leptin and Arteriosclerosis

Topics: Animals; Arteriosclerosis; Energy Metabolism; Humans; Hypertension; Leptin; Obesity; Receptors, Cell Surface; Receptors, Leptin; Risk Factors; Sympathetic Nervous System; Ventromedial Hypothalamic Nucleus

Topics: Adiponectin; Arteriosclerosis; Biomarkers; Humans; Leptin; Metabolic Syndrome

Topics: Adipocytes; Adiponectin; Animals; Arteriosclerosis; Endothelium, Vascular; Energy Metabolism; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Life Style; Mitogen-Activated Protein Kinases; Obesity; Phosphatidylinositol 3-Kinases; Receptor, Insulin; Risk Factors; Signal Transduction

Atherosclerotic CVD is the most common cause of death in the West. Yet, its pathogenesis and early development are only partially understood. Central to the early atherosclerotic process is impairment of vascular endothelial function. Endothelial dysfunction can be measured non-invasively and is evident in children before clinical manifestations of atherosclerosis in adulthood. Factors in early life, such as conventional cardiovascular risk factors, or programming by perinatal growth and nutrition strongly affect endothelial function and hence the development of atherosclerosis and CVD. For instance, low birth weight and faster growth early in infancy have a detrimental effect on vascular structure and function. Childhood obesity, a key independent risk factor for CVD, also adversely affects early vascular health. Obesity is associated with endothelial dysfunction and greater arterial stiffness from as early as the first decade of life, while weight loss is beneficial. This effect on vascular function is probably mediated in part by low-grade inflammation and insulin resistance associated with obesity or by the production by adipose tissue of cytokine-like molecules, collectively termed adipokines. A high leptin concentration, in particular, is found in obese individuals and is strongly associated with vascular changes related to early atherosclerosis. The present review focuses on the early origins of endothelial dysfunction, emphasising the role of obesity. It also considers the mechanisms by which obesity impairs endothelial function, understanding of which will be important to further scientific knowledge and to improve public health.

Topics: Arteriosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Humans; Leptin; Obesity; Risk Factors

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

Since obesity is becoming increasingly prevalent worldwide, much effort is being devoted to understanding its pathogenesis and treatment. In recent years, several candidate genes have been proposed as therapeutic targets. However, stearoyl-CoA desaturase 1 (SCD1) is of special significance, because it is the major gene target of leptin-a central mediator of energy homeostasis. There is evidence that SCD1 deficiency activates metabolic pathways that promote beta-oxidation and decrease lipogenesis in liver and skeletal muscles. One mechanism is via increased activation of AMP-activated protein kinase. SCD1 mutation results also in global changes in expression of genes involved in lipid metabolism. SCD1 deficient mice have increased energy expenditure, reduced body adiposity, and are resistant to diet-induced obesity. In this review, we examine data from our laboratory and others suggesting that SCD1 is an important component in the regulation of body metabolism.

Topics: Animals; Arteriosclerosis; Energy Metabolism; Fatty Liver; Humans; Insulin Resistance; Leptin; Liver; Metabolic Diseases; Muscle, Skeletal; Obesity; Oxidation-Reduction; Stearoyl-CoA Desaturase; Thermogenesis

Osteoporosis and atherosclerosis are both widely prevalent in an ageing population, and induce serious morbidities and death. There is growing evidence that in addition to their relationship to ageing, osteoporosis and atherosclerosis are also linked by biological associations. This article reviews their clinical interrelations, discusses the basic biology of bone and the arterial wall, and presents five examples that illustrate their biological linkages. Current therapeutic approaches emerging from these linkages, including statins, bisphosphonates, and the thiazolidinediones, have dual effects on bone and the vasculature. Additional therapies derived from experimental studies that enhance bone density and reduce atherogenesis hold further promise to diminish the morbidity and mortality of osteoporosis and atherosclerosis, with attendant benefits to society.

Topics: Adiponectin; Arteries; Arteriosclerosis; Bone and Bones; Calcinosis; Diphosphonates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Signaling Peptides and Proteins; LDL-Receptor Related Proteins; Leptin; Lipoxygenase; NF-kappa B; Osteoblasts; Osteoclasts; Osteoporosis; PPAR gamma; Thiazolidinediones

In this review article, the crucial roles of adipocytes in the development of so-called metabolic syndrome and vascular disease are reviewed, focusing on adipocyte-derived bioactive substances, adipocytokines. Recent progress in adipocyte biology shows that adipocytes are not merely energy-storing cells but that they secrete a variety of hormones cytokines, growth factors, and other bioactive substances. To search for novel adipocytokines by the large-scale random sequence analysis of expressed genes in adipocytes, we identified an adipose-specific collagen-like molecule, adiponectin. This novel adipocytokine has plural biofunctions, such as antidiabetic, antiatherosclerotic, and antiinflammatory functions. Adiponectin plasma levels decrease with the accumulation of visceral adipose tissue. In this review, we discuss the link of adiponectin to visceral adiposity, insulin resistance, and vascular diseases.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Arteriosclerosis; Diabetes Mellitus; Gene Expression Profiling; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Mice; Mice, Knockout; Models, Biological; Obesity; Organ Specificity; Proteins; Subcutaneous Tissue; Viscera

Platelet activation is involved in the pathogenesis of atherosclerosis and venous thromboembolism, and might therefore be a possible link between the two entities. Prolactin and leptin have recently been recognized as potent co-activators of ADP-dependent platelet aggregation or P-selectin expression, and are therefore suspected as additional risk factors for both arterial and venous thrombosis. There are clinical situations that have a known association with higher prolactin or leptin levels (pregnancy, obesity or anti-psychotic therapy) and increased risk of thromboembolic events. We compared the impact of both hormones on platelet activation in vitro and in vivo, indicating that prolactin has a stronger effect on platelet activation as leptin in vitro and in vivo. We have also demonstrated that prolactin levels are increased in so called idiopathic thrombosis, and that conversely, patients with prolactinoma have an increased frequency of thrombosis during the hyperprolactinemic state, in a retrospective analysis. Moreover, we have demonstrated increased prolactin values in stroke and myocardial infarction. Prospective studies have yet to be performed to give this theory its final confirmation. The involvement of hormonal factors in platelet aggregation and venous or arterial thrombosis may have important clinical implications such as for risk stratification of patients with venous and arterial thrombosis or new therapeutic options such as decreasing pro-coagulant hormone levels in certain risk situations.

Topics: Adenosine Diphosphate; Arteriosclerosis; Female; Gene Expression; Humans; Leptin; P-Selectin; Platelet Activation; Pregnancy; Prolactin; Venous Thrombosis

Topics: Adipocytes; Animals; Arteriosclerosis; Cell Differentiation; Humans; Hypertension; Insulin Resistance; Leptin; Ligands; Lipid Metabolism; Macrophage Activation; Metabolic Syndrome; Neovascularization, Pathologic; Receptors, Cytoplasmic and Nuclear; Thiazolidinediones; Transcription Factors; Vascular Endothelial Growth Factor A

Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists.

