Regulation of plasminogen activitor inhibitor-1 in human adipose tissue: interaction between cytokines, cortisol and estrogen.

To investigate further the role of plasminogen activator inhibitor-1 (PAI-1) in human adipose tissue, the regulation of cytokines, cortisol (dexamethasone) as well as estrogen on PAI-1 were determined in human adipose tissue fragments. PAI-1 activity was increased in human adipose tissue fragments incubated for 48 h with interleukin-1beta (IL-1beta) (2.6-fold, p < 0.01) and tumor necrosis factor-alpha (2.3-fold, p < 0.01). Incubation with interleukin-6 revealed a non-significant decrease in PAI-1 activity. Parallel findings were obtained when studying the PAI-1 mRNA expression. Dexamethesone increased PAI-1 activity after incubation for 8 h (p < 0.05) and enhanced the stimulation of IL-1beta after 8 h incubation. However, after 24 and 48 h, dexamethasone significantly reduced the IL-1beta induced increase in PAI-1 activity by 24-52% (p < 0.05), accordingly, PAI-1 mRNA expression was reduced 60%. Finally, the induction of PAI-1 activity and PAI-1 mRNA expression by IL-1beta was attenuated by estrogen (17.8+/-4.9%, p < 0.05 and 20.9+/-5.8%, p < 0.05, respectively). These results indicate that multiple cytokines, estrogen and dexamethasone may be involved in the regulation of PAI-1 biosynthesis in human adipose tissue, and suggest that there are interactions between cytokines and these steroid hormones. The interplay between these hormones may be of importance for the levels of PAI-1 observed in obesity and associated states.     

TNF-alpha, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue.

Plasminogen activator inhibitor-1 (PAI-1) is produced by adipose tissue, and elevated PAI-1 levels in plasma are a risk factor in the metabolic syndrome. We investigated the regulatory effects of TNF-alpha and IL-6 on PAI-1 gene induction in human adipose tissue. Twenty healthy men underwent a 3-h infusion of either recombinant human TNF-alpha (n = 8), recombinant human IL-6 (n = 6), or vehicle (n = 6). Biopsies were obtained from the subcutaneous abdominal adipose tissue at preinfusion, at 1, 2, and 3 h during the infusion, and at 2 h after the infusion. The mRNA expression of PAI-1 in the adipose tissue was measured using real-time PCR. The plasma levels of TNF-alpha and IL-6 reached 18 and 99 pg/ml, respectively, during the infusions. During the TNF-alpha infusion, adipose PAI-1 mRNA expression increased 2.5-fold at 1 h, 6-fold at 2 h, 9-fold at 3 h, and declined to 2-fold 2 h after the infusion stopped but did not change during IL-6 infusion and vehicle. These data demonstrate that TNF-alpha rather than IL-6 stimulates an increase in PAI-1 mRNA in the subcutaneous adipose tissue, suggesting that TNF-alpha may be involved in the pathogenesis of related metabolic disorders.     

Stimulation of interleukin-6 release by interleukin-1beta from isolated human adipocytes

The secretion of interleukin-6 (IL-6) is modulated by immune, hormonal and metabolic stimuli in a cell-specific manner. We investigated the effect of cytokines, TNFalpha and IL-1beta, and insulin on IL-6 release from human adipocytes and peripheral blood cells (PBC). Adipocytes released IL-6 constitutively (after 5 h: 5.64 [1.61-15.30]pg ml(-1), after 10 h: 15.95 [2.34-45.59]pg ml(-1), p = 0.007), while PBC secretion did not change significantly over this period. LPS stimulated IL-6 secretion in PBC after 5 h but was without effect on adipocytes. TNFalpha and insulin induced IL-6 production from PBC, but had no effect on adipocytes. IL-1beta, however, induced a substantial increase in IL-6 release in adipocytes and PBC (all p < 0.05). Adipose tissue production of IL-1beta was assessed in vivo by measuring arterio-venous differences across the subcutaneous abdominal adipose bed. Net release of IL-1beta was not observed, suggesting that under basal conditions there is no detectable release of this cytokine into the circulation from this depot. In conclusion (1) PBC demonstrate regulated IL-6 release, while the adipocyte release has a large constitutive component; (2) immune modulators, such as LPS, TNFalpha and IL-1beta, all induce PBC IL-6 release, but only IL-1beta stimulates adipocyte release. Though IL-1beta is not an endocrine signal from adipose tissue, it is an autocrine/paracrine stimulator of IL-6 release from human adipocytes.     

