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The Cardiovascular Institute (P.D.A., N.N.M., M.L.W., C.C.H., L.P., L.L.C., J.T.-M., M.P.R.) and the Institute for Translational Medicine and Therapeutics (M.L.W., L.P., M.P.R.), Institute of Diabetes Obesity and Metabolism (M.R.R., R.S.A., M.P.R.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160; Department of Mathematics (K.F.S.), Georgetown University, Washington, D.C. 20057; and University of Washington School of Medicine (P.D.A.), Seattle, Washington 98195
Address all correspondence and requests for reprints to: Muredach P. Reilly, Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160. E-mail: muredach{at}spirit.gcrc.upenn.edu.
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Abstract |
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Objective: The aim of the study was to examine effects of low-grade endotoxemia, a model of human inflammation, on adipokines in vivo.
Design/Setting: An open-label, placebo-controlled, fixed-sequence clinical study was conducted at a General Clinical Research Center.
Patients: There were 20 healthy male (50%) and female volunteers aged 18–40 yr.
Intervention: Serial blood sampling and adipose biopsies were performed for 24 h before and after iv bolus endotoxin [lipopolysaccharide (LPS), 3 ng/kg].
Main Outcome Measures: We measured plasma leptin, adiponectin, resistin, soluble leptin receptor, cytokines, insulin, and glucose; distribution of adiponectin among multimeric complexes; whole blood, monocyte and adipose mRNA for adipokines and their receptors.
Results: LPS induced fever, blood, and adipose TNF and IL-6 and increased homeostasis model assessment of insulin resistance. These were associated with increases in plasma leptin (from 4.1 ± 1.1 to 6.1 ± 1.9 ng/ml in men; 21.1 ± 4.4 to 27.4 ± 4.7 ng/ml in women; P < 0.005), doubling of the leptin:soluble leptin receptor ratio, and marked induction of whole blood resistin mRNA (13.7 ± 7.3-fold; P < 0.001) and plasma resistin (8.5 ± 2.75 to 43.2 ± 15.3 ng/ml; P < 0.001). Although total adiponectin levels and low and high molecular weight adiponectin complexes were unaltered by LPS treatment, whole blood mRNA for adiponectin receptors 1 (49%; P < 0.005) and 2 (65%; P < 0.001) was suppressed.
Conclusions: Modulation of adipokine signaling may contribute to the insulin resistant, atherogenic state associated with human inflammatory syndromes. Targeting of individual adipokines or their upstream regulation may prove effective in preventing acute and chronic inflammation-related metabolic complications.
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Introduction |
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The adipokines adiponectin, leptin, and resistin regulate insulin resistance, lipoprotein metabolism, and vascular inflammation. Rodent and early human studies support insulin sensitizing, antiinflammatory, and atheroprotective functions for adiponectin in vivo (3). Indeed, adipose and plasma adiponectin are reduced in human obesity and cardiovascular disease (CVD) (3, 4). In contrast, leptin levels are increased in human obesity, and leptin signaling in inflammatory and vascular cells has been linked to atherothrombosis in the setting of resistance to its central anorectic effects (5, 6). Resistin, a member of a novel family of inflammatory proteins (7), derives largely from adipose in rodents, and deficiency in mice protects against diet-induced insulin resistance and type 2 diabetes mellitus (8, 9). However, in humans resistin occurs from leukocytes and is induced during inflammation (10); its role in human insulin resistance and atherosclerosis remains controversial.
Preliminary work suggests human inflammation may modulate individual adipokine levels, but studies are small, results conflicting, and the significance of such effects remains uncertain (10, 11, 12, 13). In an effort to explore further the link between adipokines, innate immunity, and insulin resistance, we present in this article the first comprehensive examination of the effects of acute inflammation on adipokines within the same sample of healthy humans. We hypothesized that endotoxemia would increase circulating bioavailable leptin and resistin while attenuating adiponectin signaling in vivo.
