Published online before print January 22, 2008, doi: 10.1161/CIRCULATIONAHA.107.717595
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(Circulation. 2008;117:798-805.)
© 2008 American Heart Association, Inc.
Molecular Cardiology |
Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E–Deficient Mice
From the University of Michigan, Department of Internal Medicine, Division of Cardiology, Ann Arbor (M.K.Ö., Y.S., C.I.O., A.P.W., M.W., D.A.L., D.T.E.), and Ann Arbor Veterans Adminstration Hospital, Ann Arbor (D.T.E.), Mich.
Correspondence to Daniel T. Eitzman, MD, University of Michigan, Cardiology, 7301A MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109–0644. E-mail deitzman{at}umich.edu
Received May 24, 2007; accepted December 5, 2007.
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Abstract |
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Background— Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis.
Methods and Results— To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient (Lepob/ob) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lepob/ob mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E–deficient ApoE–/– mice. Plasma from ApoE–/– mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE–/– mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE–/– mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation.
Conclusions— Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.
Key Words: adipocytokine • atherosclerosis • inflammation • obesity • thiazolidinediones
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Introduction |
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Obesity is associated with an increased risk for cardiovascular disease, although there may be marked differences in the risk attributable to obesity based on heterogeneity of adipose tissue within and between individuals.1,2 Visceral fat appears to be particularly associated with increased cardiovascular risk compared with subcutaneous fat.3,4 Consistent with this, treatment with some peroxisome proliferator–activated receptor-
ligands (ie, thiazolidinediones) leads to redistribution of fat from visceral to subcutaneous stores with subsequent reduced risk for diabetes and possibly cardiovascular disease,5 although this is controversial.6 Features of adipose depots that may confer increased cardiovascular risk include leukocyte infiltration and evidence of increased adipose macrophage activity.7–9 Chemokines such as monocyte chemoattractant protein-1 (MCP-1) have been shown to be elevated in plasma and adipose tissue of obese humans and animals.10,11 MCP-1 may play an important role in mediating macrophage influx in adipose depots and atherosclerotic plaques.12 However, whether adipose tissue inflammation is a mediator or marker of increased vascular risk is unclear.
Clinical Perspective p 805
In the present study, we characterize a model of inflammatory fat and determine the effect of adipose tissue inflammation on atherosclerosis.
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Methods |
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Mice
Five- to 8-week-old wild-type (Wt), leptin-deficient (Lepob/ob), MCP-1–deficient (Mcp-1–/–), and interleukin-10–deficient (Il-10–/–) mice and 9- to 11-week-old apolipoprotein E–deficient (ApoE–/–) mice, all of the C57BL/6J background strain, were used. For further details, see the online Data Supplement.
Adipose Transplantation
Wt, Lepob/ob, Mcp-1–/–, and ApoE–/– mice were used as recipients for fat transplantation. Wt mice were used as donors for Wt, Lepob/ob, and Mcp-1–/– recipients; ApoE–/– mice were used as donors for ApoE–/– recipients. Il-10–/– mice were used as donors for a group of Wt recipients. Gonadal or subcutaneous (harvested from flank) adipose tissue was removed from donors, weighed, and implanted subcutaneously into 4 dorsal incisions for a total of 516.9±23.6 mg per recipient. For sham control operations, identical procedures were performed without fat implant. For complete details of fat transplant procedure, see the Data Supplement.
Drug Treatment
A group of 10-week-old ApoE–/– mice were treated with the thiazolidinedione pioglitazone (Takeda Pharmaceuticals, Osaka, Japan) for 10 weeks after the fat transplantation procedure. Pioglitazone was added to standard chow as a 0.014% admixture. The control group of ApoE–/– mice underwent identical fat transplantation but received no pioglitazone. Another control group of ApoE–/– mice without transplantation was fed pioglitazone admixture or standard chow for 10 weeks.
