Human resistin has been stated to influence preadipocyte cell numbers and to stimulate adipocyte triglyceride lipolysis in vivo and in vitro. However, its role in human obesity remains unclear.
Cross-sectional study for comparisons of lean and obese subjects, and subsequent longitudinal 4-month weight loss intervention study in obese subjects.
Healthy subjects, lean (n=20, BMI<25) and overweight (n=43, BMI⩾25).
Serum resistin, body weight, body fat, waist-to-hip ratio, as well as markers of insulin resistance and lipid metabolism at baseline and after 4 months of intervention.
Serum resistin was positively correlated to HOMA-IR (partial r=0.288; P=0.055), serum fructosamines (partial r=0.280; P=0.062), serum NEFA (partial r=0.276; P=0.066) and negatively to age (partial r=−0.349; P=0.019) and serum apolipoprotein A-1 (partial r=−0.363; P=0.014). During the intervention, serum resistin increased significantly (P<0.001). The increase was inversely related to changes in waist-to-hip ratio (P=0.025) and positively to serum apolipoprotein B (P=0.011). In males only, the increase in resistin during weight loss was predicted by total serum cholesterol at baseline (r=0.703, P=0.007). No relation was observed between changes in resistin and changes in HOMA-IR.
The present study indicates an association between serum resistin and markers of abdominal fat distribution as well as the regulation of lipid metabolism. However, human resistin is unlikely to play an independent role in the regulation of glucose metabolism.
Adipose tissue is the major energy depot and plays an important role in the regulation of glucose metabolism. Resistin, also called adipose tissue-specific secretory factor (ADSF) or Found in Inflammatory Zone (FIZZ3) is a hormone, which is secreted by adipose tissue cells in rodents and has been linked to insulin resistance. In humans, resistin is mainly expressed in macrophages which may infiltrate adipose tissue in obesity.1, 2 Recent studies do not suggest a major role of resistin in the regulation of glucose metabolism and insulin resistance in humans. Circulating resistin was reported to be elevated in human obesity in some,3, 4, 5 but not in all studies.6, 7, 8 Positive correlations of circulating resistin and insulin resistance9, 10 could not be confirmed in other studies.7, 11 These findings suggest that the role of resistin in the etiology of obesity and insulin resistance in humans – if there is any – is much more complex than in mice and other rodents.12 Given the low homology of mice and human resistin of about 59%,13 the physiological role of human resistin might differ from those in mice.14 Very recently, it has been shown that human resistin stimulated preadipocyte proliferation and triglyceride lipolysis in vitro and in vivo.2 In contrast, mouse resistin inhibited adipocyte differentiation and did not affect preadipocyte proliferation or lipolysis. Resistin in humans has also been linked to inflammatory processes and atherosclerosis.15, 16, 17, 18, 19
Weight loss and caloric restriction have been shown to improve insulin resistance and lipid profiles.20, 21, 22, 23, 24 The aim of the present study is to investigate the possible associations between resistin, body weight, glucose and lipid metabolism. We compared lean and overweight adults with respect to anthropometric measurements, plasma glucose, insulin, lipids, and nonesterified fatty acids (NEFA). We also investigated how these parameters relate to serum resistin levels. During a subsequent weight loss intervention among overweight subjects the medium-term effects of weight loss on serum resistin concentrations were examined. Furthermore, the relation of resistin to changes in other biomarkers was tested to confirm the associations observed in the cross-sectional study.
Subjects and study design
Overweight to obese adult subjects (n=50) with a body mass index (BMI) >25 kg/m2 were recruited via advertisements in local newspapers and consecutively enrolled in a dietary intervention program to reduce body weight during a 4-month period. Blood samples were available from 43 overweight subjects. Normal weight subjects with a BMI <25 kg/m2 were also recruited via advertisements and were used as controls (n=20).
Pregnant and lactating women were excluded. Other exclusion criteria were extreme sports, asthma, epilepsy, and cardiovascular diseases and skin/allergies. One overweight subject did not complete the study due to lack of interest. The Ethics Committee of the University of Potsdam approved the study protocol. All participants gave written informed consent.
