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      “Role of the adipocyte hormone leptin in cardiovascular diseases – a study from Chennai based Population”

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          Abstract

          Background

          Obesity is currently regarded as a pro-inflammatory condition during which leptin ( Ob gene product) might act as a risk factor for Cardiovascular Diseases (CVD) including Acute Myocardial Infarction (AMI). There is a marked increase in circulating leptin concentrations and inflammatory markers such as Tumor Necrosis Factor-α (TNF-α) in AMI patients but still the association of leptin with inflammation during AMI is not known. The present study suggest that elevated levels of leptin might elicit the risk for CVD by signaling for the secretion of inflammatory cytokines especially, TNF-α.

          Methods

          Blood samples were collected from 100 CVD subjects diagnosed for AMI immediately after their admission to the hospital and serum leptin, insulin, glucose, lipids and inflammatory marker such as TNF-α were measured. 5 ml random (non-fasting) blood was collected from 100 non-CVD (control) subjects and the results obtained in case of AMI subjects were compared with that of the control subjects. The subjects under study included both men and women belonging to the age group of 35 – 75 and they were classified based on their BMI as normal weight, overweight and obese.

          Results

          Circulating levels of leptin are found to be elevated in obese control subjects and in patients with AMI irrespective of their Body Mass Index (BMI). In addition, leptin is also found to be positively correlated to serum triglycerides, insulin and TNF-α in AMI subjects. MANOVA analysis suggests that leptin might influence the synthesis of insulin and TNF-α. This is the first report relating leptin to TNF-α in Chennai based population, India.

          Conclusions

          Hyperleptinemia might act as a risk marker for AMI. The present study suggests that at elevated levels, leptin may favor atherosclerosis by promoting the synthesis of TNF-α and insulin. However, our report warrants further investigation both in vitro and in vivo to determine the exact mechanism behind the pro-atherogenic role of leptin. The observed positive correlation between leptin and BMI in both AMI and control subjects suggests that obese subjects manifest leptin resistance and hence, they possess a greater risk for the incidence of CVD.

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          Most cited references31

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          Intracellular signalling pathways activated by leptin.

          Leptin is a versatile 16 kDa peptide hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family. It is mainly produced by adipocytes in proportion to fat size stores, and was originally thought to act only as a satiety factor. However, the ubiquitous distribution of OB-R leptin receptors in almost all tissues underlies the pleiotropism of leptin. OB-Rs belong to the class I cytokine receptor family, which is known to act through JAKs (Janus kinases) and STATs (signal transducers and activators of transcription). The OB-R gene is alternatively spliced to produce at least five isoforms. The full-length isoform, OB-Rb, contains intracellular motifs required for activation of the JAK/STAT signal transduction pathway, and is considered to be the functional receptor. Considerable evidence for systemic effects of leptin on body mass control, reproduction, angiogenesis, immunity, wound healing, bone remodelling and cardiovascular function, as well as on specific metabolic pathways, indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Consistent with leptin's pleiotropic role, its participation in and crosstalk with some of the main signalling pathways, including those involving insulin receptor substrates, phosphoinositide 3-kinase, protein kinase B, protein kinase C, extracellular-signal-regulated kinase, mitogen-activated protein kinases, phosphodiesterase, phospholipase C and nitric oxide, has been observed. The impact of leptin on several equally relevant signalling pathways extends also to Rho family GTPases in relation to the actin cytoskeleton, production of reactive oxygen species, stimulation of prostaglandins, binding to diacylglycerol kinase and catecholamine secretion, among others.
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            Insulin resistance associated to obesity: the link TNF-alpha.

            Adipose tissue secretes proteins which may influence insulin sensitivity. Among them, tumour necrosis factor (TNF)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissue from obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. The activation of proinflammatory pathways after exposure to TNF-alpha induces a state of insulin resistance in terms of glucose uptake in myocytes and adipocytes that impair insulin signalling at the level of the insulin receptor substrate (IRS) proteins. The mechanism found in brown adipocytes involves Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of MAPKs. The Ser307 residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha in myotubes, with p38 mitogen-activated protein kinase (MAPK) and inhibitor kB kinase being involved in the phosphorylation of this residue. Moreover, up-regulation of protein-tyrosine phosphatase (PTP)1B expression was recently found in cells and animals treated with TNF-alpha. PTP1B acts as a physiological negative regulator of insulin signalling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in peripheral tissues from obese and diabetic humans and rodents. Accordingly, down-regulation of PTP1B activity by treatment with pharmacological agonists of nuclear receptors restores insulin sensitivity in the presence of TNF-alpha. Furthermore, mice and cells deficient in PTP1B are protected against insulin resistance induced by this cytokine. In conclusion, the absence or inhibition of PTP1B in insulin-target tissues could confer protection against insulin resistance induced by cytokines.
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              Leptin regulates proinflammatory immune responses.

              Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor alpha expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up-regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity.
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                Author and article information

                Contributors
                nalinikrishu@gmail.com
                karthikgenetics@gmail.com
                shirin_vijay@yahoo.co.in
                manohar-g@hotmail.com
                r_malathi@hotmail.com
                Journal
                Thromb J
                Thromb J
                Thrombosis Journal
                BioMed Central (London )
                1477-9560
                4 March 2015
                4 March 2015
                2015
                : 13
                : 12
                Affiliations
                [ ]Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, 600 113 India
                [ ]Department of Cardiology, Stanley Medical College and Hospital, Chennai, 600 001 India
                Article
                42
                10.1186/s12959-015-0042-4
                4355465
                25762868
                210f105e-dcb6-4dcb-88bf-e726a80e4dd3
                © Nalini et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 June 2014
                : 16 February 2015
                Categories
                Original Clinical Investigation
                Custom metadata
                © The Author(s) 2015

                Cardiovascular Medicine
                leptin,insulin,tumor necrosis factor-α,obesity,acute myocardial infarction,cardiovascular diseases

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