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Subjects and Methods |
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Healthy volunteers were recruited from the general population of the Delaware Valley. The institutional review board of the University of Pennsylvania approved the protocol, and all subjects gave written informed consent. Inclusion criteria included healthy men or nonpregnant/lactating women, aged 18–40 yr, with a body mass index (BMI) of 18–30 kg/m2. Exclusions included any known chronic or recurrent medical disorders, including: CVD; diabetes mellitus; metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III definition); malignancy; inflammatory, rheumatological, pulmonary, and dermatological disorders; HIV-1 infection; liver or kidney disease; any abnormality at blood count or biochemical screen; tobacco use (within 1 month); use of any prescription medication (except oral contraception) or supplemental vitamins; and positive urine pregnancy test. There were 20 subjects recruited, equally divided by gender.
The study involved three General Clinical Research Center visits: visit 1 for screening; visit 2, approximately 2 wk later, for dual energy x-ray absorptiometry (DEXA) estimation of body adiposity and dietary run-in instruction (American Heart Association’s Step 2 Diet); and visit 3, which occurred 2 wk later and was timed to coincide with the first 10 d of the menstrual cycle in females. This visit consisted of a 60-h General Clinical Research Center inpatient stay comprising an overnight acclimatization phase, a 24-h saline administration control phase, and a 24-h post- lipopolysaccharide (LPS) study phase. Serial whole blood and sc adipose samples were collected before and following iv bolus infusion (0600 h on d 2) of 3 ng/kg U.S. standard reference endotoxin (LPS; lot No. CC-RE-LOT-1 + 2; Clinical Center, Pharmacy Department at the National Institutes of Health, Bethesda, MD). A total of 18 blood samples were collected, nine before and nine after LPS, for plasma and QIAGEN PAX tubes (QIAGEN, Inc., Valencia, CA) facilitated collection of whole blood RNA (10). In preliminary studies [before LPS (n = 4) and endotoxemia (n = 1), three times], we performed Ficoll-Paque Plus (GE Healthcare Bio-Sciences, Piscataway, NJ) density gradient centrifugation for isolation of peripheral blood mononuclear cells from whole blood (14), followed by positive immunomagnetic isolation of monocytes (Dynabeads CD14; Invitrogen, Corp., Carlsbad, CA) (15). sc adipose samples were collected by core needle aspiration from the gluteal region 30 min before and on three occasions (4, 12, and 24 h) after LPS. They were stored at –70 C until RNA extraction was performed using the RNeasy total RNA kit (QIAGEN, Inc.).
Laboratory measures
Plasma metabolic and inflammatory markers.
Plasma leptin, adiponectin, resistin, insulin (RIA and ELISA; Linco Research, St. Charles, MO), tumor necrosis TNF-
, IL-6 (Linco Multiplex ELISAs on Luminex IS100; Austin, TX), soluble TNF receptor superfamily, member 1B (sTNFRSF1B) (ELISA; R+D Systems, Minneapolis, MN), and soluble leptin receptor (sLEPR) (ELISA; Biovender Laboratory Medicine, Brno, Czech Republic) were measured according to the manufacturers’ guidelines. All samples were assayed in duplicate, and pooled human plasma samples were included to assess variability. The intraassay and interassay CVs of pooled human plasma were: adiponectin, 5.65%, 9.9%; leptin, 5.5%, 12.4%; resistin, 4.6%, 4.3%; insulin, 4.1%, 11.6%; TNF, 8.66%, 20.4%; IL-6, 8.7%, 10.9%; sTNFRSF1B, 5.3%, 12.1%; and sLEPR, 4.0%, 10.6%, respectively. After ultracentrifugation, plasma lipoproteins and glucose were measured enzymatically (Wako Diagnostics, Richmond, VA) on a Hitachi 912 automated chemistry system (Hitachi, Ltd., Tokyo, Japan) in a Center for Disease Control certified lipid laboratory. At 2 wks, 24 h and 5 min before, and 24 h after LPS, the homeostasis model assessment of insulin resistance (HOMA-IR) index (16) was calculated using fasting glucose and insulin values to estimate changes in insulin sensitivity.
