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Unit of Diabetes and Metabolism, Clinical Sciences Research Institute, University Hospitals Coventry and Warwickshire Trust, Walsgrave, Coventry CV2 2DX, United Kingdom
Address all correspondence and requests for reprints to: Dr. P. G. McTernan, Unit of Diabetes and Metabolism, Clinical Sciences Research Institute, University Hospitals Coventry and Warwickshire Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX, United Kingdom. E-mail: p.g.mcternan{at}warwick.ac.uk.
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Abstract |
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Objectives: The objectives of this study were to characterize resistin expression in human obesity and address the role of resistin in the innate immune pathway; to examine the influence of lipopolysaccharide, recombinant human resistin (rhResistin), insulin, and rosiglitazone in human adipocytes; and, finally, to analyze the effect of rhResistin on the expression of components of the nuclear factor-
B pathway and insulin signaling cascade.
Methods: Abdominal sc adipose tissue was obtained from patients undergoing elective liposuction surgery (n = 35; age, 36–49 yr; body mass index, 26.5 ± 5.9 kg/m2). Isolated adipocytes were cultured with rhResistin (10–50 ng/ml). The level of cytokine secretion from isolated adipocytes was examined by ELISA. The effect of rhResistin on protein expression of components of the innate immune pathway was examined by Western blot.
Results: In vitro studies demonstrated that antigenic stimuli increase resistin secretion (P < 0.001) from isolated adipocytes. Proinflammatory cytokine levels were increased in response to rhResistin (P < 0.001); this was attenuated by rosiglitazone (P < 0.01). When examining components of the innate immune pathway, rhResistin stimulated Toll-like receptor-2 protein expression. Similarly, mediators of the insulin signaling pathway, phosphospecific c-Jun NH2-terminal kinase (JNK) 1 and JNK2, were up-regulated in response to rhResistin.
Conclusion: Resistin may participate in more than one mechanism to influence proinflammatory cytokine release from human adipocytes, potentially via the integration of nuclear factor-B and JNK signaling pathways.
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Introduction |
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, and IL-6 (1). Within this context, AT is considered to integrate metabolic and immune functions. This duality of function may represent a conserved evolutionary mechanism, as suggested by observations examining the fat body in Drosophila fruit fly, in which a single cell-type serves as a primary integrator for both pathogen and nutrient-sensing pathways (2). It is acknowledged that with increasing adiposity there is profound macrophage infiltration into AT; thus, macrophages may represent the site of an innate immune response. Alternatively, macrophage recruitment may arise from phenotypic change of preadipocytes (3, 4). Nevertheless, studies indicate interrelationships among excess AT mass, inflammation, insulin resistance, and T2DM.
The adipokine resistin was originally described as a molecular link between obesity and insulin resistance in rodents; this has remained somewhat controversial in humans (5). Resistin is expressed primarily in adipocytes in rodents and employs a more metabolic role by impairing glucose tolerance and inducing liver-specific antagonism of insulin sensitivity (6). In humans, however, a more proinflammatory function for resistin has been defined (7, 8). Although resistin gene expression is largely confined to macrophages (9, 10), recent studies have reported resistin protein expression and secretion from human adipocytes (11, 12, 13, 14).
Serum profiles have highlighted increased circulating levels of resistin in obesity and T2DM that further correlate with C-reactive protein (13), a marker of inflammation and an established predictor of cardiovascular disease (15). Such a correlation has been identified by subsequent studies on prediabetic, T2DM subjects (16) and individuals with acute rheumatoid arthritis (8). Circulating levels of resistin are associated with TNF- receptor-2 and are predictive of coronary atherosclerosis, independent of C-reactive protein (17). Endotoxemia increases serum resistin levels, concurrently with soluble TNF- receptor-2 levels in T2DM patients (18). Although the majority of studies report associations between resistin and inflammatory conditions, the precise mechanistic action of resistin in inflammation, particularly in concordance with components of the innate immune pathway, is unclear.
