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DOI: 10.1530/EJE-08-0521
European Journal of Endocrinology, Vol 159, Issue 6, 713-718
Copyright © 2008 by European Society of Endocrinology
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CLINICAL STUDY

Plasma pigment epithelium-derived factor is positively associated with obesity in Caucasian subjects, in particular with the visceral fat depot

Ping Wang*, Egbert Smit*, Martijn C G J Brouwers1, Gijs H Goossens, Carla J H van der Kallen1, Marleen M J van Greevenbroek1 and Edwin C M Mariman

Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands1 Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

(Correspondence should be addressed to E C M Mariman; Email: e.mariman{at}hb.unimaas.nl)

* (P Wang and E Smit contributed equally to this work) Back


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Objective: Adipose tissue releases factors (adipokines) that influence local, peripheral as well as central processes. In the present study, we determined the relationship between plasma concentration of a recently identified adipokine, pigment epithelium-derived factor (SERPINF1), and human obesity, particularly specific adipose tissue depots, and other features of the metabolic syndrome.

Methods: We examined the plasma concentration of SERPINF1, anthropometric parameters, abdominal s.c. and visceral adipose tissue, lipid, glucose, insulin, and alanine aminotransferase level in a non-diabetic general Caucasian population (n=59).

Results: Plasma SERPINF1 level in males (6.2±2.1 µg/ml) was higher than in females (3.1±1.4 µg/ml; P<0.001). Plasma SERPINF1 was positively correlated with age and all features of metabolic syndrome. However, in multiple linear regression analysis with adjustment for age and gender, only visceral fat thickness (β=0.361, P=0.010) and body mass index (β=0.288, P=0.008) were significant independent determinants of plasma SERPINF1 level, together with gender (β=–0.424, P<0.001).

Conclusions: We conclude that the plasma SERPINF1 level is strongly associated with body adiposity, in particular with the visceral fat depot in the non-diabetic general population. This association may (partly) explain the relationship between SERPINF1 and metabolic syndrome in this population.


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Obesity is a major health problem worldwide. The dramatic rise in the prevalence of obesity contributes to the increase in obesity-associated diseases, such as type II diabetes, cardiovascular disease, and certain types of cancer (1, 2). In recent years, adipose tissue has been increasingly recognized as an important secretory organ that releases factors influencing local, peripheral, as well as central processes. These factors, called adipokines, are involved in glucose and lipid metabolism, vascularization, and other biological processes (3). Adipokines are believed to play a role in development of obesity-related diseases (4). Previously, we have identified pigment epithelium-derived factor (SERPINF1) as a novel protein secreted by preadipocytes and adipocytes (5).

The SERPINF1 protein was originally identified in retinal cell culture supernatant and characterized as a neurotrophic factor (6). In addition, SERPINF1 plays a role in the development of diabetic retinopathy in animals and humans, perhaps by acting antagonistically to vascular endothelial growth factor (7). Outside the boundaries of the eye, SERPINF1 has antitumor effects based on its anti-angiogenesis and pro-apoptosis activities (8). In a recent study, a lipase-linked receptor has been identified for SERPINF1 (9). This SERPINF1 receptor was previously characterized as adipose triglyceride lipase (ATGL). ATGL has been demonstrated to be critical in adipose lipid mobilization (10, 11) and SERPINF1 is also able to regulate hepatocyte lipid content through ATGL (12).

The SERPINF1 gene is highly expressed in adipose tissue in mice, and in adipose tissue, liver and bone marrow in humans (13, 14). The SERPINF1 protein has been detected as a secreted factor from both murine 3T3-L1 preadipocytes and adipocytes (5), and from human primary adipocytes (15). These findings suggest that adipose tissue contributes to plasma SERPINF1 levels. Interestingly, a study in a Japanese cohort demonstrated that serum SERPINF1 level is associated with central obesity and other components of metabolic syndrome (16). However, not all (abdominal) fat is equal, and since abdominal s.c. fat, visceral fat, and also hepatic fat can all contribute to central abdominal obesity, a more accurate measurement of individual fat depots would allow better discrimination of which depot is most strongly related to circulating SERPINF1 level. In the present study, we used ultrasound to more extensively measure s.c. and visceral fat depots to investigate their relation with circulating SERPINF1 in a general Caucasian population.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Declaration of interest
 References
 
Subjects

A general non-diabetic Caucasian population was composed of 59 genetically independent males and females with a continuous body mass index (BMI) of range 19–35 kg/m2. They were extracted from the spouse database of the Familial Combined Hyperlipidemia study performed in Maastricht (17, 18). The subjects were extensively characterized for body fat distribution with specific attention for the s.c. and visceral depots. The study protocol has been described in detail elsewhere (18). In brief, all subjects visited the Maastricht research clinic, between 2003 and 2005, where the plasma samples were collected. The participants were asked to come to the laboratory after an overnight fast and to refrain from smoking, drinking alcohol, and doing strenuous exercise for a period of 24 h prior to the study. Any lipid-lowering medication had been withdrawn during the last 2 weeks before blood sampling. Subject characteristics are summarized in Table 1. The study protocol was approved by the Medical Ethics Committee of Maastricht University Hospital and the clinical investigations were performed according to the Declaration of Helsinki. All subjects gave informed consent.


