Effect of telmisartan, angiotensin II receptor antagonist, on metabolic profile in fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rats.

The metabolic syndrome (MS) is a common risk factor for cardiovascular disease and type-2 diabetes. Recently, telmisartan, an angiotensin II receptor antagonist that has an antihypertensive effect, has been reported to be a partial peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. The anti-diabetic hormone adiponectin has been recognized as a marker of in vivo PPARgamma activation. Therefore, we studied telmisartan's effect on the metabolic profile and adiponectin levels in a fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rat model. Twenty-four male Sprague-Dawley rats were divided into three groups (eight in each). One group of control rats was fed standard chow for 5 weeks while a second was fed a fructose-enriched diet. A third group was fed a fructose-enriched diet for 5 weeks and treated with telmisartan 5 mg/kg/day during the last 2 weeks. Fructose feeding increased systolic blood pressure (mean+/-SEM), from 130+/-1 to 148+/-2 mmHg, insulin from 0.26+/-0.03 to 0.68+/-0.08 ng/mL, and triglycerides from 102+/-6 to 285+/-23 mg/dL (p<0.05 for all variables). Telmisartan treatment reversed these effects and reduced blood pressure to 125+/-2 mmHg, insulin levels to 0.41+/-0.07 ng/mL, and triglycerides to 146+/-18 mg/dL (p<0.05 for all variables), while attenuating the increase in body weight during weeks 3 to 5. In contrast, telmisartan did not affect plasma adiponectin levels. In conclusion, although telmisartan is considered a partial PPARgamma agonist, its beneficial effect in the fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT1 receptor.     

Effects of pioglitazone and metformin on intracellular lipid content in liver and skeletal muscle of individuals with type 2 diabetes mellitus

Both ectopic fat accumulation and changes of the amount of several adipocyte secreting proteins (adipokines) are thought to contribute to the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now investigated the effects of 2 insulin-sensitizing drugs, pioglitazone and metformin, on body fat composition and serum adipokine concentrations in individuals with type 2 diabetes mellitus. A total of 41 diabetic patients were treated with pioglitazone (n =21) or metformin (n =20) for 6 months. Intramyocellular lipid content (IMCL) and hepatic lipid content as well as the areas of subcutaneous and visceral fat deposits in the abdomen were determined by nuclear magnetic resonance spectroscopy before and after drug treatment. The serum concentrations of adiponectin and retinol binding protein 4 were also determined by enzyme-linked immunosorbent assays. Pioglitazone treatment reduced both hepatic lipid content (12.0 +/- 6.1 vs 8.4 +/- 3.7 arbitrary units [AU], P < .01) and IMCL (8.4 +/- 3.6 vs 6.3 +/- 2.4 AU/creatine, P < .01), whereas metformin reduced only IMCL (7.0 +/- 3.6 vs 5.8 +/- 2.0 AU/creatine, P < .05). Although the areas of visceral and subcutaneous fat were not significantly affected by treatment with either drug, pioglitazone induced a significant reduction in the ratio of visceral to subcutaneous fat area (0.92 +/- 0.41 vs 0.85 +/- 0.41, P < .05). Pioglitazone treatment also resulted in a marked increase in serum adiponectin concentration (5.6 +/- 4.1 vs 16.2 +/- 9.9 microg/mL, P < .0001) and a small but significant decrease in serum retinol binding protein 4 concentration (73.4 +/- 25.1 vs 65.1 +/- 23.7 microg/mL, P < .05). These results suggest that pioglitazone may improve insulin sensitivity both by affecting serum adipokine concentrations and by reducing the intracellular triglyceride content of liver and skeletal muscle in individuals with type 2 diabetes mellitus.     

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 +/- 11 years and body mass index [BMI] 23.8 +/- 3.0 kg/m(2), mean +/- SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.     

