Leptin induced endothelial dysfunction in obesity surgery – Role of Leptin in Cardiovascular Diseases

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Acta Physiol Scand ; — Drug targeting of leptin resistance. Leptin receptor isoforms and visualization of mutations in inducef human LEPR protein. Zumstein, K. This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Role of omega-3 fatty acids in obesity, metabolic syndrome, and cardiovascular diseases: a review of the evidence.

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  • Cardiometabolic implications of postpartum weight changes in the first year after delivery.

  • While insulin maintains adequate energy storage and utilization, leptin reduces continuous energy intake.


Molecular characterization of lymphatic endothelial cells. All isoforms share identical extracellular domains as well as dysfunction obesity first 29 amino acids containing box 1 motif for binding of JAK2 of the intracellular domain but they differ in the length and sequence of the C-terminal domain. Studies have shown that obesity is associated with chronic low-grade systemic inflammation, which results from changes in both the innate and the adaptive immune system 43 Proc Nutr Soc. HDL, however, is a complex lipoprotein containing more than 1, lipids and 70 proteins

In case of insulin resistance, however, endothelial cells are selectively resistant for these vasodilatory actions. Scanning and transmission electron microscopy For scanning electron microscopy, lymphatic ducts were fixed with 2. Eur J Pediatr ; — Abstract Leptin and adiponectin are differentially expressed adipokines in obesity and cardiovascular diseases.

Microparticles: protagonists of a novel communication network for intercellular information exchange. Serum immunoreactive-leptin levels are increased in patients with Cushing's syndrome. The tight junction protein claudin-5 and the adherence junction obesigy VE-cadherin are known to regulate not only barrier properties but also angiogenesis in vascular endothelial cells [ 52 ]. Obesity-causing LEPR mutations are usually inherited in an autosomal-recessive manner. Even after decades of research on rodents and clinical studies, existing differences in the underlying mechanisms and pathways between animal models and patients with obesity and T2DM make data interpretation challenging. On the other hand, fasting, testosterone, and thyroid hormone lead to a reduction in leptin expression [ 2324 ].

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Since obesity is associated with LVH [ 57 ] and leptin levels are significantly increased in obesity, many researchers believe that leptin actually contributes to LVH. The antisteatotic role of hyperleptinemia. Recommendations for treatment of child and adolescent overweight and obesity. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Endothelial dysfunction is the primum movens in the pathogenesis of atherosclerosis, appearing long before clinical symptoms arise, and might qualify as a surrogate endpoint for cardiovascular disease risk.

Kleinert, H. Prevalence and clinical implications of newly revealed, asymptomatic abnormal ankle-brachial index in patients with significant coronary artery disease. Lipoproteins, platelets and atherothrombosis. Trakia J. Address for reprint requests and other correspondence: T.

In hypertensive insulin-resistant obesith, fasting plasma leptin levels were higher than in controls and correlated with increased myocardial wall thickness. IL-6 is known as a proinflammatory cytokine that induces production of chemokines [ 4950 ] and regulates immune cells [ 51 ]. Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. At multiple regression analysis, LV mass only correlated with leptin levels.

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Leptin Signaling 2. The antisteatotic role of hyperleptinemia. Effects of diet and exercise on obesity-related vascular dysfunction in children.

Click through the PLOS taxonomy to find articles in your field. In conclusion, studies sysfunction leptin- or Lepr -deficient rodent models indicate that leptin acts as a metabolic, cardio-protective adipokine, particularly under ischemic conditions. They also observed that leptin directly leads to hypertrophy of the rat portal vein wall [ 8 ]. Ob-Re is a soluble receptor secreted in the blood that binds to circulating leptin in order to maintain the concentration of free leptin [ 172627 ].

Eur J Heart Fail. New Factors Influencing Childhood Obesity—Related Endothelial Dysfunction In obese children, multiple cardiovascular risk factors are present, which all negatively affect endothelial function Also, rapamycin, which interferes with PI3K signaling, has been shown to attenuate cardiac hypertrophy [ 70 ]. Leptin at 14 y of age: an ongoing story.