Adiponectin subfractionation. Adiponectin multimeric complex distribution was determined in a subgroup of five subjects at six time points (5 min before, and 2, 4, 8, 12, and 24 h after LPS). As previously described (17, 18), plasma was subjected to size exclusion fast protein liquid chromatography (Akta FPLC; Amersham Biosciences, Piscataway, NJ) using two Superdex 200 10/300 GL columns (Amersham Biosciences) in tandem in PBS at 6 C. Fractions (250 µl) were collected, and human adiponectin was detected in each using a commercially available ELISA as previously mentioned.
Real-time quantitative PCR. Whole blood (n = 20 subjects), isolated blood monocytes (n = 4 subjects), and adipose (n = 11 subjects) mRNA were subjected to RT-PCR and subsequent quantitative PCR on an Applied Biosystems 7300 Real-Time PCR System (ABI, Foster City, CA) for measurement of TNF, IL-6, resistin, leptin, adiponectin, adiponectin receptors [(ADIPORs) 1 and 2], and leptin receptor mRNA. In addition, macrophage marker mRNA [CD68, human epidermal growth factor-like module containing, mucin-like, hormone receptor-like 1 (EMR1), and colony stimulating factor 1 receptor] (19, 20, 21, 22, 23) was assayed in adipose.
PCRs used TaqMan Universal PCR Master Mix (ABI) under standard conditions. To control for between-sample differences in total mRNA, mRNA levels were normalized to ß-actin for each sample by subtracting the Ct for ß-actin from the Ct for the gene of interest, producing a 
Ct value. The Ct for each post-LPS sample was compared with the mean Ct for all pre-LPS samples in a single individual using the relative quantitation 2–(Ct) method to determine fold change from baseline.
Statistical analysis
These analyses tested the primary hypothesis that human endotoxemia modulates plasma adiponectin, leptin, and resistin. Additional analyses (e.g. whole blood and adipose mRNA levels) were performed to provide a comprehensive picture of effects on adipokine signaling. Data are reported as mean ± SEM or median and interquartile range (25th, 75th percentile) for continuous variables, and as proportions for categorical variables. In general, mixed effects modeling or repeated-measures ANOVA tested the effect of endotoxemia on plasma adipokines and cytokines, whole blood mRNAs, adipose mRNAs, and the HOMA-IR index. For plasma data, we considered the time-matched difference (post-LPS minus pre-LPS for each of nine matched time points: 0, 1, 2, 4, 6, 8, 12, 16, and 24 h) in adipokine or cytokine responses, and used a mixed effects model to consider the effect due to LPS and any possible gender interaction at each time point. Linear, quadratic, and cubic polynomial models were considered based on associated exploratory data analysis results, e.g. quadratic models for TNF, IL-6, resistin, and sTNFRSF1B, and a cubic polynomial model for leptin and leptin to sLEPR ratio. A similar time-matched mixed effect modeling approach was applied to whole blood mRNA data. Repeated-measures ANOVA was applied to HOMA-IR data (–24 h, –5 min, and 24 h after LPS), adipose mRNA log of fold change data (4, 12, and 24 h after LPS fold change vs. before LPS), and adiponectin subfractions (ratio of high molecular weight to total adiponectin at six time points); post hoc paired t tests were used to compare specific time points. Analyses were performed using the statistical software R, version 2.2.0 (2005, http://cram.r-project.org).
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Results |
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Participants’ baseline characteristics are shown in Table 1
. Generally, subjects were young adults (50% were male) with normal blood pressure, plasma lipoproteins, and BMI. DEXA-determined body fat percentage fell within the expected range, although these data illustrate the marked gender difference in body adiposity at similar BMI. Before endotoxin, HOMA-IR values were highly correlated (r2 = 0.94, 0.76, and 0.93; 2 wk before vs. 24 h before LPS, 2 wk before vs. 5 min before LPS, and 24 h before vs. 5 min before LPS, respectively), and pre-LPS HOMA-IR data were consistent with an insulin sensitive, nondiabetic sample (Table 1).