Comparison of effects of telmisartan and valsartan on late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients

We compared the effects of telmisartan and valsartan on late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients. This was a prospective, randomized, single-blinded, 8-month follow-up study that included hypertensive patients with significant coronary artery stenosis treated with telmisartan (n=79) or valsartan (n=80). Risk factors such as diabetes, hyperlipidemia, smoking, and obesity were similar between groups. After 8 months of follow-up, only the telmisartan group showed significant decreases in interleukin-6 and tumor necrosis factor-alpha. The decreases from baseline level in total cholesterol and low-density lipoprotein cholesterol concentrations were significantly greater in the telmisartan group. The increase in adiponectin concentrations from baseline measurements was significantly greater in the telmisartan group than in the valsartan group (1.9+/-2.7 vs 0.4+/-2.0 microg/ml, respectively, p<0.05). Moreover, late lumen loss was significantly lower in the telmisartan group than in the valsartan group (0.1+/-0.4 vs 0.3+/-0.5 mm, respectively, p=0.001). Major adverse cardiac events were similar between groups. In conclusion, compared with valsartan, telmisartan was associated with a significant decrease in late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients with significant coronary narrowing.     

Relationship of adiponectin to body fat distribution,insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

AIMS/HYPOTHESIS: Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. METHODS: We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S(I)) in 182 subjects (76 M/106F). RESULTS: Adiponectin concentrations were higher in women than in men (7.4+/-2.9 vs 5.4+/-2.3 micro g/ml, p<0.0001) as were leptin concentrations (19.1+/-13.7 vs 6.9+/-5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S(I): 6.8+/-3.9 vs 5.9+/-4.4 x 10(-5) min(-1)/(pmol/l), p<0.01) and had more subcutaneous (240+/-133 vs 187+/-90 cm(2), p<0.01), but less intra-abdominal fat (82+/-57 vs 124+/-68 cm(2), p<0.0001). By simple regression, adiponectin was positively correlated with age ( r=0.227, p<0.01) and S(I) ( r=0.375, p<0.0001), and negatively correlated with BMI ( r=-0.333, p<0.0001), subcutaneous ( r=-0.168, p<0.05) and intra-abdominal fat ( r=-0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides ( r=-0.281, p<0.001) and positively correlated with HDL cholesterol ( r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy ( r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age ( p<0.0001), sex ( p<0.005) and intra-abdominal fat ( p<0.01). S(I) was related to intra-abdominal fat ( p<0.0001) and adiponectin ( p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. CONCLUSION/INTERPRETATION: These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile.     

Adipose tissue, serum adipokines, and ghrelin in patients with ankylosing spondylitis

Adipokines such as leptin and adiponectin are involved in the regulation of inflammation. Ghrelin, a gastric peptide playing a role in the appetite regulation, possesses anti-inflammatory properties. In this study, we evaluated the circulating levels of adipokines (leptin as potential proinflammatory and adiponectin as anti-inflammatory marker) and ghrelin and the fat mass in patients with ankylosing spondylitis (AS). Serum leptin, adiponectin, and ghrelin were evaluated in 53 AS patients with active disease (mean Bath Ankylosing Spondylitis Disease Activity Index >40) and 35 controls. Fat and lean masses were determined using dual-energy x-ray absorptiometry. Fat and lean masses did not differ between patients and controls. Ankylosing spondylitis patients had lower leptin levels compared with controls, even after adjustment for fat mass (AS vs controls: leptin, 7.6 +/- 1.3 ng/mL vs 10.3 +/- 1.5 ng/mL; leptin [in nanograms per milliliter]/fat mass [in kilograms], 0.28 +/- 0.04 vs 0.44 +/- 0.04; P = .006 and P = .0003, respectively). Serum adiponectin did not differ between patients and controls, whereas circulating ghrelin was higher in AS patients (1354.6 +/- 70.5 pg/mL vs 1008.0 +/- 82.5 pg/mL; P = .001). However, all these results were significant only for male patients. No correlation was found between leptin and adiponectin, and erythrocyte sedimentation rate, C-reactive protein levels, tumor necrosis factor alpha, or Bath Ankylosing Spondylitis Disease Activity Index. Ankylosing spondylitis patients had no changes in fat mass. Leptin production was reduced in contrast with normal levels of adiponectin. These adipokine results, together with high serum ghrelin levels, may influence the inflammatory response in AS.     