The innate immune system is a candidate for the production of elevated levels of cytokines in obesity and T2DM. The innate immune pathway is activated when specific receptors, the Toll-like receptors (TLRs), bind certain antigens. For instance, TLR-4 binds the bacterial antigen lipopolysaccharide (LPS), through its coreceptor, CD14; alternatively, TLR-2 binds the fungal antigen, zymosan. Activation of TLR-4 by LPS can induce TLR-2 expression in 3T3-L1 adipocytes (19). TLR activation initiates an intracellular signaling cascade, causing nuclear factor (NF)-B to initiate the production of inflammatory factors, such as IL-6 and TNF-. Several serine/threonine kinases are activated during the innate immune response that influence insulin signaling (20). IB kinase (IKK)-ß mediates activation of NF-B, whereas c-Jun NH2-terminal kinase (JNK), a central metabolic regulator, contributes to the development of insulin resistance in obesity (20). Activation of JNK and IKK-ß within innate immunity highlights cross talk between metabolic and immune pathways.
An integration of metabolic and immune systems may reflect the mode of resistin action within adipocytes and immune cells, exerting metabolic and immune functions in both cell types. Resistin impairs insulin signaling via suppressor of cytokine signaling-3' (21) and inhibits glucose transport (22) in 3T3-L1 adipocytes; additionally, resistin promotes glucose-dependent lipogenesis and lipid accumulation in human macrophages (23). On the other hand, the proinflammatory functions of resistin in human macrophages (7) and 3T3-L1 adipocytes (22) have also been described. Resistin may thus function in adipocytes to influence both metabolic and proinflammatory changes, suggesting that the effects of resistin are to some extent linked. Such a duality in function for resistin may be a consequence of the cross-link initially proposed between metabolic and inflammatory pathways in adipocytes and immune cells (3, 4). Where resistin may influence key factors in the sequential stages from one signal transduction pathway, this may consequently alter components from another.
The aims of this study were therefore to: 1) establish the association between increasing adiposity and expression of resistin in human abdominal sc (Abd Sc) adipocytes and AT; 2) determine whether resistin levels are influenced by antigenic stimuli and inflammatory cytokines within adipocytes; 3) examine the effect of recombinant human resistin (rhResistin) on the expression of components of the innate immune pathway and insulin signaling cascade within adipocytes; 4) evaluate the combined effects of rhResistin, insulin, and rosiglitazone (RSG) on the proinflammatory response; and 5) examine the effects of NF-B inhibitor and JNK inhibitor on the level of resistin secretion from adipocytes.
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Subjects and Methods |
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Abd Sc AT was obtained from a human nondiabetic population [n = 35; age, 36–49 yr; body mass index (BMI), 26.5 ± 5.9 kg/m2] undergoing elective liposuction surgery. Patients receiving endocrine therapy (steroids, hormone replacement therapy, or thyroxine), antiinflammatory therapy (aspirin, cyclooxygenase-2 inhibitors), statins, thiozolidinediones, or any antihypertensive therapy were excluded. Studies were performed with the approval of the local ethics committee with informed consent being obtained from all subjects before enrollment.
Isolation of mature adipocytes
Abd Sc AT was digested in collagenase (2 mg/ml, Worthington Biochemicals Corp., Lakewood, NJ) to isolate adipocytes, as previously described (13). Adipocytes were resuspended in either 4% sodium dodecyl sulfate (SDS) or radioimmunoprecipitation assay (RIPA) buffer (150 mM NaCl, 1.0% IGEPAL CA-630, 0.5% sodium deoxycholate, 0.1% SDS, and 50 mM Tris) for extraction of protein. Cells were maintained in phenol red-free DMEM:F-12 medium containing 15 mM glucose, penicillin (100 U/ml), and streptomycin (100 µg/ml).