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). Consistent with a prior report of endotoxin-induced insulin resistance (1), HOMA-IR values (2.17 ± 0.83) were 39% and 46% higher 24 h after LPS (repeated-measures ANOVA F = 14.1, P = 0.001) than 24 h (1.56 ± 0.62; P < 0.001) and 5 min (1.49 ± 0.63; P < 0.001) before LPS. Similarly, plasma insulin (mU/ml) increased by 19–38% (ANOVA F = 10.1; P < 0.005) 24 h after LPS compared with 24 h and 5 min before LPS [9.4 ± 3.6 vs. 7.9 ± 2.5 (P < 0.05) and 6.8 ± 2.9 (P < 0.005) respectively]. Plasma glucose (mmol/liter) increased modestly (6–8%) (ANOVA F = 18.7; P < 0.005) 24 h after LPS (5.2 ± 0.3) compared with 24 h (4.9 ± 0.4; P < 0.005) and 5 min (4.8 ± 0.3; P < 0.005) before. No serious or unexpected adverse events occurred.
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Induction of whole blood leukocyte TNF (peak 9.0 ± 4.9-fold increase; P < 0.001) and IL-6 (peak 3.0 ± 0.7-fold; P < 0.01) mRNA was rapid and transient with levels peaking at 2 h and returning toward baseline by 4 h after LPS (Fig. 2A). In isolated blood monocytes (n = 4), mRNAs for TNF (Ct 29.4 ± 1.0) and IL-6 (Ct 32.5 ± 1.6) were readily detected, and relative to ß-actin (i.e. Ct), were equally abundant in monocytes and whole blood (TNF Ct = 7.3 ± 1.5 vs. 7.6 ± 1.6, P = 0.50; IL-6 Ct = 10.3 ± 2.7 vs. 11.3 ± 3.6, P = 0.67, respectively). Consistent with findings in whole blood, monocyte TNF and IL-6 mRNA increased after LPS [
20-fold and >200-fold at 2 h, respectively (n = 1)]. In adipose, IL-6 (ANOVA F = 9.8, P < 0.001; peak increase >100-fold at 4 h, P < 0.001) and TNF (F = 2.8, P = 0.05; peak increase 4.2-fold at 24 h, P < 0.01) mRNA increased significantly during endotoxemia (Fig. 2B). Consistent with increases in leukocyte mRNA, plasma TNF (peak 270-fold at 2-h; P < 0.001) and IL-6 (peak 106-fold at 2 h; P < 0.001) increased markedly after LPS (Fig. 2C), confirming the expected rapid transient activation of early cytokines in blood, and also suggesting specific activation of innate immune pathways in adipose during endotoxemia.
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Adiponectin.
Plasma total adiponectin did not change significantly (P = 0.84, gender interaction P = 0.55) during endotoxemia (Fig. 3A). Adiponectin complex distribution profiles (Fig. 3B) were consistent with previous reports (17, 18). Compared with 5 min before, there was no significant change in complex distribution at 2, 4, 8, 12, or 24 h after LPS in a subgroup (n = 5) (Fig. 3C) (ANOVA F = 1.08; P = 0.40).
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Ct = 7.0 ± 1.1 vs. 7.2 ± 0.9; P = 0.78), whereas ADIPOR1 mRNA was less abundant (Ct 7.0 ± 1.2 vs. 3.1 ± 1.1; P < 0.005) in monocytes compared with whole blood. Endotoxemia reduced whole blood (by 49% for ADIPOR1 at 24 h, P < 0.005 and by 65% for ADIPOR2 at 4 h, P < 0.001) and monocyte [33% and 28%, respectively, at 12 h (n = 1)] mRNA levels of both receptors, albeit with heterogeneous temporal responses (Fig. 3D
). A highly variable apparent increase in ADIPOR1 mRNA at early time points was not statistically significant.
Leptin.
As expected, plasma leptin was higher in females and demonstrated diurnal variation before LPS. Compared with pre-LPS values, plasma leptin increased modestly and late after LPS (P < 0.005) peaking at 16 h (men: peak post-LPS 6.1 ± 1.9 vs. matched pre-LPS 4.1 ± 1.1 ng/ml; women: 27.4 ± 4.7 vs. 21.1 ± 4.4 ng/ml) (Fig. 4A). Although levels varied by gender, the response to endotoxin did not (gender interaction P = 0.2484). In parallel, the ratio of leptin to sLEPR increased significantly (P < 0.005) (Fig. 4, B and C). Leptin mRNA was not reliably detected in whole blood but was abundant in adipose, where a small increase during endotoxemia did not reach global statistical significance (F = 1.6, P = 0.20; peak trend in increase of 1.6-fold at 4 h, P = 0.02). There was no change in leukocyte mRNA levels for the leptin receptor during endotoxemia (data not shown).
