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Pennington Biomedical Research Center (L.K.H., J.R., L.J., E.R., S.R.S.), Baton Rouge, Louisiana 70808; Obesity Research Center, St. Luke’s Roosevelt Hospital (J.B.A.), New York, New York 10025; and Department of Medicine, University of Pittsburgh (D.E.K.), Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Dr. Steven Smith, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail address: smithsr{at}pbrc.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionConclusionReferences |
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Introduction |
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, and resistin (1). Resistin was recently identified during an in vitro screening for genes up-regulated during adipocyte differentiation and down-regulated by peroxisome proliferator-activated receptor 
agonists (2). Further research by this group revealed that serum resistin and resistin mRNA expression from adipose tissue were increased in obese mouse models, increased by a high fat diet, and decreased by rosiglitazone treatment. Furthermore, blocking resistin (by specific antibodies), reduced 2-deoxyglucose uptake in 3T3-L1 cells, and ip administration of resistin increased peak blood glucose levels after a glucose tolerance test (2). Taken together, these results led to the hypothesis that resistin promotes insulin resistance. Two other groups independently identified resistin (3, 4). Kim et al. (3) observed that resistin inhibited adipocyte differentiation by 80% in 3T3-L1 cells. This suggests that resistin may promote insulin resistance by increasing the storage of triglycerides in muscle and liver instead of adipose tissue. Indeed, failure of adipocyte differentiation has been proposed as a cause of type 2 diabetes, possibly through an ectopic overload of fatty acids and lipotoxicity of nonadipose tissues (5, 6).
Other groups have observed the opposite results of these initial findings (2), showing that resistin expression was down-regulated in rodent models of obesity (7, 8, 9), suppressed by free fatty acids (10), and stimulated by peroxisome proliferator-activated receptor agonists (7). Thus, evidence that supports resistin as a mediator of insulin resistance remains highly controversial.
In humans, the role of resistin in regulating insulin sensitivity is also unclear. Serum resistin was related to fat mass (by bioelectrical impedance analysis) in young, healthy subjects and was significantly higher in women than in men (11). However, in another group of younger lean individuals or middle-aged overweight individuals, resistin was not related to body mass index (BMI), percent body fat, or insulin sensitivity, as determined by homeostasis model assessment (12). Resistin mRNA expression was shown to be higher in morbidly obese subjects compared with lean control subjects, although no association was observed with BMI (13). Increased expression of resistin was also found in abdominal depots (sc, n = 19; omental, n = 10) compared with thigh depots (n = 9), suggesting increased risk for type 2 diabetes due to central obesity and higher resistin (14). However, abdominal/gluteal resistin mRNA expression was not different in a larger cohort of 58 nondiabetic subjects (15).
The goals of this study were 1) to determine the relationship between serum resistin and insulin sensitivity, fat distribution, fat cell size (a marker for adipocyte differentiation), and ectopic fat deposition in subjects with wide variations in adiposity and insulin sensitivity, including subjects with type 2 diabetes; and 2) to determine the relationship between serum resistin and resistin expression from abdominal sc adipocytes.
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Subjects and Methods |
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Study 1
Twelve obese, but otherwise healthy, subjects were matched by age, sex, and BMI to 22 obese subjects with well controlled type 2 diabetes [must have had fasting glucose concentrations <180 mg/dl and not be receiving insulin or thiazolidinedione therapy to qualify for the study, which is an ancillary study of the Look AHEAD trial (16)]. Subjects were admitted to the in-patient unit and fed a standard dinner at 1800 h. The following morning, adipose tissue was collected by needle biopsy (superficial sc adipose tissue lateral to the umbilicus) to determine fat cell size. Fasting blood samples were taken, and participants underwent a 3-h hyperinsulinemic clamp to assess insulin sensitivity. Blood samples were drawn again at the end of the clamp. Fat distribution and ectopic fat deposition were determined by computed tomography (GE, High Speed Plus, General Electric, Fairfield, CT). Visceral adipose tissue was measured by multislice computed tomography (CT) scanning as previously described (17). Fat area and muscle attenuation characteristics of midthigh were also measured (x-ray attenuation value, Houndsfield units) (18). Liver fat was measured by CT scanning with splenic CT attenuation values, determined as an intrascan control and for the purposes of expressing values for liver fat as the ratio of liver to spleen CT attenuation values (19).
