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Weight Loss Reduces Adipose Tissue Cathepsin S and Its Circulating Levels in Morbidly Obese Women

Institut National de la Santé et de la Recherche Médicale U755, 75004 Paris, France; Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, 75004 Paris, France; Centre Hospitalier Régional Universitaire, Pitié Salpétrière, Service de Nutrition, Hôtel Dieu (S.T., R.C., C.P., C.R., A.B., M.G.-M., D.L., K.C.), 75004 Paris, France; Surgery Department, Hôtel Dieu Hospital, Assistance Publique Hôpitaux de Paris (P.S., P.L., J.-L.B.), Paris, France; and Biochemistry Department, Hôtel Dieu Hospital, Assistance Publique Hôpitaux de Paris (C.C.), Paris, France

Address all correspondence and requests for reprints to: Dr. Karine Clément, Institut National de la Santé et de la Recherche Médicale U755, Nutrition Department, Hôtel Dieu, Place du parvis Notre Dame, 75004 Paris, France. E-mail: karine.clement{at}htd.ap-hop-paris.fr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Human adipose tissue produces several adipokines, including the newly identified protein cathepsin S (CTSS), a cysteine protease involved in the pathogenesis of atherosclerosis. Obesity is characterized by high levels of CTSS in the circulation and in sc white adipose tissue (scWAT).

Objective: We investigated the effect of surgery-induced weight loss on circulating CTSS and its protein expression in scWAT.

Design: Fifty morbidly obese women before and 3 months after surgery and 10 healthy lean women were studied. We analyzed the relationships between circulating CTSS and clinical and biological parameters. Immunohistochemistry of the CTSS protein variations in scWAT was performed.

Results: Weight loss decreased by 42% (P < 0.0001) the circulating CTSS levels, which correlated with changes in body weight (P = 0.03). We observed a significant decrease in CTSS enzymatic activity by 25% after weight loss (P = 0.001). Adipose tissue CTSS content was reduced by 30% (P = 0.002) after surgery. The variations in CTSS expression in scWAT after surgery correlated with changes in circulating CTSS serum levels (P = 0.03). Most of the correlations between CTSS and clinical and biological parameters disappeared after adjustment for body mass index, emphasizing the strong link between CTSS and corpulence in humans.

Conclusions: Changes in CTSS scWAT might contribute to serum variations in CTSS during weight loss. The decrease in CTSS concentrations in the circulation may contribute to vascular improvement in obese subjects after weight loss.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBESITY, A KEY component of the metabolic syndrome, is associated with decreased longevity and increased morbidity due to a variety of disorders, such as diabetes and cardiovascular diseases (1, 2). The molecular links between obesity and vascular complications are still incompletely understood. Recently, the role of inflammation-related processes has been brought to light by the discovery that adipose tissue produces a variety of inflammatory factors whose blood concentrations are altered in obesity (3). This contributes to a low-grade inflammation state, which has been linked to the development of insulin resistance and endothelial dysfunction in obese subjects (4, 5, 6). Weight loss in obese subjects is associated with an improvement of the inflammatory profile together with metabolic parameters and endothelial function, in part through the reduction of inflammatory factor expression in adipose tissue (7, 8, 9).

We have recently identified a novel protein, cathepsin S (CTSS), expressed in human white adipose tissue by using a transcriptomic approach (10). The CTSS that belongs to the cathepsin family is a potent cysteine protease that has the ability to degrade many extracellular elements, such as elastin, fibronectin, laminin, collagens, and chondroitin sulfate proteoglycan (11, 12, 13). We demonstrated that CTSS was expressed, secreted, and regulated by inflammatory factors, such as TNF- and IL-1ß, in human sc adipose tissue (scWAT) (10). We showed that obesity is associated with an excess of CTSS expression in scWAT and an increase in its circulating levels (10). Importantly, CTSS was previously shown to be overexpressed in atherosclerotic lesions in humans (14). The invalidation of CTSS in atherosclerosis-prone (LDLR^–/–) mice is associated with a reduction of atherosclerotic lesions (15). We proposed that CTSS could constitute a novel biomarker of adiposity that may link enlarged fat mass to vascular pathogenesis in obesity.