替米沙坦对高血压合并糖尿病患者血清脂联素的影响

目的观察替米沙坦治疗前、后高血压合并糖尿病患者血清脂联素水平的变化。方法将50名门诊高血压合并糖尿病病人分为替米沙坦和氨氯地平两组。观察治疗前及治疗10周后患者血压、脂联素及血糖、胰岛素变化。结果与治疗前相比,替米沙坦组与氨氯地平组收缩压和舒张压均显著降低(P<0.01),替米沙坦组血清脂联素水平较治疗前显著升高(P<0.01),血糖、胰岛素和胰岛素抵抗较治疗前显著降低(P<0.01);氨氯地平组治疗前后血清脂联素、血糖、胰岛素和胰岛素抵抗无明显改变(P>0.05)。结论与氨氯地平相比,替米沙坦在降压的同时,显著增高了血清脂联素水平并显著改善胰岛素抵抗,显示其具有降压外良好的代谢效应。     

Adiponectin and inflammatory markers in peripheral arterial occlusive disease

This study was designed to examine the plasma levels of adiponectin as well as markers of inflammation and endothelial function in peripheral arterial occlusive disease (PAOD), and to investigate the pathophysiological significance of adiponectin in this disease. Eighty-eight subjects with (n=40) and without PAOD (n=48) were enrolled. Multiple regression analysis including age, sex, body mass index, hypertension, diabetes, triglycerides, high-density lipoprotein cholesterol, creatinine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecules-1 (sVCAM-1), von Willebrand factor, and high-sensitive C reactive protein (Hs-CRP) showed that adiponectin concentration was significantly lower in PAOD subjects (PAOD: 7.9+/-0.7 microg/mL versus without PAOD: 9.5+/-0.6 microg/mL, F=4.94, p<0.03). Furthermore, concentrations of adiponectin (F=8.5, p<0.01) as well as sICAM-1 (F=5.8, p<0.02), sVCAM-1 (F=5.9, p<0.02), and Hs-CRP (F=3.8, p=0.05) were independently associated with ankle-brachial index. In 27 subjects (10 with PAOD and 17 without PAOD), adiponectin levels in the femoral artery and saphenous vein were measured. A significant step-up of adiponectin from the artery to the vein was observed in subjects without PAOD (+13.0%, p<0.01), but not in subjects with PAOD (+0.4%, NS). Plasma adiponectin as well as Hs-CRP were followed before and after percutaneous transluminal angioplasty (PTA) in eight patients. Adiponectin showed a tendency to decrease after PTA (day 6, -30.6%), although Hs-CRP significantly increased. Adiponectin is decreased in patients with PAOD in proportion to the severity of the disease. Adiponectin concentration could be a marker of the existence of atherosclerosis, and measurement of its concentration may be helpful in assessment of the progress of atherosclerosis.     

Reciprocal association between visceral obesity and adiponectin: in healthy premenopausal women

BACKGROUND: Obesity is one of the well-known risk factors of vascular disorders; however, the molecular mechanisms underlying the association between the two remain undetermined. Previous studies have demonstrated that the plasma levels of adiponectin, an adipose-derived hormone, are reduced in obese subjects, and that this hypoadiponectinemia is associated with ischemic heart disease. In this study, we sought to identify the primary determinants of plasma adiponectin levels in healthy premenopausal women. METHODS AND RESULTS: We analyzed the plasma adiponectin concentrations in age-matched healthy obese premenopausal women [n=37, body mass index (BMI)> or= 25 kg/m(2)] and in healthy nonobese premenopausal women (n = 23, BMI < 25 kg/m(2)). Visceral and subcutaneous fat (VCF and SCF) areas were determined by abdominal computed tomography (CT) scan. Plasma levels of adiponectin in obese subjects were lower than in nonobese subjects (3.24 +/- 1.08 vs. 4.90 +/- 2.06 ug/ml, P < 0.01). Significant, univariate inverse correlations were observed between adiponectin levels and visceral fat areas (r = -0.643, p < 0.001), subcutaneous fat areas (r = -0.407, p < 0.01), and hsCRP (r = -0.36, p = 0.007). Plasma levels of adiponectin correlated positively with insulin sensitivity [quantitative insulin sensitivity check index (QUICKI): r = 0.38, p = 0.005] and high-density lipoprotein (HDL) cholesterol (r = 0.44, p = 0.001), and negatively with low-density lipoprotein (LDL) cholesterol (r = -0.29, p = 0.028), triglyceride (r = -0.33, p = 0.013), and BMI (r = -0.48, p < 0.001). By multivariate analysis, only visceral fat areas affected adiponectin plasma levels (beta = -0.016, p < 0.05, R(2) = 0.504). Plasma levels of HDL cholesterol remained significantly correlated to plasma adiponectin concentrations in multivariate analysis (beta = 0.067, p < 0.05). CONCLUSIONS: These results collectively indicate that plasma HDL cholesterol levels and visceral fat masses are independently associated with plasma adiponectin concentrations.     

