leptin and Vascular-Diseases

To review the latest reports of the contributions of the endothelial mineralocorticoid receptor to endothelial dysfunction and hypertension to begin to determine the clinical potential for this pathway for hypertension treatment.. Endothelial mineralocorticoid receptor expression is sex-specifically increased in female mice and humans compared with males. Moreover, the expression of endothelial mineralocorticoid receptors is increased by endothelial progesterone receptor activation and naturally occurring fluctuations in progesterone levels (estrous, pregnancy) predict endothelial mineralocorticoid receptor expression levels in female mice. These data follow many previous reports that have indicated that endothelial mineralocorticoid receptor deletion is protective in the development of obesity- and diabetes-associated endothelial dysfunction in female mouse models. These studies have more recently been followed up by reports indicating that both intact endothelial mineralocorticoid receptor and progesterone receptor expression are required for obesity-associated, leptin-mediated endothelial dysfunction in female mice. In addition, the intra-endothelial signaling pathway for endothelial mineralocorticoid receptors to induce dysfunction requires the intact expression of α-epithelial sodium channels (αENaC) in endothelial cells in females. Endothelial mineralocorticoid receptors are sex-specifically upregulated in the vasculature of females, a sex difference which is driven by endothelial progesterone receptor activation, and increased activity of these endothelial mineralocorticoid receptors is a crucial mediator of endothelial dysfunction, and potentially hypertension, in obese female experimental models.

Topics: Aldosterone; Animals; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Epithelial Sodium Channels; Female; Humans; Hypertension; Leptin; Male; Mice; Mineralocorticoid Receptor Antagonists; Obesity; Receptors, Mineralocorticoid; Receptors, Progesterone; Sex Factors; Vascular Diseases

Systemic sclerosis is a multiorgan autoimmune disease characterized by vasculopathy and tissue fibrosis of unknown etiology. Recently, adipokines (cell signaling proteins secreted by adipose tissue) have attracted much attention as a cytokine family contributing to the various pathological processes of systemic sclerosis. Adipokines, such as leptin, adiponectin, resistin, adipsin, visfatin or chemerin are a heterogenic group of molecules. Adiponectin exhibits anti-fibrotic features and affects inflammatory reactions. Leptin promotes fibrosis and inflammation. Resistin was linked to vascular involvement in systemic sclerosis. Visfatin was associated with regression of skin lesions in late-stage systemic sclerosis. Chemerin appears as a marker of increased risk of impaired renal function and development of skin sclerosis in the early stage of systemic sclerosis. Vaspin was indicated to have a protective role in digital ulcers development. Novel adipokines-adipsin, apelin, omentin and CTRP-3-are emerging as molecules potentially involved in SSc pathogenesis. Serum adipokine levels may be used as predictive and diagnostic factors in systemic sclerosis. However, further investigations are required to establish firm correlations between distinct adipokines and systemic sclerosis.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers; Humans; Inflammation; Leptin; Resistin; Scleroderma, Systemic; Signal Transduction; Vascular Diseases

Obesity has reached epidemic proportions and its prevalence is climbing. Obesity is characterized by hypertrophied adipocytes with a dysregulated adipokine secretion profile, increased recruitment of inflammatory cells, and impaired metabolic homeostasis that eventually results in the development of systemic insulin resistance, a phenotype of type 2 diabetes. Nitric oxide synthase (NOS) is an enzyme that converts L-arginine to nitric oxide (NO), which functions to maintain vascular and adipocyte homeostasis. Arginase is a ureohydrolase enzyme that competes with NOS for L-arginine. Arginase activity/expression is upregulated in obesity, which results in diminished bioavailability of NO, impairing both adipocyte and vascular endothelial cell function. Given the emerging role of NO in the regulation of adipocyte physiology and metabolic capacity, this review explores the interplay between arginase and NO, and their effect on the development of metabolic disorders, cardiovascular diseases, and mitochondrial dysfunction in obesity. A comprehensive understanding of the mechanisms involved in the development of obesity-induced metabolic and vascular dysfunction is necessary for the identification of more effective and tailored therapeutic avenues for their prevention and treatment.