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) and plasma resistin (8.5 ± 2.75 ng/ml at baseline to 43.2 ± 15.3 ng/ml at 12 h, P < 0.001; Fig. 5B) increased sharply in time-matched analyses. Resistin mRNA was equally abundant in monocytes and whole blood [ß-actin Ct 8.1 ± 0.9 vs. 9.6 ± 1.6 respectively (n = 4); P = 0.20], and, like whole blood, monocyte resistin mRNA tended to increase during endotoxemia [ 8-fold at 6 h after LPS (n = 1)].
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Discussion |
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Adiponectin has emerged as an important insulin sensitizing, lipid regulatory, and antiinflammatory hormone, and epidemiological studies suggest an inverse relationship between circulating levels and type 2 diabetes mellitus and CVD risk (3). Adiponectin circulates in distinct multimeric isoforms with different signaling properties, providing the physiological basis for recent work (17, 18) suggesting that different forms may contribute differentially to adiponectin’s multiple functions as an antiatherogenic and antiinflammatory hormone and mediator of insulin sensitivity.
Our examination of endotoxin effects on adiponectin, which is larger and of a longer time course than any other study (11), did not show increased plasma adiponectin or changes in circulating isoforms. In contrast, we observed significant reductions in whole blood ADIPOR1 and ADIPOR2 mRNA levels during endotoxemia. Preliminary studies suggest that these receptors are expressed on circulating monocytes, where levels also decrease during endotoxemia. These related G protein-coupled receptors transduce insulin sensitizing and antiinflammatory effects. ADIPOR1 exhibits strong affinity for globular adiponectin and weak affinity for full-length adiponectin, and ADIPOR2 exhibits intermediate affinity for both (26). Overall, current evidence suggests heterogenous downstream effects mediated by posttranslational processing and differential receptor interactions with distinct multimeric forms. Previous studies suggest that ADIPORs’ expression is increased by fasting, growth hormone, and peroxisome proliferator-activated receptor 
and , but down-regulated by insulin, feeding, and obesity (27). Data on cytokine and inflammatory regulation of expression of ADIPORs are limited and, in some cases, conflicting. Mice treated with concanavalin A, a potent stimulus for TNF production, exhibit no significant effect on ADIPORs’ mRNA in adipose, muscle, or liver (28). Expression of both receptors was increased by peroxisome proliferator-activated receptor coincident with improved insulin sensitivity and reduced obesity related inflammation in adipose tissue (29). If our findings of reduced expression of blood cell ADIPOR1 and R2 reflect a generalized down-regulation of ADIPOR signaling during inflammation, this may be relevant in human insulin resistance, dyslipidemia, and atherogenesis.
Leptin levels correlate with reduced insulin sensitivity, increased inflammatory markers, and atherosclerotic CVD (30, 31) independent of body fat mass. Unlike rodent models (32), several human studies failed to detect increases in plasma leptin during endotoxemia (12, 13), possibly reflecting the short duration of human experiments. Indeed, our findings are consistent with one study of longer duration in humans (33), observations during prolonged human sepsis (34), and rodent data suggesting modest but significant delayed increases in plasma leptin. Despite increased plasma leptin, we did not observe a statistically significant induction of adipose leptin mRNA. This may relate to the small sample size, the interindividual variability in adipose samples, and the possibility that increased plasma leptin derives from an adipose depot other than the sampled gluteal sc fat. Plasma sLEPR is thought to be a major determinant of leptin activity (35). sLEPR levels did not change during our study, but there was an almost 2-fold increase in the circulating leptin to sLEPR ratio, an index of leptin bioavailability and resistance (35), suggesting a clinically relevant increase in leptin activity, resistance to leptin signaling, or both. Whether increases in leptin during inflammation also promote insulin resistance (e.g. via leptin induction of suppressor of cytokine signaling proteins) remains uncertain.
