leptin and Thrombosis

A world-wide obesity epidemic is threatening to have a major impact on the prevalence of chronic and acute vascular diseases. In addition to weight loss interventions, which have met with modest success to date, it will be important to understand mechanisms by which obesity promotes vascular disease processes. Studies of leptin, a hormone produced by the adipocyte, have supported the concept that adipocyte-specific products may be mediating some of the vascular risk associated with obesity. This mini-review provides an overview of some of the preclinical studies demonstrating causal relationships between leptin and vascular endpoints. Therapeutic strategies designed to block leptin-mediated signaling events in cells contributing to vascular disease may prove beneficial in obese subjects at risk for vascular complications.

Topics: Animals; Arteries; Atherosclerosis; Endothelium, Vascular; Humans; Leptin; Models, Cardiovascular; Muscle, Smooth, Vascular; Obesity; Receptors, Leptin; Signal Transduction; Thrombosis; Tunica Intima

Epidemiological evidence strongly links excess body weight with an increased risk to develop atherothrombotic complications. Obesity is frequently associated with systemic and local inflammation as well as elevated circulating leptin levels, and clinical studies found hyperleptinemia to correlate not only with measures of adiposity, but also with circulating biomarkers of an increased metabolic and cardiovascular risk or surrogate markers of subclinical atherosclerosis. Moreover, experimental studies in mice with systemic disruption of the leptin-leptin receptor system as well as after administration or neutralization of the adipokine demonstrated that leptin promotes both arterial and venous thrombosis. In addition to directly binding to and activating platelets and thus potentiating their aggregation in response to agonist stimulation, leptin enhances the expression of prothrombotic and anti-fibrinolytic proteins in vascular and inflammatory cells. On the other hand, its ability to mobilize and recruit vascular progenitor cells from the bone marrow to sites of vascular injury was found to be impaired in hyperleptinemic, obese humans and rodents. Thus, leptin promotes thrombus formation and resolution by several different mechanisms involving primary hemostasis, the coagulation cascade as well as the integrity of the vessel wall. Dissection of the molecular mechanisms underlying each of its actions may pave the road for novel therapeutic options in targeting the increased risk of thrombosis associated with obesity, keeping in mind unresolved issues of a cell-specific leptin resistance as well as individual differences in the responsiveness to leptin.

Topics: Animals; Anticoagulants; Arteries; Humans; Leptin; Models, Cardiovascular; Molecular Targeted Therapy; Receptors, Leptin; Secondary Prevention; Signal Transduction; Thrombosis; Veins; Venous Thrombosis

1. Leptin is a 16-kDa hormone, synthesized primarily by adipocyte, which acts as a key factor for maintenance of energy homeostasis in central and peripheral tissues. In most obese individuals, serum leptin levels are increased and correlate with the individual's body mass index. 2. Abundant investigations ranging from clinical and animal model studies to in vitro analyses show that leptin plays a pivotal role in obesity-related cardiovascular diseases (CVD). Hyperleptinaemia has been confirmed to be a predictor of acute cardiovascular events. However, some studies have shown that leptin has a cardioprotective effect in leptin-deficient models. These data suggest the influences of leptin on the pathophysiology of cardiovascular diseases are complex and not completely understood. 3. In the present review, we summarize the major leptin signalling pathways, including Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI-3K) signalling pathways, and analyse the probable mechanisms of selective leptin resistance. We then provide a detailed review of the effects of leptin on the cardiovascular system, including sympathoactivation, oxidative stress, vascular inflammation, endothelial dysfunction, vascular cell proliferation, cardiomyocytes hypertrophy, as well as fatty acid metabolism, all of which contribute to the pathogenesis of cardiovascular diseases (e.g. ischaemic heart disease). The central premise of this review is to elucidate the mechanisms by which leptin affects the cardiovascular function and provide insight into obesity-related CVD.