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Another important function of adiponectin is its anti-inflammatory effect which is attributed to its ability to activate AMPK and other non-AMPK mechanisms. It contributes to vascular remodeling, hypertrophy, and angiogenesis. Although the amount of epicardial and pericardial fat correlated with the severity of LV diastolic dysfunction, increase in myocardial triglyceride levels did not act as a mere fat deposit compared to epicardial and pericardial fat Prescimone, S. Bungenstock, C.

Hanache, W. Regular physical activity improves endothelial function in patients with coronary artery endtohelial by increasing phosphorylation of endothelial nitric oxide synthase. Obesity is a prominent predictor of low EPC mobilization, and weight loss is associated with increased circulating EPC and improved macrovascular endothelial function The study by Barouch et al. Although the correlation between plasma leptin levels and LV wall thickness might be driven by insulin resistance, leptin remained independently associated with LV wall thickness in the multivariate model even after adjusting for insulin action [ 72 ]. Ahmad, J.

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A combined end point of recurrent VTE or all-cause death was used. Nitric oxide synthases: Which, where, how, and why? Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Conversely, when BP decreases, the kidney retains salt and water until arterial pressure returns to normal. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. State St.

Direct and indirect effects of leptin on preadipocyte proliferation and differentiation. Iddings, R. Modulation by leptin of proliferation and apoptosis in vascular endothelial cells. Cochrane Database Syst Rev. The combination of obesity, hypertension and other cardiovascular risk factors significantly increases the probability of adverse cardiovascular outcomes, and raises considerations for aggressive treatment strategies.

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Leptin has also been shown to augment the release of the vasoconstrictor endothelin-1 ET-1 primarily in endothelial cells, but also in cardiomyocytes, fibroblasts, and macrophages [ 84 ], also leading to an elevation in blood pressure. In recent past, Chen et al. J Clin Endocrinol Metab ; 97 :E—

Korda et al. Harrison, C. Once secreted, leptin circulates in the serum both in a free and in a bound form. Several adipokines have a direct effect on endothelial function, including leptin and adiponectin 42 Leptin resistance in obese or type 2 diabetes mellitus T2DM patients is defined as a decrease in tissue response to leptin.

However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Then, similar to the FMD method, a sphygmomanometer is insufflated to supra-systolic pressures forcing a transient occlusion of the brachial artery. Leptin exerts several actions on the vascular system. Saha et al.

Tsao, J. Table 2. Type II diabetes abrogates sex differences in endothelial function in premenopausal women. The obesity paradox in VTE was not substantially explained by a body mass—associated protein signature.

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Anal Chim Acta : 27—33, Thrombospondin-4 ablation reduces macrophage recruitment in adipose tissue and neointima and suppresses injury-induced restenosis in mice. This article has been cited by other articles in PMC. Zhang, Z.

R—R, Eur Heart J ; 29 — Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. Oncol Nurs Forum.

Curr Pharm Des ; 17 — Pediatrics ; :e— Although the pair-fed mice lost as much weight as the surgery mice, they did not have a reduction in LV wall thickness and LV mass, a similar observation to the controls [ 61 ]. AdipoR1 is ubiquitously expressed, including the cardiovascular system, whereas AdipoR2 expression is high in the liver [ ]. Absorbance in each well was measured with a microplate reader Thermo Fisher Scientific using a wavelength of nm. Increased endothelial microparticles in obese and overweight children. Circulating leptin correlates with left ventricular mass in morbid grade III obesity before and after weight loss induced by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy.

Because of this procedure, the signature was determined on the basis of only those individuals who had proteomic measurements at both time points. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. Sakaguchi T, Bray GA.

S2 Fig. Ultrathin sections were cut with a diamond knife, stained with lead citrate, and examined with a JEM transmission electron obesiry JEOL, Tokyo, Japan at an acceleration voltage of kV. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Glucose tolerance profile at 27 week of experimental protocol of obesity. Kawada, J. Lymphedema is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system.

Obese adults have reduced and dysfunctional CAC Hug, J. Eyckerman, D. This interesting study is strengthened by the large size of the sample and multiethnic nature of the group. Adolescent blood pressure hyperreactors have a higher reactive hyperemic index at the fingertip. In addition, it is generally accepted that leptin-mediated release of endothelial nitric oxide NO causes vasodilatation, which opposes the pressor effect of sympathoexcitatory activity induced by leptin Dunn, H.

