Published online before print September 6, 2007, doi: 10.1161/ATVBAHA.107.147835
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 American Heart Association, Inc.
Brief Reviews |
Inflamed Adipose Tissue
A Culprit Underlying the Metabolic Syndrome and Atherosclerosis
From the The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Correspondence to Dr Ulf Smith, The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail ulf.smith{at}medic.gu.se
Series Editor: Marja-Riitta Taskinen
 |
Abstract |
|---|
Top
Abstract
IntroductionThe metabolic syndrome is associated with a dysregulated adipose tissue; in part a consequence of adipose cell enlargement and the associated infiltration of macrophages. Adipose cell enlargement leads to a proinflammatory state in the cells with reduced secretion of adiponectin and with increased secretion of several cytokines and chemokines including interleukin (IL)-6, IL-8, and MCP-1. MCP-1 has been shown to play an important role for the associated recruitment of macrophages into the adipose tissue. The increased release of cytokines leads to an impaired differentiation of the preadipocytes with reduced lipid accumulation and induction of adiponectin, thus promoting ectopic lipid storage. In particular tumor necrosis factor (TNF)
, but also IL-6, has been shown to induce these effects in preadipocytes and this is associated with an increased Wnt signaling maintaining the cells in an undifferentiated and proinflammatory state. The proinflammatory state in the adipose tissue also leads to a local insulin resistance including an impaired inhibitory effect of insulin on FFA release. The insulin resistance further supports the proinflammatory state because insulin, by itself, is both antilipolytic and antiinflammatory by antagonizing cytokine-induced activation of STAT signaling. The Metabolic Syndrome is associated with a dysregulated adipose tissue attributable to inflammation with increased levels of several proinflammatory molecules. This alters the pattern of adipokines produced and prevents the differentiation of preadipocytes. Furthermore, insulin resistance is induced which enhances both lipolysis and the proinflammatory state because insulin has antiinflammatory effects.
Key Words: adipose tissue • cytokines • insulin • thiazolidinediones • insulin resistance
|
Introduction |
|---|
The metabolic syndrome is highly linked to the presence of obesity and, in particular, the circumference of the waist as a measure of degree of abdominal obesity. Waist circumference has been shown to correlate with the various components of the syndrome supporting the concept that the adipose tissue plays an important role. Recent advances in our understanding of adipose tissue biology and, in particular, its endocrine function and the dysregulated state associated with obesity characterized by enlarged adipose cells have provided insight into the mechanisms involved. In the present study, we briefly review adipose cell development (adipogenesis) and differentiation, pattern of adipokine secretion, as well as the changes in the adipose tissue associated with the development of obesity involving both pro- and antiinflammatory adipokines.
|
Adipogenesis |
|---|
Adipogenesis is the process by which committed precursor cells (preadipocytes) differentiate into mature adipocytes. Adipocyte differentiation includes morphological changes, cell arrest, lipid accumulation, and acquirement of insulin sensitivity and adipokine expression. Preadipocytes are committed to the adipocyte lineage but are morphologically indistinguishable from fibroblasts.1,2 A finite number of cell divisions, referred to as Mitotic Clonal Expansion (MCE), is necessary before differentiation in vitro. However, preadipocytes isolated from mammalian adipose tissue seem to be competent to undergo terminal differentiation without further divisions and are thought to have undergone the necessary cell divisions in vivo.1,3 In general, however, the commonly used cellines appear to behave similar to what happens in vivo, and cultured cells accumulate lipids and express all markers of mature adipocytes.2,4
Adipose cell differentiation is under transcriptional control, and induction of differentiation starts a coordinated cascade of events involving the early transcription factors C/EBPβ, C/EBP
, and PPAR
which then are followed by expression of C/EBP1,5—a key transcription factor for full terminal differentiation. However, more than 100 different transcription factors, coactivators, and repressors are expressed in preadipocytes, many of which are necessary for cell differentiation and induction of markers of differentiated adipocytes, eg, lipoprotein lipase (LPL), fatty acid synthase, aP2, adiponectin, GLUT4, and perilipin.6
|
Repressors of Adipogenesis |
|---|
Before the preadipocytes enter terminal differentiation, a number of factors must be downregulated: members of the GATA-binding and Forkhead families, preadipocyte factor-1 (Pref-1), CHOP proteins, and the repressor ETO (RUNX1) that binds to C/EBPβ.7,8 The importance of this coordinated series of events is illustrated by the finding that constitutive expression of GATA2 suppresses adipocyte differentiation by binding to C/EBPs and, instead, induces an inflammatory state with expression of MCP-1, GM-colony stimulating factor (CSF), and IL-4.9,10 In general, degree of adipose cell differentiation is negatively correlated with the activation of proinflammatory molecules. For instance, undifferentiated human preadipocytes express high levels of many proinflammatory genes, whereas these are reduced when the cells undergo differentiation.
|
Macrophages and Adipocytes Have the Same Origin |
|---|
An evolutionary link between adipocytes and inflammatory cells is the fat body present in insects. This has dispersed into 2 lines during evolution in vertebrates: the liver and fat tissue.11 The fat body in insects originates from the mesoderm and plays a role similar to mammalian liver during an acute-phase response. Activation of the Toll pathway exhibits similarities with the Toll-like receptor (TLR) and TNF
pathways in vertebrates.
