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Department of Medicine, Huddinge, Karolinska Institute (I.D., M.K., K.W., E.A.N., L.B., P.A.), SE-14186 Stockholm, Sweden; Biovitrum AB (A.S., M.F., A.A.), SE-11276 Stockholm, Sweden; Department of Medicine, Umea University Hospital (T.O., J.A.), SE-90187 Umea, Sweden; and Oxford Center for Diabetes, Endocrinology, and Metabolism, Churchill Hospital (G.D.T., A.S.T.B.), Oxford OX3 7LJ, United Kingdom
Address all correspondence and requests for reprints to: Dr. Peter Arner, Department of Medicine, M61, Karolinska University Hospital, SE-14186 Huddinge, Sweden. E-mail: peter.arner{at}medhs.ki.se.
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Abstract |
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Objectives: The objective of this study was to determine which inflammation markers are most overexpressed at the gene level in adipose tissue in human obesity and how this relates to corresponding protein secretion.
Design: We examined gene expression profiles in 17 lean and 20 obese subjects. The secretory pattern of relevant corresponding proteins was examined in human sc adipose tissue or isolated fat cells in vitro and in vivo in several obese or lean cohorts.
Results: In ranking gene expression, defined pathways associated with obesity and immune and defense responses scored high. Among seven markedly overexpressed chemokines, only monocyte chemoattractant protein 1 (MCP1) was released from adipose tissue and isolated fat cells in vitro. In obesity, the secretion and expression of MCP1 in adipose tissue pieces were more than 6- and 2-fold increased, respectively, but there was no change in circulating MCP1 levels. There was no net release of MCP1, but there was a net release of leptin, in vivo from adipose tissue into the circulation.
Conclusions: Obesity is associated with the increased expression of several chemokine genes in adipose tissue. However, only MCP1 is secreted into the extracellular space, where it primarily acts as a local factor, because little or no spillover into the circulation occurs. MCP1 influences the function of adipocytes, is a recruitment factor for macrophages, and may be a crucial link among chemokines between adipose tissue inflammation and insulin resistance.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Inflammatory mediators in adipose tissue are highly relevant for the contribution of this tissue to insulin resistance and to the development of type 2 diabetes among obese subjects (reviewed in Ref.5). Inflammatory proteins, such as TNF
(6, 7, 8), IL-6 (9, 10), and monocyte chemoattractant protein 1 (MCP1) (11), are secreted from adipose tissue and influence the metabolism, insulin signaling, and endocrine activity of fat cells. It has recently been shown that adipocytes secret a factor(s) that up-regulates adhesion molecules on endothelial cells and increases the chemotaxis of monocytes (12). These effects can be mimicked by leptin (12). However, important features of this inflammatory activity are poorly understood, such as the secretory pattern of proteins and their origin among fat cells or different types of stromal-vascular cells. What signals in vivo recruit macrophages into adipose tissue, and whether secreted proteins participate in the general inflammatory state seen in obesity through release from adipose tissue into the circulation are also unknown. Considering the marked differences in regulation of human and rodent adipose tissue functions, important species differences may be present (reviewed in Ref.13). As one example, adipose-derived TNF is released from adipose tissue into the circulation in rodents, but not in man (14).
We used microarrays to obtain a profile of differences in adipose tissue gene expression between obese and nonobese subjects. In ranking gene expression, defined pathways associated with obesity, terms related to defense and inflammatory responses scored high. Within these terms, several chemokines were among the most up-regulated genes in obesity. Based on the hypothesis that these chemokines could play a primary role in the inflammatory pathways of adipose tissue and its metabolic complications, the corresponding proteins were also studied for their secretory patterns in vivo and in vitro. In adipose tissue we demonstrate a unique role of MCP1 among chemokines.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Several cohorts of healthy nonobese or obese subjects were examined. A body mass index (BMI) greater than 30 kg/m2 was used as a definition of obesity. All subjects were examined in the morning after an overnight fast. Venous blood samples were taken for quantification of serum levels of MCP1 and leptin as indicated. There was no selection based on menopause, because there is no evidence that this factor influences gene expression in human adipose tissue.
