Leptin as a cardiac hypertrophic factor: a potential target for therapeutics

The satiety factor leptin has received extensive attention especially in terms of its potential role in appetite suppression and regulation of energy expenditure. Once considered to be solely derived from adipose tissue, which accounts for the greatly increased levels observed in obese subjects, it is now apparent that leptin can be produced by a multiplicity of tissues, including the heart, where it appears to function in an autocrine and paracrine manner. Plasma leptin concentrations are also elevated in patients with heart disease including those with congestive heart failure. Leptin exerts its biological effects via a family of receptors termed Ob-R. In cardiac cells, one of leptin's primary actions is to produce cardiomyocyte hypertrophy through multifaceted cell signaling mechanisms including stimulation of mitogen-activated protein kinase and activation of the RhoA/Rho kinase (ROCK) pathway. The hypertrophic effect of leptin suggests that it may contribute to myocardial remodeling after cardiac injury and offers the potential targeting of the leptin system as a novel cardiac therapy.     

Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications

Leptin, an adipocyte secreted hormone, acts in the hypothalamus to inhibit appetite and promote thermogenic metabolism, thereby reducing adiposity and body weight. Leptin has multiple autonomic and cardiovascular actions, including sympathetic activation, increases in endothelium derived nitric oxide (NO), and angiogenesis. The predominant cardiovascular effect of chronic hyperleptinemia is a pressor effect mediated by increased sympathetic activity. The sympathetic and cardiovascular actions of leptin are discussed and evidence derived from studies of obese mice for the novel concept of selective leptin resistance is reviewed. This concept holds that in some obese states, there is preservation of the sympathoexcitatory actions of leptin despite resistance to the satiety and weight-reducing actions of the hormone. Selective leptin resistance might explain how hyperleptinemia could contribute to increases in sympathetic activity and arterial pressure in obese states where there is resistance to the metabolic (satiety and weight-reducing) actions of leptin. It is speculated here, that this concept may have potential implications for human obesity, which is often associated with elevated plasma leptin and partial resistance to the satiety effects of leptin. If selective leptin resistance occurs in obese humans, then leptin could contribute to the sympathetic overactivity and hypertension despite resistance to its metabolic actions.     

脂肪因子与慢性心力衰竭研究进展

慢性心力衰竭的发病率和病死率高。肥胖、高血压和糖尿病等为慢性心力衰竭的传统危险因素,但近期研究表明发现肥胖的慢性心力衰竭患者预后较好,这一现象被人称为“肥胖悖论”。脂肪组织目前被认为是一种内分泌组织,分泌的多种脂肪因子可调控多种心血管功能。现综述可影响心血管功能的脂肪因子。     

Das Fettgewebe – ein endokrines Organ

The incidence of obesity has increased dramatically during recent decades. Obesity increases the risk for metabolic and cardiovascular diseases and may therefore contribute to premature death. With increasing fat mass, secretion of adipose tissue derived bioactive molecules (adipokines) changes towards a proinflammatory, diabetogenic and atherogenic pattern. Adipokines are involved in the regulation of appetite and satiety, energy expenditure, activity, endothelial function, hemostasis, blood pressure, insulin sensitivity, energy metabolism in insulin sensitive tissues, adipogenesis, fat distribution and insulin secretion in pancreatic β-cells. Therefore, adipokines are clinically relevant as biomarkers for fat distribution, adipose tissue function, liver fat content, insulin sensitivity and chronic inflammation and have the potential for future pharmacological treatment strategies for obesity and related diseases. This review focuses on the clinical relevance of selected adipokines as markers or predictors of obesity-related diseases and as potential therapeutic tools or targets in metabolic and cardiovascular diseases.     

Emerging role of adipokines as mediators in atherosclerosis

Atherosclerotic cardiovascular disease is a major health problem around the world. Obesity is a primary risk factor for atherosclerosis and is associated with increased morbidity and mortality of cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Adipokines are cytokines, chemokines and hormones secreted by adipose tissue that couple the regulation of lipid accumulation, inflammation, and atherogenesis, and therefore serve to link obesity with cardiovascular disorders. Obesity-related disorders including metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with dysregulated adipokine(s) expression. Recent studies demonstrate the proinflammatory effects as well as atherogenic properties of adipokines. Adipokines also participate in the regulation of endothelial function, which is an early event in atherosclerosis. By contrast, adiponectin, an adipocyte-derived hormone, exerts anti-inflammatory, anti-atherogenic and vascular protective effects. Furthermore, there is an interactive association among adipokines, by which adipokines reciprocally regulate each other's expression. Understanding this interplay may reveal plausible mechanisms for treating atherosclerosis and coronary heart disease by modulating adipokine(s) expression. In this review, we discuss insights into the role and the therapeutic potential of adipokines as mediators of atherosclerosis.     