Topics: Adipogenesis; Adipokines; Adiponectin; Adipose Tissue; Angiopoietin-Like Protein 2; Angiopoietin-like Proteins; Animals; Arginase; Cellular Senescence; Cytokines; Endoplasmic Reticulum Stress; Glucose; GPI-Linked Proteins; Humans; Inflammation; Insulin; Lectins; Leptin; Lipid Metabolism; Lipocalin-2; Metabolic Diseases; Mice; Mitochondria; Nicotinamide Phosphoribosyltransferase; Nitric Oxide; Obesity; Rats; Resistin; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha; Vascular Diseases

Adipokines, in particular adiponectin, have been highlighted in the pathogenesis of obesity-related illnesses, including type 2 diabetes, because of their role in the regulation of insulin sensitivity as well as vascular endothelial function. Since cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with diabetes, researchers are actively seeking a better understanding of the role that adipokines play in the vasculature with the hope that the use of these agents, or activation of their signaling pathways, might help prevent micro- and macrovascular complications. This brief review highlights recent work on the vascular effects of circulating adipokines, focusing on adiponectin, and includes some recent findings with leptin and resistin. This highly active area of investigation has identified novel hormonal mechanisms by which the adipose tissue mass can influence vascular function with important consequences for cardiovascular risk.

Topics: Adiponectin; Animals; Diabetes Mellitus; Humans; Leptin; Resistin; Signal Transduction; Vascular Diseases

Leptin has received extensive attention as an endogenously produced satiety factor. Although once considered to be solely derived from adipose tissue, it is now apparent that leptin can be produced by various tissues including those comprising the cardiovascular system such as blood vessels and cardiomyocytes. Moreover, leptin receptors (OBR) have been identified in cardiovascular tissues. The increased cardiovascular risk associated with obesity is well known and many of the effects of leptin appear to be compatible with its potential role as a contributing factor to increased cardiovascular morbidity associated with obesity. Evidence from both animal and human studies implicated leptin as a potential contributor to the increased incidence of cardiovascular morbidity associated with hyperleptinemic conditions. This review focuses on some of the complex vascular actions of leptin and the emerging role of leptin as a cardiovascular regulator in terms of normal homeostatic function, but particularly in cardiovascular pathology.

Topics: Animals; Humans; Leptin; Muscle, Smooth, Vascular; Receptors, Cell Surface; Receptors, Leptin; Vascular Diseases

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

To investigate the relationships among serum resistin, adiponectin, and leptin and microvascular complications in patients with type 2 diabetes mellitus (T2DM).. A total of 120 patients with T2DM were divided into non-microangiopathy and microangiopathy groups. Sixty age- and sex-matched healthy subjects were used as a normal control (NC) group. Body height, body mass, waist circumference, and blood pressure were determined, and waist/hip ratio (WHR), body mass index, blood glucose, lipids, resistin, leptin, adiponectin, free fatty acids (FFA), high-sensitivity C-reactive protein (hs-CRP), fasting insulin, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared among the three groups.. Serum levels of resistin, leptin, FFA, and hs-CRP were significantly higher and levels of adiponectin were significantly lower in patients in the non-microangiopathy (n = 60) and microangiopathy groups (n = 60) compared with the NC group (n = 60). Serum resistin and leptin levels in patients with T2DM were positively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but negatively correlated with high-density lipoprotein-cholesterol (HDL-C). Serum adiponectin levels in patients with T2DM were negatively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but positively correlated with HDL-C.. Serum resistin, adiponectin, and leptin levels correlate with the occurrence of T2DM and microvascular complications.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Resistin; Vascular Diseases

The adipocytokine leptin is an independent cardiovascular risk factor and exerts proatherogenic effect. Pre-existing vascular disease is an important cause of arteriovenous fistula (AVF) maturation failure. We explored the association between serum leptin, pre-existing vascular disease, and AVF maturation failure in incident hemodialysis patients.. Vein samples from 62 patients were collected at the time of AVF creation. Pre-existing vascular disease was evaluated with histologic changes and immunohistochemical characteristics of cellular phenotypes in intima. AVF maturation failure was defined as an AVF that could not be used successfully by the third month after its creation.. The prevalence of body mass index ≥30 kg/m. Obesity-related higher fistula maturation failure rate may be partly mediated by higher leptin level-associated pre-existing vascular diseases in end-stage renal disease patients. Decreased expression of leptin receptor may be related to this association.

Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Shunt, Surgical; Biomarkers; Body Mass Index; Female; Humans; Hyperplasia; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Receptors, Leptin; Renal Dialysis; Republic of Korea; Risk Factors; Treatment Failure; Up-Regulation; Vascular Diseases; Veins

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Leprdb/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under a standard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post -natal environments to contribute to altered vascular function in offspring of diabetic pregnancies.

Topics: Acetylcholine; Animals; Blood Pressure; Disease Models, Animal; Female; Fibrosis; Insulin; Leptin; Lipid Metabolism; Male; Maternal Exposure; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors; Vascular Diseases; Vascular Resistance

Adiponectin is expressed in adipose tissue, and is affected by smoking, obesity, and genetic factors, such as CDH13 polymorphism, contributing to the development of coronary vascular diseases (CVDs).. We investigated the effect of genetic variations of CDH13 (rs3865188) on blood chemistry and adiponectin levels in 345 CVD patients undergoing statin-free or statin treatment.. Genetic variation in CDH13 was significantly correlated with several clinical factors, including adiponectin, diastolic blood pressure, triglyceride (TG), and insulin levels. Subjects with the T allele (mutant form) had significantly lower adiponectin levels than those with the A allele. Total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), TG/high-density lipoprotein cholesterol (HDLc) ratio, and HDL3b subtype were markedly decreased in statin treated subjects regardless of having the A or T allele. TG and TG/HDL in the statin-free group with TT genotype of the rs3865188 was higher than in the others but they were not different in the statin-treated subjects. We observed a significant difference in adiponectin levels between patients with the A and T alleles in the statin-free group; meanwhile, no difference in adiponectin levels was noted in the statin group. Plasma levels of other cytokines, leptin, visfatin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were not different among the CDH13 genotypes according to statin administration. Body mass index (BMI), TG, insulin, HDL3b, and TG/HDL ratio showed negative correlations with adiponectin levels.. Plasma adiponectin levels and TG/HDL ratio were significantly different according to variants of CDH13 and statin administration in Korean patients with CVD.

Topics: Adiponectin; Adult; Aged; Alleles; Blood Pressure; Body Mass Index; Cadherins; Cholesterol; Cholesterol, LDL; Female; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Interleukin-6; Leptin; Lipoproteins, HDL; Male; Middle Aged; Obesity; Polymorphism, Genetic; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Diseases

Aging leads to increased insulin resistance and arterial dysfunction, with oxidative stress playing an important role. This study explored the metabolic and arterial effects of a chronic treatment with resveratrol, an antioxidant polyphenol compound that has been shown to restore insulin sensitivity and decrease oxidative stress, in old mice with or without a high-protein diet renutrition care. High-protein diet tended to increase insulin resistance and atheromatous risk. Resveratrol improved insulin sensitivity in old mice fed standard diet by decreasing homeostasis model of assessment-insulin resistance and resistin levels. However, resveratrol did not improve insulin resistance status in old mice receiving the high-protein diet. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and diminishing aortic distensibility. In conclusion, we demonstrate that resveratrol has beneficial or deleterious effects on insulin sensitivity and arterial function, depending on nutritional status in our models.