Topics: Animals; Cardiomegaly; Cardiovascular Diseases; Endothelium, Vascular; Extracellular Matrix; Female; Humans; Inflammation; Leptin; Male; Mice; Myocardium; Obesity; Rats; Receptors, Leptin; Risk Factors; Signal Transduction; Thrombosis

To describe the pathophysiological mechanisms by which obesity increases the propensity to thrombosis, the leading cause of death in the Western World, with particular emphasis on the role of inflammation, oxidative stress, dyslipidaemia, insulin resistance and the coagulation cascade.. Review article.. Medline (1966-2005) and Cochrane library review of literature examining the relationship between obesity and thrombosis. Search terms included obesity, overweight, body mass index, thrombosis, cardiovascular disease, venous thromboembolism, peripheral arterial disease, and coronary heart disease.. Obesity is an important and growing public health issue that is estimated to affect more than half of the UK adult population. Obesity, in particular central (visceral) obesity, is associated with significant, and largely preventable, morbidity and mortality including an increased incidence and prevalence of arterial and venous thrombotic events. The various mechanisms by which obesity may cause thrombosis include: the actions of so-called adipocytokines from adipose tissue, e.g. leptin and adiponectin; increased activity of the coagulation cascade and decreased activity of the fibrinolytic cascade; increased inflammation; increased oxidative stress and endothelial dysfunction; and disturbances of lipids and glucose tolerance in association with the metabolic syndrome.. Obesity appears to be associated with thrombosis via several mechanisms. These pro-thrombotic factors are all improved by weight loss.

Topics: Adiponectin; Global Health; Humans; Leptin; Morbidity; Obesity; Risk Factors; Thrombosis

Obesity has become a global epidemic and carries a considerable negative impact in regard to quality of life and life expectancy. A primary problem is that obese individuals are at increased risk of suffering from cardiovascular disease complications such as myocardial infarction and stroke. Because fat accumulation is a consistent aspect of obesity, mechanisms that may link adipose tissue to cardiovascular disease complications should be considered. Proteins expressed from adipose tissue, known as adipokines, are hypothesized to have important effects on the progression and incidence of cardiovascular disease complications. This review examines the evidence that adipokines play a direct role in vascular thrombosis, an important event in cardiovascular disease complications.

Topics: Adiponectin; Adipose Tissue; Animals; Hemostasis; Leptin; Mice; Obesity; Plasminogen Activator Inhibitor 1; Thrombosis; Tumor Necrosis Factor-alpha

The metabolic syndrome refers to the clustering of upper body obesity, atherogenic dyslipidemia, insulin resistance and elevated blood pressure. Both, obesity and metabolic syndrome, have the potential to influence on the incidence and severity of cardiovascular disease with serious implications for worldwide health care systems. Obesity plays a central role in the development of insulin resistance and dyslipidemia through the mediation of a pro-inflammatory and pro-thrombotic state. Adipose tissue has been shown to exert important endocrine and immune functions. Pathogenesis of obesity associated metabolic syndrome is mediated by disturbed production and release of biologically active molecules by fat cells and other cells infiltrating fat tissue. In obese subjects synthesis of several bioactive compounds--adipokines and cytokines/chemokines by adipose tissue cells is dysregulated. Those bioactive molecules participate in regulation of apetite and energy homeostasis, lipid metabolism (tumour necrosis factor alpha--TNF-alpha), insulin sensitivity (TNF-alpha, adiponectin, resistin, visfatin) immunity (monocyte chemoattractant protein-1--MCP-1, TNF-alpha, IL-6), angiogenesis, blood pressure and hemostasis (plasminogen activator inhibitor--PAI-1). The effects of major pro-/anti-inflammatory and pro-thrombotic adipokines on several physiological processes will be discussed in this review. Also, an evidence-based approach to the laboratory diagnosis and treatment of metabolic syndrome will be presented.

Topics: Adiponectin; Cardiovascular Diseases; Complement Factor D; Humans; Inflammation; Interleukin-6; Leptin; Metabolic Syndrome; Models, Biological; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Resistin; Risk; Thrombosis; Tumor Necrosis Factor-alpha

Leptin and ghrelin are novel peptide hormones which are counter-regulatory in the central control of appetite. More recently, it has become clear that these hormones have a range of effects on the cardiovascular system. Leptin increases sympathetic activity, producing a pressor effect when acting on the central nervous system. However, leptin produces vasodilation by an endothelium-dependent mechanism peripherally. Ghrelin decreases sympathetic activity and has a depressor effect when acting on the central nervous system. Peripherally, ghrelin produces vasodilation by an endothelium-independent mechanism. Ghrelin improves left ventricular function and cardiac cachexia in heart failure. Leptin may contribute to cardiac cachexia, and to obesity-related cardiomyopathy by a variety of mechanisms. Leptin has pro-inflammatory, proliferative and calcification promoting effects in the vasculature. Ghrelin has recently been shown to be anti-inflammatory in the vasculature. Leptin may also produce a pro-thrombotic state through stimulation of platelet aggregation and inhibition of coagulation and fibrinolysis. The evidence for and against these effects as well as their pathophysiological significance in obesity hypertension, heart failure, atherosclerosis and thrombosis are discussed.