Adipocyte precursor cells (preadipocytes) can achieve phagocytotic capacity and, thereby, appear to be macrophage-like cells under appropriate stimulation.12 Proliferating preadipocytes have the ability to be phagocytotic, also in the absence of external stimulation, but this function decreases when proliferation is stopped.13 Macrophages can also take up and store lipids, and adipocytes and macrophages share a number of important genes and markers like fatty acid transporters (ie, aP2/FABP4) and the transcription factor PPAR. When activated, both are able to express IL-6 and TNF and adipocytes are able to express macrophage markers.14
Obesity with enlarged fat cells is associated with an increased number of macrophages in the adipose tissue surrounding individual adipocytes.15 Methodology to measure the number of committed preadipocytes in human has been limited because of a lack of specific markers. Using a combination of the 2 markers, aP2 and CD68, Tchoukalova et al16 recently reported that the number of committed preadipocytes was reduced in obesity while the number of macrophages was increased.
|
TNF: A Key Culprit?
|
|---|
One of the most important mediators of inflammation secreted by macrophages is TNF
. Lacasa et al17 showed that conditioned medium from activated macrophages, both from differentiated monocytes and isolated human macrophages, reduced adipogenesis and induced preadipocyte proliferation. The preadipocytes also exhibited a strong induction of the proinflammatory molecules IL-6, IL-8, MCP-1, and IL1β. Addition of anti-TNF neutralizing antibodies inhibited the inflammatory state in the preadipocytes. TNF-stimulated preadipocytes showed an upregulation of the NF
B pathway consistent with the increased expression of IL-6, IL-8, MCP-1, and IL1β.17
Macrophages provide a link to inflammation, but the signal that induces the monocytes to migrate into the adipose tissue and the cells in the tissue to produce chemoattractants is still poorly understood. However, the increased concentration of free fatty acids associated with adipose cell enlargement might generate a condition of ER stress and, thereby, activation of JNK and NFB. This, in turn, can lead to the induction of MCP-1 by the adipose tissue cells and, thus, monocyte migration into the tissue. Figure 1 summarizes the sequence of events associated with obesity.
|
Mice that lack MCP-1 show a decreased infiltration of macrophages into the adipose tissue after a high fat diet.18 The macrophages in the adipose tissue are probably the major source of TNF. Although adipocyte mRNA expression of TNF also is increased, the contribution of TNF from adipocytes is low because of the low activity of adipocyte TNF converting enzyme TACE.19
Coculture experiments with 3T3-L1 adipocytes and macrophages showed induction of MCP-1. The cross-talk between macrophages and adipocytes in cell culture seems to be attributable to the release of TNF by the macrophages and free fatty acids by the adipocytes. Activation of the TLR4 by fatty acids induces inflammatory changes in both macrophages and adipocytes through NFB activation.20 In addition, both TNF and IL-6 increase the expression of MCP-1 during differentiation of 3T3-L1 preadipocytes.21 Differentiation in the presence of TNF induces expression of GATA2 (unpublished data), and upregulation of GATA2 can be one of the factors promoting an inflammatory phenotype in the preadipocytes.
|
Wnt Signaling: A Highly Conserved Pathway During Evolution |
|---|
Normal adipogenesis is dependent on the inhibition of Wnt signaling. The Wnt-family consists of a number of secreted glycosylated lipoproteins where Wnt10b is expressed in preadipocytes but not in adipocytes. Maintaining Wnt signaling in mesenchymal precursor cells promotes osteoblastogenesis and myogenesis and suppresses adipocyte differentiation.22,23 Overexpression of Wnt10b in adipocytes in transgenic mice reduces the white adipose tissue by around 50%.24 Intiguingly, other Wnts, like Wnt5a, is transiently induced during differentiation and promotes adipogenesis.25
The downstream mediator of the canonical Wnt pathway is β-catenin. During initiation of preadipocyte differentiation, β-catenin is sustained in the nucleus for up to 48 hours but then undergoes phosphorylation and degradation before the cells enter terminal differentiation. This coincides with the induction of the adipogenic transcription factors C/EBPβ and PPAR.26 Wnt-expressing preadipocytes fail to induce PPAR. However, addition of PPAR ligands, the thiazolidinediones, rescues the differentiation and stimulates the degradation of β-catenin.26
The cross-talk between inflammation and adipocyte differentiation is further underscored by our recent finding that differentiation of 3T3-L1 preadipocytes in the presence of IL-6 sustained β-catenin and the cells maintained a fibroblast-like appearance and accumulated less lipids. In contrast, addition of TNF totally inhibited adipocyte differentiation, including lipid accumulation, and maintained Wnt signaling.21
|
The Adipose Tissue: A Key Endocrine Organ With Autocrine Regulation |
|---|
The adipose tissue was once thought to be an inert tissue used solely for storage of excess energy. Identification of many bioactive proteins secreted by adipose tissue assigned the adipocyte a more important and central role in the pathophysiology of insulin resistance and the Metabolic Syndrome (Figure 2). This was further underscored by the recognition that many of the so-called adipokines have the ability to influence lipid and glucose metabolism, not only locally in the adipose tissue, but also in the skeletal muscle and liver. In addition, certain adipokines were found to have effects on appetite regulation or to have an important impact on inflammation and vascular biology.