Topics: Aging; Animals; Antioxidants; Aorta; Blood Glucose; Chemokine CCL5; Chemokine CXCL1; Dietary Proteins; Disease Models, Animal; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Nutritional Status; Oxidative Stress; Phenols; Resistin; Resveratrol; Ribonucleotide Reductases; Serum Albumin; Stilbenes; Superoxides; Tumor Necrosis Factor-alpha; Vascular Capacitance; Vascular Diseases; Vasodilation

Obesity is associated with vascular diseases that are often attributed to vascular oxidative stress. We tested the hypothesis that vascular oxidative stress could induce obesity. We previously developed mice that overexpress p22phox in vascular smooth muscle, tg(sm/p22phox), which have increased vascular ROS production. At baseline, tg(sm/p22phox) mice have a modest increase in body weight. With high-fat feeding, tg(sm/p22phox) mice developed exaggerated obesity and increased fat mass. Body weight increased from 32.16 ± 2.34 g to 43.03 ± 1.44 g in tg(sm/p22phox) mice (vs. 30.81 ± 0.71 g to 37.89 ± 1.16 g in the WT mice). This was associated with development of glucose intolerance, reduced HDL cholesterol, and increased levels of leptin and MCP-1. Tg(sm/p22phox) mice displayed impaired spontaneous activity and increased mitochondrial ROS production and mitochondrial dysfunction in skeletal muscle. In mice with vascular smooth muscle-targeted deletion of p22phox (p22phox(loxp/loxp)/tg(smmhc/cre) mice), high-fat feeding did not induce weight gain or leptin resistance. These mice also had reduced T-cell infiltration of perivascular fat. In conclusion, these data indicate that vascular oxidative stress induces obesity and metabolic syndrome, accompanied by and likely due to exercise intolerance, vascular inflammation, and augmented adipogenesis. These data indicate that vascular ROS may play a causal role in the development of obesity and metabolic syndrome.

Topics: Adipogenesis; Animals; Cytochrome b Group; Diet, High-Fat; Drug Resistance; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; NADPH Oxidases; Obesity; Oxidative Stress; Reactive Oxygen Species; Vascular Diseases

Cyclosporine (CsA) is an immunosuppressive agent frequently used in the clinic for prevention of allograft rejection and for the treatment of autoimmune diseases. Despite its desired action on the immune system, CsA treatment may present serious adverse effects, which are masked by the concomitant use of other drugs. The search for effective immunosuppression protocols which does not affect the quality of life of patients is driving research to investigate the CsA involvement in vascular diseases, frequent in patients under immunosuppression. Thus, 45 non-transplanted Wistar rats were treated for 8 weeks with vehicle or 5 or 15 mg/kg CsA (n=15/group) by gavage administration to evaluate the specific influence of cyclosporine on the levels of risk factors (metabolic and inflammatory) of vascular disease and its mechanism of action. Therefore, serum insulin levels, glucose tolerance test, serum lipids profile, total homocysteine and fibrinogen levels were assessed. The biochemical alterations reported here suggest the development of a framework straight to diabetes. Glucose homeostasis was affected as indicated by decreased insulin levels and altered glucose tolerance test in CsA 15 mg/kg group compared to other groups. Serum insulin and total homocysteine levels presented a significant negative correlation (R=- 0.76, P<0.0001). Fibrinogen and serum lipids profiles were significantly increased in CsA 15 mg/kg group compared to other groups and correlated positively with total homocysteine levels. Considering the well-established correlation among insulin resistance, lipid and total homocysteine levels, hypercoagulability and atherosclerosis, we can assume that this protocol of long-term CsA treatment in non-transplanted rats alter biochemical parameters related to cardiovascular and cerebrovascular risk, mainly in CsA 15 mg/kg group. Insulin and tHcy serum levels appear to be central in this process.