Metformin, but not thiazolidinediones, inhibits plasminogen activator inhibitor-1 production in human adipose tissue in vitro.

Biguanides and thiazolidinediones (TZDs), which are primarily used as anti-diabetic drugs, are also associated with other beneficial effects on cardiovascular risk factors such as reduced plasma plasminogen activator inhibitor-1 (PAI-1) concentration in both diabetic and non-diabetic obese subjects. Since human adipose tissue is of importance for the production of PAI-1, the aim of the present study was to investigate the possible direct effects of these anti-diabetic agents on PAI-1 mRNA and secretion by human adipose tissue. Adipose tissue was obtained from biopsies taken from the subcutaneous abdominal depot. Adipose tissue fragments, isolated mature adipocytes, and preadipocytes were incubated in vitro with metformin and various TZDs. Metformin (0.1 - 10 mM) dose-dependently decreased PAI-1 production (and PAI-1 mRNA) under both basal (43 % inhibition at 10 mM, p < 0.05) and interleukin-1beta (IL-1beta)-stimulated conditions where the levels were inhibited by 47.8 % at 1 mM metformin (p < 0.05) and by 100 % at 10 mM (p < 0.01). None of the TZDs tested (PPAR-gamma agonists: troglitazone, pioglitazone, or ciglitazone) had any effects on PAI-1 production. Moreover, no effects on PAI-1 production were observed using various PPAR-alpha agonists such as 5, 8, 11, 14-eicosatetraynoic acid (ETYA), Wy14643 and fenofibrate. Our findings indicate no direct effects of TZDs on PAI-1 secretion, whereas metformin was able to directly inhibit PAI-1 production in human adipose tissue.     

Increased plasma levels of adipokines in preeclampsia: relationship to placenta and adipose tissue gene expression

Adipokines are predominantly secretory protein hormones from adipose tissue but may also originate in placenta and other organs. Cross-sectionally, we monitored maternal plasma concentration of adiponectin, resistin, and leptin and their mRNA expression in abdominal subcutaneous adipose tissue and placenta from preeclamptic (PE; n = 15) and healthy pregnant (HP; n = 23) women undergoing caesarean section. The study groups were similar in age and BMI, whereas HOMA-IR tended to be higher in the PE group. In fasting plasma samples, the PE group had higher concentrations of adiponectin (18.3 +/- 2.2 vs. 12.2 +/- 1.1 microg/ml, P = 0.011), resistin (5.68 +/- 0.41 vs. 4.65 +/- 0.32 ng/ml, P = 0.028), and leptin (34.4 +/- 3.2 vs. 22.7 +/- 2.1 ng/ml, P = 0.003) compared with the HP group. Adiponectin and leptin concentrations were still different between PE and HP after controlling for BMI and HOMA-IR, whereas resistin concentrations differed only after controlling for BMI but not HOMA-IR. We found similar mean mRNA levels of adiponectin, resistin, and leptin in abdominal subcutaneous adipose tissue in PE and HP women. When data were pooled from PE and HP women, resistin mRNA levels in adipose tissue also correlated with HOMA-IR (r = 0.470, P = 0.012) after controlling for BMI and pregnancy duration. Resistin mRNA levels in placenta were not significantly different between PE and HP, whereas leptin mRNA levels were higher in PE placenta compared with HP. Thus increased plasma concentrations of adiponectin and resistin in preeclampsia may not relate to altered expression levels in adipose tissue and placenta, whereas both plasma and placenta mRNA levels of leptin are increased in preeclampsia.     

Proinflammatory adipocytokines induce TIMP-1 expression in 3T3-L1 adipocytes

Tissue inhibitor of metalloproteinase (TIMP)-1 is an adipocyte-secreted protein upregulated in obesity which promotes adipose tissue development. Furthermore, the proinflammatory adipocytokines tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-6 induce insulin resistance, and plasma concentrations are increased during weight gain. In the current study, the impact of TNFalpha and IL-6 on TIMP-1 mRNA and protein expression was determined in 3T3-L1 adipocytes. Interestingly, TNFalpha and IL-6 induced TIMP-1 protein secretion more than 3- and 2-fold, respectively. Furthermore, TIMP-1 mRNA was upregulated in a time- and dose-dependent fashion. Inhibitor experiments suggested that nuclear factor kappaB and p 44/42 mitogen-activated protein kinase are involved in both, basal and adipocytokine-induced TIMP-1 expression. Moreover, the thiazolidinedione troglitazone partly reversed TNFalpha- but not IL-6-induced TIMP-1 synthesis. Taken together, we demonstrate that TIMP-1 expression is selectively upregulated in fat cells by proinflammatory adipocytokines and might play a role in maintaining adipose tissue mass in obesity.     

