Peripheral metabolic actions of leptin

The adipocyte-derived hormone, leptin, regulates food intake and systemic fuel metabolism; ob /ob mice, which lack functional leptin, exhibit an obesity syndrome that is similar to morbid obesity in humans. Leptin receptors are expressed most abundantly in the brain but are also present in several peripheral tissues. The role of leptin in controlling energy homeostasis has thus far focused on brain receptors and neuroendocrine pathways that regulate feeding behaviour and sympathetic nervous system activity. This chapter focuses on mounting evidence that leptin's effects on energy balance are also mediated by direct peripheral actions on key metabolic organs such as skeletal muscle, liver, pancreas and adipose tissue. Strong evidence indicates that peripheral leptin receptors regulate cellular lipid balance, favouring beta-oxidation over triacylglycerol storage. There are data to indicate that peripheral leptin also modulates glucose metabolism and insulin action; however, its precise role in controlling gluco-regulatory pathways remains uncertain and requires further investigation.     

Leptin is synthesized in the liver and adipose tissue of the dunlin (Calidris alpina)

Fat is the main source of energy for birds during a long-distance flight. Migration routes are usually divided into several steps. In stopover sites migratory birds restore energy reserves needed for continuation of migration. During a long-distance flight and when foraging at a stopover site birds should be able to assess their actual reserves accumulated in the form of fat stores. The information about energy being stored in body reserves may be provided by circulating factors involved in body mass regulation, such as adipose-derived hormone leptin. To date, little is known about the expression and potential role of leptin in birds. The aim of the present study was to determine whether leptin is synthesized in the liver and adipose tissue of the dunlin (Calidris alpina), a long-distance migrant. Western blot analysis with leptin-specific antibody detected a protein with a molecular mass of approximately 15-16 kDa in dunlin liver and adipose tissue. To our knowledge, this is the first report demonstrating leptin expression in the liver and adipose tissue of a migratory bird. This finding raises the possibility that in birds leptin may signal the status of energy reserves during migratory flight.     

The role of leptin in the regulation of neuroendocrine function and CNS development

Leptin, a hormone produced by adipocytes in proportion to fat stores, signals the sufficiency of energy reserves to the brain to control feeding and metabolism. Leptin represents a vital link between metabolic and neuroendocrine pathways, and adequate circulating leptin levels are required to permit the expenditure of energy on reproduction, growth, and other energy-intensive endocrine outputs. Leptin mediates its effects by acting upon a distributed network of CNS neurons that express the signaling form of the leptin receptor (LRb). Nutritional status early in development influences a lifelong metabolic program that modulates risk for diabetes, obesity and other elements of the metabolic syndrome. Recent evidence has demonstrated a number of important roles for leptin in the regulation of neural development and metabolic programming. In this review, we discuss leptin action, the neural circuits on which leptin acts, and our nascent understanding of how early leptin exposure may influence neural development and the predisposition to metabolic diseases.     

Neuroendocrine Effects of Leptin

Leptin, the product of the obesity gene, is a cytokine-like circulating protein acting as a peripheral satiety signal to the hypothalamus. It was initially described as a secreted product of white adipose cells, but more recent data have demonstrated its expression by endocrine and neuroendocrine tissues like the ovary and the hypothalamus, as well as several anterior pituitary cell types. The effects of leptin on body weight homeostasis are mediated via different hypothalamic neurotransmitters regulating appetite and energy expenditure. In addition, leptin participates to the modulation of the activity of the neuroendocrine thyrotrope, somatotrope, corticotrope and gonadotrope axes. These endocrine effects of leptin have progressively emerged as important physiological functions of this molecule. Its role as a permissive factor for puberty and normal reproductive function in adulthood is becoming widely recognized. In addition, leptin participates in the fine tuning of the corticotrope axis. Thus, by signalling body fat stores to the hypothalamus and other endocrine organs, leptin serves as a metabolic integrator of several neuroendocrine functions. The precise site of action and mode of regulation of the gonadotrope and somatotrope axes by leptin are reviewed.     

Cardiovascular and sympathetic effects of leptin

Several studies have shown the association between obesity and hypertension. The pathophysiologic mechanisms of obesity-related hypertension remain unknown. Clinical and experimental studies have shown that obesity is associated with enhanced sympathetic nervous activity. Thus, sympathetic nerve activation seems to play a major role in obesity-associated hypertension. However, the factors responsible for this sympathoactivation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and food intake and by increasing energy expenditure through sympathetic stimulation to brown adipose tissue. Leptin also produces sympathoactivation to kidneys, hindlimb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, obesity is associated with leptin resistance, since high circulating levels of leptin were observed in obese subjects. Recent evidences indicate that this leptin resistance could be selective with preservation of sympathetic effects despite the loss of metabolic action of leptin. This suggests divergent central pathways underlying metabolic and sympathetic effects of leptin. Several neuropeptides have emerged as potent candidate mediators of leptin action in the central nervous system, including the melanocortin system, neuropeptide Y, and cortico-trophin releasing factor. A detailed understanding of the multitude and complexity of integrated neuronal circuits and neuropeptide-containing pathways in leptin action will help in understanding the pathogenesis of obesity and related disorders.     

