabolic and endocrine changes associated with obesity. IL-6 knockout mice exhibit adult onset obesity (182). These data, coupled with findings that IL-6 levels in cerebral spinal fluid are negatively correlated with fat mass in the obese (183) and acute intracerebral ventricular administration of IL-6 results in an increase in energy expenditure, suggest that IL-6 may protect against obesity. However, these reports are complicated by findings from another laboratory stating that IL-6 knockout mice do not exhibit adult onset obesity (184). Thus, the role of IL-6 in the metabolic and endocrine changes associated with obesity is unclear. Further efforts are required to determine a role for the central vs. peripheral and acute vs. chronic effects of elevated IL-6 on the metabolic complications associated with obesity.

C. Adipose tissue and the immune system
In addition to the chronic local and systemic elevation of IL-6 in obesity, IL-6 levels are transiently elevated during an immune challenge such as an acute infection and sepsis. Although increased systemic IL-6 in response to an immune challenge may be associated with similar metabolic and endocrine changes as those associated with increased IL-6 levels in obesity, it is important to appreciate that the etiology, magnitude of the effect, and length of exposure differ greatly between the two different conditions. Although the role of adipose tissue in the immune system is still not well understood, the systemic contribution of adipose tissue-derived IL-6 during an immune challenge suggests that adipose tissue plays a major role in the innate immune response.

D. Acute phase reactants
Although the liver has often been viewed as the primary site of acute phase reactant production, a role for adipose tissue in this process has become increasingly apparent. IL-6 is an acute phase reactant abundantly produced in visceral adipose tissue and released into the portal system, where it triggers the induction of many acute phase proteins and triglyceride secretion from the liver (185). Because systemic IL-6 levels are diminished in fatless mice after endotoxin challenge (163), adipose tissue IL-6 production may play an important role in the acute phase response during an immune challenge.

In addition to IL-6, several other acute phase reactants are produced by adipose tissue, such as complement factor C3 (186) and plasminogen activator inhibitor-1 (187). We have demonstrated expression and release of lipocalin 24p3, 1 acid glycoprotein, and serum amyloid A (SAA)-3 (188). Some of these factors are potently up-regulated by hyperglycemic conditions (188). Although several of these acute phase reactants including IL-6 are produced by the stromal vascular cells (10, 189), many, such as SAA-3, are actually produced by the adipocytes within adipose tissue (190). Thus, production of acute phase reactants is one way adipose tissue can contribute to the immune response. Furthermore, data demonstrating that increased circulating SAA is a predictor of cardiovascular disease suggest that the secretion of acute phase reactants by adipose tissue is related to disease risk and therefore may have a negative impact on overall health (191, 192).

E. Hyperglycemia-induced inflammatory response
Hyperglycemia is associated with increased acute phase reactant production and decreased insulin sensitivity in adipose tissue in vivo and in vitro (188, 193). The inflammatory response and concomitant reduction of insulin sensitivity triggered by exposure to hyperglycemia is associated with an up-regulation of mitochondrial proteins and increased levels of reactive oxygen species (ROS). Interestingly, many of these effects of hyperglycemia are independent of insulin. The effects of hyperglycemia on acute phase reactants are partially dependent on ROS production, because alteration of mitochondrial membrane production/ROS levels can modulate adipocyte acute phase reactant production. In fact, increasing the mitochondrial membrane potential through overexpression of the mDIC can result in increased ROS levels, leading to increased local inflammation and acute phase reactant production even under euglycemic conditions. Hyperglycemia and the associated increases in ROS production are tightly linked to the induction of the proinflammatory program in adipocytes. Therefore, targeting antioxidant regimens to adipose tissue has great promise in the context of therapies aimed at improvements in insulin sensitivity.

From an experimental standpoint, we were surprised to observe large differences in insulin sensitivity of 3T3-L1 adipocytes depending on whether these cells are cultured under standard conditions (i.e., severe hyperglycemic conditions at 25 mM) or whether they are differentiated under euglycemic conditions (5 mM). These cells can fully differentiate under both conditions but differ greatly in sensitivity of insulin action. The specific glucose concentration chosen in this widely used experimental system is therefore very important (193).

F. Toll-like receptors
We found that adipocytes express very high levels of several toll-like receptors (TLRs), including TLR-4 (194), the receptor for Gram-negative cell wall components. TLR-4 expression is increased during adipocyte differentiation and overexpressed in obese adipose tissue (195). Stimulation of TLR-4 results in the rapid induction of TLR-2 (the receptor for Gram-positive cell wall and fungal components) (194), triggering increased expression of IL-6 and TNF, leading to insulin resistance (195). This suggests that TLRs may have important implications for the adipocyte in its role in the immune system as well as energy homeostasis. Although the endogenous ligand for TLR-4 is not certain, there are several possible candidates; intriguingly, one type of these ligands is saturated fatty acids (196). Clearly, the ligands derived from bacterial and viral origins support the role of TLR-4 in the innate and adaptive immune responses. Yet the ability of saturated FFA to stimulate TLR-4 suggests that there may be a role for TLR-4 in metabolism and supports a connection between the immune system and energy homeostasis in adipose tissue.

The effects of TLR-4 stimulation are mediated intracellularly by activation of a variety of serine kinases that ultimately converge upon NFB. In the adipocyte, NFB expression increases upon differentiation and is activated by proinflammatory stimuli such as TNF and IL-6 (197). Interestingly, lipopolysaccharide-stimulated NFB is suppressed as differentiation progresses, suggesting that alternative pathways may play a role in lipopolysaccharide responsiveness in the mature adipocyte. Because a majority of the inflammatory cytokines released from adipose tissue are secreted primarily from the cells of the stromal vascular fraction, the NFB pathway may be less important for inflammatory cytokine production in the adipocyte compared with the macrophages within adipose tissue. Yet there is strong evidence that adipocyte secretory products promote macrophage inflammatory cytokine production, thereby highlighting the importance of the adipocyte in the process (197).