Microarray-based gene expression profiling on sc adipose tissue was performed in 17 nonobese (age, 36 ± 11 yr; BMI, 24 ± 2 kg/m2) and 20 obese, but otherwise healthy (age, 39 ± 12 yr; BMI, 40 ± 6 kg/m2), women. Subcutaneous abdominal adipose tissue biopsies were obtained with needle aspiration (1–2 g) as previously described (15). Adipose tissue was brought to the laboratory in saline. Pieces (300–600 mg) were immediately frozen in liquid nitrogen and kept at –70 C for RNA preparation as previously described (16).
In vitro protein secretion was initially examined in sc adipose tissue pieces and isolated fat cells obtained in connection with breast surgery for cosmetic reasons (n = 3 women; age, 43 ± 4 yr; BMI, 30 ± 6 kg/m2). These subjects were healthy and free of medication. Adipose tissue was brought to the laboratory in saline, where one piece was subjected to collagenase treatment as described for isolation of fat cells that were used both for measuring protein secretion and for determination of mean fat cell volume and weight (17, 18). Another piece, 300 mg, was used for protein secretion studies. Only saline was administrated iv until tissue was removed.
Abdominal sc abdominal adipose tissue biopsies were also obtained from 13 lean (age, 40 ± 10 yr; BMI, 23 ± 2 kg/m2) and 10 obese otherwise healthy (age, 43 ± 12 yr; BMI, 41 ± 5 kg/m2) women. One piece of adipose tissue (300 mg) was used for in vitro protein secretion studies, and one piece was immediately frozen in liquid nitrogen and used for RNA preparation as described below for subsequent real-time PCR (16). None of the women described above was taking continuous medication.
Finally, seven men [age 45 ± 14 yr; BMI 31 ± 8 kg/m2; homeostasis assessment model of insulin resistance (HOMAIR), 3.4 ± 2.5] and three women (age, 56 ± 22 yr; BMI, 24 ± 1 kg/m2; HOMAIR, 1.5 ± 0.2) were recruited at Norrland University Hospital (Umea, Sweden), and 12 men (age, 47 ± 7 yr; BMI, 30 ± 3 kg/m2) were recruited at Oxford University (Oxford, UK) for measuring protein secretion in vivo. Of the former subjects, one was taking an antidepressant, and two were taking antihypertensive drugs. All other subjects were healthy and not taking medications. Abdominal sc vein and arterialized blood samplings were performed for measuring protein secretion in vivo as described previously (19). Briefly, a 20-gauge 15-cm catheter was inserted into the inferior epigastric vein in the anterior abdominal wall. To ensure that the blood was collected from the sc fat and not from deeper structures, the oxygen saturation was checked to be greater than 85%. Arterialized venous blood was drawn from the cephalic vein in a retrograde direction with the hand placed in a box with air warmed to 60 C. Oxygen saturation was more than 94%. Samples were immediately put on ice, centrifuged at 3000 rounds/min for 10 min, and stored at –80 C. The local committees on ethics approved the study, which was explained in detail to each participant, and informed consent was obtained.
Microarray study
Five micrograms of adipose tissue total RNA per subject was used in the standard protocol from Affymetrix (Affymetrix, Inc., Santa Clara, CA) to obtain biotinylated cRNA. High RNA quality was confirmed by an Agilent 2100 bioanalyzer (Agilent Technologies, Kista, Sweden). The in vitro transcription reaction was performed using the Enzo BioArray High Yield RNA Transcript Labeling Kit (Enzo Diagnostics, Farmingdale, NY). Labeled cRNA was purified with RNeasy Mini Kit spin columns (QIAGEN, Valencia, CA), quantified spectrophotometrically, and fragmented in buffer according to the Affymetrix protocol. Test-3 arrays (Affymetrix Baracaldo, Vizcaya, Spain) were hybridized to check the cRNA integrity. In 50% of the cases the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) 3'/5' ratio was less than 1.5, and in the other 50% it was less than 2.0. This material was next hybridized to the individual Human Genome U95 (HG-U95) array sets from Affymetrix. The HGU95Av2 array represents approximately 10,000 full-length genes, whereas arrays B–E represent expressed sequence tag clusters.