Topics: Adipocytes; Arteriosclerosis; Autoimmune Diseases; Cardiovascular Diseases; Humans; Immunity, Cellular; Insulin Resistance; Leptin; Receptors, Leptin; Receptors, Mitogen; Signal Transduction

Diabetes mellitus and hypertension are often associated with each other, and both are risk factors for cardiovascular diseases. Insulin resistance has been noted as an etiology for diabetes, hypertension and atherosclerosis. Insulin resistance often accompanied hyperinsulinemia and it is thought to elevate blood pressure through stimulation of the sympathetic nervous system and renin-angiotensin system, promotion of sodium retention in the renal tubules, and proliferation of vascular smooth muscle cells via insulin-like growth factor. Also high blood glucose may impair vascular endothelial cells and produce oxidant stress. To prevent the occurrence of hypertension in diabetes patients, improving insulin resistance have to be considered, and primary care such as reducing body weight, salt and alcohol restriction, exercise and non-smoking are important.

Topics: Arteriosclerosis; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Leptin; Life Style; Oxidative Stress; Primary Prevention; Renin-Angiotensin System; Sympathetic Nervous System

Topics: Adiponectin; Adipose Tissue; Animals; Arteriosclerosis; Cytokines; Diabetes Mellitus; Homeostasis; Humans; Hyperlipidemias; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Diseases; Plasminogen Activator Inhibitor 1; Proteins; Tumor Necrosis Factor-alpha

Atherosclerosis starts in childhood, and is accelerated in some individuals. A cluster of clinical and biochemical factors constitute the risk profile for many of them, perhaps most important being metabolic insulin resistance syndrome. Insulin resistance and its components for children and adolescents, especially obesity and dyslipidemia, are generators of hypertension, glucose intolerance and complications of atherosclerosis in adulthood. Some individuals are genetically predisposed, particularly those with the family history of such disorders. For many subjects, there is 'tracking' of metabolic and lifestyle factors from early age to adulthood. Several new risk factors of atherosclerosis (e.g. level of lipoprotein (a), procoagulant state, hyperhomocysteinemia, low birth weight and adverse in-utero environment, and possibly inflammatory markers) are current and potentially future areas of research concerning children and young individuals. Definition of and research on new and hitherto not investigated factors and formulation of strategies to neutralize the known factors are of paramount importance for primary prevention of atherosclerosis. Simple and effective measures for prevention include increasing awareness of the diseases, maintenance of ideal body weight, regular physical exercise, avoidance of smoking and chewing of tobacco, eating a balanced diet, and early periodic monitoring of blood pressure and metabolic status. These measures, starting from childhood, should be applied to all and in particular to the susceptible offspring, predisposed individuals, and populations.

Topics: Adolescent; Adult; Age Factors; Arteriosclerosis; Birth Weight; Blood Coagulation Factors; Child; Child, Preschool; Coronary Disease; Diabetes Complications; Exercise; Female; Homocysteine; Humans; Hypertension; Infant; Infant, Newborn; Insulin Resistance; Leptin; Life Style; Lipids; Lipoprotein(a); Male; Middle Aged; Obesity; Primary Prevention; Risk Factors; Sex Factors; Smoking

Topics: Arteriosclerosis; Cholesterol, HDL; Genetic Predisposition to Disease; Hispanic or Latino; Humans; Leptin; Mexico; Pedigree; Proteins; Texas

Obesity gains increasing prevalence world-wide. Multifactorially caused it presents itself in numerous heterogeneous phenotypes with a wide spectrum of clinical symptoms. The full-blown female obesity syndrome is initiated already in childhood, associated with ovarian hyperandrogenaemia (polycystic ovary syndrome) in the reproductive phase, and characterised by increasing co-morbidity (cancer; metabolic syndrome; arteriosclerosis) in the postmenopausal state leading to shortened longevity. Due to the complexity of psychic, somatic and endocrine-metabolic disturbances a causal break-through in the treatment of the disease could not be achieved yet, but the enhanced basal understanding and recently investigated pharmaceutical principles might enable to improve the therapeutical approaches.

Topics: Adolescent; Adult; Aged; Arteriosclerosis; Child; Combined Modality Therapy; Female; Gene Expression; Humans; Insulin Resistance; Leptin; Middle Aged; Neoplasms; Obesity; Polycystic Ovary Syndrome; Pregnancy; Proteins; Risk Factors

Obesity is associated with an increased incidence of insulin resistance, dyslipoproteinemia, and hypercoagulability. In a more recently established hypothesis of body weight control and regulation of metabolism, the adipocyte secretes leptin and locally expresses TNF-alpha, the latter being responsible for the expression of metabolic cardiovascular risk factors. TNF-a mRNA expression and TNF-alpha protein are greatly increased in adipose tissue from obese animals and humans. Elevated TNF-alpha expression induces insulin resistance by downregulating the tyrosine kinase activity of the insulin receptor and decreasing the expression of GLUT-4 glucose transporters. TNF-alpha also reduces lipoprotein lipase activity in white adipocytes, stimulates hepatic lipolysis, and increases plasminogen activator inhibitor-1 content in adipocytes. Moreover, adipocytes secrete leptin, a molecule with a secondary cytokine structure whose concentrations correlate with the amount of fat tissue. Increased leptin levels downregulate appetite and increase sympathetic activity and thermogenesis in the hypothalamus. Diet-induced weight loss reduces adipose TNF-alpha expression and serum leptin levels and is associated with improved insulin sensitivity and lipid metabolism. Although exercise has also been shown to reduce leptin levels, an influence on TNF-a expression in adipocytes or muscle cells has not yet been demonstrated.

Topics: Animals; Arteriosclerosis; Coronary Disease; Diet; Exercise; Humans; Insulin Resistance; Leptin; Obesity; Proteins; Risk Factors; Tumor Necrosis Factor-alpha; Weight Loss

Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients.. A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone.. The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA(1c) levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA(1c) (n = 30) and responders showing >1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism.. This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect.

Topics: Adiponectin; Arteriosclerosis; Blood Pressure; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycolipids; Humans; Hyperglycemia; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Japan; Leptin; Male; Middle Aged; Pioglitazone; Proteins; Thiazolidinediones

Hyperleptinemia is considered to be one of predictors of early atherosklerosis complications. This stimulated us to investigate differences between leptinemia in persons with accelerated atherosclerosis and leptinemia in probands without atherosclerosis complications. The study also verified whether leptinemia and its relationship to other anthropometric and biochemical parameters can differ in hypolipemic-treated probands and hypolipemic-untreated individuals. We examined 89 probands with accelerated atherosclerosis. The controls were 20 persons without any signs of accelerated atherosclerosis. Probands with accelerated atherosclerosis had a slight hyperglycemia and were slightly obese, but they did not meet criteria of metabolic cardiovascular syndrome. No significant differences between both groups under study were found in terms of anthropometric and biochemical parameters (BMI, % body fat, glycemia, insulin, C-peptide, intact proinsulin, total proinsulin cholesterol, HDL, triglycerides, LDL, homeostatic model of insulin secretion and resistance). Leptin concentration was not different as well. Stratification into males and females showed that women had a significantly higher leptinemia and fat tissue mass. Other biochemical parameters were similar in both groups. We suppose that in individuals without signs of metabolic syndrome, leptinemia does not belong among predictors of accelerated atherosclerosis. The accelerated atherosclerosis persons were then divided into subgroups according to medication (28 probands--pravastatin Lipostat 20, 15 probands--phenofibrate Lipanthyl 200M, 9 probands--simvastatin Zocor 20, 47 probands--no hypolipemic medication). No significant differences between the groups were found in terms of the analysed anthropometric and biochemical parameters, except leptinemia. The pravastatin-medicated probands had a significantly lower leptinemia (significant at 99% significance level) which was evidently sex-related than other patients. The pravastatin-administered persons showed no correlation between leptinemia and body fat mass (in contrast to other groups where such a correlation was highly statistically significant). These findings can be explained by a still unclear effect of pravastatin on insulin metabolism and on other factors involved in leptin synthesis and elimination. Thus, a new therapeutic effect of pravastatin can be supposed. This may account for a highly favourable effect of pravastatin on reduced manifestations o

