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Serum Resistin (FIZZ3) Protein Is Increased in Obese Humans

Division of Endocrinology and Metabolism (M.D.-Y., J.E.B., R.V.C.), Division of Biostatistics (B.E.J.), Department of Medicine, and Department of Surgery (W.W., K.K.), Indiana University School of Medicine, Indianapolis, Indiana 46202-5111; Department of Surgery (R.M.J.), St. Vincent’s Hospital, Carmel, Indiana 46032; and Lilly Research Laboratories (Q.Z.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Robert V. Considine, Ph.D., Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 455, Indianapolis, Indiana 46202-5111. E-mail: rconsidi{at}iupui.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The role of resistin in obesity and insulin resistance in humans is controversial. Therefore, resistin protein was quantitated by ELISA in serum of 27 lean [13 women/14 men, body mass index (BMI) 21.7 ± 0.4 kg/m², age 33 ± 2 yr] and 50 obese (37 women/13 men, BMI 49.8 ± 1.5 kg/m², age 47 ± 1 yr) subjects. There was more serum resistin protein in the obese (mean ± SEM: 5.3 ± 0.4 ng/ml; range 1.8–17.9) than lean subjects (3.6 ± 0.4 ng/ml; range 1.5–9.9; P = 0.001). The elevation of serum resistin in obese humans was confirmed by Western blot as was expression of resistin protein in human adipose tissue and isolated adipocytes. There was a significant positive correlation between resistin and BMI (r = 0.37; P = 0.002). Multiple regression analysis with predictors BMI and resistin explained 25% of the variance in homeostasis model assessment of insulin resistance score. BMI was a significant predictor of insulin resistance (P = 0.0002), but resistin adjusted for BMI was not (P = 0.11). The data demonstrate that resistin protein is present in human adipose tissue and blood, and that there is significantly more resistin in the serum of obese subjects. Serum resistin is not a significant predictor of insulin resistance in humans.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
RESISTIN, ALSO CALLED adipocyte secreted factor (ADSF) or FIZZ3 (found in inflammatory zone), is a 12.5-kDa protein secreted by rodent adipocytes and 3T3-L1 cells (1, 2, 3). Serum resistin is increased in diet-induced obese mice, ob/ob and db/db mice, and it has been suggested that resistin may have a causative role in the insulin resistance present in these rodent models of diabetes (1). Further, resistin mRNA expression in adipocytes (1, 4), and serum resistin protein (1) is reduced in rodents treated with rosiglitazone, suggesting that a TZD-induced reduction in resistin could contribute to the improvement in insulin sensitivity achieved with these compounds. Human resistin is 59% homologous at the amino acid level to the mouse molecule (1), suggesting a relatively low degree of sequence conservation (5).

We have reported that resistin mRNA is present in human adipose tissue but that resistin expression was very low in isolated adipocytes (6). These findings are supported by results from two other studies of resistin expression in human adipose tissue (7, 8) but are in contrast to a third report (9). The low expression of resistin in human adipocytes, in contrast to observations in rodent adipocytes, has called into question a role for resistin in obesity-related insulin resistance in humans. However, in our previous study we also found that resistin mRNA was present in circulating monocytes, raising the possibility that resistin protein could also be released from these cells into the serum. Therefore, in the current study we have examined resistin protein levels in human serum to investigate the possibility that serum resistin may be elevated in obese subjects as observed in obese rodents. We also explored the hypothesis that serum resistin levels predict insulin resistance in humans. Two techniques were employed. In an initial study completed before a reliable resistin ELISA was available, serum resistin was quantitated by Western blotting. We then used a commercially available ELISA kit to measure serum resistin protein in a larger number of subjects.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Blood samples were obtained from subjects undergoing bariatric surgical procedures, outpatient adipose tissue biopsy, or venipuncture only. In the case of surgical procedures, blood samples were taken before surgery, the serum separated, and samples frozen at -70 C. Of the obese subjects, five were being treated for diabetes (taking either glyburide, glipizide, metformin, metformin/glyburide, or insulin). Adipose tissue was obtained at the site of abdominal incision from one subject undergoing bariatric surgery [white female, body mass index (BMI) 37.5 kg/m², age 42 yr]. The characteristics of the subject groups are shown in Table 1. Subjects with BMI 26 kg/m² were considered lean (35%), and subjects with BMI 30 kg/m² obese (65%). Among obese, 74% were female. The protocols were approved by the Institutional Review Boards of Indiana University-Purdue University at Indianapolis, and St. Vincent’s Hospital (Carmel, IN). All subjects provided informed consent.