Adipose tissue and adipokines: for better or worse

It is now recognized that the white adipose tIssue (WAT) produces a variety of bioactive peptIdes, collectively termed "adipokines". Alteration of WAT mass in obesity or lipoatrophy, affects the production of most adipose secreted factors. Since both conditions are associated with multiple metabolic disorders and increased risk of cardiovascular diseases, the Idea has emerged that WAT could be instrumental in these complications, by virtue of its secreted factors. Several adipokines are increased in the obese state and have been implicated in hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin resistance (ASP, TNFalpha, IL-6, resistin). Conversely, leptin and adiponectin both exert an insulin-sensitizing effect, at least in part, by favoring tIssue fatty-acId oxIdation through activation of AMP-activated kinase. In obesity, insulin resistance has been linked to leptin resistance and decreased plasma adiponectin. In lipoatrophic mice, where leptin and adiponectin circulating levels are low, administration of the two adipokines synergistically reverses insulin resistance. Leptin and adiponectin also have distinct properties: leptin, as a long-term integrative signal of energy store and adiponectin, as a potent anti-atherogenic agent. The thiazolIdinedione anti-diabetic drugs increase endogenous adiponectin production in rodents and humans, supporting the Idea that the development of new drugs targeting adipokines might represent a promising therapeutic approach to protect obese patients from insulin resistance and atherosclerosis.     

Short-term beta-adrenergic regulation of leptin, adiponectin and interleukin-6 secretion in vivo in lean and obese subjects

Aim: Adipose tissue and skeletal muscle are endocrine organs, secreting substances that have been implicated in obesity‐related disorders. This study examined short‐term β‐adrenergic regulation of circulating leptin, adiponectin and interleukin‐6 (IL‐6) concentrations and secretion from abdominal subcutaneous adipose tissue and muscle (IL‐6) in vivo in lean and obese subjects. Methods: Systemic concentrations and net fluxes of leptin, adiponectin and IL‐6 across abdominal subcutaneous adipose tissue and forearm skeletal muscle (IL‐6) were assessed before and during β‐adrenergic stimulation (intravenous isoprenaline infusion) in 13 lean and 10 obese men. Results: Basal circulating leptin concentrations were higher in the obese (p < 0.001), while circulating adiponectin (p = 0.45) and IL‐6 concentrations (p = 0.41) were not different between groups. β‐Adrenergic stimulation decreased leptin concentrations in both groups (p < 0.01), but did not reduce net abdominal subcutaneous adipose tissue leptin release. Increased leptin clearance and/or decreased leptin secretion from other fat depots may explain the reduction in leptin concentrations. Adiponectin concentrations remained unchanged during β‐adrenergic stimulation in both groups. β‐Adrenergic stimulation increased IL‐6 concentration, which was more pronounced in the obese (p = 0.01 vs. lean). This cannot be explained by increased IL‐6 release per unit abdominal subcutaneous adipose tissue and muscle but might be because of the increased fat mass and fat‐free mass at whole‐body level. Conclusions: Short‐term β‐adrenergic stimulation decreases leptin concentrations, which cannot be explained by reduced net leptin release from abdominal subcutaneous adipose tissue, while it elevates IL‐6 concentration partly by increased release from this fat depot and muscle. Finally, β‐adrenergic stimulation has no short‐term regulatory role in adiponectin secretion.     

Adipose tissue as an endocrine organ

Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFα and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity.     