Together, these data suggest that in addition to functional roles in the regulation of energy homeostasis, adipose tissue may play an important role in the innate immune response. Adipose tissue is sensitive to systemic bacterial infections through the abundant expression of pattern recognition receptors in the TLR family, thereby triggering a high level response in adipose tissue in the context of microbial invasion. Our recent work with the parasite Trypanosoma cruzi highlighted the importance of the adipocyte as a target cell for infection in the acute setting as well as a reservoir for parasites in the chronic stage of the infection in Chagas’ disease (198). Upon infection, T. cruzi induces multiple hormonal and metabolic changes at the level of the adipocyte, which contributes to the metabolic changes observed during Chagas disease.

G. The FAT-ATTAC mouse: a novel mouse model for the study of adipose tissue physiology
We have recently published a model of inducible functional inactivation of adipocytes (163) and have discussed the implications and versatility of this model in other places (70). The FAT-ATTAC (Fat Apotosis Through Targeted Activation of Caspase 8) mouse is a transgenic model of inducible fat loss generated through the transgenic expression in adipocytes of a myristoylated caspase 8-FKBP fusion protein. Transgene expression is under the control of the aP2 promoter and is therefore specifically expressed in mature adipocytes. Treatment of adipocytes with AP20187 (an FK506 analog) forces dimerization of membrane-associated caspase 8 that activates downstream signaling cascades, resulting in apoptosis of adipocytes in vitro (when expressed in 3T3-L1 adipocytes). Administration of dimerizer (AP20187) to FAT-ATTAC mice expressing the caspase 8 transgene results in adipocyte apoptosis in vivo. Within 3 d of dimerizer treatment, tissue histology reveals the near complete loss of viable adipocytes, and after 4 wk of dimerizer treatment, the adipose tissue is reduced to remnants of connective tissue and other supporting cells. In FAT-ATTAC mice, fat loss can be chronicled by the reduction of serum adipokine levels, such as adiponectin and leptin levels (>95% reduction).

The inducibility of fat loss at any stage of murine growth or development makes the FAT-ATTAC a rather unique model. Moreover, due to the nature of the transgene, the model is also fully reversible. The repopulation of adipose tissue with adipocytes after their depletion in the FAT-ATTAC mouse provides a unique opportunity to study the differentiation of adipocytes from progenitor cells in vivo. Thus, the characterization of this process in the FAT-ATTAC mouse will be invaluable to the establishment of an in vivo model of adipocyte differentiation. The ability to induce widespread and reversible loss of adipocytes at any time during development represents a major technological advance. Furthermore, inducible fat loss has highlighted a number of very interesting metabolic phenomena.

	VI. Concluding Remarks

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 
Adipose tissue has long been underestimated in terms of its physiological impact. It has gained early recognition as a storage compartment for triglycerides. However, its function as a source of secreted factors is increasingly appreciated, and the adipocyte is in fact a very active secretory cell. This is even more impressive in light of the fact that adipocytes are omnipresent in most organs, and as tissue it can contribute up to 50% of total body weight under extreme conditions. Despite its abundance, we still have so much to learn about the physiology of adipose tissue. Several key areas are currently under investigation in a number of laboratories (Fig. 4). As the transgenic and knockout technology improves further, more elaborate questions can be asked in mouse models, and we can look forward to gaining further insights into adipocyte physiology in the future through the combination of cellular techniques, rodent physiology, and clinical studies.

View larger version (70K): [in this window] [in a new window]   FIG. 4. Major extracellular targets derived from the adipocyte currently under study. These include contributions of the adipocyte toward the unique extracellular environment, the interactions with the nervous system, shaping the local nutrient and oxygen availability through synthesis and release of pro- and antiangiogenic factors, interactions with the immune system, including the local paracrine interactions with adipose tissue macrophages, and the unknown factors triggering the differentiation process. Major hormonal factors include adipokines such as leptin, adiponectin, and resistin.

	Acknowledgments

 
We thank Dr. Todd Schraw for extensive help with the graphic design of the figures.

	Footnotes

 
This work was supported by a Mentor-Based Postdoctoral Fellowship Award from the American Diabetes Association (7-05-MI-09, to M.E.T.) and National Institutes of Health Grants R01-DK55758 and R01-CA112023 (to P.E.S.). P.E.S. is also the recipient of an Irma T. Hirschl Career Scientist Award.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 20, 2006

Abbreviations: AdipoR, Adiponectin receptor; AMPK, AMP kinase; BAT, brown adipose tissue; COX-2, cyclooxygenase-2; FFA, free fatty acid; HMW, high molecular weight; LMW, low molecular weight; LPL, lipoprotein lipase; mDIC, mitochondrial dicarboxylate carrier; NFB, nuclear factor B; OVX, ovariectomy; PKA, protein kinase A; PPAR, peroxisome proliferator-activated receptor; RELM, resistin-like molecule; ROS, reactive oxygen species; SAA, serum amyloid A; TLR, toll-like receptor; TZD, thiazolidinedione.