Smith, and P. Therefore, the focus of attention has recently shifted toward HDL cholesterol. Mark, and W. Circulation ; —8.

Edelstein, X. In vitro studies done on neonatal rat ventricular myocytes exposed to 3. Leptin as a Prohypertrophic Factor. Oxid Med Cell Longev ; Hanif, J. Functional properties of leptin receptor isoforms: internalization and degradation of leptin and ligand-induced receptor downregulation.

Recent history Saved searches. Geeraert, T. Stavros V. Maloney, N. Engeli S, Sharma A. Surg Obes Relat Dis. Obesity and vascular dysfunction.

This correlation persisted after adjustment for BMI and was independent of blood pressure Kirshenbaum, and M. Santos-Alvarez et al. Science ; —7. Functional in silico analyses are available for 35 LEPR mutations, but functional in vitro data have only been described for four mutations 38 ,

Oncol Nurs Forum. Leeson, A. Ha, M. Miyata, and S. Google Scholar. Tsatsanis, and P.

Chen, M. Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in wurgery individuals. While insulin maintains adequate energy storage and utilization, leptin reduces continuous energy intake. Data Availability: All relevant data are within the paper and its Supporting information files. Opposite to the benefits of leptin replacement therapy in patients with congenital leptin deficiency, treatment of common obese patients with recombinant leptin did not result in reduced food intake and weight loss 25leading to the spread of the concept of leptin resistance. Jones, J.

Blood Pressure. Functional properties of leptin receptor isoforms: internalization and degradation of leptin and ligand-induced receptor downregulation. Nevertheless, many studies obesitt rodent obese and diabetic models demonstrate that leptin has beneficial effects on cardiac metabolism by supporting glucose metabolism and fatty acid oxidation. Huang and C. Adiponectin plays an important role in protection against cardiac remodeling by attenuating myocardial hypertrophy [ ].

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The HMW complex is the functional unit and induces anti-inflammatory, antiatherogenic, and antidiabetic effects that protect against cardiovascular and metabolic disorders [ ]. D'Amico, M. Curr Treat Options Cardiovasc Med.

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  • Microbial ecology: human gut microbes associated with obesity. Modest restriction of salt intake, low intake of saturated fats and cholesterol with increased consumption of fruits, vegetables and whole grains is recommended.

  • Summary of molecular signaling responses to leptin and their cardiac and vascular effect.

  • Higham, M. Further study is needed to clarify these mechanisms.

Microneurograhic techniques, a direct method of measuring increased SNS activity, provide evidence of high muscle SNS activity in obese subjects. Montagnani, K. Endothelial cells respond to inflammation and stimulation of MCP-1, which is described as the activation of adhesion molecules leading to proliferation and transmigration of leukocytes, which facilitates their increase in atherogenic and thromboembolic potentials. Cell Metab. The mechanisms and factors involved in the vascular disease associated with obesity are uncertain, especially in the vascular endothelium. Tangirala, S.

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Role of leptin in the endotgelial of immune cells. Bands were detected with the horseradish peroxidase-conjugated secondary antibodies and visualized by chemiluminescence Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. A model for how leptin and IL-6 regulate tube formation and cell proliferation in human lymphatic endothelial cells. Supporting Information. Postmenopausal hypertension: mechanisms and therapy.

Leptin increases proliferation and reduces apoptosis of human umbilical vein oeptin cells HUVECs [ 2526 ]. Engin, A. Leptin induced endothelial dysfunction in obesity surgery of lymphatic endothelial cells in physiological and pathological conditions. Finally, the relationship between the body mass—associated protein signature and the end point and the robustness of the obesity paradox against adjustment by this protein signature were tested using Cox proportional hazards regression models, where the same significance threshold as used previously was applied. The Journal of Endocrinology 55— Morgan-Stevenson, C. Update on the global burden of ischemic and hemorrhagic stroke in the GBD study.

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Cassuto, J. Human lymphatic ducts were cut into 1-cm pieces, washed with cold PBS, and transferred onto an uncoated well plate Corning Inc. Then small segments from the thoracic aorta were cut into rings 3 to 4 mm in length.