Treatment of isolated adipocytes
For antigenic stimuli studies, adipocytes were treated (14 h) with either bacterial endotoxin, LPS (100 ng/ml, Sigma-Aldrich Company Ltd., Poole, UK) or fungal antigen, zymosan (30 µg/ml, Sigma-Aldrich Company Ltd.). Dose and time responses for LPS and zymosan were previously established (LPS, 1–100 ng/ml, 14, 24, and 48 h; zymosan, 1–100 µg/ml, 14, 24, and 48 h) (data not shown). Cytokine secretion studies involved treatment of adipocytes with rhResistin (30 ng/ml, 48 h; Phoenix Pharmaceuticals, Belmont, CA) (endotoxin concentration < 0.1 ng/µg, at final concentrations of 10–50 ng/ml). Isolated adipocytes were also treated with insulin alone (10 nM Sigma-Aldrich Company Ltd.) or combined with RSG (10–8 M, GlaxoSmithKline, Harlow, UK). rhResistin, insulin, and RSG concentrations and time points were chosen based on data previously described (13). Adipocytes were further treated with rhTNF- (10, 50, 100 ng/ml, BioSource International, Camarillo, CA) or rhIL-6 (10, 50, 100 ng/ml, Sigma-Aldrich). For inhibitor studies, adipocytes were treated with NF-B inhibitor (SN50, CalBiochem, Nottingham, UK) (50 µg/ml; 24 h). Dose and time course studies were performed to assess resistin secretion at 14, 24, and 48 h with control and NF-B-treated adipocytes (10, 25, 50, and 100 µg/ml). Adipocytes were also treated with JNK inhibitor (SP600125, A.G. Scientific, Inc., San Diego, CA) (10 µM/ml); conditions were based on previous data (24). For protein expression analysis, adipocytes were treated with increasing concentrations of rhResistin, using previously established time points (10, 30, 50 ng/ml; 48 h). Adipocytes maintained in untreated media were used as controls. A trypan blue dye exclusion method was used to assess the viability of the adipocytes, as previously documented (Sigma-Aldrich) (13). After treatment, conditioned media were removed and stored at –80 C. Adipocyte protein was extracted as previously described (13), then stored at –80 C.
Protein determination and Western blot analysis
Human AT and isolated adipocytes were resuspended in 4% SDS or RIPA buffer, as previously detailed (13). Protein concentrations were determined using the Bio-Rad Detergent Compatible protein assay kit (Bio-Rad Laboratories, Hercules, CA) (25). Western blot analysis was performed using a method previously described (14). Human resistin polyclonal antibody (1:3000, Linco Research, Inc., St. Charles, MO) was used to assess resistin expression. rhResistin (1 µg/ml, Phoenix Pharmaceuticals) was used to confirm the specificity of the primary antibody (data not shown). Resistin was developed using an antiguinea pig horseradish peroxidase secondary antibody (Biogenesis Ltd., Poole, UK). Human TLR-2 monoclonal and TLR-4 polyclonal antibodies were used (1:500 and 1:1000, respectively; Insight Biotechnology Ltd., Wembley, UK). Polyclonal anti-JNK1 and 2 stress-activated protein kinase phosphospecific and MyD88 antibodies (1:1,750, BioSource International; and 1:250, TCS Cellworks, Buckingham, UK, respectively) were used. Protein expression of NF-B (1:250, TCS Cellworks), IKK-ß (1:500, TCS Cellworks), and IKK- (1:500, Abcam, Cambridge, UK) was assessed using mouse monoclonal antibodies. Equal protein loading was confirmed by examining -tubulin (1:5000) (The Binding Site, Birmingham, UK) protein expression. No statistical difference was observed in -tubulin expression for all samples analyzed. For reducing conditions, samples were mixed in a 1:2 ratio with sample buffer containing 20% ß-mercaptoethanol. A chemiluminescent detection system, ECL/ECL+ (Amersham Pharmacia Biotech, Little Chalfont, UK), enabled visualization of bands, whereas intensity was determined using densitometry (Genesnap, Syngene, UK).