Adipokine Measurements From Plasma and Fat Homogenates
ELISA kits and Luminex assays (Luminex Corp, Austin, Tex) were used to measure adipokine levels in plasma and fat homogenates. For details, see the Data Supplement.
Atherosclerosis Quantification
At the time of their death (either 37 or 10 weeks after fat transplantation, depending on the protocol), ApoE–/– mice were perfused with saline at physiological pressure and then fixed using formalin with a 25-gauge needle inserted into the left ventricle at a rate of 1 mL/min. The carcass was fixed in formalin, and the arterial tree was then meticulously dissected and placed in 70% ethanol. After staining with Oil Red O and pinning on wax, the surface area occupied by atherosclerosis was quantified at the aortic arch and major branches, including the brachiocephalic, carotid, and subclavian arteries, with Image-Pro Plus software (Media Cybernetics, Bethesda, Md). The lesion area was expressed as a percentage of total surface area examined.
Immunohistochemistry
Macrophages in adipose cross sections were identified with a rat anti-mouse Mac-3 monoclonal antibody (1:10 dilution, BD Biosciences, San Jose, Calif). Stained cells were expressed as percentage of total cells. For further details, see the Data Supplement.
Statistical Analysis
Values are expressed as mean±SEM. The statistical significance of differences between groups was determined by Student’s t test. Values of P<0.05 were considered significant.
The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Effect of Adipose Depot Transplantation in Lepob/ob and Wt Mice
To demonstrate the capacity of a transplanted fat pad to produce an adipocyte-specific product with clear physiological effects, wild-type C57BL6/J (Wt) epididymal fat was transplanted into Lepob/ob mice (n=6). Leptin levels in transplanted Lepob/ob mice reached physiological concentration (1.13±0.25 ng/mL) 2 weeks after the transplantation and were maintained at similar levels (1.81±0.15 ng/mL at 40 weeks postoperatively). Transplantation of Wt fat prevented obesity and infertility in all Lepob/ob mice. A control group of Wt mice (n=6) transplanted with Wt adipose tissue showed weight gain similar to a nontransplanted control group maintaining normal weight (25.04±0.01 g) until death. The leptin levels for transplanted Wt mice stayed relatively constant during a 9-week follow-up and were 1.3±0.6 ng/mL at the time of death.
Effect of Adipose Transplantation on Fat Inflammation
To characterize the inflammatory nature of transplanted fat pads, Wt visceral adipose tissue transplants were removed from Wt recipient mice (n=6) for immunohistochemical analysis 8 to 10 weeks postoperatively. In all transplanted fat depots, there were typical signs of chronic adipose tissue inflammation such as large adipocytes surrounded by a rim of macrophages (ie, crown-like structures) and multinucleated giant cells (Figure 1A and 1B). These features were absent in the recipients’ endogenous epididymal fat. Transplanted fat pads contained a greater proportion of macrophages compared with the Wt recipients’ endogenous epididymal fat depots (21.4±2.4% versus 3.5±0.8%, respectively; P=0.00008). To determine whether the fat transplantation affected recipients’ endogenous fat compared with nontransplanted mice, macrophages were quantified in endogenous epididymal fat pads in both transplanted and control mice. No difference was detected in macrophage content between the transplant recipients’ endogenous fat and that of the age-matched, nonoperated Wt mice (3.5±0.8% versus 5.7±1.2%, respectively; P=0.07).
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Regulation of Macrophage Recruitment in Transplanted Adipose Tissue
To investigate whether inflammation in transplanted fat was regulated by the same factors proposed to affect inflammation in endogenous fat such as MCP-1,13,14 we transplanted Wt fat into MCP-1–deficient (Mcp-1–/–; n=4) and Wt (n=6) recipient mice. Comparison of transplanted fat pads revealed that Mcp-1–/– recipients had lower macrophage content in their transplants compared with Wt recipients (17.9±0.7% versus 21.4±2.0%, respectively; P=0.02).