Topics: Adipose Tissue; Age of Onset; Arteriosclerosis; Body Mass Index; Female; Fenofibrate; Humans; Hypolipidemic Agents; Insulin; Leptin; Male; Middle Aged; Pravastatin; Proteins; Simvastatin

Topics: Adiponectin; Arteriosclerosis; Humans; Leptin; Obesity; Oxidative Stress

The hypertrophy of vascular smooth muscle cells (VSMCs) is critical in vascular remodeling associated with hypertension, atherosclerosis, and restenosis. Recently, leptin has appeared to play a pivotal role in vascular remodeling. However, the mechanism by which leptin induces hypertrophy in vascular smooth muscle cells is still unknown. We studied the role of leptin as a potential hypertrophic factor in rat VSMCs. In the present study, leptin significantly increased [(3)H]leucine incorporation and the total protein/DNA ratio in VSMCs. The maximal hypertrophic effect was at 100ng/ml of leptin. Leptin induced phosphorylation and activation of p38 mitogen-activated protein (p38 MAP) kinase and of signal transducers and activators of transcription 3 in a concentration- and time-dependent manner. A p38 MAP kinase inhibitor SB203580 significantly inhibited leptin-induced hypertrophy, AG490 (a JAK2 inhibitor) partially inhibited it, and other MAP kinase inhibitors, PD98059 (an ERK inhibitor) and SP600125 (a JNK inhibitor), had no effect. These results indicate that leptin directly stimulates cellular hypertrophy via p38 MAP kinase in rat VSMCs.

Topics: Animals; Anthracenes; Aorta; Arteriosclerosis; Blotting, Western; Cells, Cultured; DNA; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Hypertrophy; Leptin; Leucine; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Time Factors; Trans-Activators; Tyrphostins

Topics: Adiponectin; Arteriosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Gene Expression; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Pioglitazone; PPAR gamma; Thiazolidinediones; Tumor Necrosis Factor-alpha

Human obesity is associated with elevated leptin levels and a high risk of death from cardiovascular disease. In the present study, we investigated the effects of leptin on vascular wound healing and arterial lesion growth in mice.. Wild-type mice placed on an atherogenic, high-fat diet had elevated (9-fold) leptin levels compared with their counterparts maintained on normal chow, and the former demonstrated significantly enhanced neointimal thickening after carotid artery injury with ferric chloride. The lesions forming in response to injury strongly expressed leptin receptor mRNA and protein. Unexpectedly, the atherogenic diet had no effect on injured vessels from leptin-deficient ob/ob mice despite aggravating obesity, diabetes, and hyperlipidemia in these animals. Daily administration of leptin to ob/ob mice during the 3-week period after injury reversed this phenotype, dramatically increasing neointimal thickness and the severity of luminal stenosis. Exogenous leptin also enhanced lesion growth and increased cellular proliferation in injured arteries from wild-type mice but had no effect on vessels from leptin receptor-deficient db/db mice.. Our results raise the possibility that there might be a direct, leptin receptor-mediated link between the hyperleptinemia in human obesity and the increased risk for cardiovascular complications associated with this condition.

Topics: Animals; Aorta; Arteriosclerosis; Carotid Arteries; Chlorides; Diet, Atherogenic; Dietary Fats; Disease Models, Animal; Ferric Compounds; Gene Expression Regulation; Hyperplasia; Leptin; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Obesity; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger; Tunica Intima

Topics: Adipose Tissue; Animals; Arteriosclerosis; Dietary Fats; Disease Progression; Endothelium, Vascular; Hematopoietic Cell Growth Factors; Humans; Insulin Resistance; Leptin; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Obesity; Receptors, Cell Surface; Receptors, Leptin; Risk Factors

Recent studies have suggested that leptin, a plasma protein secreted by adipocytes, may play a role in artherothrombosis. In this study, we tested the hypothesis that leptin contributes to in vivo endothelial dysfunction in obese subjects. A cross-sectional comparison of plasma leptin, soluble thrombomodulin (sTM) and soluble vascular adhesion molecule-1 (VCAM-1) was carried out in 35 obese women (age 48+/-13) selected with a body mass index (BMI) > or =30kg/m(2) and 25 normal weight women (age 50+/-11, BMI < 25). An additional study was conducted to determine the short-term effects of weight loss induced by caloric restriction. Plasma levels of leptin, sTM and sVCAM-1 were measured before and after weight loss. Obese women had higher levels of leptin (35+/-22 versus 22+/-19, P<0.01), sTM (4.8+/-1.8 versus 1.9+/-1.5, P<0.001) and sVCAM-1 (726+/-109 versus 583+/-50, P<0.001) than non-obese women. sTM and sVCAM-1 concentrations had a positive correlation with BMI (sTM, r=0.70, P<0.001; sVCAM-1, r=0.60, P<0.001), waist circumference (sTM, r=0.66, P<0.001; sVCAM-1, r=0.37, P<0.01) and leptin levels (sTM, r=0.53, P<0.001; sVCAM-1, r=0.42, P<0.005). At multiple regression analysis leptin predicted sTM and sVCAM-1 independently of obesity measures and other covariates. Twenty-nine obese patients who completed the program of weight reduction showed a significant decrease in leptin, sTM, and sVCAM-1 levels. The magnitude of decrease of sTM and sVCAM-1 was related to the magnitude of reduction in leptin levels. Therefore, our results show that obesity is associated with enhanced levels of atherosclerosis markers. These abnormalities are related to abdominal obesity possibly mediated by leptin levels, and are reversible with weight loss.

Topics: Arteriosclerosis; Biomarkers; Body Mass Index; Cross-Sectional Studies; Female; Humans; Leptin; Middle Aged; Obesity; Receptors, Leptin; Thrombomodulin; Vascular Cell Adhesion Molecule-1; Weight Loss

To evaluate the effect of massive weight loss on insulin sensitivity, soluble adhesion molecules, and markers of the insulin resistance syndrome (IRS).. Eighteen morbidly obese patients underwent gastric banding and were evaluated before and 6 and 12 months after surgery. Total insulin secretion, hepatic insulin extraction, and insulin sensitivity were analyzed by oral glucose-tolerance test model analysis. In addition, soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, leptin, high-sensitivity C-reactive protein, plasminogen activating factor-1 (PAI-1), and tissue plasminogen activator were measured.. BMI dropped from 45.22 +/- 5.62 to 36.99 +/- 4.34 kg/m(2) after 6 months and 33.72 +/- 5.55 kg/m(2) after 12 months (both p < 0.0001). This intervention resulted in a significant reduction of blood pressure (p < 0.00001), triglycerides (p < 0.01), fasting blood glucose (p = 0.03), basal insulin (p < 0.001), and basal C-peptide (p = 0.008) levels. Total insulin secretion decreased (p < 0.05), whereas hepatic insulin extraction (p < 0.05) and oral glucose insulin sensitivity index (p < 0.0001) increased compared with baseline. Leptin (p < 0.0001) and E-selectin levels decreased significantly after 6 and 12 months (p = 0.05), whereas significantly lower levels of intercellular adhesion molecule-1 and PAI-1 were only seen after 6 months. Subclinical inflammation, measured by high-sensitivity C-reactive protein, was lowered to normal ranges. No changes were observed in vascular cell adhesion molecule-1 and tissue plasminogen activator levels.. Although gastric banding ameliorates several features of the IRS, including 29.05% improvement in insulin sensitivity and blood pressure and reduction of soluble adhesion molecules and PAI-1, considerable weight loss did not normalize all components of the IRS in morbidly obese patients.

