IP-10, but not RANTES,is upregulated by leptin in monocytic cells

We and others have previously shown that leptin has direct effects on the function of monocytes and macrophages. Since obesity is associated with an increased cardiovascular risk, as well as with markedly elevated circulating leptin levels, we examined whether leptin has any pro-inflammatory effects on the function of monocytes. Leptin strongly enhanced the expression and secretion of the interferon-gamma-inducible protein (IP-10) in a human monocytic cell line, as well as in peripheral blood mononuclear cells. In contrast, no significant effect on other inflammatory proteins was observed, such as metalloproteinases and other chemokines. In summary, we have demonstrated that leptin selectively induces the expression and secretion of IP-10 in human monocytic cells, potentially contributing to the vascular complications associated with hyperleptinemic obesity in humans.     

Mechanisms mediating renal sympathetic activation to leptin in obesity

Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity.     

Effect of peripheral administration of leptin on the renal sympathetic nerve activity in high-fat diet-related hypertensive rats

A previous study of ours demonstrated that a high-fat diet (FAT) causes body fat accumulation, as well as elevation of plasma leptin level, renal sympathetic nerve activity (RSNA), and blood pressure (BP). In the study reported here, we analyzed the role of leptin in these elevations of the RSNA and BP due to FAT feeding by assessing sympathetic and cardiovascular responses to intravenous (IV) administration of leptin in rats fed either a FAT or a high-carbohydrate diet (CHO). The results showed that baseline body fat, plasma leptin level, RSNA and BP were significantly higher in the FAT group than in the CHO group, and that IV administration of leptin elevated RSNA and plasma leptin levels but lowered BP in the CHO group. However, these effects of leptin were eliminated in the FAT group. These findings suggest that FAT-fed rats which expose basal elevation of plasma leptin levels, RSNA and BP might be hyposensitive to endogenous leptin. Therefore, leptin resistance appeared obviously in FAT-induced hypertension might indicate that leptin is implicated in generating the elevation of RSNA and BP induced by long-term FAT feeding.     

Expression of the leptin receptor in different types of vascular lesions

Clinical and experimental evidence suggests that the adipokine leptin may be important for the development of cardiovascular complications associated with obesity, possibly through interaction with its receptor on vascular cells. In the present study, we systematically analysed expression of the leptin receptor in normal and diseased vascular specimens using immunohistochemistry, immunofluorescence and quantitative real time-PCR. In particular, human atherosclerotic plaques as well as experimental vascular lesions induced in hypercholesterolemic mice and minipigs, respectively, were examined. Our results demonstrate the presence of the leptin receptor in normal vessel wall segments as well as neointimal or atherosclerotic lesions. In the latter, ObR expressing cells were predominantly localised on the luminal border and within the subintima, and coexpression of von Willebrand factor, VEGF receptor-2 or VE cadherin identified them as endothelial cells. Moreover, CD14-positive monocytes/macrophages were strongly positive for the leptin receptor. In contrast, only few ObR-expressing smooth muscle cells could be detected in human atherosclerotic plaques. The findings of the present study thus support a possible action of leptin on the cardiovascular system by demonstrating expression of the leptin receptor in different types of vascular lesions.     

Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

Urocortins and corticotropin releasing factor type 2 receptors in the hypothalamus and the cardiovascular system