Study 2
Thirty-eight nonobese, nondiabetic subjects were fed a standard diet (35% fat) for 3 d. Subjects arrived at the in-patient unit at 0630 h after a 12-h fast, and serum samples were drawn. Abdominal sc adipose tissue was collected to determine fat cell size, followed by a hyperinsulinemic clamp to assess insulin sensitivity. Subjects were then fed a high fat diet for 3 d (50% fat by energy), and fasting blood samples were redrawn. In both studies 1 and 2, body composition (QDR 4500A, Hologics, Inc., Bedford, MA) was determined within 3 d of the clamp.
Study 3
Fifty-six healthy obese subjects participated in this study (BMI range, 27.1–42.3 kg/m2). After a 12-h fast, abdominal sc adipose tissue (to measure resistin mRNA expression) and blood samples (to measure serum resistin) were collected.
Hyperinsulinemic-euglycemic clamp
An iv catheter was placed in an antecubital vein for infusion of insulin (Humulin, Eli Lily & Co., Indianapolis, IN) and glucose (Dextrose 20, Baxter, Deerfield, IL). A second catheter was placed retrograde in a dorsal vein of the contralateral hand for blood withdrawal. The hand was placed in a heating pad for arterialization of venous blood. Three blood samples were collected before a primed continuous insulin infusion (80 mU/m2·min) was started. Arterialized glucose was measured at 5-min intervals (YSI, Inc., Yellow Springs, OH), and a variable infusion of exogenous glucose was given to maintain glucose concentrations. Glucose was clamped at 100 mg/dl (study 1) and 90 mg/dl (study 2).
Fat cell size
Fat cell size was determined as previously described (20). Briefly, adipose tissue was fixed in osmium tetrachloride/collidine-HCl after disassociation by urea digestion. Cells were counted on a Multisizer-3 (Beckman Coulter, Fullerton, CA) using a 400-µm aperture (dynamic linear range, 12–320 µm). Adipocyte cell number (cells per milligram wet weight of tissue) was then determined from the amount of sample (milliliters), the quantity of cells (per milliliter), and the tissue weight (milligrams).
Resistin mRNA in adipose tissue
Total RNA was isolated from 50 mg frozen tissue using TRIzol (Life Technologies, Gaithersburg, MD). The primer-probe set and methods for amplification of human resistin mRNA were described previously (15). Briefly, forward primer (5'-AGCCATCAATGAGAGGATCCA-3'), reverse primer (5'-TCCAGGCCAATGCTGCTTA-3'), and the probe (5'-6-carboxyfluorescein-TCGCCGGCTCCCTAATATTTAGGGCA-bhq-1–3'; Biosearch Technologies, Inc., Novato, CA) were designed, and resistin mRNA levels were normalized to cyclophilin mRNA levels.
Biochemical analysis
Serum resistin was measured in duplicate using a commercially available kit (BioVendor, Brno, Czech Rebublic; intra- and interassay coefficients of variation, 4.3 and 7.2%, respectively). The antibodies in the ELISA have no detectable cross-reactivity to mouse resistin or other cytokines in human serum. Glucose was analyzed using a glucose oxidase electrode (Syncron CX7, Beckman, Brea, CA). Insulin was measured using an immunoassay (DPC 2000, Diagnostic Products Corp., Los Angeles, CA).