RNA extraction and quantitative RT-PCR
RNA was extracted from AT using the RNeasy Lipid Tissue Mini Kit (QIAGEN Ltd., Crawley, West Sussex, UK). RNA extraction was followed by a deoxyribonuclease (DNAse) digestion step to remove any contaminating genomic DNA. RNA (1 µg) was reverse transcribed using RevertAid H Minus M-MuLV reverse transcriptase (Helena Biosciences Europe, Sunderland, UK) and random hexamers in 20-µl reaction volumes, according to the manufacturer’s instructions. Messenger RNA levels were determined using an ABI 7500 real-time PCR Sequence Detection system. The reactions were performed in 25-µl volumes in reaction buffer containing TaqMan Universal PCR Master Mix, 150 nmol TaqMan probe, 900 nmol primers, and 50 ng cDNA (for CD45 expression) or 115 ng cDNA (for resistin expression). Previously determined quantitative primer and probe sequences for the resistin and CD45 genes were used (14). All reactions were multiplexed with the housekeeping gene 18S, provided as a preoptimized control probe (Applera, Cheshire, UK), enabling data to be expressed as 
cycle threshold (Ct) values (
Ct = Ct of 18S subtracted from Ct of gene of interest) to correct for differences in the efficiency of RT. Measurements were carried out on at least three occasions for each sample.
Resistin secretion from treated adipocytes
Conditioned media from adipocytes treated with LPS or zymosan were assayed using a human resistin ELISA (Phoenix Europe GmbH, Karlsruhe, Germany). Conditioned media from rhTNF-- or rhIL-6-treated adipocytes were assessed using the human resistin ELISA from R&D Systems (Abingdon, UK). The R&D Systems human resistin ELISA (resistin range, 0–10 ng/ml) was further validated for recovery of resistin and cross-reactivity with resistin-like molecules (RELMs). Known concentrations of rhResistin (1, 5, and 10 ng/ml, R&D Systems) were added to pooled serum (10.5 ng/ml). The recovery of spiked resistin was above 80% efficiency. Known concentrations of RELM- or RELM-ß partial-peptides (1, 2.5, and 5 ng/ml, Alpha Diagnostics, Eastleigh, UK) and rhResistin (5 ng/ml) were coincubated with pooled serum (10.5 ng/ml), an aqueous solution, or serum matrix containing rhResistin (5 ng/ml). The addition of RELMs to treatments did not interfere with the resistin assay or alter known and expected serum resistin concentrations. The human resistin ELISA previously validated (Phoenix Europe GmbH) was used in this study (13).
IL-6 and TNF- secretion from treated adipocytes
Conditioned media from adipocytes treated with rhResistin, insulin, or insulin in combination with RSG were assayed for IL-6 and TNF- (QuantiGlo ELISA, R&D Systems) [IL-6: intraassay coefficient of variation (CV), 3.1%; interassay CV, 2.7%; TNF-: intraassay CV, 6.7%; interassay, CV 11.0%].
Statistics
Protein expression data between control and treatments were compared using an unpaired Student’s t test. Data are presented as mean ± SEM. Analyses were carried out using SPSS (SPSS Inc. 12.0, Woking, UK) software. The threshold for significance was P < 0.05. Correlation analyses were calculated using a Pearson correlation coefficient test.
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Results |
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Results demonstrated that resistin gene expression positively correlates with increasing BMI in AT (CT range, 25.0–30.7; r2 = 0.461; P < 0.001) (BMI, 19.2–37.0 kg/m2; n = 24). Analysis of CD45 expression with increasing adiposity showed a similar but weaker correlation (CT range, 20.0–23.6; r2 = 0.226; P < 0.02) (Fig. 1
). Resistin protein data confirmed the mRNA data because resistin protein expression was 1.5-fold higher in obese AT (BMI, 33.9 ± 4.6 kg/m2; n = 8) compared with lean AT (BMI, 21.2 ± 1.4 kg/m2; n = 8) (P < 0.001) (Fig. 2A). Furthermore, in adipocytes, a 2.2-fold higher level of resistin protein expression was observed in overweight subjects (BMI, 28.3 ± 2.7 kg/m2; n = 4) in comparison with lean subjects (BMI, 23.2 ± 1.6 kg/m2; n = 4; P < 0.001; Fig. 2B).