IL-10, secreted by various cell types, including adipocytes,15 is an antiinflammatory cytokine with deactivating effects on T cells and macrophages.16 To study the effect of IL-10 on adipose tissue inflammation in this transplant model, we used Il-10–/– mice as fat donors for Wt recipient mice (n=3). Because Il-10–/– mice develop chronic colitis and anemia overtime,17,18 we did not use these mice as recipient mice. The Il-10–/– fat pads removed from Wt recipients had a significantly greater fraction of macrophages than Wt fat pads removed from Wt recipients (33.5±3.3% versus 21.4±2.0%, respectively; P=0.004).
Effect of Adipose Tissue Transplantation in ApoE–/– Mice
To test the hypothesis that inflammatory fat may directly contribute to the development of atherosclerosis, we performed visceral fat transplantation or sham operation to nondiabetic ApoE–/– mice (n=6 per group). The body weight of ApoE–/– mice was not significantly different between the sham and transplanted groups before or after the operation (supplementary Figure I). Similarly, there was no difference in the body fat percent between the sham and transplanted mice, although a trend was present for more adiposity in the transplant group (14.0±0.3% versus 15.4±0.7%, respectively; P=0.05).
To evaluate the effect of fat transplantation on systemic levels of inflammatory markers, we collected postoperative plasma samples during the 37-week follow-up and analyzed them by Luminex/ELISA. The transplanted group had higher levels of adiponectin (47.5±2.7 µg/mL in sham versus 63.6±5.1 µg/mL in transplanted; P=0.01), leptin (0.3±0.1 ng/mL in sham versus 1.1±0.3 ng/mL in transplanted; P=0.02), and resistin (1.5±0.2 ng/mL in sham versus 1.9±0.1 ng/mL in transplanted; P=0.04). Plasma levels of MCP-1 were particularly elevated in the transplanted group (278.8±37.3 in sham versus 494.6±49.8 pg/mL in transplanted; P=0.003). There was no significant difference in tumor necrosis factor alpha-
, free fatty acids, total cholesterol, glucose, or insulin levels between the groups (Data Supplement).
Analysis of total atherosclerotic lesion area in both groups of ApoE–/– mice revealed significantly greater atherosclerotic burden in the fat-transplanted group compared with the sham group (Figure 2A through 2C).
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Effect of Pioglitazone Treatment on ApoE–/– Mice Transplanted With Adipose Tissue
To determine whether drug treatment shown to reduce fat inflammation19 could affect atherosclerosis in this model, fat-transplanted ApoE–/– mice (n=7) were treated with the peroxisome proliferator–activated receptor- agonist, pioglitazone or placebo. After 10 weeks of treatment with pioglitazone, no significant difference was observed in body weight compared with the control mice (n=4), which also were transplanted but did not receive pioglitazone (27.5±1.0 g in pioglitazone-treated versus 29.1±0.6 g in control mice; P=0.09); however, total body fat was significantly increased with pioglitazone treatment (11.9±0.3% in pioglitazone-treated versus 10.7±0.1% in control mice; P=0.02).
To confirm the effectiveness of pioglitazone treatment on adipokine secretion, we measured plasma adiponectin because pioglitazone is known to increase adiponectin levels.20–23 Adiponectin levels were markedly increased in the pioglitazone treatment group compared with the control group (137.1±19.2 versus 47.4±7.1 µg/mL, respectively; P=0.02). Our finding of a marked increase in MCP-1 levels in our initial cohort of fat-transplanted ApoE–/– mice compared with sham-operated mice suggests that this factor may be playing a role in atherosclerosis, considering the well-documented importance of MCP-1 in atherosclerosis.12,24–26 MCP-1 levels in pioglitazone-treated mice were reduced 10.7-fold compared with controls (P=0.03) (Figure 3A). In contrast, there was no difference in resistin, leptin, vascular endothelial growth factor, glucose, insulin, free fatty acids, or total cholesterol between the groups (Data Supplement).