After probing and scanning 37 chip sets using the standard protocols from Affymetrix, signal values were analyzed using the software Microarray Analysis Suite 5.0 (Affymetrix, Inc.). Distinct algorithms were employed to construct and evaluate, i.e. present or absent, absolute calls for each transcript. The mathematical definitions for each of the algorithms are described in Affymetrix Microarray User’s Guide 5.0
The MAPPFinder version 1.0 software (www.genmapp.org) was used to rank the magnitude in gene expression differences of the GenMAPP pathways and Gene Ontology terms (www.genmapp.org) between obese and nonobese women (20, 21, 22). Briefly, MAPPFinder assigns to each analyzed pathway or gene set a z-score, which is based on the percentage of genes in each pathway or set that meets a user-defined criterion for change in expression. Criteria for change were significant gene expression present in more than 13 of either obese or nonobese samples (by two-sided paired t test for change in expression of individual gene, P < 0.05; mean signal fold change, >25% between these groups); 25% fold change was selected, because in other Affymetrix experiments in our laboratory, changes in expression of this magnitude consistently have been reproduced by real-time PCR.
Real-time PCR
Total RNA from adipose tissue pieces of 300 mg was quality confirmed as described above and reverse transcribed as previously described using random hexamer primers for TaqMan and oligo(deoxythymidine) primers for SYBR Green-based assays (16). TaqMan was used to quantify BRAK (for breast and kidney, where it was originally detected; CXC motif ligand 14, CXCL14; HS00171135_m1), endothelial monocyte-activating polypeptide 2, small inducible cytokine subfamily E (Hs00171131_m1), pulmonary and activation-regulated chemokine (PARC; chemokine CC motif ligand 18,CCL18; Hs00268113_m1), MCP1 (CCL2; Hs00234140_m1), macrophage inflammatory protein 1 (MIP1A; CCL3; Hs00234142_m1), MCP2 (CCL8; Hs00428422_g1), monokine induced by interferon-
(MIG; CXCL9; Hs00171065_m1), and MIP2A (CXCL2; Hs00601975), with TaqMan Pre-Developed Assay Reagent kits with GAPDH as an endogenous control (Applied Biosystems, Foster City, CA). The primer pairs for SYBR Green-based real-time PCR were designed to span exon intron boundaries and generate a single amplicon. Dissociation curves and agarose gel electrophoresis were used to check for a single product. Primer pairs were: for ß2-microglobulin, 5' TGCTGTCTCCATGTTTGATGTATCT-3' and 5'-TCTCTGCTCCCCACCTCTAAGT 3'; for GAPDH, 5'-CACATGGCCTCCAAGGAGTAAG-3' and 5'-CCAGCAGTGAGGGTCTCTCT-3'; and for MCP1, 5'-GTGTCCCAAGAAGCTGTGA-3' and 5'-GTTTGCTTGTCCAGGTGGT-3'. All samples were run in triplicate, and standard curves were created to check the PCR efficiency and reproducibility. The expression of target gene was normalized to the ß2-microglobulin and GAPDH internal control using the formula 2(Ct target calibrator – Ct target sample)/2(Ct internal control calibrator – Ct internal control sample), where calibrator is a random sample. The expression of neither of these two control genes was significantly influenced by obesity in the investigated samples.
Protein secretion
In studies of adipose tissue obtained during cosmetic surgery, 300 mg abdominal sc adipose tissue pieces or 300 mg packed isolated fat cells from the same subject were incubated at 37 C in 3 ml Krebs-Ringer phosphate buffer (pH 7.4) supplemented with glucose (1 mg/ml) and BSA (10 mg/ml) in a shaking water bath with air as the gas phase for various periods of time. Thereafter, the medium was removed and frozen in liquid nitrogen. It was kept at –70 C for later protein determination. Methodological experiments revealed that this incubation system is valid for studies of protein release in vitro, because secreted proteins show a linear increase with time during incubation (23). Furthermore, in unpublished methodological experiments, we compared the release of glycerol in vitro from adipose tissue pieces and isolated fat cells in abdominal sc adipose tissue of 250 subjects. A strong linear relationship between glycerol release from the two preparations was observed (r = 0.59). In the isolated fat cells we regularly investigated the existence of nonfat cells in the preparation when measuring the size of 200 individual cells. Zero to one nonfat cell was observed among the 200 fat cells counted; usually these were free cells, but sometimes the cells were sticking to the fat cell surface membrane. Thus, nonfat cell contamination was less than 0.5%.
