Is leptin associated with hypertensive retinopathy?

Previous studies have demonstrated that elevated plasma leptin concentrations are associated with essential hypertension. It has also recently been shown that leptin plays a promoting role in angiogenesis, and the vascular endothelium expresses the long form of leptin receptor. Those data led us to hypothesize that leptin might contribute to end-organ damage in hypertension. Thus, in the present study we evaluated the relationship between plasma leptin concentrations and hypertensive retinopathy (HR). One hundred and eleven patients newly diagnosed with essential hypertension [EHT; mean age, 43.5 +/-10.7 yr; body mass index (BMI), 28.1 +/- 4.4 kg/m2; male/female ratio, 71/40] and 79 healthy normotensive control subjects (NT; mean age, 43.6 +/- 9.2 yr; BMI, 28.2 +/- 3.3 kg/m2; male/female ratio, 50/29) were enrolled in the study. For the assessment of retinopathy according to the Keith-Wagener classification, direct and indirect ophthalmoscopy were performed in all subjects after dilatation of the pupils. Plasma leptin levels were significantly higher in EHT (11.8 +/- 11.1 ng/mL) than in NT (7.2 +/- 5.1 ng/mL) (P = 0.003). Plasma leptin concentrations were strongly correlated with BMI in both EHT (r = 0.45; P = 0.001) and NT (r = 0.38; P = 0.001) groups. Plasma leptin in patients with grade 2 HR (24.8 +/- 15.8 ng/mL; n = 22) was significantly higher than that in patients with grade 1 HR (16.1 +/- 4.9 ng/mL; n = 29; P = 0.001), grade 0 HR (5.1 +/- 3.1 ng/mL; n = 60; P = 0.001), and NT (P = 0.001). Plasma leptin in patients with grade 1 HR was also significantly higher than that in patients without retinopathy (P = 0.001) or in NT (P = 0.001). The estimated threshold of plasma leptin concentration for HR was 10.2 ng/mL. This critical leptin level served largely to separate patients with retinopathy from those without retinopathy. In summary, our results show that plasma leptin concentrations increase progressively with higher grades of hypertensive retinopathy even after correction for BMI, suggesting that a critical leptin level is needed for the development of retinopathy. Elevated concentrations of plasma leptin might be secondary to release of leptin by the vascular endothelium damaged by high blood pressure, as an epiphenomenon. However, a pathogenic role for leptin in hypertensive retinopathy cannot be excluded.     

Serum levels of transforming growth factor beta1 are significantly correlated with venous invasion in patients with gastric cancer

BACKGROUND AND AIM: The significance of serum levels of transforming growth factor (TGF)-beta1 in the development of gastric cancer is unclear. The purpose of this study is to determine whether serum TGF-beta1 correlated with the clinicopathological findings of patients with gastric cancer. METHODS: Transforming growth factor-beta1 levels in the serum of 275 gastric cancer patients and 275 gender- and age-matched healthy controls were measured with enzyme-linked immunosorbent assay (ELISA) using a commercially available kit. RESULTS: The mean level of serum TGF-beta1 of gastric cancer patients (15.9 +/- 5.9 ng/mL) was significantly higher than that (13.9 +/- 7.4 ng/mL) of healthy controls (P < 0.01). The odds ratio for the subjects in the highest quartile (16.7 ng/mL or more) was 4.03 (95% confidence interval, 2.14-7.58), as compared with that for the subjects in the lowest quartile (0-9.5 ng/mL). Patients with venous invasion compared to those without venous invasion had significantly elevated serum TGF-beta1 (17.3 +/- 7.2 vs 15.0 +/- 5.1 ng/mL; P = 0.04). There were no statistically significant differences between the two groups categorized by histological type, lymph node metastasis and distant metastasis. Logistical regression analysis showed that venous invasion was significantly correlated with elevated serum TGF-beta1 levels (P = 0.02). CONCLUSIONS: The present study showed that an elevated serum TGF-beta1 level may be significantly correlated with venous invasion in gastric cancer patients.     

Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents

Matrix metalloproteinases (MMPs) have been implicated in the atherosclerotic process and risk factors for the disease such as hypertension, hyperlipidemia, or diabetes mellitus in adults. So far, circulating levels of MMPs and their tissue inhibitors (TIMPs) have not been assessed in children and adolescents with obesity, a known risk factor for cardiovascular disease. Plasma levels of MMP-9 and TIMP-1 were measured immunoenzymatically in 45 obese children and adolescents, aged 15 +/- 1.8 years. The control group consisted of 28 healthy children, aged 14.5 +/- 2.5 years. MMP-9 and TIMP-1 concentrations were higher in obese children than in the control group (MMP-9: 553.5 +/- 311 vs 400.4 +/- 204 ng/mL, respectively; P = .02; TIMP-1: 161.2 +/- 32 vs 143.1 +/- 20.1 ng/mL, respectively; P = .03). We found significantly higher levels of MMP-9 in obese children with coexisting hypertension than in obese normotensive patients (635 +/- 308 vs 450 +/- 289 ng/mL, respectively; P = .04). MMP-9 correlated with body mass index (BMI) (r = 0.33, P = .005) and fasting insulin (r = 0.3, P = .013); TIMP-1 correlated with BMI (r = 0.35, P = .006). In the group of obese hypertensive children (n = 25), MMP-9 correlated with BMI (r = 0.41, P = .001), systolic blood pressure (r = 0.41, P = .002), fasting insulin (r = 0.37, P = .006), and homeostasis model assessment index of insulin resistance (r = 0.27, P = .03). TIMP-1 correlated with BMI (r = 0.33, P = .025) and systolic (r = 0.38, P = .008) and diastolic (r = 0.47, P = .001) blood pressure. In the regression models, MMP-9 was found to be dependent on fasting insulin (R(2) = 0.16, P = .04), and TIMP-1 on BMI (R(2) = 0.14, P = .04). In the obese hypertensive group, TIMP-1 was dependent on diastolic blood pressure (R(2) = 0.18, P = .04). Obese children and adolescents have elevated plasma concentrations of MMP-9 and TIMP-1. Coexistence of hypertension may exacerbate alterations of extracellular matrix turnover in these patients. It might be hypothesized that elevated MMP and TIMP concentrations may be related to increased cardiovascular risk in obese and particularly in obese hypertensive children and adolescents.     

Perioperative changes in circulating leptin levels in women undergoing total abdominal hysterectomy

To investigate the effects of total abdominal hysterectomy on circulating leptin levels, 16 pre- and 8 postmenopausal patients with uterine leiomyoma or carcinoma in situ of the uterine cervix were enrolled. Serum levels of leptin and fasting blood sugar (FBS) were determined before (day -7) and after surgery (day +1 and +7). Body mass index (BMI) was recorded at day -7 and +7. Anesthesia duration, surgical duration, hematology, and blood loss during surgery were recorded. Relations of these variables to serum leptin levels were investigated. Serum leptin levels rose from 7.3+/-4.7 ng/mL to 9.3+/-5.8 ng/mL at day +1 (P < 0.01), then decreased to 4.9+/-3.0 ng/mL at day +7 (P < 0.05 vs. values at day -7 and +1). FBS levels also rose from 89.4+/-7.5 mg/dL to 119.3+/-24.0 mg/dL (P < 0.01), then returned to normal at day +7 (96.2+/-9.0 mg/dL). However, there was no significant correlation observed between FBS and leptin levels at each time point (r < or = 0.22). BMI decreased from 22.7+/-3.0 kg/m2 to 21.7+/-2.9 kg/m2 at day +7 (P < 0.001). At day -7 and +7, leptin levels were positively correlatd with BMI (r = 0.79, P < 0.001 and r = 0.71, P < 0.001, respectively). Circulating leptin levels were increased on day one after total abdominal hysterectomy.     

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity.

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.     

