Circulating leptin is associated with oxidized LDL in postmenopausal women

doi:10.1016/j.atherosclerosis.2004.03.010

Atherosclerosis

Volume 175, Issue 1, July 2004, Pages 139-143

https://doi.org/10.1016/j.atherosclerosis.2004.03.010 Get rights and content

Abstract

Recently, leptin has been suggested as a possible cause of atherosclerotic disease. In the present study, we have investigated in postmenopausal women (n=60; age: 52±13) the relationship between circulating levels of leptin, oxidized LDL (Ox-LDL) and other biochemical and anthropometric variables of atherosclerotic risk. In addition, we have evaluated soluble thrombomodulin (sTM) as a marker of endothelial damage. An additional study was conducted in a subgroup of obese subjects to determine the short-term effects of weight loss on selected variables. Ox-LDL showed a positive correlation with leptin circulating levels (r=0.65, P<0.0001). A significant association was also found between Ox-LDL and body mass index (r=0.69, P<0.0001), waist-to-hip ratio (r=0.50, P<0.0001), insulin levels (r=0.65, P<0.0001), HOMA index (r=0.55, P<0.0001) and sTM (r=0.74, P<0.0001) levels. After multivariate regression analysis leptin was still related to Ox-LDL levels (P=0.007). In obese women who completed the program of weight reduction, leptin changes persisted as a significant predictor of plasma changes in Ox-LDL levels. These findings suggested a novel link between leptin and Ox-LDL, possibly involved in atherosclerotic disease.

Introduction

Leptin is a plasma protein encoded by the ob gene, secreted by adipocytes and involved in the control of body weight [1]. Plasma concentrations of leptin are increased in human obesity and positively correlated to the body fat mass in lean and obese subjects [2]. In addition to long-term regulation of the body weight, hyperleptinemia has been considered as a component of the metabolic syndrome [3] and a role for leptin as a possible cause of vascular disease has been recently suggested [4], [5], [6], [7]. In this setting, it has been shown that leptin might exert an atherogenic effect through the generation of oxidative stress in endothelial cells [8].

Oxidized LDL (Ox-LDL) is a plaque specific lipoprotein that is directly involved in the initiation and progression of the atherosclerotic disease process [9]. Substantial evidence demonstrated that Ox-LDL are present in vivo, possibly reflecting the turnover of Ox-LDL formed in the vascular wall [10]. Elevated blood levels have been shown to be present in patients in all stages of coronary artery disease [11], [12], [13], [14]. Furthermore, Ox-LDL levels have been shown to be related to intima-media thickness and plaque occurrence in the carotid and femoral arteries of clinically healthy subjects [15].

Several risk factors of atherosclerosis have been also studied with respect to their possible effects on LDL oxidation [14]. In this setting, interestingly, a multivariate analysis showed that body mass index (BMI) was one of the most significant predictors of circulating levels Ox-LDL [14].

In the light of these observations, we hypothesised an in vivo relationship between plasma leptin and Ox-LDL levels. To explore this hypothesis, we evaluated the relationship between circulating Ox-LDL, leptin plasma levels and other risk factors of atherosclerosis, in sixty postmenopausal women at baseline and after a weight loss program carried out in a subgroup of subjects with BMI≥30. Our findings showed that Ox-LDL levels are associated with leptin levels independently of other risk factors and that decrease in leptin concentration induced by weight loss is a significant predictor of circulating changes in Ox-LDL.

Section snippets

Subjects and study protocol

Since previous studies demonstrated a gender and menopausal-dependent leptin plasma concentration [16], we decided to evaluate postmenopausal women referred to our vascular ambulatory service to screen for atherosclerosis risk factors. All patients had appropriate clinical and laboratory evaluations and were subjected to carotid ultrasonography for atherosclerosis assessment as previously described [17].

