Weight Loss Reduces Adipose Tissue Cathepsin S and Its Circulating Levels in Morbidly Obese Women (original) (raw)
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The Journal of Clinical Endocrinology & Metabolism, 2010
Context: Recent studies in humans and mice suggest the implication of the cysteine proteases cathepsins S, L, and K in vascular and metabolic complications of obesity. Objective: Our objective was to identify clinically relevant forms of cathepsin in human obesity. Design and Setting: We conducted a prospective study on two independent cohorts. Participants and Interventions: The first cohort includes 45 obese women eligible for gastric surgery (age, 39 Ϯ 1.6 yr; body mass index, 47 Ϯ 0.99 kg/m 2) and 17 nonobese women (age, 38 Ϯ 1.8 yr; body mass index, 21 Ϯ 0.44 kg/m 2). The second cohort comprises 29 obese women (age, 57 Ϯ 0.8 yr; body mass index, 34 Ϯ 0.69 kg/m 2) undergoing 6 months of medically supervised caloric restriction. Main Outcomes: Cathepsin S, L, and K mRNA levels were determined in surgical adipose tissue biopsies. The proteins were measured in conditioned medium of adipose tissue explants and in circulation. Results: Obese subjects had a 2-fold increase in cathepsin S mRNA in adipose tissue as compared with normal-weight subjects and an increased rate (1.5-fold) of cathepsin S release in adipose tissue explants. Cathepsin S circulating concentrations were increased with obesity (ϩ30%) and reduced after weight reduction (P Ͻ 0.05 for both). By contrast, cathepsin L was unaffected in adipose tissue and serum; cathepsin K was undetectable in circulation and unchanged in adipose tissue. Conclusion: In humans, cathepsin S is more influenced than cathepsins L and K by changes in energy balance in adipose tissue and circulation. This opens new avenues to explore whether selective inhibition of this protease could reduce cardiovascular risk and ameliorate metabolic status in obese subjects.
Endothelial function and weight loss in obese humans
Obesity surgery, 2005
Background: Obesity is a major risk factor for the development of endothelial dysfunction. We explored the effect of different degrees of body mass on endothelial function, lipids, systemic inflammation and glucose homeostasis and the effect of surgicallyinduced weight loss on endothelial function in severely obese humans. Methods: A cross-sectional study of healthy subjects across a wide range of body fatness was performed to characterize the effect of obesity on flowmediated dilatation (FMD), systemic inflammation, blood pressure and insulin sensitivity. A longitudinal study was performed to assess the effect of bariatric surgery induced weight loss on these parameters. 73 healthy subjects across a wide range of body mass were recruited; of these, 8 underwent bariatric surgery (median BMI 52.2 kg/m 2 , interquartile range 50.3-55.9). Endothelial dependent vasodilatation was measured using the brachial artery vasodilatory response to forearm hyperemia assessed using highresolution ultrasonography.
Paradoxical Preservation of Vascular Function in Severe Obesity
The American Journal of Medicine, 2010
BACKGROUND: Obesity is associated with a high risk of coronary artery disease morbidity and mortality. Yet, postmortem studies have shown that severely obese subjects exhibit smooth coronary arteries, thus suggesting that they may be protected from atherosclerosis. We assessed vascular function and its possible determinants in a cohort of normal-weight to severely obese insulin-sensitive subjects (body mass index [BMI] 23.2-49 kg/m 2). METHODS: Seventy-one healthy, insulin-sensitive subjects (Homeostasis Model Assessment of Insulin Resistance index Ͻ2.5), divided into normal-weight (n ϭ 13; BMI ϭ 23.2 Ϯ 1.6), obese (n ϭ 35; BMI ϭ 32.6 Ϯ 2.5), and severely obese (n ϭ 23; BMI ϭ 49.0 Ϯ 7.9) groups, were enrolled. Vascular function was evaluated by flow-mediated dilation and carotid intima-media thickness. High-sensitivity C-reactive protein, leptin, adiponectin, vascular growth factors, and CD34ϩKDRϩ/CD133ϩ endothelial progenitor cells, known markers of vascular health/protection, also were measured. RESULTS: Flow-mediated dilation was higher in severely obese than in obese and normal-weight individuals (P ϭ .019 and P ϭ .011 respectively). Intima-media thickness was consistently lower in severely obese than in obese individuals (P ϭ .040) and similar in severely obese and normal-weight individuals (P Ͼ.99). Levels of high-sensitivity C-reactive protein and leptin were higher in severely obese than in obese and normal-weight individuals (high-sensitivity C-reactive protein: P ϭ .018 and P ϭ .05, respectively; leptin: P Ͻ.001 for both comparisons). CD34ϩKDRϩ endothelial progenitor cells were significantly higher in severely obese versus obese individuals (P ϭ .039). CONCLUSION: Our study demonstrates that vascular function is paradoxically better in severely obese than in obese subjects and similar to that found in normal-weight subjects. Despite higher levels of highsensitivity C-reactive protein and leptin, severely obese individuals may be partially protected from atherosclerosis, possibly by a greater mobilization of endothelial progenitor cells.
International journal of obesity (2005), 2012
Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project. To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women. Subjects, who lost ≥ 8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months. 125 overweight/obese healthy men from eight European countries who completed whole intervention. Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters. Serum ACE concentration decreased by 11.3 ± 10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain ≤ 20% after 6 months, with an odds ratio of 1.59...
Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis
Faseb Journal, 2005
The molecular mechanisms by which obesity increases the risk of cardiovascular diseases are poorly understood. The purpose of this study was to identify candidate biomarkers overexpressed in adipose tissue of obese subjects that could link expanded fat mass to atherosclerosis. We compared gene expression profile in subcutaneous adipose tissue (scWAT) of 28 obese and 11 lean subjects using microarray technology. This analysis identified 240 genes significantly overexpressed in scWAT of obese subjects. The genes were then ranked according to the correlation between gene expression and body mass index (BMI). In this list, the elastolytic cysteine protease cathepsin S was among the highly correlated genes. RT-PCR and Western blotting confirmed the increase in cathepsin S mRNA (P=0.006) and protein (P<0.05) in obese scWAT. The circulating concentrations of cathepsin S were also significantly higher in obese than in nonobese subjects (P<0.0001). Both cathepsin S mRNA in scWAT and circulating levels were positively correlated with BMI, body fat, and plasma triglyceride levels. In addition, we show that the proinflammatory factors, lipopolysaccharide, interleukin-1β, and tumor necrosis factor-α increase cathepsin S secretion in human scWAT explants. This study identifies cathepsin S as a novel marker of adiposity. Since this enzyme has been implicated in the development of atherosclerotic lesions, we propose that cathepsin S represents a molecular link between obesity and atherosclerosis.
Diabetes, Obesity and Metabolism, 2008
The mechanisms by which obesity confers increased cardiovascular risk and the effects of moderate weight loss on cardiovascular health are incompletely understood. We sought to characterize the preclinical changes in cardiac and vascular health that accompany obesity and the influence of lifestyle modification on these parameters. Methods: Preclinical markers of vasculopathy in resistance vessels and conduit arteries and left ventricular structure and function were assessed in 39 obese subjects (BMI > 30 kg/m 2 ) and 11 healthy weight controls. The influence of serum on cellular adhesion molecule (CAM) expression on human endothelial cells was studied ex vivo in a subgroup of 13 obese and nine healthy weight subjects. These analyses were repeated in all 17 of the obese subjects who complied with 4-9 months of lifestyle modification treatment (six with weight loss >5% and 11 with weight loss <5%). Results: Compared with healthy weight controls, obese subjects had decreased peak hyperaemic forearm blood flow (p ¼ 0.015), increased carotid intima-media thickness (p ¼ 0.009), increased left ventricular wall thickness and volume and evidence of systolic and diastolic dysfunction as assessed using tissue Doppler imaging (S¢, p ¼ 0.09; E¢/A¢, p ¼ 0.02), and serum from obese subjects increased the intercellular CAM-1 expression on human endothelial cells (p ¼ 0.009). However, arterial endothelial function assessed by flow-mediated dilatation was not altered (p ¼ 0.99). Lifestyle modification treatment resulted in potentially beneficial changes in fibrinogen (p ¼ 0.003), HDL cholesterol (p ¼ 0.05) and soluble vascular CAM-1 (p ¼ 0.06). In subjects with weight loss greater than 5% of body weight, there was also a decrease in low-level inflammation (high-sensitivity C-reactive protein, p ¼ 0.05), lipid peroxidation (thiobarbituric acid-reactive substances, p ¼ 0.05) and triglycerides (p ¼ 0.07). Conclusions: Obesity is associated with widespread alterations in cardiac and vascular structure and function. Moderate short-term weight loss by lifestyle modification results in some beneficial changes in serum profile; however, these are not accompanied by significant alterations to either cardiac or vascular structure and function.
Metabolic disturbances linked to obesity: the role of impaired tissue perfusion
Arquivos Brasileiros de Endocrinologia & Metabologia, 2009
Associated with elevated risk of cardiovascular events and cancer, obesity is a worldwide problem affecting developed and developing countries. Microcirculatory vessels, represented by arterioles, capillaries and venules (mean internal diameter < 100 µm), are the place where blood/tissue nutrition and exchange effectively take place. Microvascular dysfunction is an early event in obesity probably secondary to endothelial dysfunction and capillaries rarefaction. New research techniques allow the investigation of the microcirculation in different vascular beds in humans. Studies suggest a link between endothelial dysfunction and visceral obesity. Oxidative stress, inflammation and rennin-angiotensin system are among factors considered to be involved on microvascular dysfunction in obesity. Microcirculatory impairment present in obesity suggests that it could be an important causal factor in obesity-related disorders such as insulin resistance and hypertension. Arq Bras Endocrinol Metab. 2009;53(2):238-245.
Circulation, 2002
Background-Visceral fat is a key regulator site for the process of inflammation, and atherosclerotic lesions are essentially an inflammatory response. Methods and Results-Fifty-six healthy premenopausal obese women (age range 25 to 44 years, body mass index 37.2Ϯ2.2, waist to hip ratio range 0.78 to 0.92) and 40 age-matched normal weight women were studied. Compared with nonobese women, obese women had increased basal concentrations of tumor necrosis factor-␣ (TNF-␣, PϽ0.01), interleukin-6 (IL-6, PϽ0.01), P-selectin (PϽ0.01), intercellular adhesion molecule-1 (ICAM-1, PϽ0.02), and vascular adhesion molecule-1 (VCAM-1, PϽ0.05). Vascular responses to L-arginine (3 g IV), the natural precursor of nitric oxide, were impaired in obese women: reductions in mean blood pressure (PϽ0.02), platelet aggregation to adenosine diphosphate (PϽ0.05), and blood viscosity (PϽ0.05) were significantly lower as compared with those in the nonobese group. Concentrations of TNF-␣ and IL-6 were related (PϽ0.01) to visceral obesity, as well as to adhesin levels and responses to L-arginine. After 1 year of a multidisciplinary program of weight reduction (diet, exercise, behavioral counseling), all obese women lost at least 10% of their original weight (9.8Ϯ1.5 kg, range 7.5 to 13 kg). Compared with baseline, sustained weight loss was associated with reduction of cytokine (PϽ0.01) and adhesin (PϽ0.02) concentrations and with improvement of vascular responses to L-arginine.