The relationship between obesity and transforming growth factor beta on renal damage in essential hypertension

The aim of this study was to evaluate the effect of obesity on renal functions and the possible relationship between TGF-beta1 and obesity in hypertensive patients. Seventy newly diagnosed, hypertensive patients (male/female 36/34, aged 45.0 +/- 8.0 years) and 30 (male/female 17/13, aged 41.8 +/- 7.7 years) normotensive controls were included. Patients in both groups were analyzed for serum levels of glucose, creatinine, uric acid, lipids, and TGF-beta1. A 24-hour urine sample was also obtained; creatinine clearance rate and urinary albumin excretion (UEA) were investigated. TGF-beta1 levels were significantly higher (40.7 +/- 13.6 versus 34.2 +/- 12.1 pg/mL, P = 0.02), and creatinine clearance was significantly lower in patients compared with controls (98.9 +/- 25.5 versus 124.5 +/- 23.1 mL/min. per. 1.73 m(2), P = 0.001). Serum TGF-beta1 levels (45.2 +/- 14 versis 38.0 +/- 12.8 pg/mL, P = 0.03), creatinine clearance rates (109.8 29.9 versus 93.0 +/- 20.8 mL/min. per. 1.73 m(2), P = 0.001), and urinary albumin excretion (55.7 +/- 62.0 versus 12.7 +/- 12.6 mg/24 h, P = 0.002) were higher in obese hypertensive patients than in nonobese patients. In hypertensive patients, TGF-beta1 levels correlated with body mass index (r = 0.296, P = 0.01) and creatinine clearance (r = 0.238, P = 0.04). The results suggest that increased body mass index is associated with increased creatinine clearance, urinary albumin excretion, and TGF-beta1 levels in essential hypertension. In addition, TGF-beta1 is positively correlated with body mass index and creatinine clearance in patients with essential hypertension.     

Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells

Interleukin-6 (IL-6), a product of bone marrow stromal cells (BMSCs), is a growth factor for multiple myeloma (MM) cells. Transforming growth factor-beta1 (TGF-beta1) is also produced by BMSCs and can regulate IL- 6 secretion by several tissues, including BMSCs. The present study was designed to characterize in vitro tumor growth regulation by TGF-beta1 in MM. Sorted CD38+CD45RA- MM cells secreted significantly more TGF- beta1 (8.2 +/- 2.0 ng/mL) than peripheral blood mononuclear cells (P < .001), splenic B cells (P < .001), and CD40 ligand (CD40L) pretreated B cells (P < .05). TGF-beta1 secretion by MM-BMMCs (3.8 +/- 0.9 ng/mL) was significantly greater than by N-BMMCs (1.2 +/- 0.1 ng/mL, P < .001). MM-BMSCs also secreted significantly more TGF-beta1 (6.6 +/- 2.5 ng/mL, n = 11) than N-BMSCs (4.4 +/- 0.6 ng/mL, P < .02, n = 10) and N- BMSC lines (3.9 +/- 0.2 ng/mL, P < .02, n = 6). TGF-beta1 secretion was correlated with IL-6 secretion in MM-BMSCs. Anti-TGF-beta1 monoclonal antibody both blocked IL-6 secretion by BMSCs and inhibited the increments in IL-6 secretion by BMSCs induced by MM cell adhesion. Moreover, exogenous TGF-beta1 upregulated IL-6 secretion by MM-BMSCs, normal BMSCs, and CD38+ CD45RA- MM cells, as well as tumor cell proliferation. This is in contrast to the inhibitory effect of TGF- beta1 on proliferation and Ig secretion of normal splenic B cells. Finally, retinoblastoma proteins (pRB) are constitutively phosphorylated in MM cells; TGF-beta1 either did not alter or increased pRB phosphorylation. pRB are dephosphorylated in splenic B cells and phosphorylated in CD40L triggered B cells in contrast to its effects on MM cells, TGF-beta1 decreased phosphorylation of pRB in CD40L treated B cells. These results suggest that TGF-beta1 is produced in MM by both tumor cells and BMSCs, with related tumore cell growth. Moreover, MM cell growth may be enhanced by resistance of tumor cells to the inhibitory effects of TGF-beta1 on normal B-cell proliferation and Ig secretion.     

Plasma leptin levels after biliopancreatic diversion: dissociation with body mass index.