	References

Top Abstract I. Introduction II. Complexity of the... III. Adipocytes and the... IV. Endocrine Function of... V. Adipose Tissue: Paracrine... VI. Concluding Remarks References

 

1. Rodbell M 1964 Metabolism of isolated adipocytes. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 239:375–380[Free Full Text]
2. Claffey KP, Wilkison WO, Spiegelman BM 1992 Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem 267:16317–16322[Abstract/Free Full Text]
3. Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ 2002 Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA 99:10730–10735[Abstract/Free Full Text]
4. Brakenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P, Cao Y 2004 Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res 94:1579–1588[Abstract/Free Full Text]
5. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS 2005 Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355[Abstract/Free Full Text]
6. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH 2002 Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295[Abstract/Free Full Text]
7. Villena JA, Cousin B, Penicaud L, Casteilla L 2001 Adipose tissues display differential phagocytic and microbicidal activities depending on their localization. Int J Obes Relat Metab Disord 25:1275–1280[CrossRef][Medline]
8. Prunet-Marcassus B, Cousin B, Caton D, Andre M, Penicaud L, Casteilla L 2006 From heterogeneity to plasticity in adipose tissues: site-specific differences. Exp Cell Res 312:727–736[CrossRef][Medline]
9. Fried SK, Bunkin DA, Greenberg AS 1998 Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83:847–850[Abstract/Free Full Text]
10. Urs S, Smith C, Campbell B, Saxton AM, Taylor J, Zhang B, Snoddy J, Jones Voy B, Moustaid-Moussa N 2004 Gene expression profiling in human preadipocytes and adipocytes by microarray analysis. J Nutr 134:762–770[Abstract/Free Full Text]
11. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW 2003 Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808[CrossRef][Medline]
12. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H 2003 Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830[CrossRef][Medline]
13. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K 2005 Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54:2277–2286[Abstract/Free Full Text]
14. Cinti S 2005 The adipose organ. Prostaglandins Leukot Essent Fatty Acids 73:9–15[CrossRef][Medline]
15. Cannon B, Hedin A, Nedergaard J 1982 Exclusive occurrence of thermogenin antigen in brown adipose tissue. FEBS Lett 150:129–132[CrossRef][Medline]
16. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I 2005 Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307:426–430[Abstract/Free Full Text]
17. Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan JC, Gong DW 2006 Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab 290:E1253–E1261
18. Arner P 2006 Visfatin—a true or false trail to type 2 diabetes mellitus. J Clin Endocrinol Metab 91:28–30[Free Full Text]
19. Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, DePonte M, Koo A, Forse RA, Chinnappan D, Martin-Ruiz C, von Zglinicki T, Kirkland JL 2006 Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes 55:2571–2578[Abstract/Free Full Text]
20. Gesta S, Bluher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, Boucher J, Lewis C, Kahn CR 2006 Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci USA 103:6676–6681[Abstract/Free Full Text]
21. Kirkland JL, Hollenberg CH, Gillon WS 1996 Effects of fat depot site on differentiation-dependent gene expression in rat preadipocytes. Int J Obes Relat Metab Disord 20(Suppl 3):S102–S107
22. Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C 1998 Life without white fat: a transgenic mouse. Genes Dev 12:3168–3181[Abstract/Free Full Text]
23. Couldrey C, Moitra J, Vinson C, Anver M, Nagashima K, Green J 2002 Adipose tissue: a vital in vivo role in mammary gland development but not differentiation. Dev Dyn 223:459–468[CrossRef][Medline]
24. Gouon-Evans V, Pollard JW 2002 Unexpected deposition of brown fat in mammary gland during postnatal development. Mol Endocrinol 16:2618–2627[Abstract/Free Full Text]
25. Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C, Flanagan L, Tenniswood MP, Guha C, Lisanti MP, Pestell RG, Scherer PE 2003 Adipocyte secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene 22:6408–6423[CrossRef][Medline]
26. Iyengar P, Espina V, Williams TW, Lin Y, Berry D, Jelicks LA, Lee H, Temple K, Graves R, Pollard J, Chopra N, Russell RG, Sasisekharan R, Trock BJ, Lippman M, Calvert VS, Petricoin 3rd EF, Liotta L, Dadachova E, Pestell RG, Lisanti MP, Bonaldo P, Scherer PE 2005 Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115:1163–1176[CrossRef][Medline]
27. Elliott BE, Tam SP, Dexter D, Chen ZQ 1992 Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: effect of estrogen and progesterone. Int J Cancer 51:416–424[Medline]
28. Johnston PG, Rondinone CM, Voeller D, Allegra CJ 1992 Identification of a protein factor secreted by 3T3–L1 preadipocytes inhibitory for the human MCF-7 breast cancer cell line. Cancer Res 52:6860–6865[Abstract/Free Full Text]
29. McTiernan A 2005 Obesity and cancer: the risks, science, and potential management strategies. Oncology (Williston Park) 19:871–881; discussion, 881–882 and 885–886[Medline]
30. Krief S, Lonnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg AD, Ricquier D, Emorine LJ 1993 Tissue distribution of ß 3-adrenergic receptor mRNA in man. J Clin Invest 91:344–349[Medline]
31. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S 2000 Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol 279:C670–C681
32. Giorgino F, Laviola L, Eriksson JW 2005 Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiol Scand 183:13–30[CrossRef][Medline]
33. Arner P, Hellstrom L, Wahrenberg H, Bronnegard M 1990 ß-Adrenoceptor expression in human fat cells from different regions. J Clin Invest 86:1595–1600[Medline]