Differences in plasminogen activator inhibitor 1 in subcutaneous versus omental adipose tissue in non-obese and obese subjects.

Human adipose tissue can produce plasminogen activator inhibitor-1 (PAI-1). It has been suggested that high levels of PAI-1 are of importance in enhanced cardiovascular disease observed among obese subjects, especially abdominally obese individuals. In the present study, we investigated the level of mRNA and production of PAI-1 in adipose tissue from two adipose tissue depots (omental vs. subcutaneous). Adipose tissue from both depots was obtained from obese (mean BMI, 46.9 kg/m 2) and non-obese (mean BMI, 23.9 kg/m 2) women. PAI-1 mRNA was measured both in fresh adipose tissue obtained immediately after surgery and after the adipose tissue (fragments) had been incubated for up to 72 h. In immediately frozen adipose tissue, PAI-1 mRNA expression was similar in omental and subcutaneous adipose tissue. No differences between obese and non-obese women were found. However, when adipose tissue fragments were cultured, PAI-1 mRNA and PAI-1 production were significantly higher in omental than in subcutaneous adipose tissue (p < 0.05). In the culture system, the production of PAI-1 in obese subjects was higher than in non-obese subjects in both subcutaneous (p < 0.05) and in omental adipose tissue (p = 0.19). In order to test whether these regional differences observed after incubation of the adipose tissue were due to differences in local accumulation of cytokines that may stimulate PAI-1 by a paracrine or autocrine manner, we investigated the expression of transforming growth factor beta1 (TGF-beta1) mRNA and tumor necrosis factor alpha (TNF-alpha) mRNA and protein. No differences between the two fat depots were found. In conclusion, no differences in PAI-1 expression between omental and subcutaneous adipose tissue were observed in biopsies frozen immediately after removal, but after incubation of adipose tissue (which somehow stimulates PAI-1 production), higher levels of PAI-1 were found in omental adipose tissue than in subcutaneous adipose tissue. Finally, PAI-1 production in adipose tissue from obese women was higher in non-obese women after incubation for 72 h.     

The postoperative stress response and its reflection in cytokine network and leptin plasma levels

The objective of the present report was to clarify the postoperative stress response of some inflammatory markers, namely of proinflammatory cytokines and leptin levels during uncomplicated postoperative periods. The results were compared with the dynamics of these parameters during intraabdominal sepsis. We followed 20 patients after a planned resection of colorectal cancer in stage Ib-IV with uncomplicated healing and 13 obese men after laparoscopic non-adjustable gastric banding. These were compared to 12 patients with proven postoperative sepsis. The control group consisted of 18 healthy men. The observed parameters included serum levels of cytokines, tumor necrosis factor-alpha (TNFalpha), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1 ra), IL-6, IL-8, soluble receptor of interleukin-2 (sIL-2R) and leptin. It was found that during the first 24 h after resection there was a significant increase in the serum concentration of IL-6 up to 1125+/-240 ng/l, which declined within the next 48-72 h. Serum concentration of TNFalpha was highest 18-24 h after resection (205+/-22 ng/l) and after banding (184+/-77 ng/l). IL-1 beta had a stable serum concentration without significant elevation. Serum concentration of IL-8 after resection rose to 520+/-200 ng/l after 36-48 h. Maximal cytokine levels after gastric banding were quantitatively lower (IL-6 414+/-240 ng/l, TNFalpha 184+/-77 ng/l) than after resection. We found significant elevation of plasma leptin concentration (32+/-10 ng/ml) 24 h after banding compared with preoperative values (18+/-5 ng/ml, p 0.05). Leptin levels 48 and 72 h after banding rapidly returned to the level before operation. During abdominal surgery leptin shows to be an acute phase reactant. Proinflammatory cytokines can be main regulatory factors of leptin during this period. Significant correlation between leptin and TNFalpha (similarly demonstrated by other authors in models of bacterial inflammation) indicates that TNFalpha can be the crucial regulator of leptin generation in the early postoperative period. On the basis of our results we recommend to observe IL-6 and IL-8 at 24-72 h after the surgery in patients with a high risk of early postoperative septic complications.     

Regulation of leptin by steroid hormones in rat adipose tissue.