Human obesity is associated with increased leptin levels, related to body composition and fat mass (FM). Insulin has been suggested to be a regulator of in vivo leptin secretion. To further investigate the relationships between insulin and leptin levels in human obesity, we have studied 10 obese females, aged 26-57 yr [body mass index (BMI), 42.9+/-6.3], successfully treated by biliopancreatic (BPD) diversion, in an early postoperative period (2 months after surgery, post-BPD I; BMI, 37.2+/-7.5) and a late postoperative period (16-24 months after surgery; BMI, 27.6+/-3.96). Fourteen normal female subjects (18-59 yr; BMI, 27.9+/-1.4 kg/m2) were studied as controls. In pre-BPD obese subjects, leptin levels were higher than those in controls (60.5+/-18.8 vs. 28.7+/-4.8 ng/mL; P<0.001). BMI and insulin levels were also significantly greater (P<0.0001 and P<0.03, respectively). After surgery, the three parameters considered significantly decreased (P = 0.0007 for BMI, P<0.0001 for leptin, and P = 0.038 for insulin, using Friedman's test for repeated data). Concerning the correlation between leptin and FM in our patients, control subjects and pre-BPD subjects confirmed the correlation found in the general population (r = 0.78; P<0.01). On the contrary, post-BPD patients at 2 months lay outside the general correlation between FM and leptin; in fact, patients with low leptin levels still had a high FM. Moreover, in the post-BPD patients there was no longer a significant correlation between FM and leptin. Concerning the correlation between insulin and leptin levels, a significant correlation was present in control subjects and pre-BPD patients (r = 0.46; P<0.05). Using correlation analysis for repeated measures in surgically treated obese patients, a significant correlation within the subjects was present (r = 0.91; P<0.0001). After operation, BMI and leptin levels had a different pattern of decrease; leptin decreased rapidly, without correlation with BMI, indicating that body composition is not the only factor regulating leptin levels. The consistent correlation with insulin levels suggests an important interaction between these two hormones in post-BPD obese subjects.     

Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30.

We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004). The higher the entry serum leptin, the greater its reduction on metformin therapy (partial R(2) = 29%, P =.002). The greater the reduction in insulin on metformin, the greater the reduction in leptin (partial R(2) = 8%, P =.03). The higher the entry PAI-Fx, the greater the reduction in PAI-Fx on metformin (partial R(2) = 43%, P =.0001). Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action.     

An alpha1-receptor blocker reduces plasma leptin levels in hypertensive patients with obesity and hyperleptinemia.

Obesity is often complicated by hypertension, and both conditions are risk factors for atherosclerosis. Leptin has attracted attention as a possible cause of hypertension in obese persons. We investigated the effect of a slow-release alpha1-receptor blocker, bunazosin hydrochloride, on leptin levels and insulin resistance in obese hypertensive patients with hyperleptinemia. The subjects were 17 patients (12 men and 5 women aged 56.1 +/- 12.2 years) with essential hypertension who were not receiving alpha1-receptor blockers. They had a body mass index (BMI) > or = 25 kg/m2 and a plasma leptin concentration > or = 5 ng/ml. They received oral therapy with bunazosin hydrochloride at doses of up to 9 mg/day. The plasma leptin concentration, body weight, blood pressure, heart rate, fasting blood glucose, plasma insulin concentration, and free fatty acid level were compared between before and after treatment. Although there was no significant change of BMI, there was a significant decrease of plasma leptin after treatment (10.6 +/- 5.4 ng/ml vs. 8.7 +/- 3.4 ng/ml, p = 0.0128), as well as a significant decrease of plasma insulin (9.8 +/- 4.8 microU/ml vs. 8.1 +/- 4.6 microU/ml, p = 0.0494) and HOMA-R (2.9 +/- 2.1 vs. 2.2 +/- 1.5, p = 0.0237). In conclusion, bunazosin hydrochloride reduced the plasma leptin level and improved insulin resistance in hypertensive patients with obesity and hyperleptinemia.     