|
The adipose tissue in mammals consists of 2 types: white adipose tissue (WAT) and brown adipose tissue (BAT), but also mixed areas. WAT and BAT share many metabolic characteristics but, whereas WAT mainly stores excess energy for subsequent needs, BAT functions as an energy-dissipating organ. In rodents, it is well established that BAT plays an important role in preventing and reducing obesity through increased energy dissipation and heat production. However, the role of BAT is unclear in man. It is well- known that newborns are provided with a considerable amount of BAT which becomes drastically reduced shortly after birth. However, brown adipocytes are dispersed in the WAT also in adult life, with a calculated presence of 1 brown adipocyte for every 100 to 200 white adipocytes.27 The importance of brown cells within the WAT or cells with a "brownish phenotype" has been discussed. Interestingly, treatment with the thiazolidinediones (TZD) has been shown to induce a brown adipocyte phenotype in rodent white adipocytes.28 Furthermore, the expression of genes characteristic of the brown adipocyte phenotype in human adipose tissue has been shown to correlate negatively with obesity and insulin sensitivity.29,30
The WAT in man consists of subcutaneous and visceral depots. The importance of each depot for the dysmetabolic state associated with the Metabolic Syndrome has been extensively discussed. The visceral depot has been receiving most attention because it is considered to be more metabolically active and because it delivers released factors to the portal venous system and, thus, can directly have an impact on the liver. However, the amount of subcutaneous adipose tissue generally exceeds the visceral by 3 to 4 times31 and should not be disregarded. In fact, it seems that these depots can interact in a coordinate and compensatory manner and both should be considered important for the obesity-related complications.32
The adipose tissue does not only consist of preadipocytes and adipocytes, but also of other cell types such as fibroblasts, vascular cells, inflammatory cells, and mesenchymal stem cells. The mesenchymal stem cells are an important reservoir for recruitment of new preadipocytes within an expanding adipose tissue. Inability to recruit and differentiate new adipocytes is likely to be a key factor regulating degree of adipocyte enlargement in obesity and the associated ectopic lipid accumulation in skeletal muscle and liver when the existing adipocytes are not able to store excess lipids.
Adipocyte cell size has been shown to be an independent predictor of insulin resistance and risk for type 2 diabetes and to correlate with different aspects of the Metabolic Syndrome.33,34 The adipocyte is the only cell whose size may vary dramatically; around 10-fold in diameter and, thus, 1000-fold in volume! As discussed above, the size of the adipocytes influences the degree of inflammation in the adipose tissue (cf. Figure 1) as well as the rate of lipid mobilization and pattern of adipokine secretion. What initiates the proinflammatory process associated with obesity and adipose cell enlargement is not known. MCP-1 expression and secretion is elevated in large adipocytes,35 upregulated in obesity and reduced after weight reduction.36
TNF and IL-6 are important inflammatory molecules associated with obesity and insulin resistance. TNF is one of the cytokines whose expression and secretion by the adipose tissue in vitro is elevated in obese subjects.37,38 However, adipocyte TNF does not seem to be cleaved and released by the adipose cells to the systemic circulation in vivo.39 The increased level of TNF in the adipose tissue in obesity is mainly attributable to the infiltrating macrophages. TNF is a potent inducer of cytokine and chemokine expression, and secretion by adipocytes and the expression of TNF, IL-6, and other proinflammatory molecules is positively correlated to adipocyte cell size.40
Increased tissue levels of both TNF and IL-6 are detrimental to the normal preadipocyte development and differentiation as discussed above. Furthermore, in mature adipocytes, both TNF and IL-6 impair insulin signaling through different mechanisms including decreased tyrosine phosphorylation of key signaling molecules, increased inhibitory serine phosphorylation, and downregulation of the expression of several proteins in the insulin signaling pathway.41,42 These effects lead to insulin resistance, increased lipolysis and reduced glucose uptake by the adipose tissue.
One of the most widely studied secreted adipokine is adiponectin. Adiponectin has been demonstrated to have effects on many aspects of the Metabolic Syndrome and is discussed in detail below.
Leptin is another widely studied adipokine. It is mostly produced and secreted by adipocytes and the secretion, in contrast to that of adiponectin, is positively related to adipocyte size and obesity. Leptin has structural similarity with proinflammatory cytokines such as IL-6 and IL-12. It is important for appetite regulation and energy expenditure but the increased leptin levels in obesity are associated with leptin resistance.43 Leptin has also been suggested to contribute to the obesity-associated hypertension through actions on the central symphatoregulatory pathways. Furthermore, leptin has been ascribed a role in diet-induced neointimal thickening after vascular injury.44
Retinol binding protein 4 (RBP4) was recently identified as a novel adipokine that is increased in different animal models of insulin-resistance.45 It increases hepatic expression of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), and impairs insulin signaling and action in skeletal muscle. Furthermore, circulating serum levels of RBP4 in man correlate inversely with insulin sensitivity measured with the euglycemic-hyperinsulinemic clamp technique.46 It is not only elevated in subjects with obesity, type 2 diabetes, and impaired glucose tolerance but also in normoglycemic, and insulin-resistant subjects with a strong family history of type 2 diabetes.46 Moreover, circulating levels of RBP4 are associated with elevated liver fat in both cross-sectional and longitudinal analyses, a condition known to be associated with hepatic insulin resistance.47
Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of the fibrinolytic system, and the circulating levels are elevated in inflammatory states like obesity and the Metabolic Syndrome. Although it is primarily derived from platelets and endothelial cells, several studies have shown that the elevated PAI-1 levels in obesity can largely be attributable to an increased production by the adipose tissue.48,49
The acute phase-reactant serum amyloid A (SAA) has been implicated as a significant contributor to atherogenesis. SAA is secreted from several tissues in the body including mature adipocytes.50 Circulating levels of SAA are increased in obesity and type 2 diabetes, mainly attributable to enhanced proinflammatory signaling, but also by hyperglycemia.50 A suggested mechanism for the vascular effects of SAA is through binding and targeting HDL cholesterol deposition to the atherogenic foam cells.51
Adipocytes, in particular in the visceral depot, secrete angiotensinogen and angiotensinogen-converting enzymes (ACEs); both of which are systemically elevated in obesity.52 Increased activity of this system is associated with vasoconstriction and, thus, can contribute to hypertension. Furthermore, it has been shown to increase the endothelial expression of the adhesion molecules, vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule-1 (ICAM-1), as well as the chemokine MCP-1, factors contributing to the infiltration of inflammatory cells in the arterial wall.53
The adipose tissue is unique in terms of its ability to grow to accommodate the excess energy. As such, it is dependent on the continuous supply of oxygen and nutrients. It is, therefore, not surprising that the adipocytes secrete factors that will ensure this. On differentiation, the preadipocytes express vascular endothelial growth factor (VEGF) which stimulates angiogenesis.54 The expression and secretion of VEGF is insulin-dependent, and the circulating VEGF levels are increased in hyperinsulinemic state like the Metabolic Syndrome.