Statistical analysis
All data are presented as the mean ± SD. Statistics were performed using SPSS for Windows version 11.0.1. Correlations were performed using Pearson’s correlation coefficient. Differences between groups were compared by one-way ANOVA. The glucose disposal rate was normalized for fat-free mass. Due to differences in methodology of the hyperinsulinemic clamp (duration and glucose concentrations), subjects from studies 1 and 2 were analyzed separately. Resistin was log-transformed to normalize distribution.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConclusionReferences |
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. Briefly, nondiabetic and diabetic subjects from study 1 were well matched with respect to age, weight, BMI, and percent fat. As expected, fasting glucose was lower, and glucose disposal rate was higher in nondiabetic subjects. Subjects from study 2 were younger than subjects from study 1 (P < 0.001) and had significantly lower fasting insulin concentrations than the obese diabetic subjects from study 1 (P < 0.05). Despite wide variations in adiposity and insulin sensitivity across groups, serum resistin concentrations were not different among nonobese (4.1 ± 1.7 ng/ml), obese (4.2 ± 1.6 ng/ml), and diabetic subjects (3.7 ± 1.2 ng/ml). Furthermore, serum resistin was not related to percent body fat in either males or females. However, serum resistin was negatively related to glucose disposal rate in nonobese subjects (Fig 1A; r = –0.35; P = 0.05), although this association was no longer significant after adjusting for percent body fat (P = 0.22). We repeated the analysis after removing an outlier (unremarkable, slightly overweight male, aged 20 yr, with glucose and insulin concentrations within normal ranges). Removing this observation from the analysis reduced the significance of the finding before and after adjusting for percent fat (P = 0.06 and P = 0.19). Serum resistin was not related to insulin sensitivity in obese and obese diabetic subjects (r = 0.02; P = 0.7). In nonobese men only, we observed a direct relationship between fasting insulin and resistin (r = 0.42; P = 0.04). However, serum resistin was not different between men and women, and other associations (when present) were similar between men and women. Serum resistin was not associated with fat cell size, im fat, intrahepatic fat, or fasting glucose (correlation coefficients ranged from r = 0.05–0.28; all P > 0.2). Serum resistin was modestly increased after 3 h of insulin infusion (measured only in subjects from study 1; n = 34; P = 0.05; Fig. 2A), but was unchanged after 3 d of high fat feeding (measured only in subjects from study 2; n = 38; P = 0.13; Fig. 2B). Resistin mRNA expression levels were measured only in subjects from study 3 (17 women and 39 men, all nondiabetic, 42 ± 11 yr, 97.2 ± 13.8 kg, 32.4 ± 3.7 kg/m2). We observed that fasting serum resistin concentrations were directly related to the adipose expression levels of resistin (Fig. 3; r = 0.62; P < 0.001).
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Discussion |
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Serum resistin concentrations were increased in response to supraphysiological doses of insulin (steady state insulin averaged 164 ± 5 mU/ml). This effect was modest and was only measured in obese and obese diabetic subjects, but suggests that resistin expression may be acutely regulated by insulin. It implies that subjects with higher fasting insulin concentrations will have higher serum concentrations of resistin. However, this relationship was only observed in nonobese men and thus may be masked in subjects with increased fat mass. Previous reports have found that the infusion of insulin increases the expression of resistin in Zucker rats and streptozotocin-induced diabetic mice (3, 7). However, in 3T3-L1 adipocytes physiological concentrations of insulin decreased resistin expression (25). We did not find an acute effect of high fat diet on serum resistin concentrations in nonobese humans. This contrasts the results observed in mice fed a high fat diet (2), but this diet was implemented for a longer time period (8 wk vs. 3 d).
We also observed that serum resistin was highly correlated to sc abdominal mRNA expression of resistin. Two other groups were unable to consistently detect resistin mRNA from human sc adipose tissue (26, 27), suggesting that resistin expression from adipose tissue was due to the presence of mononuclear cells. However, McTernan et al. (14) conclusively showed that resistin mRNA expression and protein were detectable in sc and visceral abdominal adipocytes from lean and obese subjects and that expression was approximately 3-fold higher in preadipocytes compared with mature cells. Despite a strong correlation between serum concentrations and mRNA expression in the present study, we did not observe a correlation between serum resistin and percent body fat in nonobese, obese, or obese diabetics (or sc abdominal fat in obese and obese diabetics), indicating that resistin is not related to adiposity. However, nonobese subjects were significantly younger than our obese group, and this (or some other correlate of youth, such as physical fitness) could have affected the results. This result does contrast with a previous report in young, nonobese subjects (11), but is supported by a recently published study of more than 240 young and middle-aged subjects (12).
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Footnotes |
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Abbreviations: BMI, Body mass index; CT, computed tomography.
Received August 12, 2003.
Accepted December 19, 2003.
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action in humans. Diabetes 50:2199–2202
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