Soluble adhesion molecules (sICAM-1, sVCAM-1) and selectins (sE selectin, sP selectin, sL selectin) levels in children and adolescents with obesity, hypertension, and diabetes

The attachment of monocytes and lymphocytes to endothelial cells, which initiates atherosclerosis, arises under the influence of adhesion molecules. The preclinical phase of this disease lasts many decades, and this provides an opportunity for the presymptomatic detection of high-risk subjects. We evaluated levels of the adhesion molecules: sICAM-1 (soluble intercellular adhesion molecule 1), sVCAM-1 (soluble vascular adhesion molecule 1), sE selectin, sP selectin, and sL selectin in children with atherosclerosis risk factors (n = 123, mean age 15.1 years) (obese [n = 17], hypertensive [n = 25], obese with hypertension [n = 30], type 1 diabetic [n = 51]). Twenty-seven healthy children formed the control group, mean age 15.2 years. sICAM-1 was higher in the study group compared with control (314.1 +/- 61 vs 264.9 +/- 55 ng/mL, P < .01). The same was found for sVCAM-1 (513.7 +/- 187 vs 407.9 +/- 76 ng/mL, P < .05) and E selectin (86.04 +/- 33.6 vs 62.1 +/- 20.3 ng/mL, P < .01). sP-selectin and sL-selectin levels were not different compared with controls. E selectin correlated with body mass index (BMI; r = 0.18, P = .03), total cholesterol (r = 0.2, P = .016), and triglycerides (r = 0.22, P = .008). sICAM-1 correlated with BMI (r = 0.19, P = .019) and systolic blood pressure (r = 0.13, P = .045). In multiple linear regression analysis, sE selectin was found to be associated with triglycerides (R2 = 0.29, P = .045), sICAM-1 dependent on BMI (R2 = 0.58, P = .047), and sVCAM-1 dependent on total cholesterol (R2 = 0.51, P = .006). Elevated concentrations of sICAM-1, sVCAM-1, and E selectin were found in obese, hypertensive, and diabetic children. We conclude that endothelial activation appears in these children, and adhesion molecules are related to the earliest stages of atherosclerosis.     

IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin?

We have recently shown that human monocytic cells express functional leptin receptors and that leptin is capable of inducing the expression and secretion of the IL-1 receptor antagonist (IL-1Ra). Although IL-1Ra has anti-inflammatory and possibly anti-atherogenic properties, it has also been shown to antagonize the action of leptin at the hypothalamic level in rodents, thereby inducing leptin resistance. We have therefore examined whether IL-1Ra levels are increased in human hyperleptinemic conditions, such as obesity. To this end, we measured serum IL-1Ra levels in 20 morbidly obese nondiabetic subjects [body mass index (BMI), 45 +/- 6 kg/m(2); serum leptin, 52 +/- 20 ng/ml] as well as in 10 age- and sex-matched lean controls (BMI, 22 +/- 2 kg/m(2); serum leptin, 7 +/- 4 ng/ml). Serum IL-1Ra concentrations proved to be elevated 6.5-fold in the obese subjects, and they were positively correlated in a linear manner with the leptin levels (r(2) = 0.34; P = 0.01), although lean body mass (LBM) and the insulin resistance index were even better predictors of IL-1Ra levels (r(2) = 0.45 and 0.58, respectively; P < 0.01). Six months after 15 of the 20 obese subjects had undergone bypass surgery for their morbid obesity, their mean BMI and leptin levels decreased to 33 +/- 7 kg/m(2) and 18 plus minus 12 ng/ml, respectively. This change in leptin concentrations was associated with a significant reduction in IL-1Ra levels (P < 0.02). However, there was a better correlation between the decrease in IL-1Ra level and the change in LBM than with the reduction in leptin levels, indicating that leptin is not the sole determinant of circulating IL-1Ra in obesity. In summary, we demonstrate that IL-1Ra levels are highly elevated in human obesity and that its concentrations decrease after weight loss from bypass surgery. However, LBM and insulin resistance are better predictors of serum IL-1Ra concentrations than are leptin levels, suggesting that additional metabolic factors control the secretion of this cytokine antagonist. Although the immunological consequences of this alteration remain unknown, it is tempting to speculate that the obesity-related increase in IL-1Ra might contribute to the central resistance to leptin in obese patients, similar to the inhibition of the hypothalamic signaling of leptin by IL-1Ra in rodents.     