Adipokines: A link between obesity and cardiovascular disease

Obesity is a risk factor for various cardiovascular diseases including hypertension, atherosclerosis, and myocardial infarction. Recent studies aimed at understanding the microenvironment of adipose tissue and its impact on systemic metabolism have shed light on the pathogenesis of obesity-linked cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting multiple immune-modulatory proteins known as adipokines. Obesity leads to increased expression of pro-inflammatory adipokines and diminished expression of anti-inflammatory adipokines, resulting in the development of a chronic, low-grade inflammatory state. This adipokine imbalance is thought to be a key event in promoting both systemic metabolic dysfunction and cardiovascular disease. This review will focus on the adipose tissue microenvironment and the role of adipokines in modulating systemic inflammatory responses that contribute to cardiovascular disease.     

Direct effects of adipokines on the heart: focus on adiponectin

Cardiovascular disease, including heart failure, is a principal cause of death in individuals with obesity and diabetes. However, the mechanisms of obesity- and diabetes-induced heart disease are multifaceted and remain to be clearly defined. Of relevance to this review, there is currently great research and clinical interest in the endocrine effects of adipokines on the myocardium and their role in heart failure. We will discuss the potential significance of adipokines in the pathogenesis of heart failure via their ability to regulate remodeling events including metabolism, hypertrophy, fibrosis, and cell death. As an excellent example, we will first focus on adiponectin which is best known to confer numerous cardioprotective effects. However, we comprehensively discuss the existing literature that highlights it would be naive to assume that this was always the case. We also focus on lipocalin-2 which mediates pro-inflammatory and pro-apoptotic effects. It is important when studying actions of adipokines to integrate cellular and mechanistic analyses and translate these to physiologically relevant in vivo models and clinical studies. However, assimilating studies on numerous cardiac remodeling events which ultimately dictate cardiac dysfunction into a unifying conclusion is challenging. Nevertheless, there is undoubted potential for the use of adipokines as robust biomarkers and appropriate therapeutic targets in heart failure.     

Update on the Role of Adipokines in Atherosclerosis and Cardiovascular Diseases

Adipose tissue is now considered an active hormone-secreting organ that produces a number of biologically active proteins called adipokines. “Classic” adipokines were discovered more than a decade ago; leptin was initially described as a satiety signal limiting food intake in animal models, whereas adiponectin is suspected to play a role in promoting insulin sensitivity. As adiposity increases, macrophages may infiltrate the adipose tissue. These macrophages are a source of many cytokines (tumor necrosis factor-α, interleukin-6, resistin, retinol binding protein-4) that are suspected to participate in low-grade proinflammatory processes leading to metabolic disorders, insulin resistance, and cardiovascular diseases. New adipokines, such as visfatin, vaspin and apelin, have recently been discovered but their exact roles are still unknown. This review focuses on recent updates regarding the contribution of adipokines in atherosclerosis or cardiovascular diseases.     

Adipokines and vascular disease in diabetes

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.     

Fitness or fatness--the debate continues for the role of leptin in obesity-associated heart dysfunction

Obesity is an independent risk factor for cardiovascular diseases. As the first obese gene product identified, leptin participates in many physiological processes. Besides its well known effects on food intake and energy metabolism, leptin has been shown to regulate cardiovascular function, glucose and lipid metabolism. Although the precise role of leptin on cardiac health is still at large, the peptide may initiate both hypertrophic and anti-hypertrophic effects on hearts. Circulating leptin levels are believed to correlate closely with body mass index (BMI) and total amount of body fat, and predict change of heart morphology and function. This is evidenced by that fact that compromised cardiac function is present in both hyperleptinemic (db/db) and hypoleptinemic (ob/ob) mouse models. Leptin replenishment may reconcile depressed cardiac contractile function in ob/ob mice, indicating the permissive effect of leptin on cardiac function. Multiple signal pathways including NO, Jak/STAT, p38 MAP kinase, ET-1 and NADPH oxidase have been implicated to participate in the cardiac regulatory response of leptin. In addition, elevated plasma leptin levels are speculated to be an independent risk factor for cardiovascular diseases such as hypertension and myocardial infarction. The current dogma indicates that physiological range of leptin may be essential for normal cardiomyocyte structure and function whereas disrupted leptin signaling due to too much or too little leptin may trigger functional and morphological alterations leading to cardiac dysfunction.     