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  		Table 1 Characteristics of the study population.

 
Anthropometric measurements

Body weight, height, waist circumference, hip circumference, BMI, and waist to hip ratio (WHR) were measured in fasting state as described previously (19). The skinfold (SKF) thickness of biceps, triceps, subscapular, and suprailiac regions was measured, and body fat percentage was derived from the sum of the four SKF measurements using the method of Durnin & Womersley (20).

Ultrasound measurements

The size of abdominal s.c. adipose tissue and visceral adipose tissue were measured with an ultrasound method as described in detail previously (18), which has been validated (21). In brief, both visceral adipose tissue thickness and s.c. adipose tissue thickness were determined at the same level as waist circumference.

Biochemical analysis

Fasting venous blood samples were collected in pre-cooled EDTA vacutainer tubes and immediately processed. EDTA-plasma aliquots were stored at –80 °C until analysis. Triglycerides, total cholesterol, free fatty acids, glycerol, glucose, and insulin levels were measured as described previously (19, 22). The amount of hepatic fat was assessed by a surrogate plasma alanine aminotransferase level (23). SERPINF1 was quantified by ELISA (Chemikon, Temecula, CA, USA). According to the manufacturer, the assay sensitivity is 0.9 ng/ml; range of detection is 0.9–62.5 ng/ml, intra-assay variation is 5.3% and inter-assay variation is 16.0%. Since SERPINF1 protein strongly associates with other circulating proteins that may interfere with quantification of total SERPINF1 protein in plasma, we performed pre-treatment for plasma as recommended by the manufacturer, with urea (8 mol/l final concentration) for 60 min on ice, diluted 400 times in dilution buffer then applied to the ELISA plate. Samples were measured in duplicate and the average was used in the data analysis.

Statistical analysis

Statistical analyses were performed with SPSS for Windows version 12 (SPSS Inc., Chicago, IL, USA). Data are expressed as the mean±S.D. or medians (interquartile range) when variables significantly deviate from normal distribution. The latter ones were natural logarithmically (ln) transformed for use in later analyses. For comparing the males and females, an independent-samples t-test was used. The bivariate relationships among the parameters were assessed by Pearson correlation analysis within the groups, and by gender-adjusted analysis in the pooled subjects. Subsequently, for parameters correlated with plasma SERPINF1 level at a significance level P<0.05 in the pool, backward multiple linear regression analysis was performed to assess their independent relation with SERPINF1. Statistical calculations were performed two-tailed and P<0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Declaration of interest
 References
 
Determination of plasma SERPINF1 levels in male and female subjects

Plasma SERPINF1 levels were normally distributed inside the study population, with 6.2±2.1 and 3.1±1.4 µg/ml for males and females respectively. A significant difference between genders was observed (P<0.001).

The relation between plasma SERPINF1 level, adiposity, plasma lipid profile, blood pressure, and insulin resistance

Positive correlations were found between plasma SERPINF1 level and total body adiposity (BMI, body fat percentage) as well as abdominal adiposity (waist circumference, WHR, abdominal visceral fat thickness) for both male and female subjects (Table 2), although the relation with body fat percentage in men was only borderline significant. However, abdominal s.c. fat depot was significantly associated with SERPINF1 level only in females.


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  		Table 2 The bivariate correlation coefficients between plasma pigment epithelium-derived factor (SERPINF1) level and other parameters.

 
Plasma alanine transferase level that is fairly correlated with hepatic fat as measured by magnetic resonance spectroscopy (24), was used as a plasma surrogate marker of hepatic fat accumulation. It was positively associated with SERPINF1 in males and pooled subjects.

We also analyzed the relation between SERPINF1 and other metabolic syndrome features including blood lipid profile, blood pressure, and glucose metabolism. Only triglyceride levels were consistently positively correlated with SERPINF1 levels in both males and females. After pooling the subjects, plasma SERPINF1 also correlated positively with diastolic blood pressure, fasting glucose, and insulin concentrations (with adjustment for gender).

We observed that plasma SERPINF1 level was correlated with age of subjects in bivariate analysis. Because the features of metabolic syndrome are inter-related, and are also related with age, we performed multiple linear regression analysis to assess their independent relation with plasma SERPINF1 level. Since the correlations were similar in both males and females, we pooled the data in multiple linear regression analysis to increase the power with more subjects. Age, gender, and the significantly correlated parameters (BMI, waist, WHR, body fat percentage, visceral fat, triglyceride (ln), alanine transferase (ln), diastolic blood pressure, glucose, and insulin (ln)) were included as independent variables in a linear regression model, in which SERPINF1 level was the dependent variable. Subsequently, the variables that did not show an independent significant contribution to SERPINF1 were excluded via stepwise-backward-elimination, while adjustment for age and gender was maintained. This multiple linear regression analysis showed that thickness of the visceral fat depot and BMI were independently correlated to plasma SERPINF1 (with gender effect). Age did not show a significant independent contribution to the SERPINF1 level (Table 3).