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Effect of Pioglitazone Treatment on Adipose Tissue Inflammation and Atherosclerosis
The antiinflammatory cytokine IL-10 was measured in the transplanted adipose tissue of pioglitazone-treated and control mice and was significantly increased in transplanted fat of pioglitazone-treated compared with control mice (Figure 3B). Furthermore, macrophage content of transplanted adipose tissue was reduced in pioglitazone-treated mice compared with controls (Figure 3C). The atherosclerotic lesion surface area in the aortic arch and all major branches also was significantly reduced in pioglitazone-treated animals compared with controls (Figure 3D).
To determine whether the effect of pioglitazone on atherosclerosis in this model was dependent on the presence of an inflammatory fat depot, a nontransplanted group of ApoE–/– mice also was treated with pioglitazone (n=4) or standard (n=4) chow. After 10 weeks, there was no evidence of reduced atherosclerosis in mice treated with pioglitazone (1.5±0.4% in pioglitazone-treated versus 0.5±0.3% in control mice; P=0.05). Plasma adiponectin levels were higher in pioglitazone-treated mice compared with controls (77.2±5.5 versus 31.1±1.8 µg/mL, respectively; P=0.002).
Effect of Subcutaneous Fat Transplantation on Inflammation and Atherosclerosis
To determine whether the effect of the inflammatory adipose depot on atherosclerosis was unique to visceral fat, we transplanted subcutaneous fat into ApoE–/– mice (n=5) and compared the effects with ApoE–/– mice receiving visceral fat (n=5). Ten weeks after transplantation, analysis of atherosclerotic lesion area demonstrated a significantly greater area of atherosclerosis in mice receiving visceral fat compared with mice receiving subcutaneous fat (3.6±1.0% versus 0.5±0.3%, respectively; P=0.02; for individual data, see the Data Supplement). Thus, the subcutaneous fat did not promote atherosclerosis (compared with the previous nontransplanted control group) even though the percentage of macrophage infiltration was similar to the macrophage infiltration observed in the visceral fat transplant group (32.9±2.7% in visceral versus 39.8±2.3% in subcutaneous group; P=0.06) and showed similar histological signs of chronic fat inflammation (Figure 4).
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There was no difference in plasma levels of leptin or adiponectin in mice receiving subcutaneous fat compared with mice receiving visceral fat transplants (leptin: 2.6±0.3 versus 2.1±0.4 ng/mL, respectively, P=0.2; adiponectin: 57.5±3.4 versus 57.9±2.2 µg/mL, respectively, P=0.9). Both subcutaneous and visceral transplant groups had higher adiponectin levels than nontreated control mice in the previous experiment (P
0.002 in both comparisons). Plasma MCP-1 was significantly elevated in mice with visceral transplants compared with mice with subcutaneous transplants (219.8±51.4 versus 63.0±11.8 pg/mL, respectively; P=0.02).