Topics: Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Ghrelin; Heart Failure; Humans; Hypertension; Leptin; Obesity; Peptide Hormones; Thrombosis

Adipose tissue has recently emerged as an active endocrine organ that secretes a variety of metabolically important substances, collectively called adipocytokines or adipokines. In this review we summarize the effects of the adipokines leptin, adiponectin, and resistin on the vasculature and their potential role for pathogenesis of vascular disease. Leptin is associated with arterial wall thickness, decreased vessel distensibility, and elevated C reactive protein (CRP) levels. Leptin possesses procoagulant and antifibrinolytic properties, and it promotes thrombus and atheroma formation, probably through the leptin receptors by promoting vascular inflammation, proliferation, and calcification, and by increasing oxidative stress. Research for development of pharmacologic antagonism for the leptin receptor is currently under way. Adiponectin inhibits the expression of the adhesion molecules ICAM-1, VCAM-1, and P selectin. Therefore, it interferes with monocyte adherence to endothelial cells and their subsequent migration to the subendothelial space, one of the initial events in the development of atherosclerosis. Adiponectin also inhibits the transformation of macrophages to foam cells in vitro and decreases their phagocytic activity. Resistin, discovered in 2001, represents the newest of the adipokines and was named for its ability to promote insulin resistance. Resistin increases the expression of the adhesion molecules VCAM-1 and ICAM-1, up-regulates the monocyte chemoattractant chemokine-1, and promotes endothelial cell activation via ET-1 release. Although many aspects of its function need further clarification, it appears that resistin will add significantly to our knowledge of the pathophysiology of vascular disease and the metabolic syndrome.

Topics: Adiponectin; Animals; Arteriosclerosis; Endothelium, Vascular; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Resistin; Thrombosis; Vascular Diseases

Obesity is a common problem in much of the western world today in that is linked directly with several disease processes, notably, hypertension. It is becoming clear that the adipocyte is not merely an inert organ for storage of energy but that it also secretes a host of factors that interact with each other and may result in elevated blood pressure. Of particular importance is the putative role of leptin in the causation of hypertension via an activation of the sympathetic nervous system and a direct effect on the kidneys, resulting in increased sodium reabsorption leading to hypertension. Obesity per se may have structural effects on the kidneys that may perpetuate hypertension, leading to an increased incidence of end-stage renal disease that results in further hypertension. Adipose tissue may elaborate angiotensin from its own local renin-angiotensin system. The distribution of body fat is considered important in the genesis of the obesity-hypertension syndrome, with a predominantly central distribution being particularly ominous. Weight loss is the cornerstone in the management of the obesity-hypertension syndrome. It may be achieved with diet, exercise, medications, and a combination of these measures. Anti-obesity medications that are currently undergoing clinical trials may play a promising role in the management of obesity and may also result in lowering of blood pressure. Antihypertensives are considered important components in the holistic approach to the management of this complex problem.

Topics: Adipose Tissue; Aldosterone; Animals; Body Mass Index; Humans; Hypertension; Inflammation; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Neuropeptides; Obesity; Renin-Angiotensin System; Sympathetic Nervous System; Thrombosis

This article has discussed some of the mechanisms involved in the causal relation between obesity and hypertension. Obesity causes a constellation of maladaptive disorders that individually and synergistically contribute to hypertension, among other cardiovascular morbidities. Well-designed population-based studies are needed to assess the individual contribution of each of these disorders to the development of hypertension. In addition, because the control of obesity may eliminate 48% of the hypertension in whites and 28% in blacks, this article has offered an up-to-date on the management of this problem. It is hoped that this article will help scientists formulate a thorough understanding of obesity hypertension and form the basis for more research in this field, which has a huge impact on human life.

Topics: Adipose Tissue; Aldosterone; Body Mass Index; Cardiovascular System; Genetic Predisposition to Disease; Hormones; Humans; Hypertension; Inflammation; Kidney; Leptin; Neuropeptides; Obesity; Renin-Angiotensin System; Sympathetic Nervous System; Thrombosis

Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-alpha in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile.