34. Bronnegard M, Arner P, Hellstrom L, Akner G, Gustafsson JA 1990 Glucocorticoid receptor messenger ribonucleic acid in different regions of human adipose tissue. Endocrinology 127:1689–1696[Abstract/Free Full Text]
35. Hotamisligil GS 1999 Mechanisms of TNF--induced insulin resistance. Exp Clin Endocrinol Diabetes 107:119–125[Medline]
36. Fried SK, Russell CD, Grauso NL, Brolin RE 1993 Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest 92:2191–2198[Medline]
37. Kirkland JL, Hollenberg CH, Gillon WS 1990 Age, anatomic site, and the replication and differentiation of adipocyte precursors. Am J Physiol 258:C206–C210
38. Blaak E 2001 Gender differences in fat metabolism. Curr Opin Clin Nutr Metab Care 4:499–502[CrossRef][Medline]
39. Fried SK, Leibel RL, Edens NK, Kral JG 1993 Lipolysis in intraabdominal adipose tissues of obese women and men. Obes Res 1:443–448[Medline]
40. Edens NK, Fried SK, Kral JG, Hirsch J, Leibel RL 1993 In vitro lipid synthesis in human adipose tissue from three abdominal sites. Am J Physiol 265:E374–E379
41. Rebuffe-Scrive M, Andersson B, Olbe L, Bjorntorp P 1989 Metabolism of adipose tissue in intraabdominal depots of nonobese men and women. Metabolism 38:453–458[CrossRef][Medline]
42. Dark J, Wade GN, Zucker I 1984 Ovarian modulation of lipoprotein lipase activity in white adipose tissue of ground squirrels. Physiol Behav 32:75–78[CrossRef][Medline]
43. Hamosh M, Hamosh P 1975 The effect of estrogen on the lipoprotein lipase activity of rat adipose tissue. J Clin Invest 55:1132–1135[Medline]
44. D’Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS 2005 Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem 280:35983–35991[Abstract/Free Full Text]
45. Darimont C, Delansorne R, Paris J, Ailhaud G, Negrel R 1997 Influence of estrogenic status on the lipolytic activity of parametrial adipose tissue in vivo: an in situ microdialysis study. Endocrinology 138:1092–1096[Abstract/Free Full Text]
46. Pedersen SB, Kristensen K, Hermann PA, Katzenellenbogen JA, Richelsen B 2004 Estrogen controls lipolysis by up-regulating 2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor . Implications for the female fat distribution. J Clin Endocrinol Metab 89:1869–1878[Abstract/Free Full Text]
47. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI 2001 Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98:7522–7527[Abstract/Free Full Text]
48. Hensley LL, Ranganathan G, Wagner EM, Wells BD, Daniel JC, Vu D, Semenkovich CF, Zechner R, Kern PA 2003 Transgenic mice expressing lipoprotein lipase in adipose tissue. Absence of the proximal 3'-untranslated region causes translational upregulation. J Biol Chem 278:32702–32709[Abstract/Free Full Text]
49. Combs TP, Berg AH, Rajala MW, Klebanov S, Iyengar P, Jimenez-Chillaron JC, Patti ME, Klein SL, Weinstein RS, Scherer PE 2003 Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin. Diabetes 52:268–276[Abstract/Free Full Text]
50. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE 2003 Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 278:9073–9085[Abstract/Free Full Text]
51. Xu A, Chan KW, Hoo RL, Wang Y, Tan KC, Zhang J, Chen B, Lam MC, Tse C, Cooper GJ, Lam KS 2005 Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 280:18073–18080[Abstract/Free Full Text]
52. Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R, Jinagouda SD, el-Tawil K, Rude RK, Kamdar V 1997 Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab 82:579–584[Abstract/Free Full Text]
53. Horlick MB, Rosenbaum M, Nicolson M, Levine LS, Fedun B, Wang J, Pierson Jr RN, Leibel RL 2000 Effect of puberty on the relationship between circulating leptin and body composition. J Clin Endocrinol Metab 85:2509–2518[Abstract/Free Full Text]
54. Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS 2004 Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 53:1671–1679[Abstract/Free Full Text]
55. Hauner H 2002 The mode of action of thiazolidinediones. Diabetes Metab Res Rev 18(Suppl 2):S10–S15
56. Bogacka I, Xie H, Bray GA, Smith SR 2004 The effect of pioglitazone on peroxisome proliferator-activated receptor- target genes related to lipid storage in vivo. Diabetes Care 27:1660–1667[Abstract/Free Full Text]
57. Tordjman J, Khazen W, Antoine B, Chauvet G, Quette J, Fouque F, Beale EG, Benelli C, Forest C 2003 Regulation of glyceroneogenesis and phosphoenolpyruvate carboxykinase by fatty acids, retinoic acids and thiazolidinediones: potential relevance to type 2 diabetes. Biochimie 85:1213–1218[Medline]
58. Leroyer SN, Tordjman J, Chauvet G, Quette J, Chapron C, Forest C, Antoine B 2006 Rosiglitazone controls fatty acid cycling in human adipose tissue by means of glyceroneogenesis and glycerol phosphorylation. J Biol Chem 281:13141–13149[Abstract/Free Full Text]
59. Boden G, Zhang M 2006 Recent findings concerning thiazolidinediones in the treatment of diabetes. Expert Opin Investig Drugs 15:243–250[CrossRef][Medline]
60. Das K, Lewis RY, Combatsiaris TP, Lin Y, Shapiro L, Charron MJ, Scherer PE 1999 Predominant expression of the mitochondrial dicarboxylate carrier in white adipose tissue. Biochem J 344(Pt 2):313–320
61. Green H, Kehinde O 1974 Sublines of mouse 3T3 cells that accumulate lipid. Cell 1:113–116[CrossRef]
62. Green H, Kehinde O 1975 An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion. Cell 5:19–27[Medline]
63. Engelman JA, Lisanti MP, Scherer PE 1998 Specific inhibitors of p38 mitogen-activated protein kinase block 3T3–L1 adipogenesis. J Biol Chem 273:32111–32120[Abstract/Free Full Text]
64. Engelman JA, Berg AH, Lewis RY, Lin A, Lisanti MP, Scherer PE 1999 Constitutively active mitogen-activated protein kinase kinase 6 (MKK6) or salicylate induces spontaneous 3T3–L1 adipogenesis. J Biol Chem 274:35630–35638[Abstract/Free Full Text]
65. Lisanti MP, Scherer PE, Tang Z-L, Sargiacomo M 1994 Caveolae, caveolin, and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol 4:231–235[CrossRef][Medline]
66. Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Corley-Mastick C, Lodish HF 1994 Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles. J Cell Biol 127:1233–1243[Abstract/Free Full Text]