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Discussion |
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The prevalence of obesity is increasing in all populations and age groups worldwide.27 Obesity is an independent risk factor for cardiovascular disease,3,28,29 although mechanisms linking obesity and risk for cardiovascular disease are not completely understood. Recent studies have indicated that accumulation of adipose tissue, as occurs in states of obesity, is characterized by chronic low-grade inflammation and secretion of inflammatory cytokines and chemokines such as tumor necrosis factor alpha-
and MCP-1.7,8,30,31 Macrophages, MCP-1, and other mediators associated with chronic inflammation play a key role in the pathogenesis of atherosclerosis12,32,33; thus, inflammation in adipose tissue may be a link between obesity and cardiovascular disease. Surgical implantation of adipose tissue has previously been shown to reverse diabetes in lipoatrophic mice.34 The secretion of leptin up to 1 year, normalization of body weight, and fertility of Lepob/ob mice after Wt fat transplantation in our study further demonstrate that transplanted fat pads can be well vascularized and secrete physiological levels of adipocyte-derived cytokines. In the present study, we also have demonstrated that the histology of transplanted adipose tissue is associated with chronic macrophage infiltration characteristic of adipose tissue observed in states of severe obesity.13,31 Adipocyte death has been suggested to be a trigger of macrophage infiltration into the adipose tissue,31 leading to subsequent macrophage syncytia that sequester and scavenge the residual "free" adipocyte lipid droplet and ultimately form multinucleated giant cells. As a result of death of adipocytes during the fat transplant procedure, we suspect, macrophages infiltrate the graft tissue and begin the cycle of chronic inflammation and adipocyte death that is observed in animal models of severe obesity. This model may thus serve as a useful model of fat inflammation that is less confounded by high-fat feeding and other obesity-related comorbidities such as diabetes. The specific role of an inflammatory fat depot on the progression of vascular disease can therefore be assessed. Furthermore, adipose tissue transplantation between various strains of knockout mice can be performed to examine host or adipose transplant-derived factors on inflammation in fat.
In this model, the host endogenous adipose tissue was not affected by macrophage infiltration, although several systemic adipokines were elevated, indicating the potential of the transplanted inflammatory fat depot to markedly upregulate adipokine production. The potential of local inflammatory fat to express high levels of adipokines also was clearly demonstrated when Wt fat was transplanted into Lepob/ob mice. In this experiment, leptin levels were similar to those in Wt mice, even though the only source of leptin was the transplanted fat pad.
The absence of diabetes in the fat transplant model allows one to ascertain the specific effect of inflammatory fat on atherosclerosis. It may be that some of the vascular end points such as macrovascular disease associated with hyperglycemia are due to other underlying inflammatory mediators that are coincident with diabetes. In this model, inflammatory fat was sufficient to accelerate atherosclerosis in ApoE–/– mice. The specific mediator of the increased atherogenesis is not clear from this study, although MCP-1 has previously been shown to affect macrophage infiltration in adipose tissue13,14 and the vasculature.12,25,26 In this study, visceral fat transplantation was clearly associated with higher MCP-1 levels compared with subcutaneous or sham transplants. The degree of MCP-1 elevation in mice that received fat transplantation in this study might be expected to increase atherosclerosis as reported in other studies in which physiological levels of MCP-1 accelerated atherosclerosis compared with complete MCP-1 deficiency.12,25,26 MCP-1 also may be an important regulator of the chronic inflammation we observed in the adipose tissue. The number of macrophages detected in adipose transplants into Mcp-1–/– mice was reduced, supporting an important role of this chemokine in adipose inflammation. Our results with transplanted adipose grafts are in accordance with previous studies in which a high-fat diet induced macrophage infiltration into adipose tissue that was regulated by MCP-1.13 Weisberg and coworkers35 reported a lower fraction of adipose macrophages in epididymal fat of obese Ccr2–/– mice (16.3±3%) compared with obese Wt mice (25±5.6%). Interestingly, in our model, the recipient MCP-1 status had an effect on the recruitment of macrophages to the transplanted Wt fat. It was recently suggested that obesity leads to the recruitment of M1-polarized macrophages that gradually replace M2-polarized cells in the adipose tissue and that MCP-secreting, fat-infiltrating macrophages contribute to this polarization.36 Thus, this fat transplantation model may be helpful in further exploring the different pools of macrophages, ie, adipose tissue–resident and circulating bone marrow–derived cells, and the role of individual cytokines in their recruitment.