To evaluate the pathophysiological relevance of CTSS in obesity, the present study was designed to investigate the effect of weight loss induced by gastric surgery in morbidly obese women on circulating levels of CTSS and its systemic activity. Changes in CTSS protein levels in adipose tissue biopsies were determined in a subset of these subjects.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects and study design

This study enrolled 60 Caucasian women, including 1) the lean control group composed of 10 nonobese women and 2) 50 obese women at baseline and 3 months after gastric surgery. Obese subjects were weight stable for at least 3 months before surgery (laparoscopic adjustable gastric banding or gastric bypass) performed at the department of surgery of Hotel-Dieu hospital. In all obese patients, clinical and biochemical parameters were assessed at baseline and 3 months after gastric surgery. The clinical and biochemical parameters of these subjects are shown in Table 1.

Blood samples were obtained for biochemical and hormonal evaluation. All clinical investigations were performed according to the Declaration of Helsinki. Informed personal consents were obtained. All clinical investigations were approved by the ethics committees of Hôtel-Dieu (Paris, France).

Cultures of human adipose tissue explants

To evaluate CTSS secretion by scWAT and visceral WAT, adipose tissue explants (300 mg) were incubated in triplicate in 3 ml DMEM containing 1% BSA, penicillin (100 U/ml), streptomycin (100 mg/ml), and protease inhibitor mixture (Roche, Mannheim, Germany) for 48 h under aseptic conditions. At the end of the incubation period, supernatants were collected and stored at –20 C until measurements.

Immunohistochemical analysis of CTSS in scWAT

Surgical biopsies of scWAT from 12 lean and 12 obese subjects before and after surgery were fixed in 4% paraformaldehyde, dehydrated, paraffin embedded, and sectioned (thin sections, 5 µm thick). CTSS protein was detected with an antihuman CTSS monoclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) according to standard immunoperoxidase procedure. Dewaxed, rehydrated sections (5 µm) were processed through the following incubation steps: 1) antigen unmasking by incubating tissue sections with 0.1% trypsin in PBS as previously described (16), 2) 3% hydrogen peroxide in water for 20 min to block endogenous peroxidases, 3) Tris-buffered saline/Tween 20-casein (0.02 M solution; TBS-TC) for 15 min, 4) monoclonal antihuman CTSS antibody diluted to 1:100 (1 h in TBS-TC at room temperature), 5) multilink antimouse biotinylated Igs (DakoCytomation, Trappes, France) diluted 1:200 in TBS-TC for 20 min, 6) standard streptavidin-biotin-peroxidase complex method using a commercially available kit (ABCYS GMR4–61, Biospa, Milan, Italy), and 7) visualization of staining using diaminobenzidine and counterstaining with Mayer’s hematoxylin. Specificity tests were performed by omission of primary antibodies from staining and use of preimmune serum instead of the first antiserum. Processed slide images were acquired by a microscope-camera system (Nikon, Champigny sur Marne, France). Strong positive adipocytes were counted in four different areas (each area includes 100–120 adipocytes) of the processed slides randomly chosen. The mean number of stained adipocytes was expressed as a percentage of the total number of adipocytes in the observed areas.

Biochemical analysis

Biochemical variables were measured after an overnight fast. Plasma glucose, total cholesterol, apolipoprotein A1 (ApoA1), and high-density lipoprotein (HDL) levels (millimoles per liter) were measured enzymatically. Insulinemia (milliunits per liter) was measured with an immunoradiometric assay (Bi-INSULINE immunoradiometric assay, CisBio International, Gif-sur Yvette, France). Insulin sensitivity was evaluated using the QUICKI index (17). Serum leptin and adiponectin concentrations were determined using standard kits (Linco Research, Inc., St. Charles, MO). Serum levels of IL-6 and TNF- were measured by ultrasensitive ELISA kits (Quantikine US, R&D Systems Europe Ltd., Oxon, UK). Highly sensitive C-reactive protein (hsCRP) circulating levels were measured using an IMMAGE automatic immunoassay system (Beckman Coulter, Fullerton, CA). Serum concentrations of two soluble adhesion molecules, soluble endothelial selectin (sE-selectin) and soluble intercellular adhesion molecule-1 (sICAM-1), were determined using commercially available ELISA kits (R&D Systems). CTSS protein levels were determined in adipose tissue explant mediums and serum samples using a CTSS ELISA kit (Krka Laboratory, Inc., Novo Mesto, Czech Republic). The intra- and interassay coefficients were 11.5–3.8% and 7.3–4.3%, respectively (16). Cystatin C serum levels were measured using an ELISA kit (Biovendor Laboratory Medicine, Inc., Heidelberg, Germany). The intra- and interassay coefficients were 6–2% and 6.3–5.8%, respectively.