Resistin is a member of the resistin-like molecules’ family of inflammatory proteins (7). In mice, it derives almost exclusively from adipose, but not leukocytes. Resistin-deficient mice are protected from obesity associated insulin resistance (9), while excess resistin impairs glucose tolerance and induces hepatic (7, 8) insulin resistance. Resistin increases monocyte and vascular NF-kB and ERK-1-dependent inflammatory responses (36). In contrast to mice, human resistin is produced by leukocytes via an inflammatory cytokine pathway (10, 37), and our group reported that plasma resistin levels were associated with inflammatory markers, reduced high-density lipoprotein (HDL) cholesterol, and coronary atherosclerosis in a large, nondiabetic sample (38).
Consistent with our preliminary observations (10), we confirmed a marked induction of whole blood resistin mRNA and plasma resistin during endotoxemia, and found that monocytes are one source of increased circulating resistin in inflammation. Remarkably, before LPS, abundant whole blood and monocyte resistin mRNA contrasts with low or undetectable resistin mRNA in adipose. Adipose resistin mRNA increased during endotoxemia in some subjects, but this was modest relative to the marked induction of resistin in blood. Adipose tissue macrophages (ATMs) are likely the predominant source of adipose resistin (19, 21), and our findings may reflect between-subject differences in ATM infiltration. Indeed, we have not detected resistin mRNA in human adipocytes in response to LPS or cytokines in vitro (data not shown). This is consistent with the recently described molecular basis for myeloid-restricted resistin expression in humans (21) and with ex vivo data from human adipose explant cultures (39). Indeed, the strong positive correlation between endotoxin-induced change in mRNA levels of both resistin and EMR1, a highly specific macrophage marker (20), supports the concept that ATMs are the primary source of increased adipose resistin during endotoxemia. Given these findings, resistin, like cytokines, may function as an inflammatory endocrine or paracrine signal to antagonize insulin actions, and contribute to metabolic and atherogenic changes in human inflammation.
Our studies have several limitations. These are correlative studies that do not permit causal interpretations. Acute endotoxemia is not an ideal model for in vivo chronic inflammation and insulin resistance settings, and the relative contribution of direct or indirect effects of cytokines on liver and peripheral tissues may be difficult to distinguish from that of other counter-regulatory responses (e.g. cortisol and catecholamines) that also modulate metabolism acutely. In as much as insulin itself has direct vascular and immunomodulatory functions (40), modest increases in plasma insulin may also mediate vascular and metabolic responses to inflammation. However, our studies offer indirect evidence suggesting that integrated adipokine responses may play a role in human metabolic pathophysiologies induced by inflammation. Adipose mRNA responses had significant interindividual variability, necessitating cautious interpretation of adipose findings and larger study samples and isolation of stromal and adipocyte fractions in future work. We are pursuing such studies but were limited by relatively small adipose samples in this lean cohort. We did not adjust for multiple testing. However, analyses beyond our primary hypotheses were performed for descriptive purposes.
Our findings suggest a coordination of enhanced resistin and leptin activity with attenuated adiponectin signaling during activation of innate immunity in humans. These adipokine changes may converge in human inflammatory settings to contribute to the development of an insulin-resistant, dyslipidemic, atherogenic state. Therapeutic targeting of individual adipokines or modulation of common upstream regulatory signals may potentially block the metabolic complications of inflammation in humans.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: M.P.R. has received, within the past 2 yr, research funding from GlaxoSmithKline, Merck & Co., Eli Lilly Inc., and KOS Pharmaceuticals. R.S.A. has served as consultant to Ipsen Pharmaceuticals. N.N.M., K.F.S., and M.R.R. as well as P.D.A. and M.L.W., C.C.H., L.L.C., L.P., and J.T.-M. have no potential conflict of interest.
First Published Online March 20, 2007
Abbreviations: ADIPOR, Adiponectin receptor; ATM, adipose tissue macrophage; BMI, body mass index; CVD, cardiovascular disease; DEXA, dual energy x-ray absorptiometry; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; LPS, lipopolysaccharide; sLEPR, soluble leptin receptor; sTNFRSF1B, soluble TNF receptor superfamily, member 1B.
Received November 20, 2006.
Accepted March 8, 2007.