Blood and tissue samples were obtained in the morning after an overnight fast. Resistin was determined by ELISA (BioVender Laboratory Medicine Inc., Brno, Czech Republic) with intraassay variation of 4.3% and interassay variation of 7.2% at a standard concentration of 6.2 and 6.6 ng/ml resistin, respectively. All samples were run in a single assay. Insulin was measured by RIA (Linco Research, Inc., St. Charles, MO) and glucose quantitated with a YSI 2300STAT Plus Glucose Analyzer (YSI Inc., Yellow Springs, OH). Homeostasis model of assessment (HOMA) score was calculated as fasting insulin (µU/ml) x fasting glucose (mM) divided by 22.5 (10).

Western blotting

Adipocytes were isolated by collagenase digestion as described (11). Cells were solubilized in 20 mM Tris (pH 8.0), 150 mM NaCl, 1 mM EDTA, 1% Triton X-100 with Complete Protein Inhibitor Cocktail (Roche Molecular Biochemicals, Mannheim, Germany). Protein concentrations were determined with the DC Protein Assay (Bio-Rad Laboratories, Hercules, CA).

Adipose tissue (100 µg), isolated adipocyte (100 µg), or serum protein (400 µg) was separated on an 18% Tris-HCl gel (Bio-Rad Laboratories) under denaturing conditions, at 30 V for 3 h. Recombinant resistin (350 or 175 ng) was run as a control on each blot. Proteins were transferred to nitrocellulose membranes (Bio-Rad Laboratories) at 30 V overnight. Nonspecific binding sites were blocked for 30 min at room temperature with 5% skim milk in TBST (10 mM Tris, 15 mM NaCl, 0.05% Tween 20). Membranes were incubated for 2 h at room temperature in 5% skim milk-TBST containing rabbit antihuman resistin antiserum (Alpha Diagnostic, San Antonio, TX) at a dilution 1:200. This antibody was generated against a 14-amino acid peptide sequence near the amino terminus of human resistin, which by design is not similar to any amino acid sequence in human FIZZ1. Blots were washed three times with TBST and incubated with antirabbit IgG coupled to horseradish peroxidase (Amersham, Piscataway, NJ) for 1 h at room temperature in 5% skim milk-TBST at a dilution 1:1000. Antibody binding was visualized by chemiluminescence (Amersham Biosciences, Buckinghamshire, UK). The antibody detected a band of approximately 11 kDa that comigrated with recombinant human resistin. Preincubation of antibody with its antigenic peptide blocked binding to the 11-kDa band and recombinant resistin. To estimate the concentration of resistin in serum, the band density for each sample was normalized to that of a known amount of recombinant human resistin on each blot.

To make recombinant resistin, the human resistin gene was amplified by PCR and cloned into the PPR1 vector with a FLAG and HIS tag at the 5' end. The plasmid vector was transfected into 293 E cells and the recombinant human resistin purified using nickel-chelating resin and column chromatography.

Statistical methods

The primary outcome of the statistical analysis was to determine the relationship between insulin resistance as measured by HOMA score and resistin adjusted for other important predictors. Two outlying data points, identified as 4.31 and 6.37 SDs above the mean, were eliminated from all analyses. Serum resistin and HOMA score were highly skewed and variance was nonconstant; therefore, multiple linear regression analysis was performed using natural logarithm-transformed serum resistin and natural logarithm-transformed HOMA score. Multiple linear regression analysis examined the contribution of age, gender, BMI and resistin to HOMA score. Secondary analyses were performed using either Wilcoxon rank sums test or Fisher’s exact test to compare lean vs. obese (Table 1) and men vs. women. Spearman correlation coefficients with Bonferroni adjustment for multiple comparisons are reported for bivariate analyses of continuous variables. All mean values are reported as means ± SEM.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fasting insulin and glucose were significantly greater in the obese subjects compared with the lean; therefore, HOMA scores for the two groups were also significantly different. The obese group was older than the lean group (P < 0.0001) and the obese group was comprised of more women than men (74% vs. 26%; P = 0.03).