CTSS enzymatic activity

CTSS enzymatic activity was assessed in the plasma of 10 nonobese subjects and in a subset of 10 randomly chosen obese subjects before and after gastric surgery using a CTSS activity assay kit (Biovision Research Products, Mountain View, CA). This kit is a fluorescence-based assay that uses the preferred CTSS substrate labeled with amino-4-trifluoremethyl coumarin. The released amino-4-trifluoremethyl coumarin cleaved by CTSS is quantified using a fluorescence plate reader.

Statistical analysis

Data are expressed as the mean ± SEM. Statistical analysis was performed with JMP statistic software (SAS Institute, Inc., Cary, NC). Comparisons between the clinical and biochemical parameters of obese and nonobese subjects were achieved using the Mann-Whitney nonparametric test. Differences in means of clinical and biochemical parameters in obese subjects before and after surgery were determined using the Wilcoxon nonparametric paired test. The significance of correlations between CTSS protein or circulating levels and clinical parameters were examined using nonparametric Spearman’s rank test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Relationships between serum CTSS and clinical and biological parameters in weight-stable subjects

Table 1 shows the clinical and biochemical characteristics of 10 nonobese and 50 obese women at baseline. As expected, these obese subjects exhibited a proinflammatory profile, as shown by increased circulating levels of TNF-, serum amyloid A (SAA), IL-6, and hsCRP compared with lean individuals. By contrast, adiponectin was higher in healthy lean women (Table 1). CTSS circulating levels were significantly higher in obese (mean CTSS, 14.38 ± 0.75 ng/ml; range, 6.47–22.89) than in nonobese (mean, 4.34 ± 0.34 ng/ml; range, 2.9–6.16 ng/ml; P < 0.0001) subjects. Serum CTSS correlated positively with BMI (r = 0.54; P = 0.0001), insulin (r = 0.44; P = 0.003), and leptin (r = 0.41; P = 0.007) as well as with the proinflammatory markers SAA (r = 0.34; P = 0.02), TNF- (r = 0.70; P < 0.0001), IL-6 (r = 0.51; P = 0.0004), and hsCRP (r = 0.49; P = 0.001). Conversely, serum CTSS correlated negatively with serum adiponectin (r = –0.31; P = 0.03). After adjustment for age and BMI, the correlations disappeared, except for TNF-, which remained strongly correlated with serum CTSS (r = 0.74; P < 0.0001), and for ApoA1 and HDL, which negatively correlated with CTSS (r = –0.28; P = 0.04 and r = –0.17; P = 0.06, respectively).

To determine whether the increased concentrations of circulating CTSS in obese subjects were associated with an increase in its enzymatic activity, we evaluated CTSS serum activity using a fluorescence-based assay in 10 nonobese subjects and a subset of 10 obese subjects. As shown in Fig. 1, CTSS activity in serum of obese subjects was significantly higher than that in nonobese subjects (P = 0.001).

View larger version (12K): [in this window] [in a new window]   FIG. 1. Enzymatic activity of circulating CTSS in 10 nonobese and 10 obese subjects before (T0) and 3 months after gastric surgery (3M). Bars represent the mean CTSS activity ± SEM. **, P < 0.001, obese vs. lean subjects and obese subjects before vs. after weight loss.

The changes in clinical and biological parameters 3 months after surgery are shown in Table 1. In the obese subjects, gastric surgery led to a decrease of 16% in body weight, with an improvement of metabolic parameters, as illustrated by the decrease in fasting glucose (–14%) and insulin (–45%) levels and the increase in the QUICKI index (12%). Simultaneous decreases in the proinflammatory factors SAA (–14%) and hsCRP (–16%) and an increase in adiponectin levels (14%) were observed. In contrast to SAA and hsCRP, plasma IL-6 and TNF- concentrations remained stable 3 months after surgery. In addition, weight loss was accompanied by a reduction of two biochemical markers of endothelial dysfunction, sE-selectin (–25%; P < 0.0001) and, to a lesser extent, sICAM-1 (–8%; P = 0.09).