Topics: Animals; Blood Coagulation; Body Weight; Cyclosporine; Fibrinogen; Glucose Tolerance Test; Homocysteine; Humans; Immunosuppressive Agents; Insulin; Leptin; Lipids; Male; Rats; Rats, Wistar; Risk Factors; Vascular Diseases

Obesity is a risk factor for venous disease. We tested the associations between adipokines and the presence and severity of venous disease.. Participants for this analysis were drawn from a cohort of 2408 employees and retirees of a university in San Diego who were examined for venous disease using duplex ultrasonography. From this cohort, a case-control study sample of all 352 subjects with venous disease and 352 age-, sex- and race-matched subjects without venous disease were included in this analysis. All subjects completed health history questionnaires, had a physical examination with anthropometric measurements and had venous blood analyzed for adipokines.. After adjustment for age, sex and race, those with venous disease had significantly higher levels of body mass index (BMI), leptin and interleukin-6. Levels of resistin and tumor necrosis factor-alpha were also higher but of borderline significance (0.05 < P < 0.10). Compared with the lowest tertile and with adjustment for age, sex, race and BMI, the 2nd and 3rd tertiles of resistin (odds ratios, 1.9 and 1.7, respectively), leptin (1.7 and 1.7) and tumor necrosis factor-alpha (1.4 and 1.7) were associated with increasing severity of venous disease. Conversely, a 5 kg m⁻² increment in BMI was associated with a higher odds ratio (1.5) for venous disease, which was independent of the adipokines included in this study.. Both obesity and adipokines are significantly associated with venous disease. These associations appear to be independent of each other, suggesting potentially different pathways to venous disease.

Topics: Adipokines; Aged; Body Mass Index; California; Case-Control Studies; Cohort Studies; Female; Humans; Interleukin-6; Leptin; Lower Extremity; Male; Middle Aged; Obesity; Odds Ratio; Resistin; Tumor Necrosis Factor-alpha; Ultrasonography; Vascular Diseases

To investigate the possibility of depending on adiponectin and leptin as early predictors of microvascular complications in type 1 diabetic subjects.. We studied 63 type 1 diabetic subjects from the National Institute of Diabetes (30 normoalbuminuric and 33 microalbuminuric). Clinical, demographic characteristics and kidney function tests were monitored. Plasma levels of adiponectin, leptin, interlukein-6 (IL-6), and the high sensitive C-reactive protein (CRP) were measured in these subjects.. Microalbuminuric subjects showed a significant elevation in adiponectin levels and a significant decrease in leptin levels as compared to normoalbuminuric subjects. Adiponectin showed a significant positive correlation with microalbuminuria concentrations while leptin showed a significant negative correlation with both fasting blood glucose and glycated hemoglobin A(1c).. The results of this study introduced the possibility of depending on adiponectin and leptin as early, reliable, and sensitive predictors for the microvascular complications monitored by microalbuminuria concentration and glycemic control indices.

Topics: Adiponectin; Adolescent; Albuminuria; Biomarkers; Blood Glucose; C-Reactive Protein; Child; Child, Preschool; Diabetes Mellitus, Type 1; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Glycated Hemoglobin; Humans; Interleukin-6; Kidney Function Tests; Leptin; Male; Predictive Value of Tests; Regression Analysis; Vascular Diseases

Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults.. Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic-euglycaemic clamp studies in 1,226 EGIR RISC participants.. The LAR was highly correlated with HOMA-S in men (r = -0.58, p = 4.5 x 10(-33) and r = -0.65, p = 1.1 x 10(-66) within the Ely and EGIR RISC study cohorts, respectively) and in women (r = -0.51, p = 2.8 x 10(-36) and r = -0.61, p = 2.5 x 10(-73)). The LAR was also strongly correlated with the clamp M/I value (r = -0.52, p = 4.5 x 10(-38) and r = -0.47, p = 6.6 x 10(-40) in men and women, respectively), similar to correlations between HOMA-S and the M/I value.. The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.

Topics: Adipocytes; Adiponectin; Adult; Blood Glucose; Cohort Studies; Female; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors; Sex Characteristics; Vascular Diseases; White People

The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome.. Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake.. Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1 beta. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction.. Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG.