Perivascular Adipose Tissue and Its Role in Type 2 Diabetes and Cardiovascular Disease

Obesity is associated with insulin resistance, hypertension, and cardiovascular disease, but the mechanisms underlying these associations are incompletely understood. Microvascular dysfunction may play an important role in the pathogenesis of both insulin resistance and hypertension in obesity. Adipose tissue-derived substances (adipokines) and especially inflammatory products of adipose tissue control insulin sensitivity and vascular function. In the past years, adipose tissue associated with the vasculature, or perivascular adipose tissue (PAT), has been shown to produce a variety of adipokines that contribute to regulation of vascular tone and local inflammation. This review describes our current understanding of the mechanisms linking perivascular adipose tissue to vascular function, inflammation, and insulin resistance. Furthermore, we will discuss mechanisms controlling the quantity and adipokines secretion by PAT.     

Cardiac energy metabolism in obesity

Obesity results in marked alterations in cardiac energy metabolism, with a prominent effect being an increase in fatty acid uptake and oxidation by the heart. Obesity also results in dramatic changes in the release of adipokines, such as leptin and adiponectin, both of which have emerged as important regulators of cardiac energy metabolism. The link among obesity, cardiovascular disease, lipid metabolism, and adipokine signaling is complex and not well understood. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating cardiac dysfunction that can develop in this population. This review discusses what is presently known about the effects of obesity and the impact adipokines have on cardiac energy metabolism and insulin signaling. The clinical implications of obesity and energy metabolism on cardiac disease are also discussed.     

Differential impact of adipokines derived from primary adipocytes of wild-type versus streptozotocin-induced diabetic rats on glucose and fatty acid metabolism in cardiomyocytes

The causal relationship between obesity and cardiovascular disease is extensively acknowledged; however, the exact mechanisms linking obesity and heart failure remain unclear. Here, we investigated the influence of adipokines derived from primary adipocytes on glucose and fatty acid uptake and metabolism in isolated primary cardiomyocytes. Either co-culture of these cell types or incubation with adipocyte-conditioned medium significantly increased glucose uptake in cardiomyocytes. When streptozotocin-induced diabetic rats were used as a source of adipocytes, there was a lower ability to elicit glucose uptake in cardiomyocytes which corresponded with lower Akt and AMPK phosphorylation. The profile of glucose metabolism also differed with oxidation being favored upon co-culture with wild-type adipocytes whereas lactate production was strongly induced by adipocytes from diabetic rats. Examination of fatty acid uptake revealed that stimulation only occurred in response to adipokines secreted by wild-type rat adipocytes. Importantly, oxidation of fatty acids by cardiomyocytes was decreased by adipokines derived from diabetic rat adipocytes. Analysis of adipokine profiles in diabetic rat adipocyte-conditioned medium demonstrated the most significant decreases in adiponectin and leptin with increased IL6 expression. Taken together, these data suggest that the profile of adipokines secreted by adipocytes from diabetic rats have a deleterious influence on cardiomyocyte metabolism which may be of relevance in the pathophysiology of heart failure.     

The association between leptin and subclinical cardiovascular disease explained by body fat: Observational and Mendelian randomization analyses

Background and aimsLeptin has been associated with adverse effects on cardiovascular disease, but the effect of confounding by body fat in these associations remains unclear. To investigate associations between leptin and heart function and subclinical cardiovascular disease adjusted for total body fat, and to investigate the causal relation between leptin and cardiovascular disease using Mendelian randomisation.Methods and resultsLeptin concentrations, total body fat and diverse measures of subclinical cardiovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG measures, and carotid intima media thickness as a measure of subclinical atherosclerosis was adjusted for potential confounding factors, and additionally including total body fat. We analysed the combined effects of genetic variants from a GWAS on leptin concentrations in publicly-available summary statistics of coronary heart disease GWAS (CARDIoGRAMplusC4D, n = 184,305). As many as 6107 men and women, mean (SD) age 56 (6) years, BMI 26 (4) kg/m², and median leptin concentration 12.1 μg (IQR: 6.7–22.6) were included.In observational analyses, leptin was weakly associated with heart function and subclinical cardiovascular disease, but these associations attenuated when adjusting for total body fat. A doubling of genetically-determined leptin concentration was associated with an odds ratio of cardiovascular disease of 0.69 (0.37, 1.27).ConclusionObservational associations between leptin and subclinical measures of cardiovascular disease were largely explained by differences in total body fat. Results of analyses of genetically-determined leptin and coronary heart disease risk were inconclusive due to a large confidence interval.     