As shown in Fig. 2A and Table 1, the mean circulating levels of CTSS were reduced significantly (42%; P < 0.0001) after gastric surgery. We also observed a trend toward an increase in the CTSS endogenous inhibitor, cystatin C (15%; P = 0.1; Table 1). In agreement with changes in CTSS circulating concentrations, weight loss was associated with a 25% decrease in its enzymatic activity in a subset of 10 morbidly obese subjects (P = 0.001; Fig. 1).

View larger version (16K): [in this window] [in a new window]   FIG. 2. A, Individual modifications of circulating CTSS in response to weight loss. The mean circulating CTSS is 14.38 ± 0.75 ng/ml at baseline and 8.26 ± 0.75 ng/ml 3 months after surgery in the 50 subjects. B, Correlation between variations of weight (weight after – weight before) with changes in circulating CTSS during weight loss in the 50 subjects.

Variation in CTSS content in scWAT during weight loss

We first examined whether there was a difference in the release of CTSS by visceral and sc adipose tissues. As shown in Fig. 3, CTSS release was not significantly different between sc and visceral adipose tissues, whereas leptin and adiponectin secretion was higher in scWAT and visceral adipose tissues, respectively. We investigated by immunohistochemistry the change in CTSS protein in scWAT before and after weight loss as well as in nonobese subjects. As shown in Fig. 4, the number of CTSS-positive adipocytes was higher in obese compared with nonobese subjects (P = 0.0004). Weight loss significantly reduced (–30%; P = 0.002) the number of CTSS-stained adipocytes in obese subjects (Fig. 4). The reduction in CTSS-positive adipocytes in scWAT correlated positively with the change in CTSS circulating levels induced by weight loss (r = 0.75; P = 0.03).

View larger version (8K): [in this window] [in a new window]   FIG. 3. Comparison of CTSS release between sc vs. visceral adipose tissue explants. The bars represent the mean ± SEM ratio of the amounts of secreted proteins by scWAT over visceral adipose tissue as a percentage of results from three independent experiments performed in triplicate. The dotted line shows no difference in protein secretion between scWAT and visceral adipose tissues. The sc and visceral adipose tissue explants from three obese women (mean BMI, 52.0 ± 1.04 kg/m2) were incubated for 48 h. Leptin, CTSS, and adiponectin protein concentrations were measured in supernatants by ELISA. *, P < 0.05.

View larger version (10K): [in this window] [in a new window]   FIG. 4. Quantification (percentage) by immunohistochemistry of CTSS-positive adipocytes in scWAT of nonobese women and obese women before and after weight loss. The bars represent the mean ± SEM CTSS-positive adipocyte number as a percentage. **, P < 0.001, lean vs. obese subjects; ***, P < 0.0005, obese before and after weight loss.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

In the present study we demonstrated for the first time that weight loss, which is known to be associated with a clear improvement in vascular function in human obesity (24, 25), leads to a marked decrease in serum CTSS and its enzymatic activity.

Circulating levels of soluble cellular adhesion molecules are relevant indicators of endothelial function, whose concentrations are reduced by weight loss in obese patients (24, 26). In agreement, we showed here that sICAM-1 and sE-selectin circulating levels were decreased in response to gastric surgery-induced weight loss. Of note, a positive correlation exists between the decrease in circulating CTSS and the decreases in these two soluble adhesion markers in this cohort. These correlations are dependent on changes in BMI. It may nevertheless suggest that the reduction in CTSS serum concentrations participates in the mechanisms leading to improvement of endothelial function after weight loss. These data add CTSS to the growing list of adipose-derived factors whose circulating levels are altered in obesity and improved by weight loss and which may alter vascular endothelial function by different mechanisms (27, 28). With regard to CTSS, the mechanisms by which this protease favors atheroma are not fully understood. Incubation of macrophages with recombinant CTSS led to degradation of HDL and ApoA1 particles and reduced cholesterol efflux. This process may support foam cell accumulation in atherosclerotic lesions (29). Interestingly, we observed a negative correlation between CTSS circulating levels and HDL or ApoA1 serum concentration in obese patients that was independent from the individual’s corpulence. This result may suggest that CTSS influence HDL and ApoA1 systemic levels. It has been also proposed that CTSS, via an effect on extracellular matrix remodeling and elastin breakdown, facilitates the migration of smooth muscle cells and macrophages within the vessel, thereby contributing to the formation and progression of atherosclerotic lesions (20).