In addition to urocortin (Ucn I), Ucn II and Ucn III were identified as endogenous ligands for corticotropin-releasing factor type 2 receptor (CRF2 receptor). CRF2 receptor is abundantly located in central hypothalamic ventromedial nucleus (VMH) and in peripheral cardiovascular system. In this mini-review, we focused on the roles of these urocortins and CRF2 receptor in the hypothalamus and the cardiovascular system. Ucn II mRNA was increased in the parvocellular part or the magnocellular part of the hypothalamic paraventricular nucleus (PVN) following immobilization stress or 3 days of water deprivation, respectively. Therefore, it is thought that Ucn II may modulate CRF and vasopressin synthesis in the PVN in a paracrine or autocrine fashion through PVN CRF2 receptor. The early and later phases of Ucn I-mediated feeding suppression may be CRF1 and CRF2 receptor-mediated events, respectively. Ucn II decreases food intake at a later phase, beyond 4 h post injection. A large dose of corticosterone increased plasma leptin and insulin levels as well as the levels of CRF2 receptor mRNA. Adrenalectomy, starvation, and immobilization each lowered plasma leptin and insulin levels and were associated with decrements in CRF2 receptor mRNA levels in the VMH. Peripheral injection of leptin increased VMH CRF2 receptor mRNA, as can induce reductions of food intake and body weight, indicating that circulating leptin is involved in the regulation of VMH CRF2 receptor mRNA expression. Therefore, it is also plausible that VMH CRF2 receptor transduces the anorexogenic effects of leptin as well as those of urocortins. The systemic administration of Ucn II decreases mean arterial pressure (arterial vascular tone) and causes tachycardia via vascular CRF2 receptor in rats, similar to the effects of Ucn I. Thus, CRF2 receptor seems to mediate cardioprotective effects of urocortins.     

Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis

The growing worldwide obesity epidemic is frequently linked to an increased risk of developing diseases such as diabetes, cardiovascular disease, and cancer. These diseases are associated with the infiltration of macrophages in white adipose tissue (WAT), the artery wall, and tumors, respectively; and these macrophages likely contribute to disease progression and pathogenesis. Abdominal WAT, adipose tissue surrounding the heart and artery wall, as well as carcinoma cells, secrete many factors that could induce macrophage infiltration. Leptin is an adipocyte-secreted hormone, and deficiency of either leptin or its receptor has been shown to cause morbid obesity in animals and in humans. However, what is more commonly noted in human obesity is the presence of central leptin resistance leading to hyperleptinemia. As leptin receptors are present on macrophages, we hypothesized that leptin could act as a monocyte/macrophage chemoattractant. Our current study demonstrates: 1) leptin is a potent chemoattractant for monocytes and macrophages, inducing maximal chemotactic responses at 1 ng/ml; 2) leptin-mediated chemotaxis requires the presence of full-length leptin receptors on migrating cells; 3) leptin causes increased influx of intracellular calcium in macrophages; and 4) activation of janus kinase/signal transducers and activators of transduction (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) pathways are all necessary for leptin-induced macrophage migration. Taken together, these data demonstrate that leptin is a potent monocyte/macrophage chemoattractant in vitro and that canonical cell motility machinery is activated upon macrophage exposure to leptin. These data have implications for the impact of hyperleptinemia on obesity-related pathophysiological conditions such as diabetes, cardiovascular disease, and cancer.     

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice

Background

The global pattern of varying prevalence of diseases of affluence, such as obesity, cardiovascular disease and diabetes, suggests that some environmental factor specific to agrarian societies could initiate these diseases.

Presentation of the hypothesis

We propose that a cereal-based diet could be such an environmental factor. Through previous studies in archaeology and molecular evolution we conclude that humans and the human leptin system are not specifically adapted to a cereal-based diet, and that leptin resistance associated with diseases of affluence could be a sign of insufficient adaptation to such a diet. We further propose lectins as a cereal constituent with sufficient properties to cause leptin resistance, either through effects on metabolism central to the proper functions of the leptin system, and/or directly through binding to human leptin or human leptin receptor, thereby affecting the function.

Testing the hypothesis

Dietary interventions should compare effects of agrarian and non-agrarian diets on incidence of diseases of affluence, related risk factors and leptin resistance. A non-significant (p = 0.10) increase of cardiovascular mortality was noted in patients advised to eat more whole-grain cereals. Our lab conducted a study on 24 domestic pigs in which a cereal-free hunter-gatherer diet promoted significantly higher insulin sensitivity, lower diastolic blood pressure and lower C-reactive protein as compared to a cereal-based swine feed. Testing should also evaluate the effects of grass lectins on the leptin system in vivo by diet interventions, and in vitro in various leptin and leptin receptor models. Our group currently conducts such studies.

Implications of the hypothesis

If an agrarian diet initiates diseases of affluence it should be possible to identify the responsible constituents and modify or remove them so as to make an agrarian diet healthier.     