Topics: Adipose Tissue; Blood Coagulation Disorders; Endocrine Glands; Fibrinolysis; Hemostasis; Humans; Insulin Resistance; Leptin; Obesity; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Thrombosis

Human obesity is associated with leptin resistance, elevated leptin levels in the circulation, and increased risk of arterial and venous thrombotic disease. Our studies suggest that elevated leptin levels may directly promote arterial thrombosis in vivo. We found that leptin-deficient ob/ob mice had prolonged times to thrombosis after arterial injury with ferric chloride and that exogenously administered leptin corrected their phenotype in a dose-dependent manner. These effects appear to result from a direct, receptor-mediated effect of leptin on platelets, because leptin stimulated the aggregation of murine (wild-type and ob/ob) and human platelets, but it had no effect on platelets from leptin receptor-deficient db/db mice. Moreover, db/db mice had an attenuated thrombotic response to ferric chloride injury (indistinguishable from that of the ob/ob mice), which was unaffected by exogenous leptin. Our results raise the possibility that elevated plasma levels of leptin may contribute to the risk of atherothrombotic complications in human obesity.

Topics: Animals; Body Weight; Cardiovascular Diseases; Homeostasis; Humans; Leptin; Mice; Mice, Obese; Obesity; Platelet Aggregation; Risk Assessment; Thrombosis

In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth.. In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage.. Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays.. A total of 24 obese females (39 ± 10 years) with a mean body mass index of 35 ± 4  kg m(-2) were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r=0.534; P=0.010) and at 90 days follow-up (r=0.487; P=0.021). At 90 days, weight reduction (-9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (-38%), procoagulant platelet-derived MPs (-43%), leukocyte-derived MPs (-28%) and leptin (-32%) levels.. In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Coagulation Factors; Blood Platelets; Caloric Restriction; Endothelium, Vascular; Erythrocytes; Female; Hemostasis; Humans; Leptin; Leukocytes; Middle Aged; Obesity; Plasminogen Activator Inhibitor 1; Prospective Studies; Thromboplastin; Thrombosis; Weight Loss; Young Adult

Oral anticoagulation is effective for stroke prevention in atrial fibrillation (AF). However, strokes may still occur in high-risk individuals. We conducted a prospective trial to assess the association between adipocytokine serum levels and surrogate parameters for thromboembolic events.. Our results suggest that adiponectin and resistin may act as potential biomarkers to identify individuals with AF who are at high thromboembolic risk.

Topics: Adipokines; Adiponectin; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Biomarkers; Body Mass Index; Cross-Sectional Studies; Cytokines; Echocardiography, Transesophageal; Female; Germany; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Prospective Studies; Resistin; Risk Assessment; Risk Factors; Stroke; Thromboembolism; Thrombosis; Time Factors; Treatment Outcome

Topics: Adolescent; Adult; Blood Coagulation; Body Mass Index; C-Reactive Protein; Case-Control Studies; Child; Child, Preschool; Factor VIII; Female; Fibrinogen; Humans; Insulin; Leptin; Linear Models; Male; Obesity; Pediatric Obesity; Sex Factors; Thrombosis; Young Adult

Leptin is an adipokine, which is in humans with cardiac disease suspected to be involved in myocardial remodeling and thrombus formation. In cats, however, it is not known whether leptin plays a role in cardiac disease, i.e. hypertrophic cardiomyopathy (HCM) and the presence of an atrial thrombus (AT). The objective of the study was therefore to establish whether leptin is transcribed in the feline myocardium and to compare myocardial leptin mRNA concentrations in cats with HCM with and without AT, and in cats without cardiac diseases. Myocardial samples from 15 cats with HCM (five of these with AT), and 12 cats without cardiac diseases were investigated for leptin mRNA expression using quantitative reverse transcriptase PCR, and the transcription levels were correlated with those obtained for a range of cytokines and remodeling parameters. Leptin mRNA expression was detected in the myocardium in all heart regions, with generally higher concentrations in the atria than in the ventricles. Cats with HCM exhibited higher atria and ventricular leptin transcription than cats without cardiac diseases, but reduced ventricular transcription levels in the presence of AT. A positive correlation between leptin, cytokine and remodeling marker transcription levels was observed. The present study shows that leptin is constitutively transcribed in the feline myocardium. The observed increase in leptin mRNA concentrations in the myocardium from cats with HCM and the reduction when an AT is present suggests varying gene activation in different stages of the disease and a potential involvement of leptin in the feline cardiac remodeling process.