This review cannot cover all factors that are secreted by the adipose tissue and has focused on those most clearly associated with obesity and the Metabolic Syndrome (cf. Figure 2). The role of the dysregulated adipose tissue in insulin resistance55 is a very active research area and new adipokines will surely be detected in the near future.
|
Antiinflammatory Molecules in the Adipose Tissue |
|---|
Obesity with adipose cell enlargement is a proinflammatory state with an increased production of different cyto-/chemokines by the adipose tissue. However, the adipose tissue is also responsive to antiinflammatory factors like the thiazolidinediones and insulin and, in addition, produces adiponectin which is antiinflammatory. In obesity, the proinflammatory state leads to a reduced responsiveness by the adipose cells to insulin, ie, insulin resistance, and the production of adiponectin is also reduced. These alterations further augment the proinflammatory state seen in the Metabolic Syndrome (schematically shown in Figure 3) as outlined below.
|
|
Adiponectin |
|---|
One of the most widely studied secreted adipokine is adiponectin.56,57 Adiponectin is both an important antiinflammatory molecule and an important regulator of insulin sensitivity. It is a true adipokine, only produced by the adipose cells, and is also a marker of adipocyte differentiation. The secretion is reduced in obesity, insulin resistance, and type 2 diabetes.58–60 In contrast to leptin, obesity and adipose cell enlargement are associated with a reduced secretion of adiponectin by the adipose cells while weight loss increases the levels of adiponectin.57,58,61 Adiponectin has been shown to improve insulin signaling and glucose uptake by skeletal muscle by activation of AMPK-associated signaling. However, the strongest association is with hepatic insulin sensitivity, where adiponectin is thought to increase insulin sensitivity through effects on fatty acid oxidation.62,63
Secretion of adiponectin is inversely related to the expression of proinflammatory adipokines in the adipose tissue. Thus, both TNF and IL-6 reduce secretion of adiponectin by the adipose cells.40,64,65 The cross-talk between cytokines and adiponectin secretion is further underscored by the finding that mice having an ablated adiponectin gene have higher TNF mRNA levels in the adipose tissue.66 In addition, adiponectin reduces hepatic TNF expression, possibly by increasing hepatic fatty acid oxidation and, thus, reducing ectopically stored lipids.67 TNF and IL-6 also increase the secretion of the acute phase proteins, PAI-1 and SAA, by the adipose tissue and high circulating concentrations of these proteins are seen in obesity where they correlate inversely with the adiponectin levels.68–70
Adiponectin has also been implicated in cardiovascular health and has been shown to be a marker for future cardiovascular events.71 The mechanism for the antiatherosclerotic effect of adiponectin is not completely elucidated. However, a number of studies have shown direct effects of adiponectin on endothelial and smooth muscle cells.72
Adiponectin binds to the 2 adiponectin receptors, AdipoR1 and AdipoR2,73 but the downstream signaling process is unclear. However, receptor binding leads to the activation of PPAR, AMPK, and p38MAPK mediating both antiinflammatory effects as well as the metabolic effects. Although the precise molecular mechanisms of action of adiponectin are unclear, several studies have shown that the antiinflammatory effects involve inhibition of NFB signaling.74–76
|
Insulin |
|---|
Apart from its important metabolic effects, insulin can also exert antiinflammatory effects. This has been recently shown in both blood cells, endothelial and adipose cells. Thus, the fact that the adipose tissue becomes insulin-resistant in obesity, because of the increased production of cytokines and impaired production of adiponectin discussed above, further augments the proinflammatory state in the adipose tissue. The antiinflammatory effect of insulin has been documented in vivo where insulin infusion significantly reduced the plasma levels of PAI-1, CRP, and SAA.77 One mechanism for this seems to be related to the ability of insulin to reduce intranuclear NF-
B binding activity and to suppress induction of the proinflammatory chemokine MCP-1 as shown in human aortic endothelial cells.78 Similar results were found in mononuclear cells from subjects undergoing an insulin infusion and this was associated with an increase in the NF-B-inhibiting protein IB.79 NF-B is known to induce other proinflammatory genes like IL-6, TNF, and IL-1β. However, the underlying mechanisms for the effect of insulin on IB and NF-B require further elucidation. Recently, we have shown that insulin antagonizes the IL-6 signaling pathway in 3T3-L1 cells by activating the protein tyrosine phosphatase SHP2 and increasing the feed-back inhibitor, SOCS3.80 This results in a reduced nuclear localization and transcriptional activation of the transcription factor STAT3 together with a reduced expression of the IL-6–induced acute-phase proteins SAA3 and haptoglobin.80
|
Thiazolidinediones |
|---|
Thiazolidinediones (TZD) are agonists for the transcription factor PPAR
and have insulin-sensitizing and antiinflammatory properties. TZD promote, through PPAR, adipose cell recruitment and differentiation.81,82 One important mechanism for its antiinflammatory effect is to increase the release of adiponectin by the adipose cells as discussed. Interestingly, an atypical PPAR-response element has been identified in the adiponectin promoter. Thus, the TZD-induced transcriptional activation of adiponectin is dependent on PPAR2 for initiation but not on C/EBP. However, both these transcription factors contribute to the full activation of the gene.64,83 TZD are also antiinflammatory by virtue of inducing an appropriate storage of fat in the adipose cells and, thus, reducing lipotoxicity.81,82 In addition, lipid oxidation is increased through adiponectin and AMPK activation and this is probably one important mechanism for the finding that TZD reduce the amount of liver fat.84