We investigated if steroid hormones regulate the secretion and the expression of leptin in female and male rat adipose tissue fragments in vitro. Dexamethasone time and dose-dependently increased the secretion and mRNA expression of leptin with a half-maximal stimulation of approximately 1 nM. A time-course revealed a maximal stimulatory effect of 17 beta-estradiol after 24 hours. In male adipose tissue 17 beta-estradiol increased leptin secretion (32% by 50 nM 17 beta-estradiol, P = 0.07 and 34% by 500 nM 17 beta-estradiol, P < 1780.05) after 24 hours. An additional effect of estrogen was seen in the dexamethasone (50 nM) stimulated cells (38% with 50 nM 17 beta-estradiol, P < 0.05 and 48% by 500 nM 17 beta-estradiol, P < 0.05). Basal secretion of leptin was equal in female and male adipose tissue, whereas the effects of 17 beta-estradiol (50 nM) and dexamethasone were significantly increased in female as compared with male adipose tissue. Progesterone, testosterone, dihydrotestosterone and dehydroepiandrostendione-sulfate neither affected leptin secretion in male nor female adipose tissue in vitro. Furthermore, to investigate the effect of estrogen female rats were ovariectomized (OVX) and the adipose tissue was incubated in vitro and compared with adipose tissue leptin secretion from sham operated rats (SHAM), and with ovariectomized rats treated with 17 beta-estradiol (EST). A decreased basal and dexamethasone-stimulated leptin secretion from OVX rats compared with SHAM rats was found (P < 0.005) whereas 17 beta-estradiol treatment of ovariectomized rats maintained a normal leptin secretion. However, the dexamethasone stimulation was equally increased above basal levels in SHAM, OVX and EST rats (3.7 +/- 1.2, 2.9 +/- 0.8, 4.2 +/- 1.4, NS, ANOVA) respectively.     

Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats

The aim of the present study was to determine whether the anorexic and thermogenic effects of leptin were attenuated in overweight aged rats following intracerebroventricular (i.c.v.) injection of murine leptin. Male F344/BN rats of two ages (6 months: young (n=20) and 24 months: old (n=18)) were divided into three groups (control, pair-fed and leptin) and were treated with either vehicle (artificial cerebrospinal fluid) or leptin (15.6 microgram/day) for 3 days. There was an age-related increase in basal food intake (20+/-2%), serum leptin levels (363+/-106%) and leptin (OB) mRNA (72+/-16%) in perirenal white adipose tissue (PWAT). In contrast, basal expression of hypothalamic NPY mRNA and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) mRNA was reduced significantly (-35+/-4% and -51+/-5%, respectively) with age. I.c.v. leptin treatment had a significantly greater effect in reducing food intake (-42+/-5% vs. -23+/-4%), serum leptin levels (-55+/-7% vs. 10+/-2%) and PWAT OB mRNA (-46+/-2% vs. 10+/-5%) in young than in old rats. Similarly, central leptin treatment also had a greater effect in suppressing hypothalamic NPY mRNA expression in young (-23+/-4%) than in old (-8+/-4%) rats compared with their age-matched pair-fed treated rats. The stimulatory effect of i.c.v. leptin treatment on BAT UCP1 mRNA expression was also significantly greater in young rats (45+/-8%) than in old rats (10+/-6%) compared with age-matched pair-fed rats. Our previous report indicated that these overweight aged rats were resistant to peripheral administered leptin. The present data extend those findings and demonstrate that the impaired anorexic and metabolic effects of leptin are centrally mediated. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both. The development of leptin resistance with age may contribute to the hyperphagia, hyperleptinemia and impaired energy balance with age.     

LPS induces interleukin-6 and interleukin-8 but not tumor necrosis factor-alpha in human adipocytes

Adipose tissue-derived cytokines are presumably involved in obesity-associated pathologies including type 2 diabetes and atherosclerosis. Here we studied the lipopolysaccharide (LPS)-induced expression dynamics of tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-8 and IL-10 in human adipose tissue biopsies, in preadipocyte-derived adipocytes, and in mesenchymal stem cell (MSC)-derived adipocytes. TNFalpha, IL-6, IL-8 and IL-10 secretions by adipose tissue explants were increased 5.5-, 19.5-, 3.5- and 12.5-fold, respectively, by LPS (1 microg/mL) administration. Concordantly, IL-6 and IL-8 release was dose-dependently induced in MSC-derived adipocytes by LPS (>10 pg/mL). In contrast, TNFalpha and IL-10 remained undetectable even at the highest LPS dose (1 microg/mL) after 24h. In MSC- and preadipocyte-derived adipocytes, respectively, exposure to LPS evoked a weak and transient induction of TNFalpha mRNA whereas induction of IL-6 and IL-8 mRNA were pronounced and sustained for at least 24h. Basal glucose uptake, lipolysis and IL-6 mRNA were induced by exogenous TNFalpha (10 ng/mL) but not by IL-6 (10 ng/mL), IL-8 (100 ng/mL) and IL-10 (20 ng/mL). In this adipocyte model TNFalpha induces well known metabolic effects, but together with previous reports these data suggest that inflammation-induced TNFalpha may derive from non-adipocyte sources in adipose tissue, likely to be macrophages.     