In the clinical needle biopsy experiments in obese and nonobese subjects, 300 mg tissue pieces were incubated as described above for 2 h. The amount of protein secreted into the incubation medium was determined and related to tissue weight or number of fat cells, incubated as previously described (23). In brief, the lipids of the incubated tissue were subjected to organic extraction, and their weights were determined. A separate piece of tissue was subjected to collagenase treatment, and the mean weight of the isolated fat cells was determined. Thereafter, the number of fat cells incubated was obtained by dividing the incubated tissue lipid weight by the mean fat cell weight.
Protein quantification
Chemokines in serum of incubation medium were quantified by ELISA using the MCP1, MIP1A, MIG, MIP1B (CCL4), PARC, and MCP4 (CCL13) Duo Set ELISA Development System kits (R&D Systems, Abington, UK) according to the manufacturer’s instructions. Leptin was quantified by RIA as previously described (24).
Statistical analysis
All values reported in the text are the mean ± SD. Microarray, ELISA, and PCR results were analyzed using two-sided unpaired or paired Student’s t test. In addition, chemokine secretion over time was analyzed by two-way ANOVA. MCP1 or leptin was also compared between peripheral blood and abdominal vein when stated using Wilcoxon’s signed rank test. P < 0.05 was considered significant.
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Results |
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Some 588 genes met the MAPPFinder criteria. Of these, 493 genes were used to calculate the gene ontology results, and 92 genes were used to calculate the MAPPFinder results.
The remaining genes did not link to a map. The z-score was based on analysis of the 6069 Microarray genes annotated in the MAPPFinder database. Pathways or Gene Ontology biological function terms with a z-score greater than 3 are depicted in Table 1
. Changes in adipose tissue gene expression between obese and nonobese women ranked highest in the gene ontology terms lysosome, protein-lysine 6-oxidase genes, as well as defense and immune responses (Table 1). The gene content overlaps between the latter terms and the terms response to wounding, chemotaxis, and response to stress. Next appear a number of small terms with only three genes, whose expression is affected by diet. Their limited sizes make their biological impacts on obesity unsure, and they were not further investigated. MAPPFinder pathways fatty acid synthesis and complement activation also ranked high.
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. Fifty-three genes were up-regulated in obesity, and three were down-regulated. Among the 11 genes with fold change in expression between obese and nonobese greater than 2, seven comprised chemokines, which also encompassed the largest subgroup of immune response genes affected by obesity on the map. The chemokine genes were MCP4, PARC, MCP1, MIP1A, MIP1B, MCP2, and MIP2A (Table 2). Of 27 chemokine genes measured on the microarrays, one more, not annotated as an immune response, was up-regulated in obesity, MIG (Table 2). No chemokine gene was down-regulated in obesity.
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). Probe sets for 15 distinct chemokine receptors were present on the microarrays used in the study. Only four of those were expressed in adipose tissue of more than 13 subjects: chemokine CXC motif receptor 4 (change obese vs. nonobese, 1.37-fold; P = 0.047), chemokine CC motif receptor-like 2 (change, 1.1-fold), chemokine CC motif receptor 7 (change, 0.87-fold), and chemokine CX3C motif receptor 1 (change, 1.34-fold; P = 0.044).
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). The rate of release was approximately three times more rapid from tissue pieces than from isolated adipocytes (P = 0.01).
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). The differences in MCP1 secretion between groups was approximately 10-fold when secretion was expressed per number of fat cells (values not shown). In contrast, there was no difference in the serum concentration of MCP1 between these groups (Table 4). In the same subjects who were investigated for adipose secretion of MCP1, the amount of mRNA for MCP1 in the adipose tissue pieces was 2-fold increased in obesity (P < 0.05; Table 4). The adipose tissue source of MCP1, adipocytes or vascular stromal cells, was not investigated in these subjects, because it has been determined previously (see Discussion and Refs.3 ,25 , and 26).