Topics: Animals; Cardiomyopathy, Hypertrophic; Cat Diseases; Cats; Cytokines; Gene Expression Regulation; Heart Atria; Leptin; Male; Myocardium; RNA, Messenger; Thrombosis

Topics: Animals; Biomedical Research; Clopidogrel; Drug Resistance; Humans; Leptin; Mice; Obesity; Thrombosis; Ticlopidine

A prothrombotic state in obesity may be partially responsible for the higher incidence of atherosclerotic complications. However the factors responsible for this prothrombotic state, linked with high levels of plasminogen activator inhibitor-1 (PAI-1), are not fully known. Leptin is elevated in obesity and studies have shown a positive correlation between leptin and PAI-1 levels in human subjects, along with a negative correlation with tissue-type plasminogen activator (tPA). We tested the hypothesis that leptin induces PAI-1 and inhibits tPA expression using human coronary artery endothelial cells (HCAEC) in culture as these cells play an important role in atherosclerosis. We demonstrate that leptin induces the transcription and translation of PAI-1 in HCAEC. The leptin dependent upregulation of PAI-1 mRNA and protein was comparable to insulin-induced PAI-1 expression. We show leptin concentration (0-150 ng/ml) dependent increases in PAI-1 mRNA and protein after 6 and 12h of leptin administration, respectively. Increased intracellular PAI-1 expression correlates with increased PAI-1 activity in conditioned media and inhibition of specific ERK1/2 pathway by treatment with PD98059 (20-40 microM) inhibits leptin dependent PAI-1 expression. However no changes in tPA expression were seen with time or increasing concentrations of leptin. Also leptin treatment did not alter total tPA concentration or tPA activity in conditioned media. In conclusion, our study shows that leptin upregulates the expression of PAI-1 in vascular endothelial cells via activation of ERK1/2 but does not regulate tPA expression. These studies demonstrate a novel mechanism for the prothrombotic role of leptin in development of atherosclerosis.

Topics: Atherosclerosis; Cells, Cultured; Endothelium, Vascular; Flavonoids; Humans; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Obesity; Plasminogen Activator Inhibitor 1; Protein Kinase Inhibitors; Thrombosis; Up-Regulation

1. The relationship between inflammation, obesity-related proteins and tissue factor (TF), the major initiator of the extrinsic clotting cascade, is not well understood. We examined if basal and stimulated peripheral blood mononuclear cell (PBMC) TF-procoagulant activity (PCA) was higher in obese subjects and examined the effects of leptin, resistin and serum amyloid A (SAA). 2. PBMC from 12 obese (six male, aged 29±4years, body mass index 46.0±8.7kg/m(2) ) and 12 age- and sex-matched lean controls were cultured either unstimulated or stimulated by lipopolysaccharide (LPS; 10ρg/mL and 100ng/mL, for 4-16h) or SAA (1 ng/mL, 25ng/mL, 250ng/mL, for 4h). Separately, PBMC from lean subjects were cultured unstimulated with leptin (100ρg/mL, 1ng/mL, 10ng/mL, 100ng/mL, 1 μg/mL), resistin (0.1ng/mL, 1ng/mL, 10ng/mL, 100ng/mL) or leptin (100ng/mL) plus LPS (100ρg/mL). TF-PCA was determined by a 1-stage plasma recalcification assay. 3. Four-hour unstimulated PBMC TF-PCA was greater in the obese (90.4±16.5 vs 39.9±4.7mu TF/10(6) PBMC, P=0.01). After 4h stimulation with SAA or LPS the TF-PCA was similar. Unstimulated TF-PCA correlated with log serum high sensitivity C- reactive protein (hs-CRP) (r=0.42, P=0.04) and insulin (r=0.44, P=0.048), but not with log serum SAA (r=0.192, P=0.55). Physiological concentrations of leptin or resistin and leptin plus LPS did not increase TF-PCA in PBMC from lean subjects. 4. Basal PBMC TF-PCA is higher in the obese and is associated with serum hs-CRP. The obesity-related proteins SAA, leptin and resistin are unlikely to play a major role in increasing PBMC TF-PCA.