About 10 years ago it was reported that ligand activation of PPAR in monocytes and macrophages reduced cell activation and inhibited the expression of nitric oxide synthase (NOS), gelatinase B and scavenger receptor A. The transcriptional activation of NF-kappaB, AP-1, and STAT1 was also reduced by TZD treatment as well as cytokine (TNF, IL-6, and IL-1β) secretion.85,86 Results from these studies, together with subsequent studies,87–89 suggest that TZD may also have antiatherogenic effects. Some evidence for this has also been found using surrogate measurements, such as intima/media thickness, whereas a positive final outcome on cardiovascular disease in diabetes was not clearly documented in the large ProActive study.90
TZD also reduce the expression of both TNF and IL-6 in liver and adipose tissue from lean and obese mice and in human monocytes.84,91 The plasma levels of TNF and IL-6 as well as the acute-phase proteins SAA, CRP, and PAI-1 were reduced by TZD treatment in obese and diabetic patients.92–95
|
Conclusions |
|---|
The adipose tissue plays a key role for the insulin resistance and dysregulated state seen in obesity and the Metabolic Syndrome. Adipose cell enlargement in obesity induces a proinflammatory state in the tissue with infiltration of macrophages. The increased tissue levels of cytokines (like TNF
, IL-6, IL-8, MCP-1) further promote a proinflammatory state, impair the normal differentiation of the preadipocytes, alter the pattern of secreted adipokines by the adipose tissue (eg, reducing adiponectin secretion), and induce insulin resistance locally and in other peripheral tissues. Insulin resistance in the adipose tissue also augments the proinflammatory state because insulin exerts antiinflammatory effects.
|
Acknowledgments |
|---|
We thank current and former colleagues in the laboratory for their contributions to the work reviewed.
Sources of Funding
The studies referred to by the authors’ laboratory were supported by grants from the European Community’s FP6 EUGENE2 (LSHM-CT-2004-512013) and HEPADIP (LSHM-CT-2005-018734), the Swedish Diabetes Association, the Swedish Research Council, the Novo Nordisk Foundation, the Sonya Hedenbratt Memorial Fund, the Martina and Willhelm Lundgren Foundation, the IngaBritt and Arne Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, the Gothenburg Royal Society of Arts, and the Swedish Foundation for Strategic Research.
Disclosures
None.
|
Footnotes |
|---|
The authors contributed equally to this work
Original received May 10, 2007; final version accepted August 28, 2007.
|
References |
|---|
1. Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol. 2000; 16: 145–171.[CrossRef][Medline] [Order article via Infotrieve]
2. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006; 7: 885–896.[CrossRef][Medline] [Order article via Infotrieve]
3. Tang QQ, Otto TC, Lane MD. Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc Natl Acad Sci U S A. 2003; 100: 44–49.
4. Rosen ED. The transcriptional basis of adipocyte development. Prostaglandins Leukot Essent Fatty Acids. 2005; 73: 31–34.[CrossRef][Medline] [Order article via Infotrieve]
5. Otto TC, Lane MD. Adipose development: from stem cell to adipocyte. Crit Rev Biochem Mol Biol. 2005; 40: 229–242.[CrossRef][Medline] [Order article via Infotrieve]
6. Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev. 1998; 78: 783–809.
7. Rochford JJ, Semple RK, Laudes M, Boyle KB, Christodoulides C, Mulligan C, Lelliott CJ, Schinner S, Hadaschik D, Mahadevan M, Sethi JK, Vidal-Puig A, O’Rahilly S. ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis. Mol Cell Biol. 2004; 24: 9863–9872.
8. Farmer SR. Transcriptional control of adipocyte formation. Cell Metab. 2006; 4: 263–273.[CrossRef][Medline] [Order article via Infotrieve]
9. Menghini R, Marchetti V, Cardellini M, Hribal ML, Mauriello A, Lauro D, Sbraccia P, Lauro R, Federici M. Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation. 2005; 111: 1946–1953.
10. Tong Q, Tsai J, Tan G, Dalgin G, Hotamisligil GS. Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation. Mol Cell Biol. 2005; 25: 706–715.
11. Tzou P, De Gregorio E, Lemaitre B. How Drosophila combats microbial infection: a model to study innate immunity and host-pathogen interactions. Curr Opin Microbiol. 2002; 5: 102–110.[CrossRef][Medline] [Order article via Infotrieve]
12. Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L, Casteilla L. Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem. 2003; 278: 9850–9855.
13. Cousin B, Munoz O, Andre M, Fontanilles AM, Dani C, Cousin JL, Laharrague P, Casteilla L, Penicaud L. A role for preadipocytes as macrophage-like cells. FASEB J. 1999; 13: 305–312.
14. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005; 115: 1111–1119.[CrossRef][Medline] [Order article via Infotrieve]
15. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112: 1796–1808.[CrossRef][Medline] [Order article via Infotrieve]
16. Tchoukalova Y, Koutsari C, Jensen M. Committed subcutaneous preadipocytes are reduced in human obesity. Diabetologia. 2007; 50: 151–157.[CrossRef][Medline] [Order article via Infotrieve]
17. Lacasa D, Taleb S, Keophiphath M, Miranville A, Clement K. Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. Endocrinology. 2007; 148: 868–877.
18. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006; 116: 1494–1505.[CrossRef][Medline] [Order article via Infotrieve]
19. Xu H, Uysal KT, Becherer JD, Arner P, Hotamisligil GS. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes. 2002; 51: 1876–1883.
20. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol. 2007; 27: 84–91.
21. Gustafson B, Smith U. Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3–L1 preadipocytes. J Biol Chem. 2006; 281: 9507–9516.
22. Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005; 102: 3324–3329.
23. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA. Inhibition of adipogenesis by Wnt signaling. Science. 2000; 289: 950–953.
24. Longo KA, Wright WS, Kang S, Gerin I, Chiang SH, Lucas PC, Opp MR, MacDougald OA. Wnt10b inhibits development of white and brown adipose tissues. J Biol Chem. 2004; 279: 35503–35509.
25. Kanazawa A, Tsukada S, Kamiyama M, Yanagimoto T, Nakajima M, Maeda S. Wnt5b partially inhibits canonical Wnt/beta-catenin signaling pathway and promotes adipogenesis in 3T3–L1 preadipocytes. Biochem Biophys Res Commun. 2005; 330: 505–510.[CrossRef][Medline] [Order article via Infotrieve]
26. Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR. Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochem J. 2003; 376: 607–613.[CrossRef][Medline] [Order article via Infotrieve]
27. Oberkofler H, Dallinger G, Liu YM, Hell E, Krempler F, Patsch W. Uncoupling protein gene: quantification of expression levels in adipose tissues of obese and non-obese humans. J Lipid Res. 1997; 38: 2125–2133.[Abstract]
28. Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S, Czech M, Corvera S. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol. 2003; 23: 1085–1094.
29. Semple RK, Crowley VC, Sewter CP, Laudes M, Christodoulides C, Considine RV, Vidal-Puig A, O’Rahilly S. Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord. 2004; 28: 176–179.[CrossRef][Medline] [Order article via Infotrieve]
30. Hammarstedt A, Jansson PA, Wesslau C, Yang X, Smith U. Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. Biochem Biophys Res Commun. 2003; 301: 578–582.[CrossRef][Medline] [Order article via Infotrieve]
31. Chowdhury B, Sjostrom L, Alpsten M, Kostanty J, Kvist H, Lofgren R. A multicompartment body composition technique based on computerized tomography. Int J Obes Relat Metab Disord. 1994; 18: 219–234.[Medline] [Order article via Infotrieve]
32. Yang X, Smith U. Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer? Diabetologia. 2007; 50: 1127–1139.[CrossRef][Medline] [Order article via Infotrieve]
33. Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000; 43: 1498–1506.[CrossRef][Medline] [Order article via Infotrieve]
34. Lundgren M, Svensson M, Lindmark S, Renstrom F, Ruge T, Eriksson JW. Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’. Diabetologia. 2007; 50: 625–633.[CrossRef][Medline] [Order article via Infotrieve]
35. Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007; 92: 1023–1033.
36. Christiansen T, Richelsen B, Bruun JM. Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes (Lond). 2005; 29: 146–150.[CrossRef][Medline] [Order article via Infotrieve]
37. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95: 2409–2415.[Medline] [Order article via Infotrieve]
38. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001; 280: E745–E751.
39. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997; 82: 4196–4200.
40. Sopasakis VR, Sandqvist M, Gustafson B, Hammarstedt A, Schmelz M, Yang X, Jansson PA, Smith U. High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator. Obes Res. 2004; 12: 454–460.[Medline] [Order article via Infotrieve]
41. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3–L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003; 278: 45777–45784.
42. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002; 277: 1531–1537.
43. Enriori PJ, Evans AE, Sinnayah P, Cowley MA. Leptin resistance and obesity. Obesity (Silver Spring). 2006; 14 Suppl 5: 254S–258S.
44. Schafer K, Halle M, Goeschen C, Dellas C, Pynn M, Loskutoff DJ, Konstantinides S. Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol. 2004; 24: 112–117.
45. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005; 436: 356–362.[CrossRef][Medline] [Order article via Infotrieve]
46. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006; 354: 2552–2563.
47. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Schleicher E, Fritsche A, Haring HU. High circulating retinol-binding protein 4 is associated with elevated liver fat, but not with total-, subcutaneous-, visceral-, or intramyocellular fat in humans. Diabetes Care. 2007; 30: 1173–1178.
48. Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord. 2004; 28: 1357–1364.[CrossRef][Medline] [Order article via Infotrieve]
49. Loskutoff DJ, Samad F. The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol. 1998; 18: 1–6.
50. Yang RZ, Lee MJ, Hu H, Pollin TI, Ryan AS, Nicklas BJ, Snitker S, Horenstein RB, Hull K, Goldberg NH, Goldberg AP, Shuldiner AR, Fried SK, Gong DW. Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med. 2006; 3: e287.[CrossRef][Medline] [Order article via Infotrieve]
51. Meek RL, Urieli-Shoval S, Benditt EP. Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A function. Proc Natl Acad Sci U S A. 1994; 91: 3186–3190.
52. Cooper R, McFarlane-Anderson N, Bennett FI, Wilks R, Puras A, Tewksbury D, Ward R, Forrester T. ACE, angiotensinogen and obesity: a potential pathway leading to hypertension. J Hum Hypertens. 1997; 11: 107–111.[CrossRef][Medline] [Order article via Infotrieve]
53. Tham DM, Martin-McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, Dole W, Rutledge JC. Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs. Physiol Genomics. 2002; 11: 21–30.[Medline] [Order article via Infotrieve]
54. Claffey KP, Wilkison WO, Spiegelman BM. Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem. 1992; 267: 16317–16322.