Topics: Adult; Arteriosclerosis; C-Peptide; Cell Adhesion Molecules; E-Selectin; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Leptin; Male; Obesity, Morbid; Plasminogen Activators; Stomach; Vascular Cell Adhesion Molecule-1; Weight Loss

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.

Topics: Arteriosclerosis; Female; Humans; Leptin; Lipoproteins, LDL; Middle Aged; Obesity; Postmenopause; Receptors, Leptin; Risk Factors; Thrombomodulin; Weight Loss

Subclinical inflammation has been implicated in the initiation and/or progression of atherosclerosis. Diabetes mellitus and obesity are risk factors for atherosclerosis, and asymptomatic low grade inflammation occurs prior to overt vascular lesions in these patients. In contrast to adults, little information exists concerning low grade inflammation in young type 1 diabetes and juvenile obesity.. To investigate low grade inflammation and immune activation in juvenile diabetes mellitus and obesity.. hs-CRP, soluble interleukin-2 receptor (sIL-2R), C-peptide, insulin, cortisol, vitamin B12, folic acid, leptin, and homocysteine were determined in 148 patients with juvenile type 1 diabetes, 86 obese children and 142 normal weighted age-matched healthy controls. Intima-media thickness (IMT) and lumen diameter of both common carotid arteries (CCA) was measured by ultrasonography in 52 healthy pediatric controls, 10 diabetics, and 34 obese juveniles.. Serum hs-CRP was significantly elevated in patients with type 1 diabetes (p < 0.0001), and obese children (p < 0.0001) as compared to the control group. The obese juveniles (p < 0.0001) and the diabetics (p < 0.0001) showed significantly increased values for IMT of CAAs. Levels of homocysteine, sIL-2R, insulin, cortisol, vitamin B12, and folic acid did not differ from the controls. The elevation of hs-CRP was more pronounced in obesity as compared to type 1 diabetes (p < 0.0001), and the hs-CRP values correlated significantly with body mass index standard deviation score (BMI-SDS) values. Furthermore, the IMT and the luminal diameter of CCAs showed significant correlations with BMI-SDS values.. A low grade inflammation as determined by serum hs-CRP is significantly increased in children with type 1 diabetes, and even more pronounced in apparently healthy juveniles with obesity. The increased IMT of CCAs strongly argues for an association between this low grade inflammation and early atherosclerotic vessel injury.

Topics: Adolescent; Arteriosclerosis; Body Mass Index; C-Peptide; C-Reactive Protein; Carotid Artery, Common; Child; Diabetes Mellitus, Type 1; Female; Folic Acid; Homocysteine; Humans; Inflammation; Leptin; Male; Obesity; Receptors, Interleukin-2; Tunica Intima; Vitamin B 12

Topics: Adiponectin; Age Factors; Arteriosclerosis; Biomarkers; Body Composition; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Probability; Prognosis; Prospective Studies; Reference Values; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sex Factors

Leptin and insulin-like growth factor-1 (IGF-1) have been suggested to be involved in the pathogenesis of atherosclerosis. The aim of this study was to evaluate the relationship between serum leptin, IGF-1 and intima-media thickness (IMT) and functions of common carotid artery (CCA) in children and adolescent patients with type 1 diabetes.. Serum leptin and IGF-1 levels were measured in 45 diabetic patients (23 girls and 22 boys). Age, diabetes duration as well as major cardiovascular risk factors, including anthropometric and metabolic parameters, were matched between girls and boys. The relation of serum leptin and IGF-1 levels to CCA structure and functions were measured by ultrasonography as IMT, cross-sectional compliance (CSC), cross-sectional distensibility (CSD), diastolic wall stress (DWS) and incremental elastic modulus (IEM).. Serum leptin levels of diabetic girls were higher than those in the boys (21.8 +/- 14.5 microg/l vs 8.9 +/- 10.6 micro/l, p = 0.002). However, the difference for serum IGF-I levels was not significant between diabetic girls and boys (240.7 +/- 96.8 ng/ml vs 234.7 +/- 93.2 ng/ml; p > 0.05). In all subjects, leptin levels were correlated with CSC (p = 0.04), CSD (p = 0.04) and IEM (p = 0.01), and IGF-1 levels were only correlated with CSC (p = 0.01). Leptin did not show any correlation with ultrasonographic measurements in both girls and boys separately. IGF-1 was correlated with CSC (p = 0.001), CSD (p = 0.002) and IEM (p < 0.001) in boys but not in girls. In a multivariate regression model, IGF-1 emerged as independent correlates for mean CSD and IEM in boys but not in girls.. Serum leptin and IGF-1 levels in children and adolescent patients with type 1 diabetes are associated with functions of common carotid artery, and the association of IGF-1 levels is influenced by sex.

Topics: Adolescent; Adult; Arteriosclerosis; Carotid Artery, Common; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Multivariate Analysis; Tunica Intima; Ultrasonography, Doppler

Diseases due to mutations in the lamin A/C gene (LMNA) are highly heterogeneous, including neuromuscular and cardiac dystrophies, lipodystrophies, and premature ageing syndromes. In this study we characterized the neuromuscular and cardiac phenotypes of patients bearing the heterozygous LMNA R482W mutation, which is the most frequent genotype associated with the familial partial lipodystrophy of the Dunnigan type (FPLD). Fourteen patients from two unrelated families, including 10 affected subjects, were studied. The two probands had been referred for lipoatrophy and/or diabetes. Lipodystrophy, exclusively observed in LMNA-mutated patients, was of variable severity and limited to postpubertal subjects. Lipodystrophy and metabolic disturbances were more severe in women, even if an enlarged neck was a constant finding. The severity of hypertriglyceridemia and hirsutism in females was related to that of insulin resistance. Clinical muscular alterations were only present in LMNA-mutated patients. Clinical and histological examination showed an invalidating, progressive limb-girdle muscular dystrophy in a 42-yr-old woman that had been present since childhood, associated with a typical postpubertal FPLD phenotype. Six of eight adults presented the association of calf hypertrophy, perihumeral muscular atrophy, and a rolling gait due to proximal lower limb weakness. Muscular histology was compatible with muscular dystrophy in one of them and/or showed a nonspecific excess of lipid droplets (in three cases). Immunostaining of lamin A/C was normal in the six muscular biopsies. Surprisingly, calpain 3 expression was undetectable in the patient with the severe limb-girdle muscular dystrophy, although the gene did not reveal any molecular alterations. At the cardiac level, cardiac septal hypertrophy and atherosclerosis were frequent in FPLD patients. In addition, a 24-yr-old FPLD patient had a symptomatic second degree atrioventricular block. In conclusion, we showed that most lipodystrophic patients affected by the FPLD-linked LMNA R482W mutation show muscular and cardiac abnormalities. The occurrence and severity of the myopathic and lipoatrophic phenotypes varied and were not related. The muscular phenotype was evocative of limb girdle muscular dystrophy. Cardiac hypertrophy and advanced atherosclerosis were frequent. FPLD patients should receive careful neuromuscular and cardiac examination whatever the underlying LMNA mutation.