Topics: Adult; Case-Control Studies; Cell Culture Techniques; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serum Amyloid A Protein; Thromboplastin; Thrombosis

Topics: Blood Platelets; Humans; Leptin; Obesity, Morbid; Platelet Aggregation; Risk Assessment; Risk Factors; Signal Transduction; Thrombosis; Up-Regulation

Clinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. We examined the effects of leptin on platelet aggregation in morbidly obese subjects (n = 40; BMI, 41.6 +/- 1.1 kg/m2; leptin, 49.7 +/- 3.4 ng/ml) in comparison to normal-weight controls (n = 36; BMI, 23.3 +/- 0.4 kg/m2; leptin, 6.5 +/- 0.7 ng/ml). The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 microM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p = 0.99). Western blotting revealed that leptin induced phosphorylation of JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADP-induced platelet aggregation.

Topics: Adenosine Diphosphate; Adult; Blood Platelets; Body Mass Index; Case-Control Studies; Female; Humans; Janus Kinase 2; Leptin; Male; Obesity, Morbid; Phosphorylation; Platelet Aggregation; Platelet Function Tests; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Risk Assessment; Risk Factors; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thrombosis; Up-Regulation

Leptin is an adipocyte-derived cytokine primarily involved in the regulation of body weight and energy balance. In vivo studies suggest that leptin promotes platelet aggregation and thrombosis. Neutrophils are involved in the crosstalk between inflammation and thrombosis in clinical disorders. Leptin is also involved in the regulation of inflammation.. We examined the in vitro effects of leptin on the expression of tissue factor (TF), the primary initiator of coagulation, in healthy neutrophils.. The effects on TF expression were assayed functionally using a modified prothrombin time (mPT), as well as at mRNA and protein levels. The same experiments were performed in parallel with PBMC. Leptin induced functional TF and increased TF mRNA and protein expression in both cell types, as determined by mPT, real-time RT-PCR, western blot, flow cytometry, immunocytochemistry. Inhibition studies revealed that the effect of leptin on TF expression is mediated, at least in part, by JAK2 and PI3K. Our findings, after neutralising TNFalpha in supernatants of leptin-treated cells, also suggest the involvement of TNFalpha in the leptin-induced TF expression in leukocytes.. This study indicates a novel link between inflammation, obesity and thrombosis by showing that leptin is able to trigger the extrinsic coagulation cascade. This work suggests a possible mechanism of the thrombotic effects of hyperleptinemic-associated clinical disorders.

Topics: Blood Coagulation; Humans; Inflammation; Janus Kinase 2; Leptin; Leukocytes, Mononuclear; Neutrophils; Obesity; Phosphatidylinositol 3-Kinases; Platelet Aggregation; Prothrombin Time; RNA, Messenger; Thromboplastin; Thrombosis; Tumor Necrosis Factor-alpha

In this study, the levels of fibronectin, vitronectin, leptin, tissue plasminogen activator (t-PA), and lipid parameters were investigated in patients with coronary artery disease (CAD) and control group. The average plasma fibronectin levels in CAD patients group were significantly higher compared with the control group (p=0.006). Moreover, in patients with triple-vessel disease, plasma fibronectin levels were found to be significantly higher than those in the control group (p<0.05). Plasma vitronectin levels in patients with CAD were found to be significantly higher than those in the control group (p=0.000). In addition, in patients with double vessel disease plasma vitronectin levels were significantly higher than no vessel disease and control group, triple vessel disease was significantly higher as compared with no vessel disease, single vessel disease, and control group (p<0.05). We could not find any significant differences in t-PA values between CAD patients and control group. On the other hand, the average leptin levels in the group of patients were higher than those in the control group but there were no statistically significant differences found between them (p>0.05) because of high SD values. There was strong (+) correlation between fibronectin, vitronectin, and severity of disease [vitronectin/severity of disease, r = 0.5074 (p = 0.000), fibronectin/severity of disease, r = 0.2971 (p = 0.007)]. In conclusion, we can say that fibronectin and vitronectin have become greatly important in pathogenesis of coronary artery disease. High leptin levels may be contribute to platelet aggregation in patients with coronary artery disease. But, elevated serum levels of leptin cannot be useful diagnostic and monitoring markers in patients with coronary artery disease.