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LPS was shown to stimulate a 2.2-fold increase in resistin secretion (control, 1.24 ± 0.2 ng/ml; LPS, 2.75 ± 0.4 ng/ml; P < 0.001; n = 8) (Fig. 3). Similarly, zymosan stimulated a 2.5-fold increase in resistin secretion from adipocytes compared with control (control, 1.24 ± 0.2 ng/ml; zymosan, 3.1 ± 0.3 ng/ml; P < 0.001; n = 8) (Fig. 3).
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and IL-6 secretion: effects of rhResistin, insulin, and RSG
rhResistin alone, and in combination with insulin, significantly increases the level of TNF- secretion from adipocytes (control, 74 ± 10 pg/ml; rhResistin, 435 ± 36.5 pg/ml; P < 0.001). Furthermore, RSG significantly reduces this resistin-stimulated increase in TNF- secretion from adipocytes (P < 0.001). After this reduction, TNF- secretion levels remain higher than the control (P < 0.01) (Fig. 4A). Similarly, rhResistin and insulin significantly increase IL-6 secretion (control, 1962 ± 130 pg/ml; rhResistin, 2906.4 ± 297.0 pg/ml; P < 0.01); RSG further reduces this resistin-induced increase in IL-6 secretion from adipocytes (Fig. 4B). Further analysis of cytokine secretion demonstrated that antiresistin (10 µg/ml) antibody reduces the level of TNF- [rhResistin, 89.2 ± 4.6 pg/ml; antiresistin antibody (10 µg/ml), 71.5 ± 5.9 pg/ml; P = 0.039] and IL-6 [rhResistin, 1115.5 ± 40.6 pg/ml; antiresistin antibody (10 µg/ml), 351.5 ± 55.9 pg/ml; P < 0.01] secretion from adipocytes.
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and rhIL-6 on the level of resistin secretion
To establish whether a cytokine feedback mechanism exists within adipocytes, we examined the level of resistin secretion from rhTNF-- and rhIL-6-treated adipocytes. Resistin secretion was unaffected by rhTNF- at any concentration up to 100 ng/ml (control, 135 ± 19 pg/ml; 10 ng/ml rhTNF-, 129 ± 15 pg/ml; 50 ng/ml rhTNF-, 141 ± 11 pg/ml; 100 ng/ml rhTNF-, 116 ± 11 pg/ml; n = 12). Furthermore, rhIL-6 also had no significant effect on the level of resistin secretion (control, 129 ± 12 pg/ml; 10 ng/ml rhIL-6, 135 ± 13 pg/ml; 50 ng/ml rhIL-6, 123 ± 10 pg/ml; 100 ng/ml rhIL-6, 125 ± 12 pg/ml; n = 8).
Effect of rhResistin on TLR-2 and TLR-4 protein expression in adipocytes
For protein expression studies, rhResistin stimulated TLR-2 expression in adipocytes (control, 1.00 ± 0.11; TLR-2, 1.28 ± 0.10; P < 0.001, n = 6; BMI, 23.5 ± 3.8) (Fig. 5A). No significant change in TLR-4 protein expression was observed when compared with control (data not shown); this was expected because of the known constitutive expression of TLR-4 in other tissues.
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B pathway
rhResistin stimulated MyD88 expression in adipocytes (control, 1.00 ± 0.13; 50 ng MyD88, 1.80 ± 0.04; 
P < 0.01, n = 6) (Fig. 5B
). rhResistin further up-regulated the expression of phosphospecific JNK1 (control, 1.00 ± 0.03; 50 ng JNK1-P, 1.29 ± 0.05; P < 0.05, n = 6) and phosphospecific JNK2 (control, 1.00 ± 0.08; 50 ng JNK2-P, 1.53 ± 0.03; P < 0.001, n = 6) (Fig. 5B). Similarly, NF-B (control, 1.00 ± 0.04; 50 ng NF-B, 1.37 ± 0.02; P < 0.05, n = 4) expression was increased in response to rhResistin (Fig. 5B). Additionally, IKK-ß and IKK- were up-regulated in response to rhResistin (control, 1.00 ± 0.04; 50 ng IKK-ß, 1.17 ± 0.03; P < 0.01, n = 4) (control, 1.00 ± 0.06; 50 ng IKK-, 1.50 ± 0.02; P < 0.01, n = 4) (Fig. 5C).