Topics: Adolescent; Adult; Arteriosclerosis; Calpain; Cardiomegaly; Child; Diabetes Mellitus, Lipoatrophic; Female; Humans; Lamin Type A; Leptin; Male; Middle Aged; Muscles; Muscular Dystrophies, Limb-Girdle; Mutation; Triglycerides

Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown.. We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia, and insulin resistance are associated with hypertension, impaired left ventricular function, and accelerated atherosclerosis in those mice. Compared with lean mice, peroxisome proliferator-activated receptors (PPAR)-alpha and PPAR-gamma expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-alpha and PPAR-gamma, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs. Changes in gene expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. PPAR-alpha and PPAR-gamma expression was inversely related to plaque volume and to oxidized LDL content in the plaques.. Induction of PPAR-alpha and PPAR-gamma in adipose tissue, heart, and aortic arch is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight loss. Improved lipid metabolism and insulin signaling is associated with decreased tissue deposition of oxidized LDL that increases cardiovascular risk in persons with the metabolic syndrome.

Topics: Adipose Tissue; Animals; Aorta, Thoracic; Arteriosclerosis; Autoantibodies; Circadian Rhythm; Echocardiography; Gene Expression Regulation; Genotype; Glucose; Heart Function Tests; Hypertriglyceridemia; Inflammation; Insulin Resistance; Leptin; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Myocardium; Obesity; Oxidative Stress; PPAR alpha; PPAR gamma; Receptors, LDL; Transcription, Genetic; Up-Regulation; Weight Loss

The aging process is characterized by a number of gradual changes in circulating hormone concentrations as well as a gradual increase in the degree of atherosclerosis. The authors studied whether serum hormone levels are related to atherosclerosis of the carotid artery in independently living, elderly men. In 1996, 403 men (aged 73-94 years) were randomly selected from the general population of Zoetermeer, the Netherlands. Carotid artery intima-media thickness was determined. Serum concentrations of testosterone; estrone; estradiol; dehydroepiandrosterone and dehydroepiandrosterone sulfate; insulin-like growth factor I (IGF-I) (total and free) and its binding proteins IGFBP-1, IGFBP-2, and IGFBP-3; and leptin were measured. After the authors adjusted for age, serum testosterone, estrone, and free IGF-I were inversely related to intima-media thickness. The strength of these relations was as powerful in subjects with as in those without prevalent cardiovascular disease. Serum estradiol; dehydroepiandrosterone sulfate; total IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3; and leptin showed no association. These findings suggest that endogenous testosterone, estrone, and free IGF-I levels may play a protective role in the development of atherosclerosis in aging men.

Topics: Aged; Aged, 80 and over; Aging; Arteriosclerosis; Carotid Artery Diseases; Case-Control Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estrone; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Netherlands; Prevalence; Risk Factors; Testosterone; Tunica Media; Ultrasonography

Inflammation has been suggested as a risk factor for the development of atherosclerosis, while some components of metabolic syndrome X have been related to inflammatory markers. We hypothesized that adipocyte secreting protein, adiponectin and leptin, for which have been demonstrated an association with metabolic syndrome X and coronary artery disease, may be associated with inflammatory markers in nondiabetic humans.. We measured high-sensitivity C-reactive protein (hs-CRP), as an inflammatory marker, and adiponectin and leptin concentrations in 384 nondiabetic Japanese women (mean+/-s.e.m. age 53.6+/-0.8 Years, body mass index (BMI) 23.0+/-0.2 kg/m(2)) undergoing measurement of markers of metabolic syndrome X.. The women who had a low-grade hs-CRP elevation (>2.0 mg/l) were significantly older and had higher BMI, body fat mass (BFM), total cholesterol (TC), triglyceride (TG), atherogenic index (AI=(TC-HDLC)/HDLC), where HDLC is high-density lipoproten-cholesterol), fasting blood glucose and leptin concentrations before and after adjustment for BMI or BFM, while lower HDLC and adiponectin concentrations before and after adjustment compared with women with normal CRP levels (<0.5 mg/l). BMI, BFM, TG, AI and leptin before and after adjustment were found to be correlated with hs-CRP levels, while HDLC and adiponectin before and after adjustment were inversely correlated (all P<0.0001). hs-CRP was independently associated with white blood cell count, blood urea nitrogen and AI and inversely with adiponectin/BFM in the stepwise regression analysis model.. These data demonstrate a significant decrease in plasma adiponectin in low-grade chronic inflammation, and suggest that there is an important linkage between inflammation/adipose tIssue/atherosclerosis.

Topics: Adiponectin; Adolescent; Adult; Aged; Aged, 80 and over; Arteriosclerosis; Biomarkers; Body Mass Index; C-Reactive Protein; Cholesterol, HDL; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Leukocyte Count; Metabolic Syndrome; Middle Aged; Proteins; Sensitivity and Specificity; Triglycerides; Uric Acid

Recent data suggest that plasma leptin may represent a cardiovascular risk factor in diabetic patients. To gain further insight into the role of leptin in atherogenesis associated with diabetes, we investigated in the present study the role of this hormone in the regulation of macrophage lipoprotein lipase (LPL), a proatherogenic cytokine overexpressed in patients with type 2 diabetes. Treatment of human macrophages with leptin (1-10 nmol/l) increased LPL expression, at both the mRNA and protein levels. Pretreatment of these cells with anti-leptin receptor (Ob-R) antibody, protein kinase C (PKC) inhibitors, calphostin C, and GF109203X, or the antioxidant N-acetylcysteine (NAC) blocked the effects of leptin. Similar results were observed in leptin-treated J774 macrophages. In these cells, leptin increased the membrane expression of conventional PKC isoforms and downregulation of endogenous PKC expression abolished the effects of leptin on macrophage LPL expression. In leptin-treated J774 cells, enhanced LPL synthetic rate and increased binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL gene promoter were also observed. This latter effect was abrogated by GF109203X. Overall, these data demonstrate that binding of leptin at the macrophage cell surface increases, through oxidative stress- and PKC-dependent pathways, LPL expression. This effect appears to be exerted at the transcriptional level and to involve AP-1 activation.

Topics: Animals; Arteriosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Expression Regulation, Enzymologic; Humans; Leptin; Lipoprotein Lipase; Macrophages; Mice; Monocytes; Nuclear Proteins; Oxidative Stress; Promoter Regions, Genetic; Protein Kinase C; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Transcription Factor AP-1; Tumor Cells, Cultured

The metabolic syndrome in association with obesity is a major clinical problem inducing hypertension, diabetes mellitus, and atherosclerosis. Leptin induces angiogenesis by its proliferative effects on endothelial cells (ECs) via OB receptor (OB-Rb) gene. We evaluated the growth of ECs and intracellular signalings in response to leptin in vitro and the angiogenic effects of leptin in the cornea in vivo with and without adenovirus-mediated transfer of the OB-Rb gene in Zucker fatty (ZF) rats as a model for the metabolic syndrome. Recombinant adenovirus vector encoding rat OB-Rb (Ad.OB-Rb) or Escherichia coli. LacZ (Ad.LacZ) was transfected into cultured ECs from Zucker lean (ZL) rats and ZF rats. Leptin increased DNA synthesis dose-dependently in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb, but not with Ad.LacZ, improved the growth effects of leptin in ECs from ZF rats. Leptin induced phosphorylation of Janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, and extracellular signal-regulated kinase (ERK) in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb restored phosphorylation of JAK2 and STAT3 in ECs from ZF rats. Leptin induced angiogenesis in cornea from ZL rats, but not from ZF rats. Coadministration of leptin and Ad.OB-Rb induced angiogenesis in cornea from ZF rats. Ad.LacZ did not influence the angiogenic effects of leptin. The impaired endothelial function with the leptin resistance may be one of causes of the atherosclerosis in the metabolic syndrome.