Body mass index (BMI) was used to distinguish between patients with normal weight (18–25 kg/m²

Results

The study group, whose characteristics are shown in Table 1, consisted of 60 postmenopausal women (age: 52±13 years). At the time of assessment, all of the study subjects were free of history of cardiovascular events (i.e. ischemic heart disease, cerebrovascular disease) and had no clinical evidence of atherosclerotic diseases. The mean intimal-media thickness (IMT) was 0.88±0.14 mm, no significant plaque was found at ultrasonographic assessment. All subjects were non-smokers, had normal fasting

Discussion

This study extends the observation of a relationship between circulating Ox-LDL and cardiovascular risk factors to circulating levels of leptin, a plasma protein recently suggested as a component of cardiovascular risk [3], [4], [5], [6], [7]. This association was present at univariate analysis and persisted after multivariate analysis including other cardiovascular risk factors and after changes induced by a weight loss program.

Several studies have tested circulating Ox-LDL in patients with

Acknowledgements

We thank Augusto Di Castelnuovo for the excellent assistance in statistical analysis. This work was supported by a grant from the Italian Ministry of Research to the Centre of Excellence on Aging of the University of Chieti.

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Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes
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Further studies will be needed to confirm whether OxLDL actually participates in the increased expression of PAI-1 in adipocytes in vivo. Evidence is accumulating that circulating OxLDL is positively associated with metabolic syndrome, including insulin resistance and obesity [7–9]. As shown above, OxLDL enhances PAI-1 expression in adipocytes.
Plasminogen activator inhibitor-1 (PAI-1) is secreted from adipose tissue and is considered to be a risk factor for both atherosclerosis and insulin resistance. Here we report for the first time that PAI-1 expression is enhanced by oxidized low-density lipoprotein (OxLDL) and its lipid component lysophosphatidylcholine (LPC) in mouse 3T3-L1 adipocytes. In fully differentiated 3T3-L1 cells, OxLDL treatment increased the mRNA expression and protein secretion of PAI-1 in a dose- and time-dependent manner, whereas native LDL had no effect. The addition of an anti-CD36 antibody suppressed OxLDL-stimulated PAI-1 expression by 50%, suggesting that adipose-derived CD36 contributes to roughly half of the PAI-1 expression stimulated by OxLDL. In addition, pharmacological experiments showed that the OxLDL-stimulated enhancement in PAI-1 expression was mediated through the generation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinase 1/2. Furthermore, LPC, a major lipid component of OxLDL, was responsible for the enhanced expression of PAI-1 as phospholipase A₂-treated acetyl LDL, which generates LPC, strongly stimulated PAI-1 expression, whereas acetyl LDL itself had no such activity. These data demonstrate that the uptake of OxLDL and, in particular, its lipid component LPC into adipocytes triggers aberrant ROS-mediated PAI-1 expression, which may be involved in the pathogenesis of metabolic syndrome.
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In obese postmenopausal women we assessed leptin and adiponectin, high-sensitive C-reactive protein (hsCRP), serum lipids and lipoxidative stress products: oxidized LDL (oxLDL) and malondialdehyde (MDA), in relation to impaired glucose tolerance (IGT).
Thirty-eight overweight/obese postmenopausal women were included in the study. Eighteen with normal glucose metabolism (NGT) and twenty with IGT, as it is diagnosed by OGTT. Serum leptin, adiponectin, hsCRP and MDA were measured at time 0 and 120 min of OGTT while total-cholesterol, LDL, HDL, triglycerides, oxLDL and anti-oxLDL autoantibodies at time 0. Insulin resistance (HOMA)/sensitivity (QUICKI) indexes were estimated.
In subjects with NGT, hsCRP was positively correlated with fasting leptin and HOMA, while in subjects with IGT negatively with QUICKI. In both groups, hsCRP was positively correlated with fasting insulin, body mass index and waist circumference. Fasting adiponectin was positively associated with HDL in both groups and negatively with triglycerides in subjects with NGT as well as with serum glucose levels at time 120 min of OGTT in subjects with IGT. No association was observed between oxLDL and adipokines. A significant positive association was found between oxLDL and HOMA in subjects with IGT. During OGTT there was a significant increase of leptin and MDA levels in both groups.
A relationship exists between obesity, insulin and sub-clinical inflammation. Leptin and lipid peroxidation are linked to hyperglycaemic state while oxLDL might be considered as a predictor of insulin resistance. Adiponectin could exert its antiatherogenic effect through HDL independently of the presence of IGT.