Hypoadiponectinemia in patients with cerebral infarction: comparison with other atherosclerotic disorders

The present study was undertaken to determine serum adiponectin level in patients with cerebral infarction and to further analyze any difference in serum adiponectin levels among atherosclerotic disorders. One hundred fifty-two subjects with atherosclerotic disorders were enrolled, 110 males and 42 females, with the age of 67.0 +/- 9.9 years (mean +/- SD). They were divided into 62 patients with cerebral infarction, 48 patients with ischemic heart disease, and 42 patients with arteriosclerosis obliterans. Thirty-two subjects matched by age, gender, and body mass index served as controls. Serum adiponectin levels were 7.2 +/- 0.6 microg/mL (mean +/- SE) in the patients with cerebral infarction, 7.2 +/- 0.8 microg/mL in those with ischemic heart disease, and 6.9 +/- 0.9 microg/mL in those with arteriosclerosis obliterans. They were significantly less than the level of 12.6 +/- 1.9 microg/mL in the control group (P < 0.01). However, there was no difference in serum adiponectin level among three groups of atherosclerotic disorders. In the patients with acute cerebral infarction, serum adiponectin level was temporarily reduced from 7.3 +/- 0.9 to 6.2 +/- 0.8 microg/mL 14 days after the hospitalization (P < 0.01), followed by recovery to the basal value. The present findings indicate that serum adiponectin levels are equivalently reduced in patients with atherosclerotic disorders, and that serum adiponectin is changeable under acute phase of cerebral infarction.     

Elevated circulating plasma adiponectin in underweight patients with COPD

BACKGROUND: Adiponectin is an adipose tissue-derived specific protein that has antiinflammatory as well as anti-atherosclerotic effects. In the United States, many patients with COPD are obese and die of cardiovascular diseases. However, in Japan, patients with COPD are frequently cachexic and die of respiratory failure. This study was designed to investigate the role of adiponectin in these differences in characteristics of COPD. METHODS: We enrolled normal-weight and underweight male patients with COPD (n = 31; age, 71 +/- 1 years; body mass index [BMI], 20.1 +/- 0.6 kg/m(2)) and age-matched, healthy, male, control subjects (n = 12). The adiponectin levels were measured by enzyme-linked immunosorbent assay. Correlation of adiponectin levels with pulmonary function and serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin-6) were estimated. RESULTS: Adiponectin levels in patients with COPD were significantly higher than those in control subjects (p<0.01) and inversely correlated with BMI (r = - 0.55, p<0.01). Even in the normal-weight patients with COPD, adiponectin levels were significantly higher than those in control subjects (p<0.01). Adiponectin levels in patients with COPD significantly correlated with percentage of predicted residual volume (r = 0.40, p<0.05). In patients with TNF-alpha levels > 5 pg/mL, there was a significant correlation between plasma adiponectin and serum TNF-alpha levels (r = 0.68, p<0.05). CONCLUSIONS: Plasma adiponectin levels in patients with COPD were elevated and correlated with body weight loss, hyperinflation, and systemic inflammation. Increased adiponectin may reduce cardiovascular events in underweight patients with COPD.     

Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease

BACKGROUND: There is evidence that adipocytokines play an important role in metabolism and in inflammation. Because human metabolism dramatically changes in inflammatory bowel disease (IBD) and chronic inflammation is the hallmark of the disease, we studied serum levels of leptin, adiponectin, resistin, and ghrelin in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with healthy controls (HC). METHODS: Leptin, adiponectin, resistin, and active ghrelin serum levels were measured in 100 IBD patients (46 UC and 54 CD) and in 60 matched HC using commercially available enzyme-linked immunosorbent assays. Leptin, adiponectin, resistin, and ghrelin levels were correlated with disease activity, type, localization, and treatment. RESULTS: Mean serum leptin levels were 10.6+/-2.0 ng/mL in UC patients, 12.5+/-2.6 ng/mL in CD patients, and 15.0+/-1.8 ng/mL in HC (P=.01). Mean serum adiponectin levels were 9514.8+/-787.8 ng/mL in UC patients, 7651.1+/-613 ng/mL in CD patients, and 7270.6+/-559.4 ng/mL in HC (P=.05). Mean serum resistin levels were 21.2+/-2.2 ng/mL in UC patients, 18.7+/-1.6 ng/mL in CD patients and 11.8+/-0.6 ng/mL in HC (P=.0002). Mean serum ghrelin levels were 48.2+/-4.2 pg/mL in UC patients, 49.4+/-4.6 pg/mL in CD patients and 14.8+/-3.0 pg/mL in HC (P<.0001). Serum levels of these adipocytokines were not correlated with either C-reactive protein levels or the clinical indices of activity. No association between serum adipocytokines levels and disease localization in both UC and CD patients was found. Only serum ghrelin was significantly higher in ileal compared with colonic CD (P=.04). CONCLUSIONS: Serum levels of adiponectin, resistin, and active ghrelin are increased whereas serum levels of leptin are decreased in patients with IBD. Further studies are needed to elucidate the role of adipocytokines in IBD.     