Topics: Adenoviridae; Animals; Arteriosclerosis; beta-Galactosidase; Corneal Neovascularization; DNA; Endothelial Cells; Gene Transfer Techniques; Genetic Vectors; Leptin; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transfection

The serum uric acid level has been said to be an independent predictor of cardiovascular disease death, mainly for women, and to be linked with the metabolic Syndrome X of insulin resistance, obesity, hypertension, and dyslipidemia. Recently, it has been suggested that the elevation of serum leptin, the ob gene product, may have a role in metabolic Syndrome X. Therefore, we studied the relationship of uric acid to leptin in 822 Japanese women in a cross-sectional manner. To estimate the effect of uric acid on the variables of metabolic Syndrome X, we calculated mean values of various components of the syndrome according to tertiles of uric acid (UA < 4.0 mg/dl, 4.0 < or = UA < 5.5, 5.5 < or = UA). Age, systolic and diastolic blood pressure (BP), body mass index (BMI), percent body fat mass (BFM), serum total cholesterol, triglyceride, atherogenic index, leptin, fasting immunoreactive insulin and homeostasis model assessment-ratio (HOMA-R: calculated insulin resistance) were significantly different across the uric acid tertiles with higher levels in the highest tertile in comparison to the first (ANOVA, p < 0.001, 0.001, 0.002, 0.001, 0.001, 0.025, 0.001, 0.001, 0.001, 0.001, 0.001, respectively), while high density lipoprotein cholesterol showed lower levels (p < 0.001). Serum leptin concentrations were also elevated in hyperuricemic women after adjusting for BMI or BFM (both p < 0.001), and were weakly correlated with serum uric acid concentrations (r = 0.22, p < 0.0001). BMI, HOMA-R, serum triglyceride, diastolic BP and age-adjusted serum leptin concentrations were calculated for each tertile of serum uric acid. Compared with the lowest tertile of uric acid level, BMI, HOMA-R, serum triglyceride, diastolic BP and age-adjusted leptin concentrations were higher in the highest tertile. In the stepwise regression analysis, serum leptin was the significant independent variable for uric acid values. These results indicate an independent relationship between leptin and uric acid, further supporting the involvement of leptin in metabolic Syndrome X.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arteriosclerosis; Blood Glucose; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Female; Humans; Hyperuricemia; Insulin; Leptin; Metabolic Syndrome; Middle Aged; Triglycerides; Uric Acid

Anorexia and protein malnutrition, occasionally associated with obesity, are frequently observed in peritoneal dialysis (PD) patients. Both are recognized risk factors for cardiovascular (CV) morbidity and mortality. Leptin is produced by adipocytes and regulates body-fat mass through a satiety central effect. Leptin accumulates in the uremic state. We analyzed the relationship between plasma leptin levels, nutritional status, obesity, CV risk factors, and atherosclerosis in PD patients. Leptin was determined using a polyclonal antibody [radioimmunoassay: Linco Research, St. Louis, MO, U.S.A.]. The normal range was 1-7.8 ng/mL. We studied 38 PD patients. Mean leptin levels were 59.1 +/- 57.5 ng/mL (elevated in 32 patients). Women (n = 21) showed higher leptin levels than did men (80.4 +/- 60 ng/mL vs. 32.3 +/- 43.3 ng/mL, p < 0.01), in spite of both groups having a similar body mass index (BMI). A statistically significant direct correlation was found between leptin and BMI (r = 0.7, p < 0.01) and triceps skin-fold measurement (r = 0.77, p < 0.01). Leptin levels and renal creatinine clearance (CCr) showed no significant correlation. Independent of BMI, higher leptin levels were associated with parameters considered to be CV risk factors (Framingham study), such as serum triglycerides < 150 mg/dL (n = 29) as compared with > 150 mg/dL (44.2 +/- 53.2 ng/mL vs. 80 +/- 58.4 ng/mL, p < 0.05), cholesterol < 250 mg/dL (n = 28) as compared with > 250 mg/dL, (50 +/- 55.6 mg/dL vs. 84.7 +/- 57.7 mg/dL, p < 0.05), uric acid < 7 mg/dL (n = 28) as compared with > 7 mg/dL (47 +/- 53.7 mg/dL vs. 93.1 +/- 56.6 mg/dL, p < 0.05), and the presence or lack of presence of left ventricular hypertrophy [68.8 +/- 60 (n = 30) vs. 29.5 +/- 23.7 (n = 5), p < 0.05]. The patients were classified into two groups according to a clinical atherosclerosis score (CAS). Nineteen patients had low CAS scores, and they showed higher plasma leptin values than did the other patients (82.4 +/- 65.7 ng/mL vs 35.8 +/- 36.6 ng/mL, p < 0.05). Twelve patients with anorexia had lower leptin values than did patients with normal appetite (19.2 +/- 15.8 ng/mL vs. 91.3 +/- 58.8 ng/mL, p < 0.001). In non obese patients (BMI < 25 and CCr < 3 mL/min, n = 14), leptin had a statistically significant direct linear correlation with markers of nutrition, including albumin (r = 0.63, p < 0.05), transferrin (r = 0.4, p < 0.05), cholesterol (r = 0.65, p < 0.05), and triglycerides (r = 0.6, p < 0.05). Finally, plasma l

Topics: Adult; Aged; Aged, 80 and over; Arteriosclerosis; Biomarkers; Cardiovascular Diseases; Female; Humans; Kidney; Leptin; Logistic Models; Male; Middle Aged; Nutrition Disorders; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Risk Factors

Topics: Alcohols; Animals; Apolipoproteins E; Arteriosclerosis; Biomarkers; Carbohydrate Metabolism; Cardiovascular Diseases; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Feeding Behavior; Fish Oils; Flavonoids; Garlic; Genes; Glycine max; Health Education; Homocysteine; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Life Style; Lipid Metabolism; Nutritional Physiological Phenomena; Obesity; Phenols; Polymers; Polyphenols; Probiotics

To characterize the developmental changes in adipose and muscle lipoprotein lipase (LPL) activity in the atherosclerosis-prone JCR:LA-corpulent rat, and to test the hypothesis that tissue-specific abnormalities in LPL activity precede the establishment of obesity.. Lean (+/?) and obese cp/cp male JCR:LA rats were studied at 4, 5 and 8 weeks of age, that is at the onset of obesity, and at a time when obesity is well established. Assessment was made of plasma variables related to glucose and lipid metabolism and of LPL activity in several adipose depots, skeletal muscles and the heart.. At week 4, body weights were identical in both genotypes and began to diverge at week 5. Eight-week-old cp/cp rats weighed 35% more than their lean counterparts. Perirenal and epididymal adipose depot weights were also identical in both genotypes at week 4 and began to increase in cp/cp rats at week 5, whereas the subcutaneous depot of 4-week-old cp/cp rats was slightly enlarged. At week 4, the cp/cp rats were hyperinsulinemic (5-fold), hyperleptinemic (30-fold) and hypertriglyceridemic (3-fold) compared to their lean counterparts, and their liver contained twice as much triglyceride. The 4-week-old cp/cp rats displayed 2-7-fold higher LPL specific activity in the various adipose depots compared to lean rats, and enzyme activity remained higher in obese than in lean rats at all subsequent ages. In contrast, LPL activity in the vastus lateralis, gastrocnemius and heart muscles of 4-week-old obese rats was approximately half that observed in lean animals.. Profound, persistent alterations in the tissue-specific modulation of LPL activity are established in the JCR:LA cp/cp rat prior to the development of frank obesity. The increase in adipose tissue LPL activity and its decrease in muscle tissues are likely to be related to the concomitant alterations in insulinemia and triglyceridemia, respectively. The pre-obesity, tissue-specific alterations in LPL activity may be considered as an integrated adaptation to increased lipid flux aimed at driving lipids toward storage sites and limiting their uptake by triglyceride-laden muscles.