Topics: Acetylcholine; Adiponectin; Animals; Blood Glucose; Body Weight; Deoxyglucose; Dose-Response Relationship, Drug; Eating; Female; In Vitro Techniques; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Nitroprusside; Obesity; Phenylephrine; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Renal Circulation; Time Factors; Vascular Diseases; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Topics: Blood Vessels; Cardiovascular Diseases; Compliance; Endothelium, Vascular; Humans; Leptin; Obesity; Vascular Diseases; Vasodilation

Leptin, the product of the ob gene, regulates food intake, energy expenditure, and other physiological functions of the peripheral tissues. Leptin receptors have been identified in the hypothalamus and in extrahypothalamic tissues. Increased circulating leptin levels have been correlated with cardiovascular disease, obesity, aging, infection with bacterial lipopolysaccharide, and high-fat diets. All these conditions have also been correlated with increased vascular calcification, a hallmark of atherosclerotic and age-related vascular disease. In addition, the differentiation of marrow osteoprogenitor cells is regulated by leptin. Thus, we hypothesized that leptin may regulate the calcification of vascular cells. In this report, we tested the effects of leptin on a previously characterized subpopulation of vascular cells that undergo osteoblastic differentiation and calcification in vitro. When treated with leptin, these calcifying vascular cells had a significant 5- to 10-fold increase in alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells. Prolonged treatment with leptin enhanced the calcification of these cells, further supporting the pro-osteogenic differentiation effects of leptin. Furthermore, the presence of the leptin receptor on calcifying vascular cells was demonstrated using reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blot analysis. We also identified the presence of leptin receptor in the mouse artery wall, localized to subpopulations of medial and adventitial cells, and the expression of leptin by artery wall cells and atherosclerotic lesions in mice. Taken together, these results suggest that leptin regulates the osteoblastic differentiation and calcification of vascular cells and that the artery wall may be an important peripheral tissue target of leptin action.

Topics: Alkaline Phosphatase; Animals; Arteries; Calcinosis; Calcium; Carrier Proteins; Cattle; Cells, Cultured; Female; Gene Expression Regulation; Immunohistochemistry; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Muscle, Smooth, Vascular; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Vascular Diseases

To define the metabolic profile relevant to vascular risks in obstructive sleep apnea (OSA) and the role of leptin resistance in this risk profile.. Case control study.. Sleep Laboratory, Queen Mary Hospital, University of Hong Kong, China.. Thirty OSA subjects were matched with 30 non-OSA subjects for body mass index (BMI), age, sex, and menopausal status. Neck, waist, and hip girth, skinfold thickness, and fasting serum levels of lipids, glucose, insulin, and leptin were compared between these two groups.. Compared with control subjects with a similar BMI but without OSA, the OSA group had a significantly more adverse vascular risk factor profile, including dyslipidemia, higher diastolic BP, insulin resistance, and greater adiposity reflected by skinfold thickness. OSA subjects also had higher circulating leptin levels (9.18+/-4.24 ng/mL vs 6.54+/-3.81 ng/mL, mean +/- SD, p = 0.001). Serum leptin levels correlated positively with BMI, skinfold thickness, serum cholesterol, low-density lipoprotein cholesterol, insulin, insulin/glucose ratio, apnea-hypopnea index, and oxygen desaturation time; multiple stepwise regression analysis identified skinfold thickness, waist/hip ratio, serum low-density lipoprotein cholesterol, and diastolic BP as independent correlates, while only serum insulin and diastolic BP were independent correlates in OSA subjects. After treatment with nasal continuous positive airway pressure for 6 months, there was a significant decrease in circulating leptin (p = 0.01) and triglyceride levels (p = 0.02) without change in other parameters.. Despite controlling for BMI, OSA subjects showed distinct profiles with clustering of vascular risk factors. Hyperleptinemia was present in the OSA subjects, but it can be normalized by treatment with nasal continuous positive airway pressure, suggesting that increased leptin resistance was not the cause of OSA or its associated vascular risks.

Topics: Adult; Biomarkers; Body Mass Index; Case-Control Studies; Female; Humans; Leptin; Male; Positive-Pressure Respiration; Radioimmunoassay; Risk Factors; Sleep Apnea, Obstructive; Vascular Diseases