The association of leptin and C-reactive protein with the cardiovascular risk factors and metabolic syndrome score in Taiwanese adults

ABSTRACT: BACKGROUND: Serum C-reactive protein (CRP) and leptin levels have been independently associated with the cardiovascular risk factors. The aim of the present study was to determine if their serum levels were associated with cardiovascular risk factors or metabolic syndrome as well as their correlation in the Taiwanese population. METHODS: This retrospective study included 999 subjects (> 18 y), who underwent a physical examination in Chang-Gung Memorial Hospital-Linkou and Chiayi in Taiwan. The associations between CRP and/or leptin levels and cardiovascular risk factors and metabolic syndrome were determined using independent two sample t-tests to detect gender differences and chi-square tests to evaluate differences in frequencies. To compare the means of the variables measured among the four groups (high and low leptin and high and low CRP), analysis of variance (ANOVA) was used. RESULTS: Both CRP and leptin levels were independently associated with several cardiovascular risk factors, including diabetes, hypercholesterolemia and metabolic syndrome in both men and women (P < 0.05). In addition, a positive correlation between leptin and CRP levels was observed in both genders. Both high-CRP and high-leptin were associated with high blood glucose, waist circumference and serum triglyceride. Whereas increased metabolic syndrome incidence was observed in males with elevated leptin regardless of CRP levels, females with elevated CRP or leptin had increased incidence of metabolic syndrome. CONCLUSION: Both leptin and CRP levels were associated with cardiovascular risk factors as well as metabolic syndrome score in both men and women although gender-specific differences were observed. Thus, CRP and leptin may represent useful biomarkers for predicting the onset of cardiovascular disease or metabolic syndrome in Taiwanese adults. Trial registration IRB/CGMH 100-3514B.     

Arsenic and weight loss: At a crossroad between lipogenesis and lipolysis

Arsenic is found in soil, food, water and earth crust. Arsenic exposure is associated with chronic diseases such as cancer, cardiovascular disease as well as diabetes. One of complex effects of arsenic is on weight gain or loss. Involvement of arsenic in both weight loss and gain signaling pathways has previously been reported; however, too little attention has been paid to its weight reducing effect. Animal studies exhibited a role of arsenic in weight loss. In this regard, arsenic interference with endocrine system, leptin and adiponectin hormones as well as thermogenesis is more evidence. Apparently, arsenic-induced weight lossis generally meditated by its interaction with thermogenesis. In this review we have discussed the irregularities in metabolic pathways induced by arsenic that can lead to weight loss.     

瘦素与软骨代谢

瘦素最初发现是在白色脂肪组织产生并且与脂肪组织量有强相关性的激素物质。它最初发现于1994年,并且在中枢神经系统起到限制食物摄入,刺激能量消耗的作用。目前发现在几乎所有的组织内都有瘦素受体的表达,而且在细胞层面瘦素参与各种各样的生物学功能,包括免疫反应、炎性疾病以及心血管、呼吸系统的病理生理过程。目前大量研究表明,瘦素在软骨代谢也发挥了重要作用,现综述如下。     

Nutritional modulation of leptin expression and leptin action in obesity and obesity-associated complications

In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.     

Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms

MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.     

Leptin signaling pathways in the central nervous system: interactions between neuropeptide Y and melanocortins.

No other hormone has drawn more attention than leptin in recent studies on the control of appetite, body weight and obesity. This hormone is produced by adipose tissue and enters the brain via a saturable specific transport mechanism. Leptin acts in the hypothalamus to modulate food intake and heat production as well as several other neuroendocrine pathways. The mechanisms through which leptin exerts its central nervous effects are now better understood. Proopiomelanocortin- and neuropeptide Y-containing neurons in the hypothalamus have emerged as potent candidate mediators of leptin action. These two neuropeptides have been shown to exert opposing effects using different pathways. Recently, Cowley et al. (2001) described a new circuit in the regulation of neuronal activity by leptin with an interaction between these two pathways. These data add complexity to the mechanisms by which leptin achieves its effects in the central nervous system, but they also offer potential mechanisms to explain the phenomenon of leptin resistance observed in obesity.     