67. Ikonen E, Vainio S 2005 Lipid microdomains and insulin resistance: is there a connection? Sci STKE 2005:pe3
68. Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE, Lisanti MP 2002 Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem 277:8635–8647[Abstract/Free Full Text]
69. Cohen AW, Razani B, Schubert W, Williams TM, Wang XB, Iyengar P, Brasaemle DL, Scherer PE, Lisanti MP 2004 Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes 53:1261–1270[Abstract/Free Full Text]
70. Trujillo ME, Pajvani UB, Scherer PE 2005 Apoptosis through targeted activation of caspase 8 ("ATTAC-mice"): novel mouse models of inducible and reversible tissue ablation. Cell Cycle 4:1141–1145[Medline]
71. Cohen AW, Razani B, Wang XB, Combs TP, Williams TM, Scherer PE, Lisanti MP 2003 Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am J Physiol Cell Physiol 285:C222–C235
72. Cohen AW, Schubert W, Brasaemle DL, Scherer PE, Lisanti MP 2005 Caveolin-1 expression is essential for proper nonshivering thermogenesis in brown adipose tissue. Diabetes 54:679–686[Abstract/Free Full Text]
73. Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR, Spiegelman BM 1987 Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237:402–405[Abstract/Free Full Text]
74. Flier JS, Cook KS, Usher P, Spiegelman BM 1987 Severely impaired adipsin expression in genetic and acquired obesity. Science 237:405–408[Abstract/Free Full Text]
75. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432[CrossRef][Medline]
76. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749[Abstract/Free Full Text]
77. Scherer PE 2006 Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55:1537–1545[Abstract/Free Full Text]
78. Yoda-Murakami M, Taniguchi M, Takahashi K, Kawamata S, Saito K, Choi-Miura NH, Tomita M 2001 Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver. Biochem Biophys Res Commun 285:372–377[CrossRef][Medline]
79. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin MJ 1998 The stomach is a source of leptin. Nature 394:790–793[CrossRef][Medline]
80. Rajala MW, Obici S, Scherer PE, Rossetti L 2003 Adipose-derived resistin and gut-derived resistin-like molecule-ß selectively impair insulin action on glucose production. J Clin Invest 111:225–230[CrossRef][Medline]
81. Hu E, Liang P, Spiegelman BM 1996 AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703[Abstract/Free Full Text]
82. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M 1996 Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem (Tokyo) 120:803–812[Abstract/Free Full Text]
83. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K 1996 cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221:286–289[CrossRef][Medline]
84. Berg AH, Combs TP, Scherer PE 2002 ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13:84–89[CrossRef][Medline]
85. Wang Y, Lam KS, Chan L, Chan KW, Lam JB, Lam MC, Hoo RC, Mak WW, Cooper GJ, Xu A 2006 Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem 281:16391–16400[Abstract/Free Full Text]
86. Wang Y, Xu A, Knight C, Xu LY, Cooper GJ 2002 Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J Biol Chem 277:19521–19529[Abstract/Free Full Text]
87. Wang Y, Xu LY, Lam KS, Lu G, Cooper GJ, Xu A 2006 Proteomic characterization of human serum proteins associated with the fat-derived hormone adiponectin. Proteomics 6:3862–3870[CrossRef][Medline]
88. Shapiro L, Scherer PE 1998 The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 8:335–338[CrossRef][Medline]
89. Fruebis J, Tsao T-S, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF 2001 Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010[Abstract/Free Full Text]
90. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB 2002 Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313[Abstract/Free Full Text]
91. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T 2002 Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295[CrossRef][Medline]
92. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE 2001 The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953[CrossRef][Medline]
93. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L 2001 Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108:1875–1881[CrossRef][Medline]
94. Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, Russell RG, Lindemann D, Hartley A, Baker GR, Obici S, Deshaies Y, Ludgate M, Rossetti L, Scherer PE 2004 A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145:367–383[Abstract/Free Full Text]
95. Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE 2006 Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor agonists. J Biol Chem 281:2654–2660[Abstract/Free Full Text]
96. Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS 2004 Adiponectin acts in the brain to decrease body weight. Nat Med 10:524–529[CrossRef][Medline]
97. Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N, Maeda K, Shibata R, Walsh K, Funahashi T, Shimomura I 2006 Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47:1108–1116[Abstract/Free Full Text]
98. Ouchi N, Shibata R, Walsh K 2006 Cardioprotection by adiponectin. Trends Cardiovasc Med 16:141–146[CrossRef][Medline]
99. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K 2004 Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10:1384–1389[CrossRef][Medline]
100. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, Funahashi T, Ouchi N, Walsh K 2005 Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11:1096–1103[CrossRef][Medline]
101. Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K 2004 Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling. J Biol Chem 279:28670–28674[Abstract/Free Full Text]
102. Trujillo ME, Scherer PE 2005 Adiponectin: journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med 257:167–175[CrossRef][Medline]
103. Berg AH, Scherer PE 2005 Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96:939–949[Abstract/Free Full Text]
104. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83[CrossRef][Medline]