Our results indicate that pharmacological therapy capable of reducing fat inflammation and/or MCP-1 may be useful in the treatment of obesity-associated vascular disease. The thiazolidinediones have previously been shown to reduce fat inflammation and to downregulate MCP-1.19 In this transplant model, pioglitazone treatment reduced MCP-1, fat inflammation, and atherosclerosis. Pioglitazone therapy also produced elevations in adiponectin, which may play a role in the reduced inflammation37 observed with pioglitazone treatment. However, we do not believe changes in adiponectin expression were entirely responsible for the effects of fat inflammation on atherosclerosis observed in this model because adiponectin levels were actually increased in the initial transplant group compared with sham-operated mice. Thus, contrary to previous reports that show a decrease in adiponectin levels with obesity and visceral adiposity in humans,38,39 adiponectin levels were not reduced with fat inflammation in our study. Adiponectin levels were higher in both subcutaneous and visceral transplant groups compared with nontreated chow-fed control mice. Some studies have indicated that the degree of hypoadiponectinemia is related more closely to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity in humans.40,41 We also found that levels of leptin and resistin were elevated in ApoE–/– mice receiving fat transplantation. Both of these factors have been implicated in atherosclerosis.42–45 Thus, in addition to MCP-1, these cytokines may contribute to the link between inflammatory adipose tissue and atherosclerosis in this model.
It is particularly interesting that pioglitazone produced beneficial effects on fat inflammation and atherosclerosis in our nondiabetic ApoE–/– animal model. This effect was observed only in the presence of the fat transplantation. Nontransplanted mice treated with pioglitazone did not show protection against atherosclerosis. Other studies have shown that thiazolidinediones inhibit plaque formation in fructose-fed, nondiabetic low-density lipoprotein receptor–deficient mice.46 It has been reported in humans that pioglitazone may exert an antiatherogenic effect regardless of its antidiabetic effect, suggesting that the antiatherogenic effect of pioglitazone is mediated primarily via mechanisms distinct from its effects on hyperglycemia.47 In nondiabetic patients, pioglitazone treatment did not significantly change fasting glucose, fasting insulin, or glycosylated hemoglobin but reduced neointimal hyperplasia.48
IL-10 is a cytokine with multifaceted antiinflammatory properties16 that has been implicated in atherosclerosis49 and cardiovascular morbidity.50 In our model of inflammatory fat, increased IL-10 was associated with reduced macrophage infiltration to fat. In a recent study, pioglitazone also was shown to increase IL-10 levels in lung tissue of a murine model for asthma.51 Taken together, these findings suggest that IL-10 could be one of the paracrine mechanisms leading to lower systemic MCP-1 levels in thiazolidinedione-treated mice.
Inflammation involving any tissue may promote atherosclerosis. However, visceral adiposity seems to be the major link between obesity and cardiovascular disease in humans.3 Distinct adipose depot expression profiles have been described that are determined by fat location.52 These differences appear intrinsic to the type of adipocyte because they are present even when examined during in vitro culture and differentiation. In our study, transplantation of subcutaneous fat had no effect on atherosclerosis and was associated with lower plasma MCP-1 levels compared with visceral transplantation mice despite a similar inflammatory response. This indicates that the vascular effects of adipose tissue are not due solely to inflammation but to an interaction between inflammatory cells and visceral adipocytes.
In summary, this study demonstrates that adipose tissue transplantation may be used as a tool to study fat inflammation and that there is a direct effect of inflammatory visceral fat on atherosclerosis in the absence of diabetes or generalized obesity. Inflammatory visceral fat may be a potent stimulus for promoting vascular complications and may represent a link between obesity and vascular disease. Therapies targeting fat inflammation may be particularly effective in subjects with visceral obesity, who are at risk for vascular disease. Additional studies are needed to dissect individual factors responsible for inflammatory fat-mediated acceleration of atherosclerosis.
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Acknowledgments |
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We thank Kevin Wickenheiser and Wei Luo for excellent technical assistance.
Sources of Funding
This work was supported by National Institutes of Health grants HL57346 and HL073150 to Dr Eitzman and training grant T32HL007853 to Dr Öhman.
Disclosures
None.
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The online Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.717595/DC1.
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