Cytokine and eicosanoid regulation by Schistosoma mansoniduring LSE penetration

Cercarial penetration, in low to moderate numbers, does not cause a normal skin inflammatory response; therefore, the authors sought to determine whether cercariae can down-regulate keratinocyte activation and thus the secretion of pro-inflammatory cytokines and eicosanoids. Human living skin equivalent (LSE, Organogenesis) consisting of dermal, epidermal and stratum corneum-like layers was used as the skin substrate. The surface of the LSE membrane was exposed to 100 ng IFNgamma or ~850 cercariae for 18 h. Incubation media and tissue was then assayed for IL-1alpha, IL-6, IL-8, TNFalpha, 5-HETE, 12-HETE, PGF(2), LTB(4), and LTC(4) via RIA and Western Blots. TNFalpha was not detected. Secreted IL-1alpha levels were (mean +/- S.E.M. (n)): Control, 1.03 ng +/- 0.15 (11); IFNgamma 1.90 ng +/- 0.48 (5); cercariae, 1.79 ng +/- 0.22 (22). In spite of this increase, cercariae down-regulated IL-8 (cercariae 11.13 +/- 1.70 ng vs. IFNgamma = 16.47 +/- 0.29 ng, p = 0.04) and LTB(4) (cercariae = 98.86 +/- 19.65 pg/0.1 ml vs. IFNgamma = 193.42 +/- 44.21 pg/0.1 ml p = 0.02). No changes were seen in IL-6, 12-HETE, 5-HETE, and PGE(2) levels. It is concluded that cercarial penetration causes a release of IL-1alpha consistent with skin trauma; however, schistosomulae may regulate the production of chemotactic (neutrophils, macrophages, T-cells, etc.) and activation factors such as IL-8 and LTB(4).     

Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors

Adipose tissue is a major source of inflammatory and thrombotic cytokines. This study investigated the relationship of abdominal subcutaneous adipose tissue cytokine gene expression to body composition, fat distribution, and metabolic risk during obesity. We determined body composition, abdominal fat distribution, plasma lipids, and abdominal subcutaneous fat gene expression of leptin, TNF-alpha, IL-6, PAI-1, and adiponectin in 20 obese, middle-aged women (BMI, 32.7 +/- 0.8 kg/m2; age, 57 +/- 1 yr). A subset of these women without diabetes (n = 15) also underwent an OGTT. In all women, visceral fat volume was negatively related to leptin (r = -0.46, P < 0.05) and tended to be negatively related to adiponectin (r = -0.38, P = 0.09) gene expression. Among the nondiabetic women, fasting insulin (r = 0.69, P < 0.01), 2-h insulin (r = 0.56, P < 0.05), and HOMA index (r = 0.59, P < 0.05) correlated positively with TNF-alpha gene expression; fasting insulin (r = 0.54, P < 0.05) was positively related to, and 2-h insulin (r = 0.49, P = 0.06) tended to be positively related to, IL-6 gene expression; and glucose area (r = -0.56, P < 0.05) was negatively related to, and insulin area (r = -0.49, P = 0.06) tended to be negatively related to, adiponectin gene expression. Also, adiponectin gene expression was significantly lower in women with vs. without the metabolic syndrome (adiponectin-beta-actin ratio, 2.26 +/- 0.46 vs. 3.31 +/- 0.33, P < 0.05). We conclude that abdominal subcutaneous adipose tissue expression of inflammatory cytokines is a potential mechanism linking obesity with its metabolic comorbidities.     