Dietary and physical activity intervention
Nutritional consulting was provided for a time period of 16 weeks, weekly during the first 8 weeks and biweekly for another 8 weeks. According to dietary instructions recommended by the German Nutrition Society (www.dge.de), the study participants were instructed on how to reduce the dietary fat intake and to enhance vegetable and dietary fiber consumption in an ad libitum fashion. For enhancing total energy expenditure, the study participants were advised on how to increase physical activity level during their daily routine (taking stairs instead of escalators, standing during a telephone call instead of sitting). Walking, light jogging, and gymnastics were recommended as programmed sports activities.
Subjects entered the study center between 0700 and 0800 h. after an overnight fast of at least 10 h. Only little physical activity was allowed in the morning. With light underwear and empty bladder, the body weight was assessed using an electronic calibrated scale to the nearest 0.1 kg (Soehnle, Murrhardt, Germany). Height was determined with a GPM anthropometer (Siber & Hegner, Zurich, Switzerland) to the nearest 0.1 cm. Body mass index (BMI) was calculated as body weight (kg)/height (m)2. Body fat and lean body mass were measured by air displacement plethysmography (Life Measurement Inc., Concord, CA, USA).
The food consumption of the study participants was assessed by a semiquantitative, self-administered food record for four consecutive days before the beginning of the intervention and after 4-months. Trained staff delivered the record and subjects were instructed to record their entire food intake at the time of the consumption. The food record consisted of a food list containing 270 food items, subdivided into 27 food groups. For every food item, both typical household measures and the corresponding portion size are provided. The coding of nutrient and energy intake was carried out on the basis of the German Food Code and Nutrient Data Base BLS II.3.25 The accuracy and validity of energy intake estimated by the food record was validated against total energy expenditure estimated by doubly labeled water technique.26
Blood samples were taken after an overnight fast. The samples were collected in ethylendiamine tetraacetic acid (EDTA)-coated polypropylene tubes kept on ice, centrifuged immediately at 1800 × g for 20 min at 0°C, and the clear plasma supernatant was then stored until analyzed. For serum analyses, blood was collected in tubes containing a serum clot activator and allowed to clot. All plasma and serum samples of one subject were analyzed in the same batch.
Serum resistin levels were measured by sandwich enzyme-linked immunosorbent assay (Biovendor Laboratory Medicine Inc., Palackeho, Czech Republic). The intra-assay coefficient of variation (CV) was 3.4% and the inter-assay CV 5.6%. The serum leptin was analyzed using Human Leptin RIA Kit (Linco Research, St Charles, Missouri 63304, USA). The intra-assay CV was 3.9% and the inter-assay CV was 4.0%. Plasma glucose was measured in duplicate by hexokinase method using commercially available colorimetric reagents (ADVIA® 1650 Chemistry System, GLUH, Bayer, Leverkusen, Germany) with an intra- and inter-assay CV of 1.2 and 2.2%, respectively. Serum insulin was determined by ADVIA Centaur Immunoassay (Bayer, Leverkusen, Germany) with an intra- and inter-assay CV of 2.6 and 3.2%, respectively. Homeostasis Model Assessment Insulin Resistance (HOMA-IR) was calculated as fasting insulin (IU/l) × fasting glucose (mmol/l)/22.5. Plasma triglycerides were analyzed on using enzymatic colorimetric agents TRIG for ADVIA® Chemistry System 1650 (Bayer, Leverkusen, Germany). The intra- and inter-assay CVs were 1.2 and 1.7%, respectively. Serum nonesterified fatty acids (NEFA) were analyzed using ACS-ACOD-MEHA (Wako Chemicals, Neuss, Germany) on an ADVIA® Chemistry System 1650 (Bayer, Leverkusen, Germany) with an inter-assay CV of 2.7%.