Oh, S. Motooka, H. Smith, J. Tsao, E. Six months of exercise training facilitated a tendency toward the improvement of HDL function, for which the authors speculated that the training was not intensive enough to achieve statistical significance

View at: Google Scholar P. Tarnavski et al. Kaneda, M. They found that fasting plasma leptin levels were significantly higher in hypertensive subjects than in normotensive controls, with no change in these results after adjustment for BMI [ 72 ]. Zeidan and M. Leptin is a hormone produced by adipose tissue that regulates various physiological processes.

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  • Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats.

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  • The arterial pressure control mechanism of diuresis and natriuresis according to the principle of infinite feedback gain seems to be shifted toward higher BP values in obese patients. Agouti-related peptide is expressed during fasting and leads to increased food consumption.

  • Several studies have shown that the functional leptin receptor is also found in a variety of organs such as the heart, liver, kidneys, and pancreas [ 9 — 13 ]. Leptin resistance or leptin signaling deficiency results in the risk increase of cardiac dysfunction and heart failure, which is a leading cause of obesity- and T2DM-related morbidity and mortality.

Recent Activity. The relationship between arterial stiffness and heart failure with preserved ejection fraction: a systemic meta-analysis. Wang, A. Inflammation and atherosclerosis. Effect of Spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trialspironolactone in patients with heart failure.

Pharmacological Reports 58 Suppl : 81— Components and nutritional values of diets. Lackner, Stavros V. Naunyn Schmiedebergs Arch Pharmacol : —, Bitar, M. Victor, R. T-helper cell type 2 Th2 memory T cell-potentiating cytokine IL has the potential to promote angiogenesis in asthma.


Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. In obese adults, leptin resistance of CAC can be defeated by weight loss A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.

Similar mechanisms are brought into operation because of elevated serum levels of glucose and FFAs. Animals and diets. Int J Oncol. Notes The costs of publication of this article were defrayed in part by the payment of page charges.

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Another vascular effect of leptin is its ability to promote angiogenesis. Fig 5. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Modulation by leptin of proliferation and apoptosis in vascular endothelial cells. IL-6 is known as a proinflammatory cytokine that induces production of chemokines [ 4950 ] and regulates immune cells [ 51 ]. Not only are leptin concentrations directly increased as a result of hypertension [ 8 ], leptin itself contributes to the development of hypertension.

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  • Physiological Reviews — The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea.

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  • Diabetes ; 57 : —

  • In the cardiovascular system, leptin resistance exhibits the adverse effect on the heart's response to stress conditions and promoting cardiac remodeling due to impaired cardiac metabolism, increased fibrosis, vascular dysfunction, and enhanced inflammation. Mariman and P.

Matarese, J. Gan, L. Importantly, two recent studies have proposed that hyperleptinemia-associated sufgery resistance is dysfunction obesity a driving force for obesity and its associated various metabolic disorders, suggesting that new therapeutic tools to restore leptin sensitivity could offer a new strategy to promote weight loss in obese patients and to treat obesity-associated complications 78. These escalating healthcare problems of monumental proportions represent a serious hazard of developing cardiovascular diseases with significant morbidity and mortality 2. Caselli, A. Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms.

Johansen, D. B Selection of overlapping proteins between the baseline and follow-up measurement time points. J Clin Invest ; : 83— Miyata, and S.


Dincer, C. PubMed Google Scholar Download references. Fig 4. Leptin exerts an anti-apoptotic effect on human dendritic cells via the PI3K-Akt signaling pathway.

Left ventricular hypertrophy generally develops in inducef to factors like age, hypertension, aortic valve stenosis, and obesity [ 57 ]. Cardiac steatosis and left ventricular function in men with metabolic syndrome. Human lymphatic ducts were cut into 1-cm pieces, washed with cold PBS, and transferred onto an uncoated well plate Corning Inc. Rodents exposed to intravenous infusion and intracerebroventricular leptin administration demonstrated increased arterial pressure and heart rate [ 7479 ], while blocking the adrenergic system diminished leptin-induced hypertension [ 80 ]. Goetze, A.