Changes in serum leptin levels during GnRH agonist therapy

The purpose of the present study was to investigate changes in serum leptin levels during GnRH agonist therapy. Twenty regularly menstruating women with uterine leiomyomas were enrolled. These subjects were given GnRH agonist (leuprorelin acetate, 3.75 mg) monthly for 4 months. Serum leptin and estradiol (E2) levels were measured at the two time points of day 1 or 2 of the menstrual cycle and the end of GnRH agonist therapy. Weight, total body fat mass, percentage of body fat, and total body lean mass were measured by whole body scanning with dual-energy X-ray absorptiometry. The ratio of serum leptin levels to total body fat mass (leptin-fat mass ratio), and the ratio of serum leptin levels to total body lean mass (leptin-lean mass ratio) were calculated. All subjects became amenorrheic after the initial administration of GnRH agonist. Baseline E2 levels were 45.4 +/- 21.0 pg/mL, which significantly decreased after GnRH agonist therapy (13.3 +/- 4.2 pg/mL, p<0.01). Baseline leptin levels were 8.7 +/- 8.1 ng/mL, which did not differ from the values after 4 months of GnRH agonist administration (8.9 +/- 6.8 ng/mL). Total body fat mass significantly increased from 20.0 +/- 10.4 to 21.0 +/- 9.4 kg (p<0.05), while total body lean mass significantly decreased (34.5 +/- 4.2 kg to 33.3 +/- 3.9 kg, p<0.01). However, leptin-fat mass ratio after GnRH agonist therapy did not differ from the baseline values (0.39 +/- 0.16 ng/mL/kg vs 0.38 +/- 0.16 ng/mL/kg). Hypogonadism does not have a major impact on circulating leptin levels.     

Telmisartan, an angiotensin II type 1 receptor blocker, improves coronary microcirculation and insulin resistance among essential hypertensive patients without left ventricular hypertrophy

Hypertension and insulin resistance are associated with reduced coronary vasodilatory capacity, possibly caused by structural changes in the coronary resistance vessels. The goal of this study was to compare the effect of an angiotensin receptor blocker (ARB) with that of a calcium channel blocker (CCB) on coronary flow reserve and insulin resistance among essential hypertensive patients without left ventricular hypertrophy. A total of 40 consecutive essential hypertensive patients were randomized to daily 40 mg telmisartan or 20 mg nifedipine coat-core treatment. Coronary flow velocity reserve (CFVR) measurement using transthoracic Doppler echocardiography and blood tests were performed before and after 12 weeks of treatment. At baseline, blood pressure, CFVR, and homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly different between the two groups. At the end of the treatment period, the telmisartan and nifedipine groups exhibited similar declines in blood pressure. CFVR was improved in the telmisartan group (2.4+/-0.4 to 2.9+/-0.4; p<0.01), but there was no difference in the nifedipine group (2.5+/-0.3 to 2.5+/-0.3; n.s.). HOMA-IR was improved in the telmisartan group (3.1+/-1.1 to 1.6+/-0.7; p<0.01), but there was no difference in the nifedipine group (2.8+/-1.1 to 2.4+/-0.7; n.s.). In conclusion, this study demonstrates that antihypertensive therapy with telmisartan, but not nifedipine, has a beneficial effect on coronary microcirculation and insulin resistance among essential hypertensive patients.     