Leptin and mechanisms of endothelial dysfunction and cardiovascular disease

Leptin, a product of the obesity gene, is a molecule that has received much attention since its cloning in 1994. Initially, most work centered around the effects of leptin on satiety and energy balance. However, in recent years there has been an intense focus on leptin as it relates to the cardiovascular system. Plasma leptin concentration is markedly elevated in obesity and the metabolic syndrome, both of which are associated with increased incidence of cardiovascular pathologies. In many studies, hyperleptinemia has been linked to endothelial dysfunction (a known precursor to atherosclerotic cardiovascular disease) and activation of the sympathetic nervous system. Additionally, recent evidence suggests that leptin released from perivascular adipose tissue may also have deleterious effects on the underlying vasculature, including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, leptin-mediated sympathetic activation, and leptin as a significant perivascular adipose-derived factor.     

Adipokines influencing metabolic and cardiovascular disease are differentially regulated in maintenance hemodialysis

Adipokines including leptin, adiponectin, visfatin, resistin, and interleukin (IL)-6 significantly influence energy metabolism, insulin sensitivity, and cardiovascular health. In the current study, we investigated serum levels of these adipokines in diabetic and nondiabetic patients on maintenance hemodialysis (MD) as compared with controls with a glomerular filtration rate greater than 50 mL/min. Serum leptin, adiponectin, high-molecular-weight (HMW) adiponectin, visfatin, resistin, and IL-6 were determined by enzyme-linked immunosorbent assay in control (n = 60) and MD (n = 60) patients and correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. Adiponectin, visfatin, resistin, and IL-6 were significantly elevated in MD patients as compared with controls. In multivariate analyses, sex and body mass index were independently correlated with serum leptin levels in both controls and MD patients. Furthermore, insulin resistance was independently and negatively associated with adiponectin and HMW adiponectin in both groups. Moreover, circulating resistin levels were independently correlated with serum visfatin concentrations in control and MD patients. However, various independent associations were only found in either controls or patients on MD. Thus, serum IL-6 levels were strongly and independently associated with C reactive protein and resistin in MD patients but not control subjects. We show that levels of various adipokines are significantly increased in MD patients. Furthermore, regulation of adipokines in vivo strongly depends on renal function. Regulation of HMW adiponectin is similar as compared with total adiponectin in the patients studied.     

Inter‐relationships of the chronobiotic,melatonin, with leptin and adiponectin: implications for obesity

Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie‐rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo‐adiponectinemia have been linked to the pathophysiology of the obesity‐related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti‐inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders.     

Adipokines in diabetes and cardiovascular diseases

Recent studies suggest that adipocyte-secreted factors called adipokines are involved in obesity-associated complications including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Among those, adiponectin is an antidiabetic and antiatherogenic protein, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. In contrast, leptin, tumor necrosis factor a, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 are upregulated in obesity and contribute to the development of diabetes and vascular disease. In this review, the relevance of adipokines in obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular diseases is discussed.     

The role of adipokines in the modulation of lymphoid lineage cell development and activity: An overview

Adipokines are predominantly known to play a vital role in the control of food intake, energy homeostasis and regulation of glucose and lipid metabolism. However, evidence supporting the concept of their extensive involvement in immune system defence mechanisms and inflammatory processes continues to grow. Some of the adipokines, that is, leptin and resistin, have been recognized to exhibit mainly pro‐inflammatory properties, whereas others such as visfatin, chemerin, apelin and vaspin have been found to exert regulatory effects. In contrast, adiponectin or omentin are known for their anti‐inflammatory activities. Hence, adipokines influence the activity of various cells engaged in innate immune response and inflammatory processes mainly by affecting adhesion molecule expression, chemotaxis, apoptosis and phagocytosis, as well as mediators production and release. However, much less is known about the role of adipokines in processes involving lymphoid lineage cells. This review summarizes the current knowledge regarding the importance of different adipokines in the lymphopoiesis, recirculation, differentiation and polarization of lymphoid lineage cells. It also provides insight into the influence of selected adipokines on the activity of those cells in tissues.