Cystatin C is an ubiquitous protein that is the most important extracellular inhibitor of cysteine proteases. It was suggested that the imbalance between the levels of cysteine proteases (CTSS) and antiproteases (cystatin C) may determine extracellular matrix remodeling in vessels. Indeed, in human atherosclerotic plaques, cystatin C protein is reduced, whereas increased CTSS protein levels are found (30). Patients with aortic aneurysms had lower circulating cystatin C levels than healthy subjects (30). However, a more recent study showed increased circulating cystatin C levels in patients with coronary heart disease (31). In our study we observed that weight loss tended to increase the levels of circulating cystatin C in obese patients, an effect that could contribute to reduce CTSS enzymatic activity. Additional studies are necessary to unravel the physiological role of circulating cystatin C in humans.

The factors responsible for the increased circulating levels of CTSS in obesity still remain to be examined. In the present study we observed a strong correlation between the circulating levels of CTSS and TNF-, which remained significant after BMI adjustment. Accordingly, previous studies have revealed that TNF- induces CTSS expression and secretion in human smooth muscle cells and macrophages (20) and stimulates CTSS secretion in human adipose tissue explants (10). These observations suggest that TNF- might increase CTSS secretion, particularly in the context of the low-grade inflammatory environment of obesity. The mechanisms mediated by TNF- that lead to CTSS increase need to be explored, particularly in adipose tissue of obese subjects.

The main tissue responsible for the observed serum CTSS increase in obesity is still unknown. In agreement with our previous observations showing that CTSS gene expression is similar in scWAT and omental adipose tissues of obese women (10), we observed in this study that CTSS release is not different between these adipose depots. In the same experiments we confirmed that leptin release is higher in scWAT (32), whereas adiponectin release is higher in omental adipose tissue (33). We found a positive correlation between the decrease in CTSS circulating concentrations and adipose CTSS content during weight loss, suggesting that scWAT contributes to CTSS secretion in the circulation. Although it is classically established that obesity complications are attributable to increased visceral WAT mass and its secretion products, these observations indicate that the contribution of scWAT to the circulating pool of CTSS might be substantial, particularly in extreme obesity.

In conclusion, this is the first study in humans showing that weight loss is associated with a decrease in CTSS circulating levels as well as adipose CTSS content along with soluble adhesion markers. We suggest that the observed circulating CTSS decrease results from its reduced secretion by adipose tissue. These observations reinforce the implication of CTSS in obesity-related disorders and point out this protease as a potential therapeutic target to reduce cardiovascular risks in obese patients.

	Acknowledgments

 
We thank Dr. Pierre Niccolo (Plastic Surgery Department, Hôpital Louis Mourrier, Assistance Publique Hôpitaux de Paris, Colombes, France) for adipose tissue availability. We thank Jean-François Bedel and Annie Legall for their excellent technical assistance, and Dr. Florence Marchelli for managing the clinical database.

	Footnotes

 
First Published Online January 4, 2006

Abbreviations: ApoA1, Apolipoprotein A1; BMI, body mass index; CTSS, cathepsin S; HDL, high-density lipoprotein; hsCRP, highly sensitive C-reactive protein; SAA, serum amyloid A; scWAT, sc white adipose tissue; sE-selectin, soluble endothelial selectin; sICAM-1, soluble intercellular adhesion molecule-1; TBS-TC, Tris-buffered saline/Tween 20-casein.

This work was supported by the Direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programe Hospitalier de Recherche Clinique (AOR 02076), the Contrat de Recherche Clinique ALFEDIAM, the Bonus Quality Research of Paris 6 University, and the Institut National de la Santé et de la Recherche Médicale. S.T. and R.C. were supported by grants from Institut National de la Santé et de la Recherche Médicale/Conseil Regional Ile de France. K.C. received a grant from Benjamin Delessert Institute, Groupe Lipid Nutrition, and the French National Agency of Research.

Received July 18, 2005.

Accepted December 23, 2005.

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