Serum fructosamines were determined according to a method of Johnson et al. (1983) using Roche FRUC reagents (Roche Diagnostics GmbH, Mannheim, Germany). The intra- and inter-assay CVs were 0.9 and 1.9%, respectively. Total serum cholesterol was analyzed using CHOD-PAP method (Roche Diagnostics GmbH, Mannheim, Germany) with an intra- and inter-assay CV of 0.8 and 1.7%. Apolipoprotein A-1 und B were measured by a immunoturbimetrical method using Turbiquant® reagents (Dade Behring GmbH, Marburg, Germany) with an intra-assay CV of 2.6 and 1.3, and an inter-assay CV of 2.8 and 3.2%, respectively.
All data are shown as mean and standard error (s.e.). Dietary data are presented as median and percentiles 25 and 75; dietary changes were tested by performing Wilcoxon rank test. Adiponectin and leptin data were log-transformed due to skewed distributions. Two-factorial ANOVA models were used to compare lean and obese subjects with simultaneous adjustment for gender and age. Normal distribution of residuals of all ANOVA models was approved. To estimate changes during weight loss intervention in overweight subjects, Student's t-test was used. Zero order and partial correlations were calculated and Pearson's coefficient of correlation is presented. For multiple regression analysis, separate models were fitted for anthropometric measures and biomarkers of glucose metabolism using variables shown to be of interest during correlation analysis only (dimension reduction). The statistical models did not consist of more than six (cross-sectional) and four (intervention) variables. Normal distribution of residuals of all regression models was approved. The statistical analyses were performed using SPSS for Windows 12.0 (SPSS Inc., Chicago, IL, USA).
Cross-sectional differences in serum resistin concentrations in lean and overweight subjects
Lean and overweight subjects differed significantly in age and slightly in gender (Table 1). After adjustment for age and gender, lean and overweight subjects differed in BMI, waist circumference and waist-to-hip ratio. They also differed in serum leptin, serum apolipoprotein B, serum insulin and HOMA-IR, but were not significantly different in resistin levels.
Serum resistin levels were marginally higher in females than in males (3.9±0.2 vs 3.5±0.2 ng/ml; P=0.062). In females, serum resistin decreased with age (r=−0.473, P=0.041) independent of body weight. In premenopausal women (n=22), serum resistin was higher than in postmenopausal women (n=20; 4.1±0.3 vs 3.4±0.2 ng/ml; P=0.049).
In a multiple linear regression analysis, serum resistin was best predicted by age with a β coefficient of −0.032 ng/ml per year (partial r=−0.349; P=0.019), HOMA-IR and fructosamines with a β coefficient of 0.090 ng/ml per unit HOMA-SI (partial r=0.288; P=0.055) and 0.009 ng/ml per unit fructosamines (μmol/l; partial r=0.280; P=0.062), serum NEFA with a β coefficient of 0.014 ng/ml per unit NEFA (μmol/l; partial r=0.276; P=0.066), and serum apolipoprotein A-1 with a β coefficient of −0.014 ng/ml per unit apolipoprotein A-1 (partial r=−0.363; P=0.014 and with Radj2=0.268; P=0.016). After inclusion of body mass index as a measure of adiposity, the relation between serum resistin and other markers remained significant with similar β coefficients.
No clear association was observed between serum resistin and macronutrient intake in lean subjects. In overweight subjects, the consumption of carbohydrates expressed as % energy was positively related to serum resistin (r=0.408, P=0.025) with a β coefficient of 0.050 ng/ml per unit carbohydrates (data not shown).
Changes in serum resistin concentrations during the ad libitum weight loss intervention
The mean reported energy intake failed to decrease significantly (Table 2), although most subjects reduced body weight (Table 3). A significant decrease in the percentage of energy consumed as fat and an increase in the percentage of energy consumed as carbohydrates and protein was observed. During the weight loss intervention, on average overweight subjects lost 4.5±0.6 kg body weight and 3.3±0.6% body fat. Weight loss was similar in both genders. In one subject, a weight gain of 1.7 kg was observed. In five subjects the weight reduction was <1 kg.