55. Yang X, Jansson PA, Nagaev I, Jack MM, Carvalho E, Sunnerhagen KS, Cam MC, Cushman SW, Smith U. Evidence of impaired adipogenesis in insulin resistance. Biochem Biophys Res Commun. 2004; 317: 1045–1051.[CrossRef][Medline] [Order article via Infotrieve]
56. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995; 270: 26746–26749.
57. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996; 271: 10697–10703.
58. 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. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999; 257: 79–83.[CrossRef][Medline] [Order article via Infotrieve]
59. Jansson PA, Pellme F, Hammarstedt A, Sandqvist M, Brekke H, Caidahl K, Forsberg M, Volkmann R, Carvalho E, Funahashi T, Matsuzawa Y, Wiklund O, Yang X, Taskinen MR, Smith U. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. FASEB J. 2003; 17: 1434–1440.
60. 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. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004; 279: 12152–12162.
61. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM. Weight reduction increases plasma levels of an adipose-derived antiinflammatory protein, adiponectin. J Clin Endocrinol Metab. 2001; 86: 3815–3819.
62. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang Cc C, Itani SI, Lodish HF, Ruderman NB. 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 U S A. 2002; 99: 16309–16313.
63. 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. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002; 8: 1288–1295.[CrossRef][Medline] [Order article via Infotrieve]
64. Gustafson B, Jack MM, Cushman SW, Smith U. Adiponectin gene activation by thiazolidinediones requires PPAR gamma 2, but not C/EBP alpha-evidence for differential regulation of the aP2 and adiponectin genes. Biochem Biophys Res Commun. 2003; 308: 933–939.[CrossRef][Medline] [Order article via Infotrieve]
65. Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev. 2003; 14: 447–455.[CrossRef][Medline] [Order article via Infotrieve]
66. 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. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 2002; 8: 731–737.[CrossRef][Medline] [Order article via Infotrieve]
67. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003; 112: 91–100.[CrossRef][Medline] [Order article via Infotrieve]
68. Mertens I, Ballaux D, Funahashi T, Matsuzawa Y, Van der Planken M, Verrijken A, Ruige JB, Van Gaal LF. Inverse relationship between plasminogen activator inhibitor-I activity and adiponectin in overweight and obese women. Interrelationship with visceral adipose tissue, insulin resistance, HDL-chol and inflammation. Thromb Haemost. 2005; 94: 1190–1195.[Medline] [Order article via Infotrieve]
69. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation. 2003; 107: 671–674.
70. Liu J, Young TK, Zinman B, Harris SB, Connelly PW, Hanley AJ. Lifestyle variables, non-traditional cardiovascular risk factors, and the metabolic syndrome in an Aboriginal Canadian population. Obesity (Silver Spring). 2006; 14: 500–508.[Medline] [Order article via Infotrieve]
71. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004; 291: 1730–1737.
72. Goldstein BJ, Scalia R. Adiponectin: A novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab. 2004; 89: 2563–2568.
73. 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. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003; 423: 762–769.[CrossRef][Medline] [Order article via Infotrieve]
74. Kobashi C, Urakaze M, Kishida M, Kibayashi E, Kobayashi H, Kihara S, Funahashi T, Takata M, Temaru R, Sato A, Yamazaki K, Nakamura N, Kobayashi M. Adiponectin inhibits endothelial synthesis of interleukin-8. Circ Res. 2005; 97: 1245–1252.
75. 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. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation. 2000; 102: 1296–1301.
76. Ajuwon KM, Spurlock ME. Adiponectin inhibits LPS-induced NF-kappaB activation and IL-6 production and increases PPARgamma2 expression in adipocytes. Am J Physiol Regul Integr Comp Physiol. 2005; 288: R1220–R1225.
77. Chaudhuri A, Janicke D, Wilson MF, Tripathy D, Garg R, Bandyopadhyay A, Calieri J, Hoffmeyer D, Syed T, Ghanim H, Aljada A, Dandona P. Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation. 2004; 109: 849–854.
78. Aljada A, Ghanim H, Saadeh R, Dandona P. Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab. 2001; 86: 450–453.
79. Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001; 86: 3257–3265.
80. Andersson CX, Sopasakis VR, Wallerstedt E, Smith U. Insulin Antagonizes Interleukin-6 Signaling and Is Anti-inflammatory in 3T3–L1 Adipocytes. J Biol Chem. 2007; 282: 9430–9435.
81. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest. 1998; 101: 1354–1361.[Medline] [Order article via Infotrieve]
82. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004; 351: 1106–1118.
83. Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes. 2003; 52: 1655–1663.
84. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355: 2297–2307.
85. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998; 391: 82–86.[CrossRef][Medline] [Order article via Infotrieve]
86. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998; 391: 79–82.[CrossRef][Medline] [Order article via Infotrieve]
87. Tannock LR, Little PJ, Tsoi C, Barrett PH, Wight TN, Chait A. Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans. Diabetologia. 2004; 47: 837–843.[CrossRef][Medline] [Order article via Infotrieve]
88. Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol. 2001; 21: 372–377.
89. Collins AR, Meehan WP, Kintscher U, Jackson S, Wakino S, Noh G, Palinski W, Hsueh WA, Law RE. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 365–371.
90. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366: 1279–1289.[CrossRef][Medline] [Order article via Infotrieve]
91. Sigrist S, Bedoucha M, Boelsterli UA. Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes. Biochem Pharmacol. 2000; 60: 67–75.[CrossRef][Medline] [Order article via Infotrieve]
92. Katsuki A, Sumida Y, Murata K, Furuta M, Araki-Sasaki R, Tsuchihashi K, Hori Y, Yano Y, Gabazza EC, Adachi Y. Troglitazone reduces plasma levels of tumour necrosis factor-alpha in obese patients with type 2 diabetes. Diabetes Obes Metab. 2000; 2: 189–191.[CrossRef][Medline] [Order article via Infotrieve]
93. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002; 106: 679–684.
94. Ebeling P, Teppo AM, Koistinen HA, Viikari J, Ronnemaa T, Nissen M, Bergkulla S, Salmela P, Saltevo J, Koivisto VA. Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes. Diabetologia. 1999; 42: 1433–1438.[CrossRef][Medline] [Order article via Infotrieve]
95. Kruszynska YT, Yu JG, Olefsky JM, Sobel BE. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes. 2000; 49: 633–639.[Abstract]
Related Article:
Arterioscler. Thromb. Vasc. Biol. 2007 27: 2275.
This article has been cited by other articles:
 |
|
 |
|
  P. Isakson, A. Hammarstedt, B. Gustafson, and U. Smith Impaired Preadipocyte Differentiation in Human Abdominal Obesity: Role of Wnt, Tumor Necrosis Factor-{alpha}, and Inflammation Diabetes, July 1, 2009; 58(7): 1550 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Hwang, N. Afifiyan, D. Sand, V. Naik, J. Said, S. J. Pollock, B. Chen, R. P. Phipps, R. A. Goldberg, T. J. Smith, et al. Orbital Fibroblasts from Patients with Thyroid-Associated Ophthalmopathy Overexpress CD40: CD154 Hyperinduces IL-6, IL-8, and MCP-1 Invest. Ophthalmol. Vis. Sci., May 1, 2009; 50(5): 2262 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Riant, A. Waget, H. Cogo, J.-F. Arnal, R. Burcelin, and P. Gourdy Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice Endocrinology, May 1, 2009; 150(5): 2109 - 2117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Ghosh, H. D. Massey, R. Krieg, Z. A. Fazelbhoy, S. Ghosh, D. A. Sica, I. Fakhry, and T. W. B. Gehr Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1146 - F1157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Lee, M. C. Carr, S. J. Murdoch, E. Mitchell, N. F. Woods, M. H. Wener, W. L. Chandler, E. J. Boyko, and J. D. Brunzell Adipokines, Inflammation, and Visceral Adiposity across the Menopausal Transition: A Prospective Study J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1104 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Molgat, A. Gagnon, and A. Sorisky Preadipocyte apoptosis is prevented by macrophage-conditioned medium in a PDGF-dependent manner Am J Physiol Cell Physiol, April 1, 2009; 296(4): C757 - C765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chen, S. R. Srinivasan, and G. S. Berenson Influence of Birth Weight on White Blood Cell Count in Biracial (Black-White) Children, Adolescents, and Young Adults: The Bogalusa Heart Study Am. J. Epidemiol., January 15, 2009; 169(2): 214 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Traish, A. Guay, R. Feeley, and F. Saad The Dark Side of Testosterone Deficiency: I. Metabolic Syndrome and Erectile Dysfunction J Androl, January 1, 2009; 30(1): 10 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Traish, F. Saad, and A. Guay The Dark Side of Testosterone Deficiency: II. Type 2 Diabetes and Insulin Resistance J Androl, January 1, 2009; 30(1): 23 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-A. Cornier, D. Dabelea, T. L. Hernandez, R. C. Lindstrom, A. J. Steig, N. R. Stob, R. E. Van Pelt, H. Wang, and R. H. Eckel The Metabolic Syndrome Endocr. Rev., December 1, 2008; 29(7): 777 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Eriksson, P.-A. Jansson, B. Carlberg, A. Hagg, L. Kurland, M. K. Svensson, H. Ahlstrom, C. Strom, L. Lonn, K. Ojbrandt, et al. Hydrochlorothiazide, but not Candesartan, Aggravates Insulin Resistance and Causes Visceral and Hepatic Fat Accumulation: The Mechanisms for the Diabetes Preventing Effect of Candesartan (MEDICA) Study Hypertension, December 1, 2008; 52(6): 1030 - 1037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Nunemaker, M. Chen, H. Pei, S. D. Kimble, S. R. Keller, J. D. Carter, Z. Yang, K. M. Smith, R. Wu, M. H. Bevard, et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by western diet Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1065 - E1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Murdolo, C. Herder, Z. Wang, B. Rose, M. Schmelz, and P.-A. Jansson In situ profiling of adipokines in subcutaneous microdialysates from lean and obese individuals Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1095 - E1105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yue, J. W. Christman, and T. Mazzone Tumor Necrosis Factor-{alpha}-Mediated Suppression of Adipocyte Apolipoprotein E Gene Transcription: Primary Role for the Nuclear Factor (NF)-{kappa}B Pathway and NF{kappa}B p50 Endocrinology, August 1, 2008; 149(8): 4051 - 4058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Arner, B. M. Stenson, E. Dungner, E. Naslund, J. Hoffstedt, M. Ryden, and I. Dahlman Expression of Six Transmembrane Protein of Prostate 2 in Human Adipose Tissue Associates with Adiposity and Insulin Resistance J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2249 - 2254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sanz, P. R. Moreno, and V. Fuster The year in atherothrombosis. J. Am. Coll. Cardiol., March 4, 2008; 51(9): 944 - 955. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||