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). Similar results were obtained in nonobese (n = 11) and obese (n = 11) subjects. In addition, there was no difference in MCP1 between nonobese and obese subjects when either abdominal vein or arterialized blood was analyzed. Sex, age, HOMAIR, or center (Oxford/Umea) had no impact on the net export of MCP1 from adipose tissue (results not shown). The concentration of leptin in these samples was significantly higher in the abdominal vein than in arterialized blood in both nonobese and obese subjects. In both blood compartments, leptin concentrations were higher in obese than in nonobese subjects (P = 0.02; Fig. 2). Furthermore, in all subjects there was a positive correlation between leptin extraction and BMI (r = 0.68; P = 0.0005). Similar results were obtained if parametrical or nonparametrical statistical tests were used.
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Discussion |
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The results of gene expression profiling by Affymetrix showed that eight chemokines were more than 2-fold up-regulated in sc adipose tissue of the obese. These were MCP1, MIP1A, MIP1B, MCP2, MCP4, PARC, MIG, and MIP2A. There was no or little change in the expression of chemokine receptors. Only four nonchemokine immune response genes were more than 2-fold up-regulated by obesity. This also stresses the major effect on chemokines by obesity among immune and defense response genes in our set of experiments.
It is of interest to compare our data with a recent global microarray of changes in adipose tissue gene expression after weight loss (3). Forty-one inflammatory genes were overexpressed, and 50 were down-regulated after 28 d of a very low calorie diet. The expression of five chemokine genes was affected by weight reduction, but of those, only MCP1 overlaps with the obesity-associated chemokines reported in our study.
To elucidate the importance of the chemokines to adipose function, their secretory patterns were investigated by an in vitro system allowing analysis of the linear release of proteins from human adipose tissue pieces into the incubation medium (16). These studies showed that MCP1, but no other investigated chemokine, was secreted in a time-dependent fashion from pieces of human adipose tissue. The MCP1 data confirm the results of a recent study showing significant release of MCP1 from visceral as well as sc adipose tissue pieces (25). There was no detectable secretion of MIP1A, MIP1B, MCP4, or MIG. Therefore, we conclude that these proteins are not secreted in human adipose tissue. However, we cannot exclude minor secretion, which is too low to be detected by currently availably ELISAs. Some PARC was detected in the incubation medium, but the concentration did not increase with incubation time. We therefore conclude that the findings with PARC are artifacts.
The next question was whether fat cells secrete MCP1. For this purpose we used a pure preparation of fat cells. These studies showed that for both isolated fat cells and adipose tissue pieces, MCP1 was released into the incubation medium in a fashion that was linear with time. However, the rate of release was three times less rapid from adipocytes than from tissue. This difference may be more apparent than real. Fat cells might need some factor in the stromal-vascular compartment to allow full secretory capacity. Alternatively, collagenase isolation per se may change the secretion of certain proteins from fat cells. However, it is also possible that fat cells have a lesser capacity to release MCP1 than other cell types within the adipose tissue. At least three studies have compared MCP1 in different compartments of adipose tissue. These studies show that MCP1 mRNA expression levels in isolated adipocytes are 10–15%, 17%, and 44%, respectively, of expression levels in the stromal vascular fraction of adipose tissue (3, 25, 26). The fact that MCP1 release was linear with time suggests that it is actually secreted and not just released into the medium due to cell or tissue damage.
Increased secretion and adipose tissue mRNA levels of MCP1 in human obesity have recently been reported (25, 26). We confirm these observations. Thus, the secretion of MCP1 from adipose tissue was six to 10 times increased among the obese compared with the nonobese, and the MCP1 mRNA level was doubled in obesity. However, unlike previous reports (26), we observed no increase in the circulating MCP1 concentration among the obese. This discrepancy may be explained by the inclusion of men and younger subjects in the study by Christiansen et al. (26). In addition, our study groups were much larger than those previously investigated (11 vs. three nonobese and 11 vs. five obese subjects). Our subsequent quantification of MCP1 levels in the abdominal veins of nonobese and obese subjects demonstrates that adipose tissue does not contribute to circulating levels of MCP1. This is in contrast to leptin, for which we found some net extraction from adipose tissue in vivo in all samples, although it was more apparent among the obese. Furthermore, the data for abdominal vein catheterization also revealed no effect of obesity on the circulating MCP1 concentration.