Serum resistin increased significantly, whereas serum insulin decreased (Table 3). Increase in serum resistin tended to be higher in females (Δ serum resistin 0.72±0.17 ng/ml) than in males (0.28±0.15 ng/ml, P=0.069). HOMA-IR and fasting plasma glucose decreased only marginally. A significant decrease was also observed in serum leptin and total cholesterol. Triglycerides, apolipoprotein A-1 and B remained unchanged, whereas serum NEFA decreased slightly.
Changes in serum resistin were not related to age or to changes in plasma glucose and serum insulin concentrations or HOMA-SI. Decrease in serum leptin and NEFA was neither associated with changes in serum resistin. Baseline serum resistin was inversely associated with changes in serum resistin (r=−0.447, P=0.013), indicating an increase in serum resistin in subjects with low levels at baseline.
In a multiple linear regression model adjusted for baseline serum resistin concentrations, changes in serum resistin were explained by markers of fat distribution. Serum resistin increased by 0.021 ng/ml per unit of waist circumference at baseline (P=0.059) and by 6.02 ng/ml per unit of decrease in waist-to-hip ratio during weight loss intervention (P=0.025; Figure 1). This model explained 40% of the variation in serum resistin changes (P=0.001). Changes in serum resistin were also related to changes in serum apolipoprotein B (r=0.424; P=0.011; Figure 1). This association was independent of changes in either waist-to-hip ratio or body weight. Changes in serum resistin and changes in other markers of lipid or glucose metabolism were unrelated.
In males, but not in females, total serum cholesterol and changes in serum resistin were highly correlated (r=0.703, P=0.007; Figure 2), independent of changes in body weight, fat mass, waist and hip circumferences or waist-to-hip ratio.
In the present study, we compared serum resistin concentrations and markers of glucose and lipid metabolism between lean to overweight subjects. We further investigated changes of these parameters during a 4-month intervention of subsequent weight loss in overweight individuals. The results of the study did not indicate an independent association between resistin and insulin resistance in humans. After the 4-month weight loss intervention with a mean weight reduction of 4.5 kg, serum resistin significantly increased. This increase cannot be explained by the physiological understanding of resistin action derived from mice experiments, where a strong relationship between adiposity, insulin resistance and resistin was observed.9, 13, 27
Similar to other human and rodent studies4, 7, 28, 29, 30, 31 our findings indicate that resistin levels were slightly higher in females than in males and decreased with age. Resistin concentrations were not significantly different between lean and overweight subjects. The lack of differences in serum resistin levels between lean and overweight subjects does not support the hypothesis that human resistin is originated from adipose tissue. Indeed, it has been shown that human resistin is mainly expressed by macrophages and not by adipocytes.1 Some cross-sectional human studies failed to show differences in resistin expression between lean and obese subjects6, 7, 31 while others observed a direct association between resistin and markers of adiposity.3, 10, 32 Also, human intervention studies produced inconsistent results with respect to changes in body weight or other measures of adiposity. Studies on weight reduction show contradictory findings. Some investigators observed a decrease in serum resistin during weight loss5, 10 or an increase during weight gain,32 while others reported no changes in serum resistin.33, 34
In the present study, serum resistin was positively correlated to serum fructosamines and HOMA-SI. Nevertheless, favorable changes in markers of glucose metabolism and insulin resistance during weight loss were not related to changes in serum resistin during the intervention. These results do not indicate a crucial role of resistin in the development of insulin resistance in humans which is in accordance with other human studies.3, 7, 30, 35, 36 Changes in resistin were related to both waist circumference at baseline and changes in waist-to-hip ratio, indicating an increase in resistin expression despite favorable changes in markers of adiposity in subjects with a higher waist circumference. This increase in resistin occurred despite beneficial effects of the intervention on many other metabolic markers such as serum insulin and total serum cholesterol.
Very recently, human resistin has been linked to lipid metabolism. In rats, resistin expression seems to be inhibited by NEFA.37 Human resistin has also been shown to stimulate lipolysis and reduce the size of cellular lipid droplets in mature adipocytes.2 Acute administration of human resistin led to a significant increase in serum glycerol concentrations, but not in serum NEFA.2
In the present study, serum resistin was positively related to serum NEFA and inversely to apolipoprotein A-1. In males, total serum cholesterol was inversely associated with serum resistin. Changes in serum resistin during weight loss intervention were positively related to changes in apolipoprotein B, although it has to be noted that overall changes in this apolipoprotein during intervention were not significant. In males only, total serum cholesterol concentration at baseline was also a strong predictor of changes in serum resistin during weight loss with the highest increase in resistin levels in those with high-baseline serum total cholesterol.