Effects of JNK or NF-B inhibitor on resistin secretion
The level of resistin secretion from adipocytes was significantly reduced with NF-B inhibitor treatment (control, 83.1 ± 20.5 pg/ml; NF-B inhibitor, 61.6 ± 16.6 pg/ml; n = 7, P < 0.05) (Fig. 6A). However, no significant difference in resistin secretion was observed for JNK inhibitor-treated adipocytes (control, 101.5 ± 29.3 pg/ml; JNK inhibitor, 77.0 ± 17.2 pg/ml; n = 4, P = not significant) (data not shown).
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Discussion |
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Although a more proinflammatory role for resistin is emerging in humans, the metabolic actions of resistin remain uncertain. Rodent studies implicate the liver as the major physiological target of resistin action because exogenous resistin impairs glucose tolerance and hepatic insulin resistance (26). Similarly, adenovirus-mediated hyperresistinemia abrogates hepatic and peripheral insulin action (27). Conversely, resistin-null mice exhibit low fasted blood glucose levels because of reduced hepatic glucose production (28). In vitro adipocyte studies highlight that resistin impairs insulin-stimulated glucose uptake (21) and the insulin signaling cascade itself (29). Recent reports further highlight that human resistin has properties similar to its murine counterpart, whereby mouse and human resistin impair glucose transport (29). Here, we demonstrate the proinflammatory actions of resistin in human adipocytes. Collectively, these studies suggest an overlap between metabolic and immune functions for human resistin.
mRNA studies demonstrate that resistin is predominantly expressed in human macrophages (9, 10). Our initial and current studies demonstrate resistin protein expression and secretion from human adipocytes; this has been affirmed by recent observations (11, 12). Such quantitative differences in mRNA expression and circulating resistin levels have been highlighted previously (1, 30). The adipocyte may thus be an undervalued contributor to the circulating levels of resistin in obesity.
We also show that LPS increases resistin secretion from isolated adipocytes. This coincides with recent studies demonstrating that endotoxemia induces circulating resistin levels in healthy subjects (18); highlighting antigenic stimuli can increase resistin levels in vivo. We further demonstrate that resistin increases the level of TNF- and IL-6 secretion from adipocytes, consistent with recent reports, whereby human resistin increases TNF- and IL-12 secretion from macrophages (7). It is acknowledged that circulating levels of TNF- and IL-6 are elevated in obesity (31). We further demonstrate that treatment with antiresistin antibodies reduces the level of cytokine secretion, suggesting that resistin may directly contribute to an altered proinflammatory cytokine status by promoting inflammation. Additionally, we observed that LPS can directly stimulate TNF- and IL-6 secretion from human adipocytes (32).
We additionally examined whether rhResistin influences the expression of key components of the innate immune pathway and observed that resistin up-regulates the expression of TLR-2, MyD88, and NF-B in adipocytes. When examining the key intermediate activating NF-B, the IKK complex, rhResistin further increases the expression of the catalytic subunits IKK-ß and IKK-. Interestingly, JNK expression is up-regulated in response to rhResistin, suggesting NF-B activation may overlap into a JNK-mediated pathway. Such an overlap between JNK and NF-B has been identified in macrophages and alveolar epithelial cells (33, 34), consistent with cross talk between metabolic and inflammatory pathways. Alternatively, elevated TNF- and IL-6 levels induced by resistin may activate JNK and NF-B systems, rather than via a direct effect of resistin. To further examine the significance of NF-B and JNK signaling on resistin action in human adipocytes, we treated cells with NF-B or JNK inhibitors. Although NF-B inhibition appeared to reduce resistin secretion, no effect was observed with the JNK inhibitor. Although an overlap of JNK and NF-B systems has been suggested, resistin may have more prominent effects on the NF-B pathway; the importance of the NF-B pathway for resistin-induced inflammation has been highlighted (8).