Our demonstration of secretion of MCP1 from adipose tissue and isolated fat cells points toward specific roles of this chemokine within the tissue, such as direct induction of insulin resistance (11) as well as, by secretion into the local circulation, recruitment of monocytes, thus contributing to the observed macrophage infiltration of adipose tissue in obesity (31, 32, 33). The recruitment of monocytes could be either direct interaction with these cells or positive stimulation of leptin, which can act as a recruitment factor for monocytes and up-regulate adhesion molecules in endothelial cells (12, 29, 34). By contrast, there is no evidence that MCP1 up-regulates adhesion molecules on endothelial cells (32, 33).
All investigations of MCP1 release were performed under basal conditions. At present we do not know how MCP secretion is regulated. A number of factors, such as insulin or other hormones and hypoxia, could be involved. However, hypoxia during our short-term acute incubation conditions may be of less importance according to methodological experiments.
Based on present and previous findings, we propose the following role of chemokines in adipose tissue and insulin resistance of the obese. Obesity leads to a local increase in the release of MCP1, which is the only chemokine that is secreted from adipose tissue. MCP1 recruits macrophages, resulting in altered metabolic and endocrine activities of fat cells, including insulin resistance. However, adipose tissue is not an important contributor to circulating MCP1 levels.
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Acknowledgments |
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Footnotes |
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First Published Online August 9, 2005
Abbreviations: BMI, Body mass index; BRAK, breast and kidney; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HOMAIR, homeostasis assessment model of insulin resistance; MCP1, monocyte chemoattractant protein 1; MIG, monokine induced by interferon-; MIP1A, macrophage inflammatory protein 1; PARC, pulmonary and activation-regulated chemokine.
Received February 18, 2005.
Accepted July 29, 2005.
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References |
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: direct role in obesity-linked insulin resistance. Science 259:87–91 inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 91:4854–4858 stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 51:2929–2935, in vivo. J Clin Endocrinol Metab 82:4196–4200. J Biol Chem 278:52298–52306This article has been cited by other articles:
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M. Kolak, J. Westerbacka, V. R. Velagapudi, D. Wagsater, L. Yetukuri, J. Makkonen, A. Rissanen, A.-M. Hakkinen, M. Lindell, R. Bergholm, et al. Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity Diabetes, August 1, 2007; 56(8): 1960 - 1968. [Abstract] [Full Text] [PDF]
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I. Harman-Boehm, M. Bluher, H. Redel, N. Sion-Vardy, S. Ovadia, E. Avinoach, I. Shai, N. Kloting, M. Stumvoll, N. Bashan, et al. Macrophage Infiltration into Omental Versus Subcutaneous Fat across Different Populations: Effect of Regional Adiposity and the Comorbidities of Obesity J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2240 - 2247. [Abstract] [Full Text] [PDF]
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H. Poirier, J. S. Shapiro, R. J. Kim, and M. A. Lazar Nutritional Supplementation With trans-10, cis-12-Conjugated Linoleic Acid Induces Inflammation of White Adipose Tissue Diabetes, June 1, 2006; 55(6): 1634 - 1641. [Abstract] [Full Text] [PDF]
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I. Dahlman, M. Forsgren, A. Sjogren, E. A. Nordstrom, M. Kaaman, E. Naslund, A. Attersand, and P. Arner Downregulation of Electron Transport Chain Genes in Visceral Adipose Tissue in Type 2 Diabetes Independent of Obesity and Possibly Involving Tumor Necrosis Factor-{alpha} Diabetes, June 1, 2006; 55(6): 1792 - 1799. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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) derived from human sc adipose tissue. Nine experiments were performed. Three hundred milligrams of tissue or 3 ml packed isolated fat cells/3 ml incubation medium were used.