Topics: Adult; Aged; Body Mass Index; Cholesterol; Coronary Disease; Female; Fibronectins; Humans; Hypertension; Leptin; Male; Middle Aged; Smoking; Thrombosis; Tissue Plasminogen Activator; Vitronectin

Obesity is associated with elevated levels of leptin in the blood. Elevated leptin is a risk factor for thrombosis in humans, and leptin administration promotes platelet activation and thrombosis in the mouse. The current study examines the effect of leptin on human platelets, and provides initial insights into the nature of the leptin receptor on these platelets. Leptin potentiated the aggregation of human platelets induced by low concentrations of ADP, collagen and epinephrine. However, the response varied significantly between donors, with platelets from some donors (approximately 40%) consistently responding to leptin (responders) and those from other donors (approximately 60%) never responding (non-responders). Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) experiments showed that platelets from both groups only express the signaling form of the leptin receptor, and that responder platelets express higher levels of this receptor than non-responders. Ligand-binding assays demonstrate specific, saturable binding of leptin to platelets from both groups with apparent K(d) values of 76 +/- 20 nM for responders and 158 +/- 46 nM for non-responders. Thus, the decreased sensitivity of non-responder platelets to leptin does not result from the absence of the signaling form of this receptor, but may reflect differences in its level of expression and/or affinity for leptin. These preliminary studies demonstrate that platelets are a major source of leptin receptor in the circulation, and suggest that leptin-responsive individuals may have a higher risk for obesity-associated thrombosis than non-responsive individuals.

Topics: Adenosine Diphosphate; Blood Platelets; Blotting, Western; Body Mass Index; Cell Line, Tumor; Collagen; Dose-Response Relationship, Drug; Epinephrine; Female; Humans; Kinetics; Leptin; Ligands; Male; Microscopy, Electron, Transmission; Obesity; Platelet Activation; Platelet Aggregation; Protein Binding; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Thrombosis; Time Factors

The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice.. Sixteen-week-old, male apolipoprotein E-deficient mice were treated with injections of recombinant leptin (125 microg per day IP; n=10) or vehicle (n=10) for 4 weeks. Leptin treatment resulted in reduced epididymal fat (352+/-30.7 versus 621+/-61.5 mg; P=0.005) and fasting insulin (0.57+/-0.25 versus 1.7+/-0.22 ng/mL; P=0.014). Despite these metabolic benefits, leptin treatment resulted in an increase in atherosclerosis (8.0+/-0.95% versus 5.4+/-0.59% lesion surface coverage; P<0.05). Leptin treatment also resulted in a shortened time to occlusive thrombosis after vascular injury (21+/-2.1 versus 34.6+/-5.4 minutes; P=0.045).. These studies indicate that exogenous leptin promotes atherosclerosis and thrombosis and support the concept that elevations of leptin may increase the risk for cardiovascular disease.

Topics: Adiposity; Animals; Apolipoproteins E; Atherosclerosis; Body Weight; Cholesterol; Cytokines; Fasting; Fluorescent Dyes; Insulin; Leptin; Male; Mice; Mice, Mutant Strains; Recombinant Proteins; Rose Bengal; Thrombosis; Triglycerides

Topics: Animals; Humans; Leptin; Obesity; Platelet Aggregation; Thrombosis

Complications of atherosclerosis are the leading cause of morbidity and mortality in industrialized societies. Obesity has emerged as an independent risk factor for complications of atherosclerotic vascular disease. Leptin, a hormone produced by the adipocyte, increases with obesity and appears to modulate energy balance and food intake. In addition, other actions of leptin have been proposed, including an in vitro effect on platelet aggregation. Thus, the elevated plasma leptin levels in obese individuals may promote vascular thrombosis.. To test the hypothesis that leptin contributes to in vivo thrombosis via the leptin receptor.. Between September 2000 and September 2001, a vascular thrombosis model was used to test male 10- to 12-week-old mice completely deficient in leptin or the leptin receptor and mice with platelet leptin-receptor deficiency.. Time to formation of an occlusive thrombus in the common carotid artery following experimentally induced endothelial injury.. Following onset of vascular injury, wild-type mice (n = 8) formed occlusive thrombosis in a mean (SD) of 42.2 (4.6) minutes, whereas leptin-deficient (n = 5) and leptin receptor-deficient mice (n = 7) formed occlusive thrombosis in 75.2 (10.1) and 68.6 (10.3) minutes, respectively (leptin deficient vs wild-type mice, P =.008; leptin-receptor-deficient vs wild-type, P =.03). When recombinant murine leptin was administered to leptin-deficient mice (n = 4), the time to occlusion was reduced to 41.8 (6.6) minutes (P =.035 vs vehicle control). Following bone marrow transplantation from leptin receptor-deficient (donor) mice to wild-type (recipient) mice, the time to occlusion was prolonged from 22.3 (2.8) minutes in wild-type mice receiving wild-type marrow (n = 3) to 56.8 (5.0) minutes in wild-type mice receiving leptin receptor-deficient bone marrow (n = 5) (P =.003).. Leptin contributes to arterial thrombosis following vascular injury in vivo and these prothrombotic effects appear to be mediated through the platelet leptin receptor.