Serum resistin protein was detectable by ELISA in fasting serum samples obtained from all lean and obese subjects. As shown in Fig. 1, there was on average 47% more resistin in serum from obese subjects compared with lean subjects (5.3 ± 0.4 ng/ml; range 1.8–17.9 vs. 3.6 ± 0.4 ng/ml; range 1.5–9.9; P = 0.002). In subgroup analyses, there was significantly more resistin in obese than lean females (n = 37 and 13, respectively, P = 0.002). There was no difference in resistin between obese and lean males (n = 13 and 14, respectively). The power of the subgroup analyses is unequal between genders and very low for males (approximately 70% for females and 17% for males). Significant positive correlations between BMI and HOMA (r = 0.50; P < 0.0001), BMI and resistin (r = 0.37; P = 0.001), and HOMA and resistin (r = 0.33; P = 0.003) were identified by Spearman’s rank correlation with Bonferroni adjustment for multiple comparisons.

View larger version (17K): [in this window] [in a new window]   FIG. 1. Serum resistin is significantly greater in obese subjects (BMI 49.8 ± 1.5; n = 50) than in lean subjects (BMI 21.7 ± 0.4; n = 27). Mean serum resistin in each population illustrated by a line. Insulin-resistant obese subjects (HOMA 5.0) illustrated with black diamonds.

View larger version (52K): [in this window] [in a new window]   FIG. 2. Western blot for resistin in human adipose tissue, isolated adipocytes and serum. A, Resistin is detectable in sc adipose tissue and isolated adipocytes of an obese subject (BMI 37.5 kg/m2) as an approximately 11-kDa band that comigrates with recombinant human resistin. B, In serum from lean (L) and obese (O) subjects resistin is also detected as a band of approximately 11 kDa that comigrates with recombinant human resistin. Note that there is no difference in the density of the nonspecific band above the resistin band demonstrating equal protein loading.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study, we examined resistin protein in human serum using two different techniques. By both methods we found that resistin protein was present in human serum and that it was significantly increased in obese subjects. In multiple regression analysis, BMI was a significant predictor of insulin resistance measured as HOMA score. Overall these findings demonstrate that resistin protein is increased in the serum of obese humans but that there is no significant contribution of resistin, adjusted for adiposity, to insulin resistance in humans.

Steppan et al. (1) demonstrated that resistin was increased in three different murine models of obesity-related diabetes. These investigators further suggested that resistin could cause insulin resistance based on the following observations: 1) in obese diabetic mice, antiresistin IgG induced a small but significant reduction in blood glucose and improved insulin sensitivity determined by insulin tolerance test; 2) ip recombinant resistin increased peak glucose 28% during a glucose tolerance test in normal weight C57Bl/6J mice; and 3) antiresistin IgG potentiated insulin-stimulated glucose uptake 42%, and recombinant resistin reduced insulin-stimulated glucose uptake 37%, in 3T3-L1 adipocytes. Taking these findings together, Steppan et al. (1) concluded that resistin is a strong candidate to explain the mechanism by which excess adiposity leads to insulin resistance. However, controversy exists over a role for resistin in obesity-related insulin resistance in rodent models. Way et al. (12) have reported that adipose tissue resistin mRNA is decreased in ob/ob, db/db, tub/tub, and KKA^y mice and that rosiglitazone treatment increases resistin expression in ob/ob mice and ZDF rats. Levy et al. (13) concluded that resistin did not play a role in the insulin resistance characteristic of young Fischer 344 rats, based on their finding of no difference in resistin expression in the epididymal fat pad of Fischer 344 rats compared with age-matched, insulin-sensitive Sprague Dawley rats. Although observations from these two groups therefore do not support a role for resistin in insulin resistance, more recently Rajala et al. (14) have reported that acute increases (2- to 15-fold) in serum resistin in rats result in severe hepatic insulin resistance and increased hepatic glucose output during physiologic insulin infusion. There was no effect of resistin on peripheral tissue insulin sensitivity in this study (14).