Topics: Adipose Tissue; Aging; Animals; Arteriosclerosis; Blood Glucose; Body Composition; Body Weight; Fatty Acids, Nonesterified; Genotype; Insulin; Leptin; Lipoprotein Lipase; Male; Muscle, Skeletal; Myocardium; Obesity; Organ Size; Rats; Rats, Mutant Strains; Triglycerides

Previous studies have reported modest associations between measures of obesity and the Trp64-Arg variant of the beta3-adrenergic receptor (ADRbeta3) and the Pro12Ala variant of the peronisome proliferator-activated receptor (PPAR)-gamma2. We hypothesized that these single gene variants may mark mutations that act through convergent pathways to produce synergistic effects on obesity.. The sample included 453 subjects from 10 large Mexican-American families participating in the population-based San Antonio Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framework. Analyses were conditioned on the pedigree structures to account for the correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustment for age, sex and diabetes status.. The allele frequencies for the ADRbeta3 Trp64Arg and PPARgamma2 Pro12Ala variants were 18 and 12%, respectively. The ADRbeta3 variant was not significantly associated with any of the obesity-related traits, but subjects with the PPAR-gamma2 variant (n = 98) had significantly higher levels of lasting insulin (P = 0.03), leptin (P = 0.009), and waist circumference (P = 0.03) than those without. Subjects with the gene variants (n = 32) had significantly higher BMI, insulin, and leprtin levels than those with only the PPARgamma2 variant (n = 66) (P for interaction: 0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively).. Our results suggest that epistatic models with genes that have modest individual effects may be useful in understanding the genetic underpinnings of typical obesity in humans.

Topics: Adipose Tissue; Adult; Amino Acid Substitution; Arteriosclerosis; Body Mass Index; DNA; DNA-Binding Proteins; Female; Genetic Variation; Humans; Insulin; Leptin; Lymphocytes; Male; Mexican Americans; Obesity; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Texas; Transcription Factors

Over a century ago it was recognized that the vessel wall is a predominant site for ectopic calcification which is a hallmark of clinically significant atherosclerotic lesions. Old observational studies, which characterized vascular calcification as osteogenesis, and recent identification of common molecular mechanisms in bone and vascular calcification have led to the new recognition that atherosclerotic calcification is an actively regulated process similar to osteogenesis and distinct from a metastatic passive mineralization. Since the atherosclerotic lesion is composed of a multitude of cells and inflammatory mediators, elucidation of the role of these components in induction and acceleration of calcification is of fundamental importance in better understanding its pathogenesis and identifying possible interventional targets. This article will focus on four important mediators of vascular calcification: 1) calcifying vascular cells, 2) oxidized lipids, 3) cytokines, and 4) leptin.

Topics: Arteriosclerosis; Calcinosis; Cytokines; Endothelium, Vascular; Humans; Leptin; Lipid Metabolism; Muscle, Smooth, Vascular; Ossification, Heterotopic

Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-;ob/ob) exhibited striking elevations in both total plasma cholesterol (TC) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an apoB-containing broad-beta remnant lipoprotein fraction. While fasting, diet restriction, and low level leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggest that leptin deficiency increased hepatic triglyceride production but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes, and atherosclerosis.

Topics: Animals; Arteriosclerosis; Diet; Disease Models, Animal; Hypercholesterolemia; Hypertriglyceridemia; Leptin; Lipoproteins; Mice; Mice, Inbred C57BL; Receptors, LDL; Receptors, Leptin

Leptin, the product of ob gene, is an endocrine hormone that regulates adipose tissue mass. Recently, leptin has been found to generate a growth signal involving a tyrosine kinase-dependent intracellular pathway and promote angiogenic processes via activation of leptin receptor (Ob-R) in endothelial cells. However, it is not clear how leptin functions to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. We have examined the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and Ob-R in human atherosclerotic lesions, leptin-mediated angiogenesis in vivo and in vitro. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of Ob-R in the intima of neorevascularized regions and of both MMPs and TIMPs predominantly in the endothelial lining of intimal neovessels and macrophages/foam cells. In the rat corneal angiogenesis assay, leptin elicited a comparable sensitivity of angiogenic activity to those of vascular endothelial growth factor (VEGF). The immunohistological analysis of the leptin-treated rat cornea showed definitive rises in Ob-R, MMPs and TIMPs expression as well as those of VEGF receptor (VEGFR-1). Leptin (10-40 ng/ml) induced proliferation of the human umbilical vein endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP-9, TIMP-1, and Up-regulated the human coronary artery smooth muscle cells (HCASMCs). These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, plays a role in matrix remodeling by regulating the expression of MMPs and TIMPs. Taken together, our findings further provide evidences for leptin's role as an angiogenesis inducer in the normal organ (rat cornea) and in aberrant vasculature under duress like atherosclerosis.

Topics: Animals; Arteriosclerosis; Blotting, Western; Cell Division; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Growth Factors; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 2; Immunohistochemistry; Leptin; Lymphokines; Matrix Metalloproteinases; Neovascularization, Pathologic; Rats; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Leptin; Receptors, Vascular Endothelial Growth Factor; Recombinant Proteins; Tissue Inhibitor of Metalloproteinases; Umbilical Veins; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Endothelial cell activation is an early event in atherogenesis, and previous studies have reported correlations between indirect markers of endothelial cell activation and CRP concentration. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in nine healthy subjects (mean age 53+/-8.1 years; body mass index 27+/-3.2 kg/m(2); mean arterial blood pressure 101+/-9.0 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of N(G)-monomethyl-L-arginine (L-NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a non-specific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with (i) the percentage decrease in forearm blood flow (FBF) during L-NMMA infusion (r=0.85, P=0.004); and (ii) the serum leptin concentration (r=0.65, P=0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to L-NMMA remained significant when age and leptin (t=2.65, P=0.045), age and BMI (t=3.69, P=0.014), or age and low-density-lipoprotein-cholesterol plus high-density-lipoprotein-cholesterol (t=3.37, P=0.044), were included in regression models. In contrast, the response of FBF to noradrenaline was not significantly related to CRP concentration. These data demonstrate for the first time a relationship between low-grade chronic inflammation and basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disease.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; C-Reactive Protein; Chronic Disease; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Inflammation; Leptin; Lipids; Male; Middle Aged; omega-N-Methylarginine

We demonstrated that leptin showed effects on both platelets and endothelial cells through its functional receptor. These effects are the vector to inducing thrombotic tendency. Leptin concentrations used in our experiments correspond to that of leptin in the circulation of obese individuals. Thus we suggest that increased leptin may act as a risk factor for thrombosis in obese individuals.