Relation of plasma leptin to lipoproteins in overweight children undergoing weight reduction

BACKGROUND: In obese children, plasma leptin is elevated and correlates with the body mass index (BMI). In obese adults, plasma leptin decreases during weight reduction. Since the leptin system changes dynamically in puberty, we asked whether weight reduction in obese adolescents has similar consequences for plasma leptin as in overweight adults. In plasma, a portion of leptin is bound to several as yet uncharacterised proteins. We therefore studied the possible association of leptin with plasma lipoproteins. SUBJECTS AND METHODS: We measured plasma leptin, lipoprotein cholesterol and apolipoproteins (apo) A-I and B in 34 obese children (age 12.5+/-1.9 y, relative BMI 165.0+/-28.1%) before and after three weeks of weight reduction in a dietary camp. Lipoprotein binding of endogenous and exogenously radiolabelled leptin was studied by preparative ultracentrifugation. RESULTS: Plasma leptin was higher in obese children than in normal weight controls and fell from 16.5+/-9.8 ng/ml to 10.0+/-8.6 ng/ml after weight reduction (P < 0.001). In multivariate regression, relative BMI and apoA-I were significant predictors of baseline leptin and accounted for 38% (P = 0.003) and 15% (P = 0.006) of the variance of baseline leptin concentrations in obese children. Only the difference in plasma high-density lipoprotein (HDL)-cholesterol independently predicted the change of plasma leptin that was associated with weight reduction, explaining 29% of the variance of leptin changes (P = 0.0032). A substantial portion of both endogenous and exogenously labelled leptin was recovered with HDL isolated by ultracentrifugation. CONCLUSIONS: We conclude that plasma leptin decreases in overweight children undergoing short term weight reduction. In obese children, plasma apoA-I and HDL-cholesterol are independent predictors of leptin concentrations during weight loss, respectively. In addition, HDLs transport a variable portion of leptin in the circulation.     

Difference of plasma leptin levels in venous and arterial cord blood: relation to neonatal and placental weight

To investigate the physiological significance of umbilical plasma leptin in the fetal growth and its possible origin of production during pregnancy, plasma leptin concentrations in venous and arterial cord bloods were measured in 42 neonates (male = 23, female = 19, gestational age 36-41 weeks, birth weight 2600-4000 g). Leptin concentrations in umbilical veins (5.65 +/- 0.53 ng/mL, n = 42) and umbilical arteries (0.56 +/- 0.07 ng/mL, n = 42) were significantly (P < 0.001) lower than those in maternal peripheral veins (22.36 +/- 1.06 ng/mL, n = 42). Mean plasma leptin concentration (+/- SEM) in venous cord blood was significantly (P < 0.001) higher than that of arterial cord blood. There was significantly positive correlation (r = 0.447, P < 0.01) between umbilical venous leptin levels and neonatal body mass index (BMI). A positive correlation (r = 0.435, P < 0.01) was also found between umbilical arterial leptin and neonate BMI. There was no positive correlation between umbilical leptin levels in venous cord blood and placental weight. We thus conclude that umbilical plasma leptin may play an essential role in the fetal growth and metabolism during pregnancy and placenta is one of the major sources of leptin production, but the level of leptin in umbilico-placental circulation is independent of the weight of placenta.     

Serum leptin levels in patients with idiopathic thrombocytopenic purpura

OBJECTIVES: The purpose of this study was to evaluate serum leptin levels in idiopathic thrombocytopenic purpura (ITP), in order to determine the influence of leptin on the pathogenesis of ITP. SUBJECTS AND METHODS: Forty-six untreated patients with chronic ITP were compared with 40 healthy people of similar age, sex and body mass index (BMI). Serum leptin levels (ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that the mean serum leptin levels in patients with ITP (22.11 +/- 15.84 ng/mL) were significantly (P < 0.001) higher than that in healthy control volunteers (5.44 +/- 4.84 ng/mL). Furthermore, serum leptin levels in patients with ITP were inversely related (r = -0.86, P < 0.001) to the platelet counts and positively related to the platelet-associated IgG (PAIgG) levels (r = 0.7, P < 0.001). The levels of PAIgG and platelet counts were significantly different between leptin-positive (level greater than mean +/- 2 SD control value) and leptin-negative patients. CONCLUSION: These findings suggest that leptin might play an important role in the pathogenesis of ITP.     