To add to the controversy over the role of resistin in insulin resistance, we (6), and others (7, 8) have previously reported that resistin mRNA in human adipocytes is low and that resistin expression did not correlate with BMI as might be expected for a factor linking obesity to insulin resistance. In the current study, we found that resistin protein was present in human adipocytes, but that expression was lower than that for an equivalent amount of adipose tissue protein. This finding supports our previous observations on resistin mRNA expression and suggests that resistin expression in adipose tissue is a combination of that from adipocytes and from other cells in the tissue. In agreement with this interpretation, McTernan et al. (9) reported that resistin protein was present in both adipocytes and stromal vascular cells of the adipose tissue. It is important to point out that in our study of resistin mRNA expression, and those of others, adipose tissue samples were taken after an overnight fast. Fasting has been shown to reduce adipose tissue resistin expression in rodents (1, 2), and a fasting-induced reduction in resistin mRNA may explain the lack of correlation between resistin mRNA and BMI. In the current study, serum resistin protein was readily detectable in human adipose tissue after the overnight fast, which could be explained by a slower turnover of resistin protein compared with resistin mRNA. Additional work will be needed to understand the relationship between resistin mRNA expression and protein synthesis and release from the adipose tissue and other cells.

In the current study, we found that serum resistin protein was significantly increased in obese subjects, although the correlation between resistin and BMI was weak (Spearman’s correlation coefficient = 0.37). In agreement with this finding, Yannakoulia et al. (15) recently reported that serum resistin was weakly correlated (Spearman’s correlation coefficient = 0.25; P < 0.01) with body fat in young, healthy Greek students. Yannakoulia et al. (15) also found that serum resistin was higher in females than males after adjustment for body fat mass. Our study is not balanced with respect to distribution of gender and adiposity; therefore, we cannot confirm or refute a gender difference in resistin. The contribution of gender to serum resistin levels will need to be addressed in future work with a more balanced study design. Although serum resistin and HOMA score were weakly correlated in bivariate analysis (Spearman’s Correlation Coefficient = 0.33), in multiple regression analysis, resistin adjusted for BMI was not a significant predictor of HOMA score. Our findings in humans, therefore, do not support the hypothesis that resistin is a strong link between obesity and insulin resistance. However, it is important to note that in our study with only 77 subjects the power to detect a significant effect of resistin in the multiple regression analysis with covariate BMI and = 0.05 is only 29%. It is therefore possible that the predictive value of serum resistin to HOMA score would improve in a larger study population with greater power. In support of our finding that resistin does not contribute to insulin resistance in obesity, resistin was not associated with insulin resistance in 30 normal weight patients with renal disease (16) or in 18 obese subjects with acromegaly (17). Finally, inspection of Fig. 1 shows that many obese insulin-resistant subjects have serum resistin concentrations that are not different (7 ng/ml or less) from that in lean subjects. Therefore, increased serum resistin may play a role in, or be a marker for, insulin resistance in a specific population of obese subjects in which it is elevated.

In summary, resistin protein is present in human adipose tissue and blood. Serum resistin protein is greater in obese subjects but is not a significant predictor of insulin resistance when adjusted for adiposity. Further work will be needed to fully elucidate the role of resistin in insulin resistance in humans.

	Acknowledgments

 
The authors thank Simeon Taylor, M.D. (Eli Lilly Inc.), for helpful insight and comments on the manuscript, and Helena Caffrey (Indiana University) for assistance with the statistical analyses.

	Footnotes

 
This work was supported by a grant from the American Diabetes Association (to R.V.C.) and the NIH (General Clinical Research Center M01RR000750; Indiana University Diabetes Research and Training Center Physiology Core and Biostatistics Core P60DK20542).

Abbreviations: ADSF, Adipocyte secreted factor; BMI, body mass index; FIZZ, found in inflammatory zone; HOMA, homeostasis model assessment of insulin resistance.

Received November 18, 2002.

Accepted August 14, 2003.

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