Hyperrestinemia is known to contribute to an inflammatory response (22). rhResistin was shown to alter the level of cytokine release when compared with control. Insulin was used to observe the effects of RSG in this system; as such, we demonstrated that the peroxisome proliferator-activated receptor-
agonist, RSG, attenuates resistin-induced secretion of TNF- and IL-6. Although the mechanisms for this are unclear, the resistin gene promoter contains a proliferator-activated receptor- binding site (10), through which RSG may coordinate the recruitment of transcriptional corepressors (35), thereby suppressing resistin expression at the genetic level. However, this does not appear to be the mechanism through which our observations are being mediated because we used exogenous resistin to stimulate cytokine production. This suggests that RSG may act downstream of the resistin promoter to mitigate resistin-mediated TNF- and IL-6 stimulation, potentially via NF-B.
Visceral adiposity, in addition to BMI, confers a high risk of insulin resistance and T2DM. Moreover, levels of resistin, ILs, and TNF- differ between visceral and sc AT (36, 37). Although rodent studies have highlighted an increase in resistin expression in visceral AT (38), limited analysis has addressed this in humans. We previously reported higher levels of resistin expression in abdominal depots in comparison with thigh (14), consistent with a role for resistin in obesity-related insulin resistance. Further examination of resistin levels in human AT depots, particularly the proinflammatory actions of resistin in visceral AT in comparison with sc AT, may shed further light on the nature of resistin action in humans.
In conclusion, our study suggests that adipocytes may be a contributory source of resistin in human obesity. Furthermore, resistin responds to LPS treatment and can influence the secretion of inflammatory cytokines from human adipocytes. The intracellular mechanism for such mediation of resistin on cytokine release appears to act primarily via the NF-B pathway. Elevated levels of cytokines, induced by resistin, may thus contribute to the proinflammatory milieu proposed in obesity-related insulin resistance.
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Footnotes |
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First Published Online October 24, 2006
Abbreviations: Abd Sc, Abdominal sc; AT, adipose tissue; BMI, body mass index; Ct, cycle threshold; CV, coefficient(s) of variation; IKK, IB kinase; JNK, c-Jun NH2-terminal kinase; LPS, lipopolysaccharide; NF, nuclear factor; RELM, resistin-like molecule; rh, recombinant human; RSG, rosiglitazone; SDS, sodium dodecyl sulfate; T2DM, type 2 diabetes mellitus; TLR, Toll-like receptor.
Received May 30, 2006.
Accepted October 12, 2006.
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References |
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and IL-12 in macrophages by NF-B-dependent pathway. Biochem Biophys Res Commun 334:1092–1101[CrossRef][Medline] action in humans. Diabetes 50:2199–2202 activators. Biochem Biophys Res Commun 300:472–476[CrossRef][Medline] in human obesity and insulin resistance. J Clin Invest 95:2409–2415[Medline]B and c-Jun kinase in the innate immune pathway in human abdominal isolated adipocytes and explants. European Association for the Study of Diabetes, Copenhagen, Denmark 0121 (Abstract)B-inducing kinases. Am J Physiol Lung Cell Mol Physiol 285:L464–L475 B and c-Jun/activator protein-1 via toll-like receptor 2 in macrophages by antimycotic-treated Candida albicans. J Infect Dis 190:1318–1326[CrossRef][Medline]This article has been cited by other articles:
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  J. Lo, L. E. Bernstein, B. Canavan, M. Torriani, M. B. Jackson, R. S. Ahima, and S. K. Grinspoon Effects of TNF-{alpha} neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E102 - E109. [Abstract] [Full Text] [PDF]
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 K. Kos, A. L. Harte, N. F. da Silva, A. Tonchev, G. Chaldakov, S. James, D. R. Snead, B. Hoggart, J. P. O'Hare, P. G. McTernan, et al. Adiponectin and Resistin in Human Cerebrospinal Fluid and Expression of Adiponectin Receptors in the Human Hypothalamus J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 1129 - 1136. [Abstract] [Full Text] [PDF]
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