Transforming growth factor beta-1 level in pleural effusion

OBJECTIVE: Transforming growth factor-beta1 is an important immunomodulator. The diagnostic role of TGF-beta1 has not been systematically investigated in pleural effusion. METHODOLOGY: A prospective clinical study of 45 patients (23 men, 22 women; mean age 49 +/- 21 years) with pleural effusion was performed. Of these patients, 19 had malignant pleural effusion, 14 had tuberculous pleural effusion, seven had empyema/parapneumonic pleural effusion, and five had transudative pleural effusion due to congestive heart failure. The concentrations of TGF-beta1 were measured by ELISA in all pleural fluid samples and in serum samples only from patients with malignant and tuberculous pleural effusions. RESULTS: The median TGF-beta1 levels of malignant, tuberculous and empyema/parapneumonic pleural effusions were 7.25 ng/mL, 7.81 ng/mL, and 9.75 ng/mL, respectively. There was no significant difference between them. The median TGF-beta1 level was 5.62 ng/mL in the transudate pleural effusion group and it was significantly lower than that in the empyema/parapneumonic group (P < 0.05). The pleural fluid TGF-beta1 levels did not correlate with cell profiles of the pleural fluid. The median serum TGF-beta1 levels in malignant and tuberculous pleural effusion groups were 7.38 ng/mL and 7.38 ng/mL, respectively. There was no significant difference between the levels of TGF-beta1 in paired samples of serum and pleural fluid. CONCLUSIONS: This study shows that TGF-beta1 concentrations in exudative pleural effusions are higher than those in transudative effusions secondary to congestive heart failure but TGF-beta1 concentrations do not assist in differentiating exudative effusions.     

Comparative analysis of plasma leptin levels in both genders of patients with essential hypertension and healthy subjects

While pathogenesis of hypertension is not clearly deciphered yet, increase in body weight, most of the time, is associated with hypertension. There are reports indicating that leptin, product of the Ob gene mainly synthesized in adipocytes, may have role(s) in hypertension, but contribution of the gender is rather contradictive. In the present study, plasma leptin levels in patients of both genders with hypertension and normotensive controls were measured and the relationship between plasma leptin levels and BMI were evaluated in both sexes. Total of 62 patients (31 M/31 F) diagnosed with essential hypertension who were not under any antihypertensive medication were admitted into the study. The control group was composed of 56 (25 M/31 F) age-, BMI- and sex-matched healthy normotensive volunteers. Plasma leptin levels were determined by a commercial ELISA kit. Plasma leptin and leptin/BMI levels (Mean +/- SEM) of women (n:62) were significantly higher than men (n:56) (20.10 +/- 1.47 ng/ml versus 4.72 +/- 0.50 ng/ml; p < 0.0001). Plasma leptin and leptin/BMI levels of patients of both genders with hypertension were significantly higher than in normotensive subjects (p < 0.05). Leptin and leptin/BMI levels in obese hypertensives were higher than obese normotensives (p < 0.05). Obese hypertensive women had higher leptin and leptin/BMI levels than obese normotensive women (p < 0.05). In conclusion, these results support the hypothesis that a possible link exists between leptin and hypertension. Further studies are needed to clarify how increased levels of leptin affects the pathophysiology of hypertension.     

阻塞性睡眠呼吸暂停患者血清瘦素水平的研究

目的　探讨瘦素在阻塞性睡眠呼吸暂停综合征 (OSAS)患者体内的变化。方法　选择年龄及体重指数 (BMI)差异无显著性的OSAS患者 5 8例和单纯肥胖者 2 1例 ,用多导睡眠呼吸监测仪进行监测 ,用放射免疫法测定所有对象的血清瘦素。结果　 (1)无论男性还是女性 ,OSAS患者瘦素水平 [(6 1± 1 7) μg/L ,(19 5± 9 9) μg/L]平均高于单纯肥胖者 [(4 5± 1 7) μg/L ,(10 5± 2 4) μg/L](P <0 0 1,P <0 0 5 )。 (2 )单纯肥胖者及OSAS患者血清瘦素水平分别与BMI呈显著正相关 (r=0 5 9,P <0 0 1;r=0 6 4,P <0 0 1) ,同时OSAS患者血清瘦素水平分别与呼吸暂停及低通气指数 (AHI) (r=0 47,P <0 0 1)和颈围 (r=0 6 4,P <0 0 1)也有明显的正相关。结论　OSAS患者血清瘦素水平比单纯肥胖者更高 ,除了肥胖、颈围宽外 ,OSAS本身也是引起瘦素水平升高的原因。     