The relation of serum adiponectin and leptin levels to metabolic syndrome in women before and after the menopause

INTRODUCTION: It is well known that there is a higher prevalence of cardiovascular risk factors and metabolic syndrome (MS) in postmenopausal women. Recently it has become evident that adiponectin and leptin secreted by adipose tissue may be involved in the pathophysiology of MS. The aim of the study: was to assess the effects of the menopause on the relationships between adiponectin and leptin and different cardiovascular and metabolic risk factors. MATERIALS AND METHODS: A total of 56 postmenopausal women and 75 premenopausal subjects were enrolled in this study. We measured blood pressure, BMI, waist circumference and WHR, triglycerides (TG), high density lipoprotein cholesterol (cHDL) levels and fasting glucose and applied the oral glucose tolerance test (OGTT). Women were categorised as having 0, 1, 2, 3 or more risk factors. The presence of at least 3 abnormalities was defined as MS. Serum was assayed for adiponectin and leptin by the radioimmunoassay (RIA) method. RESULTS: A decline in adiponectin was related to an increased number of MS variables in postmenopausal and premenopausal women. Postmenopausal women with MS had significantly lower adiponectin concentrations than premenopausal women with MS. Serum adiponectin concentrations were inversely correlated to leptin in postmenopausal women. In premenopausal women no clear relationships were found between serum leptin and the number of metabolic disturbances. In contrast to young women, postmenopausal women showed an increase in leptin secretion with a growing number of MS elements. Compared to premenopausal women with MS, postmenopausal women with MS had higher levels of leptin. We found associations between leptin and different risk factors, mainly in the postmenopausal group. When the presence of MS was used as a dependent variable (yes/no) and adiponectin, leptin and menopause status as independent factors, adiponectin and leptin remained significant variables related to MS. CONCLUSION: The significant role of adiponectin in the pathophysiology of MS in premenopausal and postmenopausal women is confirmed in this study. Leptin is correlated with several MS components but this adipocytokine appears to play a role only in postmenopausal women.     

Leptin improves membrane fluidity of erythrocytes in humans via a nitric oxide-dependent mechanism--an electron paramagnetic resonance investigation

Abnormalities in physical properties of the cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. Recently, there has been an indication that leptin, the product of the human obesity gene, actively participates not only in the metabolic regulations but also in the control of cardiovascular functions. In the present study, to assess the role of leptin in the regulation of membrane properties, the effects of leptin on membrane fluidity of erythrocytes in humans are examined. The membrane fluidity of erythrocytes in healthy volunteers by means of an electron paramagnetic resonance (EPR) and spin-labeling method is determined. In an in vitro study, leptin decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS obtained from EPR spectra of erythrocyte membranes in a dose-dependent manner in healthy volunteers. The finding indicated that leptin increased the membrane fluidity and improved the microviscosity of erythrocytes. The effect of leptin on the membrane fluidity was significantly potentiated by the nitric oxide (NO) donors, L-arginine and S-nitroso-N-acetylpenicillamine (SNAP), and a cyclic guanosine monophosphate (cGMP) analog, 8-bromo-cGMP. In contrast, the change evoked by leptin was significantly attenuated in the presence of the NO synthase inhibitors, N(G)-nitro-L-arginine-methyl-ester (L-NAME) and asymmetric dimethyl-L-arginine (ADMA). The results of the present study showed that leptin increased the membrane fluidity and improved the rigidity of cell membranes to some extent via an NO- and cGMP-dependent mechanism. Furthermore, the data also suggest that leptin might have a crucial role in the regulation of rheological behavior of erythrocytes and microcirculation in humans.     

Impaired activation of phosphatidylinositol 3-kinase by leptin is a novel mechanism of hepatic leptin resistance in diet-induced obesity