Circulating oxidized LDL levels, current smoking and obesity in postmenopausal women
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The aim of the present study was to estimate circulating oxidized low-density lipoprotein (oxLDL) levels in postmenopausal women and evaluate their association with obesity and smoking status.
The study included 135 postmenopausal women aged 52–75 years. Forty of them were overweight (BMI 32.4 ± 6.4) and non-smokers (Group A), 40 non-overweight (BMI 22.6 ± 1.8) and smokers (Group B) and 55 non-overweight (BMI 23.5 ± 1.4) and non-smokers (Group C). oxLDL and antibodies against them (anti-oxLDL) were measured using ELISA. Serum total cholesterol, LDL, HDL and triglycerides were measured in an automated analyzer.
Total cholesterol, LDL, HDL and oxLDL serum levels were significantly elevated in Group A as compared to Group B or C, as well as oxLDL in Group B in comparison to Group C (p < 0.001). Triglycerides and anti-oxLDL were increased in Group A in comparison to Group C (p = 0.043 and 0.023). Total cholesterol, LDL, triglycerides and anti-oxLDL did not differ between Groups B and C, while HDL was decreased in Group B as compared to Group C (p < 0.001). A significant positive correlation was found between oxLDL and LDL in Group A (r = 0.53, p < 0.001) as well as in Group C (r = 0.955, p ≤ 0.001) and a negative one between oxLDL and HDL in Group C (r = −0.933, p < 0.001). Regression analysis revealed that obesity was a stronger predictor of LDL oxidation than smoking.
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The study population included 421 obese Japanese outpatients (185 men and 236 women, mean age: 51.1 years) enrolled in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The novel oxidized low-density lipoprotein markers, serum SAA-LDL and AT-LDL, were measured in all participants.
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Effects of leptin on cardiovascular physiology
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Citation Excerpt :
Leptin increases the accumulation of cholesterol esters in foam cells66 and serum leptin inversely correlates with plasma high density lipoprotein cholesterol and apolipoprotein AI.67,68 Leptin may also contribute to the “pro-inflammatory” state associated with obesity in that it correlates strongly with acute phase reactants such as C-reactive protein and serum amyloid A.69,70 Leptin also increases oxidative modification of plasma lipoproteins (oxidized low density lipoprotein)71 and increases DNA-binding activity of proinflammatory transcription factors AP-1 and NFkB as well as increases expression of monocyte chemoattractant protein-1.59 Therefore, leptin may be a key mediator of augmented inflammatory/oxidative stress environment associated with obesity.
Since the discovery of leptin, numerous studies have established a central role for this adipose tissue hormone in the regulation of body weight. Further it is now recognized that obesity is a state of hyperleptinemia resulting from increased synthesis and release of leptin from the greater adipose tissue mass present in this condition. Leptin has been implicated in the regulation of a number of physiological processes in addition to body weight homeostasis, and in many cases the hyperleptinemia of obesity may result in pathologic consequences. Leptin appears to have a central role in the development of obesity related hypertension and a number of observations implicate leptin as contributing to atherogenesis and atherosclerosis. Although significant progress has been made in our understanding of the pathologic effects of leptin on cardiovascular function, additional work remains to be done to fully understand the consequences of hyperleptinemia on cardiovascular physiology.

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Circulating leptin is associated with oxidized LDL in postmenopausal women

Abstract

Introduction

Section snippets

Subjects and study protocol

Results

Discussion

Acknowledgements

Atherosclerosis

Leptin. Lancet

J. Biol. Chem.

Atherosclerosis

J. Biol. Chem.

The role of leptin in human obesity and disease: a review of current evidence

Ann. Intern. Med.

Serum immunoreactive-leptin concentrations in normal-weight and obese human

N. Engl. J. Med.

Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk

Arterioscer. Thromb. Vasc. Biol.

Plasma leptin and the risk of cardiovascular disease in West of Scotland Coronary Prevention Study (WOSCOPS)

Circulation

Influence of leptin on arterial distensibility. A novel link between obesity and cardiovascular disease?

Circulation

Plasma leptin is independently associated with the intima-media thickness of the common carotid artery

Intern. J. Obes.

Does leptin cause vascular disease?

Circulation

Leptin induces oxidative stress in human endothelial cells

FASEB J.

Atherosclerosis: an inflammatory disease

N. Engl. J. Med.