Plasma apolipoproteins play a major role in the synthesis, processing and removal of plasma lipoproteins. Apolipoprotein A-I is the major apolipoprotein associated with high-density lipoprotein (HDL) cholesterol and is stated to have protective effects for acute myocardial infarction.38 Therefore, the results of the present study are consistent with another study observing an inverse relation between HDL cholesterol and resistin.39
Apolipoprotein B exists in two isoforms: apo B-48 is synthesized in the gut and is present in chylomicron particles together with dietary triglycerides and free cholesterol, while apo B-100 is synthesized in the liver and is present in low-density-lipoprotein (LDL), intermediate-density-lipoprotein (IDL) and very-low-density-lipoprotein (VLDL) particles. Apolipoprotein B is a risk factor for acute myocardial infarction.38, 40 The regulation of hepatic VLDL secretion mainly depends on apolipoprotein B synthesis, and the availability of triglycerides, NEFA and cholesterol.41 In humans, an increase in serum NEFA stimulates VLDL production.42 These data suggest that resistin might be involved in lipid metabolism by enhancing lipolysis, resulting in an increase in serum NEFA and apolipoprotein B.
The absence of correlations between total cholesterol and resistin in females might be explained by a putative regulation of resistin by estrogen as it was reported in mice.43 Estrogen downregulated resistin expression in mice adipocytes43 while circulating resistin was also higher in female mice compared to male mice.28
Recent studies suggest that human resistin may act as a regulator of lipid metabolism in order to maintain adipose tissue stores and induce re-esterification of fatty acids.2 In cell studies, resistin has been shown to regulate NEFA uptake in muscle cells.44 Our results also suggest an association between resistin and lipid metabolism and may contribute to the growing evidence, that resistin in humans might be a cardiovascular risk factor. In humans, resistin is positively associated with levels of inflammatory markers36 and predicts coronary artery calcification.17 Human resistin has also been shown to stimulate pro-inflammatory cytokines and is secreted from macrophages in atheromas.15, 16, 45
Possible limitations of this study warrant consideration when interpreting the observed findings. Our results on resistin, markers of glucose and lipid metabolism are based on a small sample size and need to be confirmed in larger studies. Nevertheless, the associations found at baseline in the cross-sectional study were mainly consistent with those observed during the intervention study, and suggest a role of resistin in lipid rather than in glucose metabolism in humans. The study was somewhat unbalanced with respect to age and gender. This limitation was addressed by stratification and controlling for age and gender effects. However, we cannot finally exclude an confounding influence of these factors. In addition, weight loss intervention during the present study was based on nutritional counseling and an ad libitum and self-directed diet. Future studies with a controlled dietary composition instead of an ad libitum diet, controlled especially with respect to fat and carbohydrate content, are necessary to further explore the increase in resistin concentrations observed in this study and to identify nutritional components inducing a resistin increase during weight loss.
In conclusion, the present study does not provide evidence that resistin is independently associated with obesity or obesity-related metabolic disorders in humans. Furthermore, human resistin is unlikely to modulate insulin sensitivity. However, in contrast to mouse resistin, human resistin might have functions linking lipid metabolism, inflammation, and atherosclerosis.
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This study was carried out with financial support from the Commission of the European Communities, BodyLife IST-2000-25410, specific RTD programme ‘User-friendly Information Society’. It does not necessarily reflect its views and in no way anticipates the Commission's future policy in this area.
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Koebnick, C., Wagner, K., Garcia, A. et al. Increase in serum resistin during weight loss in overweight subjects is related to lipid metabolism. Int J Obes 30, 1097–1103 (2006) doi:10.1038/sj.ijo.0803242
- weight loss
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