Topics: Animals; Bone Marrow Transplantation; Carotid Arteries; Carrier Proteins; Disease Models, Animal; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Thrombosis

Obesity is related to cardiovascular disease (CVD) morbidity and mortality, however, the mechanisms for the development of obesity-induced CVD risk remain unclear. Hyperinsulinemia and insulin resistance are considered key components in the metabolic cardiovascular syndrome and as independent risk factors for CVD. Plasma leptin and tumor necrosis factor-alpha (TNF-alpha), two adipocyte products, are also proposed to be associated with the development of CVD risk. The purpose of this study is to evaluate the association of plasma leptin, soluble TNF receptors (sTNF-R), and insulin levels as possible mediators of the effect of obesity on atherogenic and thrombogenic CVD risk factors among men. From the Health Professionals Follow-up Study (HPFS), we selected 268 men, aged 47--83 years, who were free of CVD, diabetes, and cancer (except non-melanoma skin cancer), and who had provided a fasting blood sample in 1994. We measured plasma insulin and leptin levels by radioimmunoassay and sTNF-R levels by ELISA. Men in the highest quintile of body mass index (BMI, mean=30.5 kg/m(2)) were less physically active and had a more adverse cardiovascular lipid and homeostatic profile, as indicated by levels of insulin, triglyceride (TG), tissue plasminogen activator (t-PA) antigen levels, and apolipoprotein A1 (Apo-A1). In a multivariate regression model controlling for age, smoking, alcohol intake, physical activity and diet, BMI was inversely associated with HDL-cholesterol (HDL-C) and Apo-A1 and positively associated with TG, Apo-B and t-PA antigen levels. The associations between BMI and these CVD risk factors were only slightly changed after adjusting for leptin and/or sTNF-R; but were substantially attenuated after controlling for insulin levels. These data suggest that the association between obesity and biological predictors of CVD may be mediated through changes in plasma insulin, rather than leptin or sTNF-R levels. However, plasma leptin may still play a role in CVD through independent effects on lipid metabolism.

Topics: Adult; Aged; Arteriosclerosis; Body Mass Index; Cardiovascular Diseases; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Risk Factors; Solubility; Thrombosis

Obesity is associated with increased cardiovascular morbidity and mortality and with elevated circulating levels of the satiety factor leptin. This study provides evidence for a direct link between leptin and the risk for thrombotic complications in obese individuals. For example, although arterial injury provokes thrombosis in both lean and obese (ob/ob) mice, the time to complete thrombotic occlusion is significantly delayed in the ob/ob mice, and the thrombi formed are unstable and frequently embolize. The ob/ob mice lack leptin, and intraperitoneal administration of leptin to these mice before injury restores the phenotype of lean mice by shortening the time to occlusion, stabilizing the thrombi, and decreasing the patency rate. The thrombi that form when leptin receptor-deficient obese (db/db) mice are injured also are unstable. However, in this instance, leptin has no effect. Platelets express the leptin receptor, and leptin potentiates the aggregation of platelets from ob/ob but not db/db mice in response to known agonists. These results reveal a novel receptor-dependent effect of leptin on platelet function and hemostasis and provide new insights into the molecular basis of cardiovascular complications in obese individuals. The results suggest that these prothrombotic properties should be considered when developing therapeutic strategies based on leptin.

Topics: Adenosine Diphosphate; Animals; Arteries; Blood Platelets; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phenotype; Platelet Aggregation; Thrombosis