  • This remodeling may lead to an increased risk of cardiovascular diseases [ 58 ], such as heart failure, arrhythmia, ischemic heart disease, or myocardial infarction [ 5659 ].

  • IL-6 has a compensatory effect on leptin-induced modification of tube formation and cell proliferation in human lymphatic endothelial cells. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I.

  • Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: focus on fat browning and macrophage polarization.

  • Health Care Women Int. Clinically significant proteinuria is rare among obese subjects.

  • Glioblastoma-derived leptin induces tube formation and growth of endothelial cells: comparison with VEGF effects. Szanto and C.

  • Correlation of habitual physical activity levels with flow-mediated dilation of the brachial artery in year old children. Another important function of adiponectin is its anti-inflammatory effect which is attributed to its ability to activate AMPK and other non-AMPK mechanisms.

Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation? Ethnic-specific prevalence of peripheral arterial disease in the United States. J Immunol. Tsikas, and S. Leptin 0. Plasma renin activity, angiotensinogen, angiotensin II and aldosterone values display significant increase during obesity.

Serum immunoreactive-leptin levels are increased in patients with Cushing's syndrome. Sahu A. Nutr Rev 60 :S1—14; discussion S68—84, 85—7. Mechanisms underlying the development of leptin resistance have been discussed previously [reviewed in 35 — 37 ].

At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products. Mundhekar, M. Ellis, M.

Fiorentino, T. In addition, leptin decreases the levels of tight junction proteins such as zonula occludens-3, claudin-5 and occludin via a leptin receptor-dependent signaling pathway in intestinal epithelial cells [ 53 ]. Marliss, E. Obesity, inflammation, and exercise training: relative contribution of iNOS and eNOS in the modulation of vascular function in the mouse aorta. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. HUVEC, blood serum, and aortic endothelial tissue were homogenized in sulfosalicylic acid.

Zeidan, S. Motooka, H. These microparticles are covered with surface antigens from the parental endothelial cell, making quantification possible using specific flow cytometry markers. Studies have revealed that adiponectin preserves the normal physiology of the heart by protecting the heart and blood vessels against atherosclerosis, inflammatory, and oxidative stress.

Childhood obesity and vascular phenotypes: a population study. Lam, and A. Reduced flow-mediated vasodilation of brachial artery in children with primary snoring. Data obtained from different studies using both animal models and in vitro studies have demonstrated the multiple beneficial effects of adiponectin on the cardiovascular system, through direct and indirect actions on both cardiac and vascular cells Figure 2. Leptin induces tube formation in first-trimester extravillous trophoblast cells.

Intestinal microbiota is influenced by gender and body mass index. Wang, H. European Journal of Pharmacology — Shu, X. Sechi and Leonardo 37 have shown that high dietary salt in normal Sprague—Dawley rats causes a dose-dependent downregulation in the number of insulin receptors in the kidney. On the other hand, secondary lymphedema is caused by surgery or radiation for cancer treatment, infection or trauma [ 5 ]. Diabetes 49 : —,

  • More research on pentraxin-3 as a new biomarker in the setting of childhood obesity could be of interest.

  • Quality of life in patients with heart failure: do gender differences exist? Edelstein, S.

  • In this regard, leptin enhances the migratory activity of CAC in normal-weight adults Leptin is believed to cause atherosclerosis by promoting the proliferation and migration of vascular smooth muscle and endothelial cells, thus inducing neointimal growth [ 90, ].

  • Search Search articles by subject, keyword or author. Plasma leptin concentrations are elevated in cases of cardiovascular diseases, such as hypertension, congestive heart failure, and myocardial infarction.

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Eur J Prev Cardiol ; 21 — Casto, J. Vanhoutte, K. Published 03 May Huang, T. The prominent effects of leptin in reducing high triglyceride levels have been confirmed in an acyl CoA synthase transgenic mouse model showing severe lipotoxic cardiomyopathy

Chen, D. Kohler, H. There were no differences in intake of antithrombotic medications between classes detailed overview provided in supplemental Table 2. Data Data that cites the article This data has been provided by curated databases and other sources that have cited the article. Konings, J.