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References |
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. Metabolism 55:555–559[CrossRef][Medline] activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPAR, PPAR, and their combination. Diabetes 54:3358–3370This article has been cited by other articles:
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  R. Shah, Y. Lu, C. C. Hinkle, F. C. McGillicuddy, R. Kim, S. Hannenhalli, T. P. Cappola, S. Heffron, X. Wang, N. N. Mehta, et al. Gene Profiling of Human Adipose Tissue During Evoked Inflammation In Vivo Diabetes, October 1, 2009; 58(10): 2211 - 2219. [Abstract] [Full Text] [PDF]
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 L. Johansson, A. Linner, J. Sunden-Cullberg, A. Haggar, H. Herwald, K. Lore, C.-J. Treutiger, and A. Norrby-Teglund Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections J. Immunol., September 15, 2009; 183(6): 4047 - 4054. [Abstract] [Full Text] [PDF]
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|
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|
 |
|
 F. C. McGillicuddy, M. de la Llera Moya, C. C. Hinkle, M. R. Joshi, E. H. Chiquoine, J. T. Billheimer, G. H. Rothblat, and M. P. Reilly Inflammation Impairs Reverse Cholesterol Transport In Vivo Circulation, March 3, 2009; 119(8): 1135 - 1145. [Abstract] [Full Text] [PDF]
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 A. Shah, N. Mehta, and M. P. Reilly Adipose Inflammation, Insulin Resistance, and Cardiovascular Disease JPEN J Parenter Enteral Nutr, November 1, 2008; 32(6): 638 - 644. [Abstract] [Full Text] [PDF]
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 |
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 M. I. Lefterova, Y. Zhang, D. J. Steger, M. Schupp, J. Schug, A. Cristancho, D. Feng, D. Zhuo, C. J. Stoeckert Jr., X. S. Liu, et al. PPAR{gamma} and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale Genes & Dev., November 1, 2008; 22(21): 2941 - 2952. [Abstract] [Full Text] [PDF]
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|
|
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G. Cohen, D. Ilic, J. Raupachova, and W. H. Horl Resistin Inhibits Essential Functions of Polymorphonuclear Leukocytes J. Immunol., September 15, 2008; 181(6): 3761 - 3768. [Abstract] [Full Text] [PDF]
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|
|
|
 |
|
 H. Nave, G. Mueller, B. Siegmund, R. Jacobs, T. Stroh, U. Schueler, M. Hopfe, P. Behrendt, T. Buchenauer, R. Pabst, et al. Resistance of Janus Kinase-2 Dependent Leptin Signaling in Natural Killer (NK) Cells: A Novel Mechanism of NK Cell Dysfunction in Diet-Induced Obesity Endocrinology, July 1, 2008; 149(7): 3370 - 3378. [Abstract] [Full Text] [PDF]
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|
|
|
 |
|
 R. S. Ahima and M. A. Lazar Adipokines and the Peripheral and Neural Control of Energy Balance Mol. Endocrinol., May 1, 2008; 22(5): 1023 - 1031. [Abstract] [Full Text] [PDF]
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Y. Li, C. Jiang, G. Xu, N. Wang, Y. Zhu, C. Tang, and X. Wang Homocysteine Upregulates Resistin Production From Adipocytes In Vivo and In Vitro Diabetes, April 1, 2008; 57(4): 817 - 827. [Abstract] [Full Text] [PDF]
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 |
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 B.-Y. Kang, S. Tsoi, Shan Zhu, Shenghui Su, and H. H. Kay Differential Gene Expression Profiling in HELLP Syndrome Placentas Reproductive Sciences, March 1, 2008; 15(3): 285 - 294. [Abstract] [PDF]
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 |
|
 G. Vila, C. Maier, M. Riedl, P. Nowotny, B. Ludvik, A. Luger, and M. Clodi Bacterial Endotoxin Induces Biphasic Changes in Plasma Ghrelin in Healthy Humans J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3930 - 3934. [Abstract] [Full Text] [PDF]
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J. M. Wentworth and L. C. Harrison Does Insulin Resistance Need Resistin? J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2036 - 2037. [Full Text] [PDF]
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