Tissue inhibitor of metalloproteinase-1 predicts adiposity in humans

OBJECTIVE: Tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated in fat of obese rodents and promotes adipose tissue development in these animals. However, it is unclear whether TIMP-1 independently predicts adiposity in humans and whether serum levels are increased in s.c. and visceral obesity. DESIGN: Twenty-four lean, 16 s.c. obese, and 20 visceral obese subjects were studied. METHODS: Plasma TIMP-1 concentrations were quantified using ELISAs and correlated to clinical parameters. RESULTS: Plasma TIMP-1 levels were significantly different between lean (156 +/- 42 microg/l), s.c. obese (186 +/- 52 microg/l), and visceral obese (198 +/- 42 microg/l) subjects (P < 0.01). Furthermore, TIMP-1 correlated positively with body mass index (BMI), waist-to-hip ratio (WHR), % body fat, fasting insulin, free fatty acids, cholesterol, leptin, interleukin-6, and negatively with adiponectin (P < 0.05). Moreover, TIMP-1 serum levels predicted % body fat but not WHR independent of age, sex, and plasma insulin. CONCLUSIONS: We demonstrate that increased TIMP-1 serum levels are found with increased adiposity in humans.     

Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model

BACKGROUND: The health hazard of the metabolic syndrome (MS) is increasing, yet there is no effective pharmacologic treatment to this entity as a whole. Recently, hypoadiponectinemia was found to play an important role in the development of MS. We studied the effect of the PPAR-gamma agonist rosiglitazone on adiponectin and the metabolic profile in the fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic rat model. METHODS: Thirty male Sprague-Dawley rats were divided into three groups. Ten were fed standard rat chow for 5 weeks, 10, a fructose-enriched diet for 5 weeks, and 10, a fructose-enriched diet for 5 weeks, with rosiglitazone 10 mg/kg/d added during the last 2 weeks. Blood pressure (BP), oral glucose tolerance test (OGTT), plasma insulin, triglycerides, and adiponectin were recorded, as well as mRNA levels of the adiponectin gene in visceral adipose tissue. RESULTS: Fructose-fed rats developed MS as manifested by the increase in systolic BP (from 139 +/- 3 to 158 +/- 4 mm Hg, P < .05), insulin (from 26 +/- 1.6 to 40 +/- 2.5 muU/mL, P < .05), triglycerides (from 91 +/- 9 to 304 +/- 24 mg/dL, P < .05), and impaired OGTT (area under the curve from 13,894 +/- 246 to 17,725 +/- 700 mg/dL/min). Treatment with rosiglitazone reversed these effects and reduced BP to 133 +/- 7 mm Hg, insulin levels to 30 +/- 2.8 muU/mL, triglycerides to 116 +/- 9 mg/dL, and the OGTT to 15,415 +/- 372 mg/dL/min (P < .05 for all variables). In addition, rosiglitazone increased plasma levels of adiponectin fourfold from 4.3 +/- 0.1 to 18.4 +/- 0.6 mug/mL (P < .05). This increase was coupled with 3.8-fold increase in adiponectin mRNA in visceral adipose tissue. CONCLUSIONS: This study shows for the first time that in an animal model of MS, the insulin sensitizer, rosiglitazone, improves the metabolic profile and increases plasma levels of adiponectin and its gene expression. It is possible therefore that rosiglitazone exerts its beneficial effects by increasing the levels of adiponectin.     

Sibutramine improves fat distribution and insulin resistance, and increases serum adiponectin levels in Korean obese nondiabetic premenopausal women

The aim of this study was to evaluate the effects of sibutramine on body composition and fat distribution, insulin resistance, and serum adiponectin levels in obese women. A total of 28 obese, premenopausal women (mean age, 34.5 +/- 13.7 years; BMI, 31.00 +/- 4.10 kg/m2) was studied before and after 12-week-course of sibutramine (10mg/day). Sibutramine treatment reduced body mass index (P < 0.05) and total body fat (P < 0.05). Abdominal subcutaneous and visceral fat areas (ASFA and AVFA) and mid-thigh low density muscle areas (LDMA) measured by computed-tomography decreased significantly (all, P < 0.05). Insulin resistance (IR) calculated from the homeostasis model assessment (HOMA) method decreased (P < 0.05) and serum adiponectin levels increased significantly (P < 0.05). In our sequential data, the changes of fasting serum insulin levels and the HOMA-IR scores, serum free fatty acids and triglyceride levels, serum adiponectin levels and the mid-thigh LDMA preceded significant changes of body weight, total body fat, and abdominal fat distribution, suggesting sibutramine might improve insulin sensitivity directly by alterations of fatty acid metabolism or secondarily by increasing serum adiponectin levels. Conclusively, sibutramine improved fat distribution and insulin resistance, and increased serum adiponectin levels in Korean obese nondiabetic premenopausal women.     