Regulation of ob gene expression: evidence for epinephrine-induced suppression in human obesity.

Leptin acts as satiety factor and increases energy expenditure. Studies conducted on animals and in vitro on adipocytes culture have shown that infusion of catecholamines leads to a significant reduction of ob gene expression; it appears of interest to evaluate the in vivo effects of adrenergic activation on the expression of the ob gene in humans. We studied ob gene expression in adipose tissue samples from 13 obese subjects before and after epinephrine (25 ng/min x kg ideal body weight for 3 h) and 6 obese patients during saline infusion. Hormonal infusion led to a significant increase in epinephrine plasma levels (from 27 +/- 4 to 339 +/- 75 pg/mL; P < 0.001), plasma free fatty acids (from 0.73 +/- 0.05 to 0.98 +/- 0.07; P < 0.05), heart rate (13.5 +/- 3.1 beats/min; F = 2.9; P < 0.03), and systolic blood pressure (F = 2.7; P < 0.05), whereas diastolic blood pressure did not show significant variation. Plasma leptin levels decreased by the end of the infusion (from 63 +/- 13 to 49 +/- 11 ng/mL; P < 0.05), and ob messenger ribonucleic acid levels were significantly reduced (decrease amounting to 47 +/- 5% of basal values). Our study shows that adrenergic activation contributes to regulate ob messenger ribonucleic acid levels in humans. The interaction between epinephrine and leptin may operate during metabolic and psychological stress to regulate energy expenditure and food intake.     

Increased transforming growth factor-beta(1) circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin

OBJECTIVES: We sought to determine whether inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase with pravastatin affects transforming growth factor-beta(1) (TGF-beta(1)) circulating levels and its production in the monocytes of hypercholesterolemic patients. BACKGROUND: Transforming growth factor-beta(1) is a multifunctional growth factor/cytokine involved in many physiologic and pathologic processes, such as vascular remodeling and atherogenesis. Statins have been reported to have a modulatory role in cytokine expression in the monocytes of hyperlipidemic patients. METHODS: We evaluated, in a cross-over study design, plasma TGF-beta(1) levels and ex vivo TGF-beta(1) production in the monocytes of hypercholesterolemic patients before and after four to six weeks of lipid-lowering treatment with diet or diet plus 40 mg/day of pravastatin. In addition, isolated blood monocytes were subjected to pravastatin treatment and evaluated for TGF-beta(1) messenger ribonucleic acid (mRNA) expression and TGF-beta(1) in vitro production. RESULTS: Lipid-lowering treatment significantly decreased total cholesterol and low-density lipoprotein cholesterol plasma levels. Pravastatin, but not a low lipid diet, induced a significant increase in TGF-beta(1) plasma levels (from 1.7 +/- 0.5 ng/ml to 3.1 +/- 1.1 ng/ml, p < 0.001) and in ex vivo monocyte production (from 1.8 +/- 0.8 ng/ml to 3.9 +/- 1.0 ng/ml, p < 0.001). The increase in TGF-beta(1) levels was not related to the changes in the lipid profile observed with pravastatin. An increase of approximately twofold in TGF-beta(1) production and in mRNA expression was also observed after in vitro treatment of human monocytes with pravastatin (5 microM). Co-incubation with mevalonate reversed the in vitro effect of pravastatin. CONCLUSIONS: 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition with pravastatin increases TGF-beta(1) plasma levels, as well as monocyte production, in hypercholesterolemic patients. The mevalonate pathway plays a role in the regulation of TGF-beta(1) expression in human monocytes. A possible implication in the biologic and clinical effects of statins can be suggested.