Isoproterenol Decreases Leptin Expression in Adipose Tissue of Obese Humans

RICCI, MATTHEW R. AND SUSAN K. FRIED. Isoproterenol decreases leptin expression in adipose tissue of obese humans. Obes Res. Objective: We investigated the effects of the non-selective β-adrenergic agonist, isoproterenol (Iso), on leptin expression in human adipose tissue. Research Methods and Procedures: Subcutaneous (SQ) and omental adipose (OM) tissue taken during surgery from 12 morbidly obese subjects (10 women and 2 men) were cultured for up to 24 hours with insulin (7 nM) and/or dexamethasone (25 nM), a synthetic glucocorticoid, in the presence or absence of isoproterenol (10 μM). Adipose tissue was also acutely incubated for 3 hours in media alone with or without isoproterenol. Leptin secretion and leptin mRNA abundance were measured. Results: Iso acutely decreased leptin release by −30% (vs. no hormone controls) in fragments of OM and SQ adipose tissue. In 24-hour culture, addition of Iso (in the presence of insulin) resulted in lower leptin accumulation in the medium (−20–30%) and leptin mRNA levels (−40–50%) from both tissue depots. Culture with insulin and dexamethasone increased leptin expression vs. insulin alone. Addition of Iso with insulin and dexamethasone decreased media leptin (−40–60%) and leptin mRNA levels were lower (−65%) in Iso-treated adipose tissue from both depots after 24 hours. Iso effects were not detectable after 5 hours of culture. Discussion: We conclude that stimulation of β-adrenergic receptors may modulate leptin expression in human adipose tissue by two mechanisms: an acute effect on leptin release and a longer-term antagonism of stimulatory effects of insulin and dexamethasone on leptin mRNA expression. These mechanisms may contribute to the decline in serum leptin that occurs during fasting.     

Relationship between IL-6, leptin and adiponectin and variables of fibrinolysis in overweight and obese hypertensive patients.

Impaired fibrinolysis is a common finding in obese humans. This condition is now considered as an established risk factor for thromboembolic complications. Furthermore, obesity is characterized by a specific pattern of circulating concentrations of fat-cell products interleukin-6 (IL-6), leptin, and adiponectin. The aim of our study was to investigate the relationship between these proteins and selected variables of the fibrinolytic system in 74 mildly hypertensive, overweight subjects. Circulating IL-6 and leptin levels showed a positive association with BMI (r = 0.24, p = 0.04 and r = 0.70, p < 0.0001), whereas adiponectin was not correlated to BMI. Interestingly, IL-6 was also positively associated with t-PA/PAI-1 complexes after adjustment for BMI and other anthropometric variables. Leptin was positively correlated with PAI-1 activity and antigen (r = 0.32, p = 0.006 and r = 0.37, p < 0.001, respectively) and negatively with t-PA activity (r = -0.27, p = 0.03). However, these associations lost significance after correction for BMI or HOMA, an insulin sensitivity index. In contrast, adiponectin levels were independently and negatively correlated with PAI-1 antigen (r = -0.26, p = 0.04, after correction for BMI). In conclusion, our study provides further evidence that IL-6, leptin, and adiponectin are associated with impaired fibrinolysis in overweight hypertensive humans.     

Cigarette smoking may reduce plasma leptin concentration via catecholamines

BACKGROUND: Leptin might influence body weight among smokers. DESIGN: (A) Screening of plasma leptin levels in 222 sedentary, smoking and non-smoking middle-aged men. (B) Double-blind, placebo-controlled smoking intervention on smokers (n=31). (C) Non-smokers (n=40) received chewing gum with nicotine (2mg nicotine, n=23) or without nicotine (n=19). (D) The effects of nicotine (0.05 and 0.5 microg/mL) were monitored on leptin secretion and mRNA levels in a human placental cell line (BeWo) expressing leptin, a murine adipocyte cell line (3T3-L1) and human adipose tissue explants. RESULTS: (A) Plasma leptin levels in smoking men (8.4+/-8.4 ng/mL, n=100) was lower as compared to non-smokers (10.3+/-7.3 ng/mL, n=122) (P<0.001), even when adjusted for differences in body mass index (BMI) (P<0.001). (B) A significant reduction (P=0.02) in plasma concentration of leptin was found already after smoking one cigarette. Concomitant with the 3-5 fold increase in plasma nicotine concentration after the first cigarette, we observed increased plasma adrenaline levels (P=0.005). (C) There was no effect of nicotine on plasma leptin levels in non-smokers receiving nicotine-containing chewing gum, and plasma concentrations of catecholamines were unaltered. (D) There was no effect of nicotine on leptin mRNA expression after incubation with cells or adipose tissue. CONCLUSION: Cigarette smoking reduced plasma leptin concentration in vivo, whereas nicotine had no direct effect on leptin expression in vitro. Nicotine might indirectly reduce leptin secretion via enhanced plasma catecholamine concentration.