105. Kojima S, Funahashi T, Sakamoto T, Miyamoto S, Soejima H, Hokamaki J, Kajiwara I, Sugiyama S, Yoshimura M, Fujimoto K, Miyao Y, Suefuji H, Kitagawa A, Ouchi N, Kihara S, Matsuzawa Y, Ogawa H 2003 The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart 89:667[Free Full Text]
106. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y; Osaka Coronary Artery Disease Study Group 2003 Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23:85–89[Abstract/Free Full Text]
107. Baratta R, Amato S, Degano C, Farina MG, Patane G, Vigneri R, Frittitta L 2004 Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies. J Clin Endocrinol Metab 89:2665–2671[Abstract/Free Full Text]
108. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB 2004 Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291:1730–1737[Abstract/Free Full Text]
109. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935[Abstract/Free Full Text]
110. Stefan N, Stumvoll M, Vozarova B, Weyer C, Funahashi T, Matsuzawa Y, Bogardus C, Tataranni PA 2003 Plasma adiponectin and endogenous glucose production in humans. Diabetes Care 26:3315–3319[Abstract/Free Full Text]
111. Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Ravussin E, Weyer C, Tataranni PA 2002 Plasma adiponectin levels are not associated with fat oxidation in humans. Obes Res 10:1016–1020[Medline]
112. Ranheim T, Haugen F, Staff AC, Braekke K, Harsem NK, Drevon CA 2004 Adiponectin is reduced in gestational diabetes mellitus in normal weight women. Acta Obstet Gynecol Scand 83:341–347[CrossRef][Medline]
113. Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R 2003 Adipocyte-derived hormone levels in HIV lipodystrophy. Antivir Ther 8:9–15[Medline]
114. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599[Abstract/Free Full Text]
115. Abbasi F, Chu JW, Lamendola C, McLaughlin T, Hayden J, Reaven GM, Reaven PD 2004 Discrimination between obesity and insulin resistance in the relationship with adiponectin. Diabetes 53:585–590[Abstract/Free Full Text]
116. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y 2001 Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50:1126–1133[Abstract/Free Full Text]
117. Stefan N, Bunt JC, Salbe AD, Funahashi T, Matsuzawa Y, Tataranni PA 2002 Plasma adiponectin concentrations in children: relationships with obesity and insulinemia. J Clin Endocrinol Metab 87:4652–4656[Abstract/Free Full Text]
118. Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, Tanen M, Berg AH, O’Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, Moller DE 2002 Induction of adipocyte complement-related protein of 30 kilodaltons by PPAR agonists: a potential mechanism of insulin sensitization. Endocrinology 143:998–1007[Abstract/Free Full Text]
119. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE 2004 Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152–12162[Abstract/Free Full Text]
120. Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T 2006 Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem 281:8748–8755[Abstract/Free Full Text]
121. Laplante M, Sell H, MacNaul KL, Richard D, Berger JP, Deshaies Y 2003 PPAR- Activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion. Diabetes 52:291–299[Abstract/Free Full Text]
122. De Vries R, Wolffenbuttel BH, Sluiter WJ, van Tol A, Dullaart RP 2005 Post-heparin plasma lipoprotein lipase, but not hepatic lipase activity, is related to plasma adiponectin in type 2 diabetic patients and healthy subjects. Clin Lab 51:403–409[Medline]
123. von Eynatten M, Schneider JG, Humpert PM, Rudofsky G, Schmidt N, Barosch P, Hamann A, Morcos M, Kreuzer J, Bierhaus A, Nawroth PP, Dugi KA 2004 Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. Diabetes Care 27:2925–2929[Abstract/Free Full Text]
124. Retnakaran R, Hanley AJ, Connelly PW, Maguire G, Sermer M, Zinman B 2006 Low serum levels of high-molecular weight adiponectin in Indo-Asian women during pregnancy: evidence of ethnic variation in adiponectin isoform distribution. Diabetes Care 29:1377–1379[Free Full Text]
125. Bodles A, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ 2006 Pioglitazone increases secretion of high molecular weight adiponectin from adipocytes. Am J Physiol Endocrinol Metab 291:E1100–E1105
126. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T 2006 Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 29:1357–1362[Abstract/Free Full Text]
127. Richards AA, Hickman IJ, Wang AY, Jones AL, Newell F, Mowry BJ, Whitehead JP, Prins JB, Macdonald GA 2006 Olanzapine treatment is associated with reduced high molecular weight adiponectin in serum: a potential mechanism for olanzapine-induced insulin resistance in patients with schizophrenia. J Clin Psychopharmacol 26:232–237[CrossRef][Medline]
128. Ebinuma H, Miyazaki O, Yago H, Hara K, Yamauchi T, Kadowaki T 2006 A novel ELISA system for selective measurement of human adiponectin multimers by using proteases. Clin Chim Acta 372:47–53[CrossRef][Medline]
129. Nakano Y, Tajima S, Yoshimi A, Akiyama H, Tsushima M, Tanioka T, Negoro T, Tomita M, Tobe T 2006 A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin. J Lipid Res 47:1572–1582[Abstract/Free Full Text]
130. Wang AY, Hickman IJ, Richards AA, Whitehead JP, Prins JB, Macdonald GA 2005 High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection. Am J Gastroenterol 100:2717–2723[CrossRef][Medline]
131. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT 2006 Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 55:249–259[Abstract/Free Full Text]
132. Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert MO, Mohlig M, Pfeiffer AF, Spranger J 2005 Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes 54:2712–2719[Abstract/Free Full Text]
133. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD, Kahn SE 2003 Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459–469[Medline]
134. Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K, Okazaki Y, Ishii T, Nishikai K, Saruta T 2002 Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin Sci (Lond) 103:137–142[Medline]
135. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Nagasawa A, Kobayashi H, Hiraoka H, Komai N, Kaibe M, Rakugi H, Ogihara T, Matsuzawa Y 2003 Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42:231–234[Abstract/Free Full Text]
136. Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K 2003 Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 14:561–566[CrossRef][Medline]
137. Krakoff J, Funahashi T, Stehouwer CD, Schalkwijk CG, Tanaka S, Matsuzawa Y, Kobes S, Tataranni PA, Hanson RL, Knowler WC, Lindsay RS 2003 Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care 26:1745–1751[Abstract/Free Full Text]
138. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T 2002 Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866[Abstract/Free Full Text]
139. Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara S, Nagai R, Funahashi T, Matsuzawa Y 2002 Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 277:37487–37491[Abstract/Free Full Text]
140. Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T 2003 Globular adiponectin protected ob/ob mice from diabetes and apoE-deficient mice from atherosclerosis. J Biol Chem 278:2461–2468[Abstract/Free Full Text]
141. Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y 2002 Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106:2767–2770[Abstract/Free Full Text]
142. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y 2002 Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737[CrossRef][Medline]
143. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 2000 Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-B signaling through a cAMP-dependent pathway. Circulation 102:1296–1301[Abstract/Free Full Text]
144. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 1999 Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100:2473–2476[Abstract/Free Full Text]
145. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y 2001 Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103:1057–1063[Abstract/Free Full Text]
146. Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 2002 Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105:2893–2898[Abstract/Free Full Text]
147. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T 2003 Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769[CrossRef][Medline]
148. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K 2006 Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792[CrossRef][Medline]
149. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF 2004 T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci USA 101:10308–10313[Abstract/Free Full Text]
150. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409:307–312[CrossRef][Medline]
151. Rajala MW, Lin Y, Ranalletta M, Yang XM, Qian H, Gingerich R, Barzilai N, Scherer PE 2002 Cell type-specific expression and coregulation of murine resistin and resistin-like molecule- in adipose tissue. Mol Endocrinol 16:1920–1930[Abstract/Free Full Text]
152. Kim KH, Lee K, Moon YS, Sul HS 2001 A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 276:11252–11256[Abstract/Free Full Text]
153. Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale Jr FV, Shelton DL, Hebert CC 2000 FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 19:4046–4055[CrossRef][Medline]
154. Jackson MB, Ahima RS 2006 Neuroendocrine and metabolic effects of adipocyte-derived hormones. Clin Sci (Lond) 110:143–152[Medline]
155. Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L 2004 Disulfide-dependent multimeric assembly of resistin family hormones. Science 304:1154–1158[Abstract/Free Full Text]
156. Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, Rossetti L, Lazar MA 2004 Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes 53:1937–1941[CrossRef][Medline]
157. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE, Steppan CM, Ahima RS, Obici S, Rossetti L, Lazar MA 2004 Regulation of fasted blood glucose by resistin. Science 303:1195–1198[Abstract/Free Full Text]
158. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB 2005 Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436:356–362[CrossRef][Medline]
159. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB 2006 Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 354:2552–2563[Abstract/Free Full Text]
160. Polonsky KS 2006 Retinol-binding protein 4, insulin resistance, and type 2 diabetes. N Engl J Med 354:2596–2598[Free Full Text]
161. Susulic VS, Frederich RC, Lawitts J, Tozzo E, Kahn BB, Harper ME, Himms-Hagen J, Flier JS, Lowell BB 1995 Targeted disruption of the ß 3-adrenergic receptor gene. J Biol Chem 270:29483–29492[Abstract/Free Full Text]
162. Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB 1997 ß3-Adrenergic receptors on white and brown adipocytes mediate ß3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. J Biol Chem 272:17686–17693[Abstract/Free Full Text]
163. Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, Scherer PE 2005 Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 11:797–803[CrossRef][Medline]
164. Somm E, Cettour-Rose P, Asensio C, Charollais A, Klein M, Theander-Carrillo C, Juge-Aubry CE, Dayer JM, Nicklin MJ, Meda P, Rohner-Jeanrenaud F, Meier CA 2006 Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents. Diabetologia 49:387–393[CrossRef][Medline]
165. Somm E, Henrichot E, Pernin A, Juge-Aubry CE, Muzzin P, Dayer JM, Nicklin MJ, Meier CA 2005 Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure. Diabetes 54:3503–3509[Abstract/Free Full Text]
166. Straczkowski M, Dzienis-Straczkowska S, Stepien A, Kowalska I, Szelachowska M, Kinalska I 2002 Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor- system. J Clin Endocrinol Metab 87:4602–4606[Abstract/Free Full Text]
167. Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Szelachowska M, Kinalska I 2003 Plasma interleukin 8 concentrations in obese subjects with impaired glucose tolerance. Cardiovasc Diabetol 2:5[CrossRef][Medline]
168. Netea MG, Joosten LA, Lewis E, Jensen DR, Voshol PJ, Kullberg BJ, Tack CJ, van Krieken H, Kim SH, Stalenhoef AF, van de Loo FA, Verschueren I, Pulawa L, Akira S, Eckel RH, Dinarello CA, van den Berg W, van der Meer JW 2006 Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat Med 12:650–656[CrossRef][Medline]