Topics: Adenosine Diphosphate; Arteriosclerosis; Blood Platelets; Blood Proteins; Carrier Proteins; Endothelium, Vascular; Humans; Leptin; Obesity; Phosphorylation; Platelet Aggregation; Receptors, Cell Surface; Receptors, Leptin; Thrombomodulin

This cross sectional study was undertaken to determine whether serum leptin levels were associated with multiple risk factor (MRF) clustering syndrome. We examined the relationship between serum leptin concentrations and blood pressure (BP), serum lipids levels, calculated insulin resistance (HOMA-ratio) and adiposity among 581 Japanese adult women. The serum leptin was increased in female subjects with systolic (> or =160 mmHg) and diastolic > or =90 mmHg) hypertension compared with the normotensive females (mean+/-SE; 9.3+/-0.5 vs 7.7+/-0.3; 10.2+/-0.6 vs 7.1+/-0.3 ng/ml, both p<0.001). Serum leptin was elevated in those with hyper-cholesterolemia (C; > or =220 mg/dl) and triglyceridemia (TG; > or =150 mg/dl) compared with the normolipidemia (9.4+/-0.4 vs 7.8+/-0.3; 11.7+/-0.6 vs 7.5+/-0.2 ng/ml, both p <0.001). Serum leptin was also elevated in those with adiposity (BMI > or =26.4 kg/m2) and insulin resistance (HOMA-ratio > or =2.5) compared with the normal females (14.8+/-0.7 vs 5.2+/-0.2; 11.3+/-1.1 vs 7.1+/-0.4ng/ml, both p<0.001). Even after adjusting for BMI or percent body fat mass (BFM), leptin levels remained to be elevated significantly in all these diseases. There was a positive correlation between serum leptin and systolic, diastolic BP, TC, TG, BMI, BFM, IRI and HOMA-ratio (r=0.12, p=0.005; r=0.24, p<0.0001; r=0.19, p<0.0001; r=0.35, p<0.0001; r=0.72, p<0.0001; r=0.73, p<0.0001; r=0.47, p< 0.0001; r=0.44, p<0.0001), and a negative correlation with HDL-C levels (r= -0.20, p< 0.0001). These correlations were also observed in leptin levels after adjusting for the BMI or BFM. Multiple regression analysis showed that BFM, HOMA-ratio and TG were significant determinants of leptin concentration before (t=12.6, p<0.0001; t=3.33, p=0.001; t=3.22, p=0.001) and after adjusting for BMI or BFM. These results suggest that because serum leptin levels were elevated in components of MRF clustering syndrome, leptin may have a pathophysiological role in MRF clustering syndrome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arteriosclerosis; Blood Pressure; Body Mass Index; Cholesterol; Cross-Sectional Studies; Female; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Japan; Leptin; Middle Aged; Obesity; Risk Factors; Syndrome; Triglycerides

Human umbilical vein endothelial cells (HUVEC) express functional receptors to leptin, the product of the ob gene. As human obesity is associated with atherosclerosis and hyperleptinemia, we investigated whether leptin, in addition to its angiogenic properties, exerts atherogenic effects through the generation of oxidative stress in endothelial cells. In HUVEC leptin increased the accumulation of reactive oxygen species (ROS), as assessed by the oxidation of 2', 7'- dichlorodihydrofluorescein, in a time- and concentration-dependent manner. In addition, leptin activated the NH2-terminal c-Jun kinase/stress-activated protein kinase pathway as demonstrated by enhanced JNK activity and AP-1 DNA binding. Both effects were sensitive to antioxidant treatment with N-acetylcysteine. NF-kappaB, another redox-sensitive transcription factor, was also activated by leptin stimulation in an oxidant-dependent manner. Finally, activation of both AP-1 and NF-kappaB was associated with an enhanced expression of the monocyte chemoattractant protein-1 in HUVEC. These findings demonstrate that ROS are second messengers involved in leptin-induced signaling in endothelial cells. Thus, chronic oxidative stress in endothelial cells under hyperleptinemia may activate atherogenic processes and contribute to the development of vascular pathology.

Topics: Arteriosclerosis; Base Sequence; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Chemokine CCL2; DNA Primers; Endothelium, Vascular; Humans; JNK Mitogen-Activated Protein Kinases; Leptin; Mitogen-Activated Protein Kinases; NF-kappa B; Oxidative Stress; Proteins; Reactive Oxygen Species

To study the relationship between hyperinsulinaemia, insulin resistance, leptin and atherosclerosis in subjects with familial hypercholesterolaemia (FH).. Case-control cross-sectional study.. Lipid clinic, Johannesburg Hospital, South Africa.. Fasting serum lipid, glucose, insulin and leptin levels were measured in 24 homozygous FH subjects; 20 FH heterozygotes without coronary artery disease (CAD); 22 heterozygotes with documented CAD; and 20 healthy normocholesterolaemic subjects. Insulin resistance was calculated using the homeostasis model assessment (HOMA) formula.. Mean glucose and insulin levels were similar in all 4 groups. There was no significant difference in calculated insulin resistance between any of the groups. There was also no relationship between the degree of insulin resistance and total or LDL-cholesterol levels. Using Spearman's correlation coefficient (Rs) calculated insulin resistance correlated with triglyceride (Rs = 0.27; P<0.05) and inversely with HDL-cholesterol (Rs = -0.26; P<0.05). Fasting insulin concentrations and calculated insulin resistance were similar in FH subjects with overt CAD compared to those without. Leptin levels were higher in the FH subjects with CAD. However, these subjects were older and had a larger body mass index (BMI), and when adjusted for age and BMI, only BMI correlated with leptin levels (multiple r = 0.65; P<0.001).. In the absence of other causes of insulin resistance, FH subjects have normal fasting insulin levels and, in general, they are not insulin resistant. Insulin resistance appears to play little role in the pathogenesis of accelerated atherosclerosis in FH.

Topics: Adolescent; Adult; Arteriosclerosis; Blood Glucose; Body Mass Index; Coronary Disease; Female; Heterozygote; Homozygote; Humans; Hyperinsulinism; Hyperlipoproteinemia Type II; Insulin; Insulin Resistance; Leptin; Lipids; Male; Proteins

Leptin receptors are supposed to have signal effects and are located in most tissues in the organism but we failed to find literary data on concentration (measurement) of leptin receptors in the system circulation. We examined by the method of randomized selection the group of 20 patients with manifested atherosclerosis in whom BMI was calculated. Then we analyzed concentration of leptin receptor (double sandwich ELISA, standard recombinant human leptin), leptin, glucose, insulin, proinsulin, CRP and uric acid in the serum. The control group consisted of 103 probands without signs of atherosclerosis or other manifested diseases. The control group was subjected to determination of BMI, leptin and leptin receptor in the serum. Concentration of leptin receptor does not differ significantly between the patients with atherosclerosis and normal population. Probands with atherosclerosis showed a very close negative correlation between concentration of leptin receptor and leptinemia which is absent in normal population.

Topics: Arteriosclerosis; Blood Glucose; Body Mass Index; Carrier Proteins; Humans; Insulin; Leptin; Random Allocation; Receptors, Cell Surface; Receptors, Leptin; Reference Values

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Topics: Adipose Tissue; Analysis of Variance; Arteriosclerosis; Chromosome Mapping; Chromosomes, Human, Pair 2; Diabetes Mellitus, Type 2; Family; Female; Genetic Linkage; Genetic Markers; Humans; Leptin; Lod Score; Male; Obesity; Pedigree; Proteins; Risk Factors

Topics: Animals; Arteriosclerosis; Brain; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Drug Industry; Humans; Leptin; Lipid Metabolism; Obesity; Proteins