Obesity is associated with the development of leptin resistance. However, the effects of leptin resistance on leptin-regulated metabolic processes and the biochemical defects that cause leptin resistance are poorly understood. We have addressed in rats the effect of dietinduced obesity (DIO), a situation of elevated tissue lipid levels, on the well described lipid-lowering effect of leptin in liver, an action that is proposed to be important for the prevention of tissue lipotoxicity and insulin resistance. In addition, we have addressed the role of phosphatidylinositol 3-kinase (PI 3-kinase) in mediating the acute effects of leptin on hepatic lipid levels in lean and DIO animals. A 90-min leptin ( approximately 10 ng/ml) perfusion of isolated livers from lean animals decreased triglyceride levels by 42 +/- 5% (p = 0.006). However, leptin concentrations ranging from approximately 10 to approximately 90 ng/ml had no effect on triglyceride levels in livers from DIO animals. The acute lipid-lowering effect of leptin on livers from lean animals was mediated by a PI 3-kinase-dependent mechanism, because wortmannin and LY294002, the PI 3-kinase inhibitors, blocked the effects of leptin on hepatic triglyceride levels and leptin increased liver PI 3-kinase activity by 183 +/- 6% (p = 0.003) and insulin receptor substrate 1 tyrosine phosphorylation by 185 +/- 30% (p = 0.02) in the absence of PI 3-kinase inhibitors. Contrary to the effects of leptin in lean livers, leptin did not activate PI 3-kinase in livers from DIO rats. These data present evidence for a role for 1). leptin resistance in contributing to the excessive accumulation of tissue lipid in obesity, 2). PI 3-kinase in mediating the acute lipid-lowering effects of leptin in liver, and 3). defective leptin activation of PI 3-kinase as a novel mechanism of leptin resistance.     

Adipocytokines - novel link between inflammation and vascular function?

Obesity and obesity related diseases are a major public health problem. Recent studies have shown that fat tissue is not a simple energy storage organ, but exerts important endocrine and immune functions. These are achieved predominantly through release of adipocytokines, which include several novel and highly active molecules released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines released possibly by inflammatory cells infiltrating fat, like TNF-alpha, IL-6, MCP-1 (CCL-2), IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation and may also affect vascular (endothelial) function by modulating vascular nitric oxide and superoxide release and mediating obesity related vascular disorders (including hypertension, diabetes, atherosclerosis, and insulin resistance) but also cancer or non-alcoholic fatty liver diseases. Present review, in a concise form, focuses on the effects of major adipocytokines, characteristic for adipose tissue like leptin, adiponectin, resistin and visfatin on the immune system, particularly innate and adaptive immunity as well as on blood vessels. Macrophages and T cells are populating adipose tissue which develops into almost an organized immune organ. Activated T cells further migrate to blood vessels, kidney, brain and other organs surrounded by infiltrated fat leading to their damage, thus providing a link between metabolic syndrome, inflammation and cardiovascular and other associated disorders. Ceretain treatments may lead to significant changes in adipocytokine levels. For example include beta-2 adrenoreceptor agonists, thiazolidinediones as well as androgens lead to decrease of plasma leptin levels. Moreover future treatments of metabolic system associated disorders should focus on the regulation of adipocytokines and their modes of action.     

Circulating leptin and stress-induced cardiovascular activity in humans

Obesity is associated with an elevated risk of hypertension and cardiovascular disease. The adipocyte hormone leptin, which stimulates energy expenditure in animals by activating the sympathetic nervous system (SNS), is believed to play a role in this association. However, evidence in humans remains sparse. We investigated the relationship between circulating leptin and cardiovascular and inflammatory responses to acute psychological stress in humans. Participants were 32 men and 62 women aged 18-25 years. Cardiovascular activity was assessed using impedance cardiography at baseline, during acute laboratory stress, and during a 45-min recovery period. Plasma cytokines were measured in blood drawn at baseline and 45-min poststress. In women only, baseline plasma leptin was significantly associated with stress-induced changes in heart rate (beta = 0.53, P = 0.006), heart rate variability (HRV) (beta = -0.44, P = 0.015), and cardiac preejection period (PEP) (beta = -0.51, P = 0.004), independent of age, adiposity, and smoking. Women's plasma leptin levels also correlated with stress-induced elevations in the proinflammatory cytokine interleukin-6 (IL-6) (beta = 0.35, P = 0.042). Circulating leptin is an independent predictor of sympathetic cardiovascular activity, parasympathetic withdrawal, and inflammatory responses to stress in women. Because cardiovascular and inflammatory stress responses are predictive of future cardiovascular disease, leptin may be a mechanism mediating the adverse effects of stress and obesity on women's cardiovascular health.