Expression of long pentraxin PTX3 in human adipose tissue and its relation with cardiovascular risk factors

Pentraxin 3 (PTX3) is an acute phase protein strongly expressed by advanced atherosclerotic lesions. We investigated (a) PTX3 expression and secretion in subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (VAT) obtained from 21 obese (37.4+/-8.15 yr) and 10 normal weight subjects (43.7+/-11.07 yr) and (b) the relationships of adipose PTX3 with tumour necrosis factor alpha (TNFalpha) and adiponectin expression and with cardiometabolic risk factors. Real-time PCR was used to quantify specific mRNA for PTX3, CD68 (macrophage marker), TNFalpha and adiponectin. Fresh adipose tissue was cultured and PTX3 measured in the medium. Serum insulin, glucose, HDL and LDL cholesterol, triglycerides, C-reactive protein (CRP), fibrinogen, adiponectin, TNFalpha and PTX3 were measured. PTX3 expression was similar in the two fat compartments and tended to be higher in obese than in normal weight subjects in VAT only (p=0.05). CD68 and PTX3 expressions were correlated with each other in SAT but not in VAT. After adjustment for age and sex, VAT-PTX3 expression and release were correlated with VAT-TNFalpha expression (p<0.01 for both) and with LDL/HDL ratio (p<0.01 and p<0.001). VAT-PTX3 expression was also correlated with BMI, triglycerides, CRP, fibrinogen and adiponectin (p<0.05 for all). In the multivariate analysis with VAT-PTX3 RNA levels as dependent variable, LDL/HDL ratio and fibrinogen remained independently associated with VAT-PTX3 expression (p<0.01 for both). These associations were not seen within SAT. CONCLUSIONS: Human adipose tissue expresses and releases PTX3 likely under TNFalpha control. VAT production of PTX3 seems to contribute to the mechanisms underlying the development of atherosclerosis.     

Adiponectin independently predicts metabolic syndrome in overweight Latino youth

CONTEXT: Adiponectin may be important in the pathogenesis of insulin resistance and the metabolic syndrome in youth. OBJECTIVE: The objective of the study was to determine the unique effect of adiponectin on the metabolic syndrome in overweight Latino youth. PARTICIPANTS: Participants included 175 overweight children (aged 11.1 +/- 1.7 yr, body mass index percentile 97.3 +/- 2.9) with a family history of type 2 diabetes. METHODS: Metabolic syndrome was defined according to a pediatric adaptation of the Adult Treatment Panel III report and included dyslipidemia, abdominal obesity, elevated blood pressure, and prediabetes (impaired fasting glucose or impaired glucose tolerance from a 2-h oral glucose tolerance test). Body composition was estimated via dual-energy x-ray absorptiometry, insulin sensitivity was quantified by the frequently sampled iv glucose tolerance test, visceral fat was measured using magnetic resonance imaging, and adiponectin was determined in fasting serum. RESULTS: In simple linear regression, adiponectin was significantly and inversely related to systolic blood pressure (P < 0.05), waist circumference (P < 0.001), triglycerides (P < 0.001), and 2-h glucose levels (P < 0.05) and positively related to high-density lipoprotein-cholesterol (P < 0.001). In multiple linear regression, adiponectin was significantly related to triglycerides (P < 0.01) and high-density lipoprotein-cholesterol (P < 0.01) independent of age, gender, Tanner stage, body composition, and insulin sensitivity. Analyses of covariance established that adiponectin levels were approximately 25% higher in healthy overweight youth, compared with those with the metabolic syndrome (12.5 +/- 3.5 vs. 9.4 +/- 2.8 microg/ml; P < 0.05). In multiple logistic regression, adiponectin was a significant independent predictor of the metabolic syndrome, even after adjustment for confounders including insulin sensitivity and visceral fat. CONCLUSIONS: Hypoadiponectinemia is an independent biomarker of the metabolic syndrome, and thus, adiponectin may play a role in the pathophysiology of the disorder in overweight youth.