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  		Table 3 Multiple linear regression analysis on plasma pigment epithelium-derived factor (SERPINF1) level.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Declaration of interest
 References
 
Using ultrasound, we were able to determine the relations of circulating SERPINF1 and the different fat depots. Our work provides the first evidence that circulating SERPINF1 levels are closely related to visceral fat, but not s.c. fat. Our data showed that in a general non-diabetic Caucasian population, circulating SERPINF1 level was positively related to aspects of the metabolic syndrome, including obesity, triglyceride levels, diastolic blood pressure, glucose, and insulin levels, consistent with the findings of Yamagishi and coworkers in a general Japanese population (16). Furthermore, multiple linear regression analysis indicated that the strong correlation between SERPINF1 level and adiposity may explain the association between SERPINF1 and multiple features of metabolic syndrome.

In this study, the size of the cohort was limited, and cross-sectional data could not provide details on mechanism. However, recent studies on the function of SERPINF1 support our finding that SERPINF1 is related to fat. ATGL that catalyzes the initial step in triglyceride hydrolysis and together with hormone-sensitive lipase co-ordinately catabolises triglycerides stored in adipose tissue, is the receptor for SERPINF1 (11). In humans, ATGL is expressed in various tissues, most abundantly in adipocytes, as shown in the NCBI Unigene database (25) and by a tissue-specific transcriptomics study (13). The high expression level of both SERPINF1 and ATGL in adipocytes strongly implies that SERPINF1 may act as an autocrine factor in adipose tissue lipid metabolism. ATGL protein level and lipase activity are reduced in the s.c. fat depot of obese compared with lean subjects, but not in the visceral fat depot (26). This suggests that ATGL is more active in visceral fat and that SERPINF1 signaling through ATGL is more relevant for visceral fat, especially in obesity. The fact that we did not observe a clear link between circulating SERPINF1 level and an indicator of whole body lipolysis (glycerol) is in line with a localized activity of SERPINF1 in the visceral fat depot.

We found that plasma alanine transferase level, a surrogate marker of hepatic fat accumulation, was also positively correlated with plasma SERPINF1 level, even though most of the subjects did not have fatty liver. The significant association between SERPINF1 and hepatic fat accumulation may reflect that the hepatic fat content is also closely associated with abdominal obesity (27). In this cohort, plasma alanine transferase level was positively associated with liver steatosis stage measured by ultrasound (data not shown). Interestingly, a study in rodents suggests that SERPINF1 deficiency induces steatosis (12), while in our present human study, hepatic fat accumulation is associated with high circulating level of SERPINF1. Elevated circulating SERPINF1 in humans has been suggested as a counter action for increased triglycerides (16). It is tempting to speculate that in the human obese situation SERPINF1 resistance exists in the liver.

It is well known that obesity, in particular central/visceral obesity, is associated with insulin resistance (28). These two components, together with hyperlipidemia and hypertension, are clustered in the so-called metabolic syndrome, because of their close correlations (29, 30). It is not unexpected that the plasma SERPINF1 level that is strongly related to obesity, particularly to visceral obesity, correlated with other components of this syndrome. The positive relation of plasma SERPINF1 level with these components has been observed in diabetic populations as well (31, 32). However, in those studies, obesity was neither considered nor identified as a significant independent determinant. This could reflect the difference between diabetic and non-diabetic conditions. In diabetic subjects, the relation of SERPINF1 with obesity might be masked by other determinants.

Although plasma SERPINF1 level is associated with BMI and visceral fat with the same strength in both genders, we observed a very significant gender difference in our study population for the absolute circulating SERPINF1 level. This is in contrast to Jenkin's work (31), but in line with the work by others (16, 32). Since the visceral fat depot is much larger in males than in females, and visceral fat could be a major contributor to the SERPINF1 level, a higher plasma SERPINF1 level in males compared with females seems reasonable. However, in multiple linear regression analysis, we showed that gender has its own independent effect, beyond the visceral fat. We suspect that sex hormones that were not investigated here may play a role in the regulation of circulating SERPINF1 level.

In conclusion, plasma SERPINF1 level is strongly associated with body adiposity, particularly with the visceral fat depot in the Caucasian non-diabetic general population. This association may partly explain the relationship between plasma SERPINF1 level and features of the metabolic syndrome in this population.


   Declaration of interest
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
References
 
The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.


   Funding
 
Funding was received from the Centre for Human Nutrigenomics in the Netherlands and the KP6 DIOGENES project (P Wang, Contract no. FOOD-CT-2005-513946), and from the Dutch NutriGenomics Consortium (E Smit, NGC-TIFN).


   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 

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Received 6 August 2008
Accepted 9 September 2008




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