169. Juge-Aubry CE, Somm E, Pernin A, Alizadeh N, Giusti V, Dayer JM, Meier CA 2005 Adipose tissue is a regulated source of interleukin-10. Cytokine 29:270–274[Medline]
170. Hotamisligil GS 1999 The role of TNF and TNF receptors in obesity and insulin resistance. J Intern Med 245:621–625[CrossRef][Medline]
171. Trujillo ME, Lee MJ, Sullivan S, Feng J, Schneider SH, Greenberg AS, Fried SK 2006 Tumor necrosis factor and glucocorticoid synergistically increase leptin production in human adipose tissue: role for p38 mitogen-activated protein kinase. J Clin Endocrinol Metab 91:1484–1490[Abstract/Free Full Text]
172. Moller DE 2000 Potential role of TNF- in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11:212–217[CrossRef][Medline]
173. Uysal KT, Wiesbrock SM, Hotamisligil GS 1998 Functional analysis of tumor necrosis factor (TNF) receptors in TNF--mediated insulin resistance in genetic obesity. Endocrinology 139:4832–4838[Abstract/Free Full Text]
174. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS 1997 Protection from obesity-induced insulin resistance in mice lacking TNF- function. Nature 389:610–614[CrossRef][Medline]
175. Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose tissue expression of tumor necrosis factor : direct role in obesity-linked insulin resistance. Science 259:87–90[Abstract/Free Full Text]
176. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R 1996 Effects of an engineered human anti-TNF- antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885[Abstract]
177. Gentile S, Guarino G, Bizzarro A, De Bellis A, Torella R 2002 Infliximab does not interfere with insulin secretion, insulin resistance and production of GAD and islet cell antibodies in patients with Crohn’s disease. Diabetes Obes Metab 4:276–277[CrossRef][Medline]
178. Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA 2005 Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 64:765–766[Abstract/Free Full Text]
179. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW 1997 Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-, in vivo. J Clin Endocrinol Metab 82:4196–4200[Abstract/Free Full Text]
180. Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK 2004 Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab 89:5577–5582[Abstract/Free Full Text]
181. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK 2003 Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88:3005–3010[Abstract/Free Full Text]
182. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO 2002 Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79[CrossRef][Medline]
183. Stenlof K, Wernstedt I, Fjallman T, Wallenius V, Wallenius K, Jansson JO 2003 Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects. J Clin Endocrinol Metab 88:4379–4383[Abstract/Free Full Text]
184. Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA 2004 Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity. Am J Physiol Endocrinol Metab 287:E182–E187
185. Nonogaki K, Fuller GM, Fuentes NL, Moser AH, Staprans I, Grunfeld C, Feingold KR 1995 Interleukin-6 stimulates hepatic triglyceride secretion in rats. Endocrinology 136:2143–2149[Abstract]
186. Choy LN, Rosen BS, Spiegelman BM 1992 Adipsin and an endogenous pathway of complement from adipose cells. J Biol Chem 267:12736–12741[Abstract/Free Full Text]
187. Samad F, Yamamoto K, Loskutoff DJ 1996 Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor- and lipopolysaccharide. J Clin Invest 97:37–46[Medline]
188. Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE 2001 Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem 276:42077–42083[Abstract/Free Full Text]
189. Bastelica D, Morange P, Berthet B, Borghi H, Lacroix O, Grino M, Juhan-Vague I, Alessi MC 2002 Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat: evidence of differences between visceral and subcutaneous deposits. Arterioscler Thromb Vasc Biol 22:173–178[Abstract/Free Full Text]
190. Kratchmarova I, Kalume DE, Blagoev B, Scherer PE, Podtelejnikov AV, Molina H, Bickel PE, Andersen JS, Fernandez MM, Bunkenborg J, Roepstorff P, Kristiansen K, Lodish HF, Mann M, Pandey A 2002 A proteomic approach for identification of secreted proteins during the differentiation of 3T3–L1 preadipocytes to adipocytes. Mol Cell Proteomics 1:213–222[Abstract/Free Full Text]
191. Johnson JA, Albu JB, Engelson ES, Fried SK, Inada Y, Ionescu G, Kotler DP 2004 Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy. Am J Physiol Endocrinol Metab 286:E261–E271
192. Ogasawara K, Mashiba S, Wada Y, Sahara M, Uchida K, Aizawa T, Kodama T 2004 A serum amyloid A and LDL complex as a new prognostic marker in stable coronary artery disease. Atherosclerosis 174:349–356[Medline]
193. Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE 2005 The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 280:4617–4626[Abstract/Free Full Text]
194. Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE 2000 LPS activated TLR-4 receptor induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem 275:24255–24263[Abstract/Free Full Text]
195. Song MJ, Kim KH, Yoon JM, Kim JB 2006 Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun 346:739–745[CrossRef][Medline]
196. Lee JY, Sohn KH, Rhee SH, Hwang D 2001 Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276:16683–16689[Abstract/Free Full Text]
197. Berg AH, Lin Y, Lisanti MP, Scherer PE 2004 Adipocyte differentiation induces dynamic changes in NF-B expression and activity. Am J Physiol Endocrinol Metab 287:E1178–E1188
198. Combs TP, Nagajyothi, Mukherjee S, de Almeida CJ, Jelicks LA, Schubert W, Lin Y, Jayabalan DS, Zhao D, Braunstein VL, Landskroner-Eiger S, Cordero A, Factor SM, Weiss LM, Lisanti MP, Tanowitz HB, Scherer PE 2005 The adipocyte as an important target cell for Trypanosoma cruzi infection. J Biol Chem 280:24085–24094[Abstract/Free Full Text]

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