Molecular pathways to obesity

Obesity results from a chronic imbalance between energy intake and energy expenditure. Environmental factors, such as the increased availability of high caloric food or the decreased need for physical activity, contribute to its development and their influence is amplified by genetic predisposition. In recent years remarkable progress has been made in the understanding of the pathophysiology of obesity. Although most of the insights into the regulation of energy balance have been obtained in rodent models, the rare clinical cases of monogenic obesity provided evidence for the importance of several of these mechanisms in humans. The identification of leptin as a factor originating from adipose tissue and informing the brain about the status of energy reserves firmly established the concept of long-term regulation of body fat stores. The disappointing therapeutic results with leptin in obese patients could be explained by the fact that during evolution this hormone developed rather as a starvation signal than as an adiposity signal. It is conceivable that the pharmacological interference with mechanisms downstream of leptin, for example with the melanocortin pathway, might be therapeutically more promising. The discovery of new molecular mechanisms involved in the regulation of the differentiation and proliferation of adipocytes and the elucidation of their paracrine and endocrine functions have changed the traditional view of adipose tissue as an inert depot for triglycerides. The identification of new uncoupling proteins could modify the current concepts of the regulation of thermogenesis in humans. The remarkable progress in the identification of novel targets involved in the regualtion of energy balance should have a positive impact on the search for new antiobesity agents.     

CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health

Insulin resistance, dyslipidaemia and obesity are the major cardiometabolic risk factors contributing to the development of type 2 diabetes and cardiovascular disease (CVD). Owing to the increasing prevalence of obesity, type 2 diabetes, and CVD, new and effective pharmacologic therapies are urgently needed. In this regard, the endogenous cannabinoid system (ECS), a neuromodulatory system involved in the regulation of various aspects of energy balance and eating behaviour through central and peripheral mechanisms, may present the potential to meet this need. In the central nervous system (CNS), cannabinoid type 1 (CB1) receptors and their respective ligands, the endocannabinoids, have a significant role in the modulation of food intake and motivation to consume palatable food. CB1 receptors have also been found in organs involved in the regulation of metabolic homeostasis, such as liver, white adipose tissue, muscle and pancreas. Dysregulation of the ECS has been associated with the development of dyslipidaemia, glucose intolerance, and obesity, and CB1 receptor blockade may have a role in ameliorating these metabolic abnormalities. Thus, pharmacologic options targeting the ECS may provide a novel, effective approach to the prevention and management of CVD, type 2 diabetes and obesity.     

Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction

There is a close anatomical and functional relationship between adipose tissue and blood vessels. The crosstalk between these two organs is vital to both metabolic and vascular homeostasis. On the one hand, adipose tissue is highly vascularized, and maintenance of ample supply of blood flow is essential for both expansion and metabolic functions of adipose tissue. Vascular endothelium also secretes many factors to regulate adipogenesis and adipose tissue remodeling. On the other hand, almost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which regulates vascular function by producing a large number of “vasocrine” molecules. Under the normal conditions, PVAT exerts its anti-contractile effects by release of vasorelaxants (such as adipocyte-derived relaxation factors and adiponectin) that promote both endothelium-dependent and –independent relaxations of blood vessels. However, PVAT in obesity becomes highly inflamed and induces vascular dysfunction by augmented secretion of vasoconstriction factors (such as the major components of renin-angiotensinogen-aldosterone system and superoxide) and pro-inflammatory adipokines (such as TNF-α and adipocyte fatty acid binding protein), the latter of which are important contributors to endothelial activation, vascular inflammation and neointimal formation. Furthermore, several adipocyte-derived adipokines impair vascular function indirectly, by acting in the brain to activate sympathetic nerve system (such as leptin) or by exerting their actions in major metabolic organs to induce vascular insulin resistance, which in turn aggravates endothelial dysfunction. Aberrant secretion of adipokines and other vasoactive factors in adipose tissue is a major contributor to the onset and progression of obesity-related metabolic and vascular complications.     

White adipose tissue mitochondrial metabolism in health and in obesity

White adipose tissue is one of the largest organs of the body. It plays a key role in whole‐body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well‐being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity‐associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole‐body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long‐term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue.     

Leptin–cytokine crosstalk in breast cancer

Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman’s laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin–cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth factors essential for tumor development, angiogenesis and potential role in BCSC.     

瘦素抵抗的机制及其临床意义

瘦素的发现揭示了控制食欲和能量代谢平衡的神经内分泌机制,标志着肥胖研究的巨大突破.瘦素通过降低热量摄入以及增加能量消耗,调节自主神经系统、内分泌系统以及免疫系统,从而将能量平衡的神经内分泌调节作用与体内脂肪水平联系在一起.由瘦素引发的细胞内信号转导机制非常复杂,涉及到很多与瘦素各种功能活性相关的信号通路.肥胖和代谢综合征患者普遍存在高瘦素血症,瘦素抵抗及其机制近年来成为研究热点,而对于瘦素抵抗的药物治疗也将成为相关疾病的治疗新靶点.     

Gastrointestinal hormones and food intake

Despite dramatic fluctuations in calorie intake, animals maintain a very stable body weight. The reason is that energy intake and expenditure are precisely matched. Long-term regulation of energy balance is dependent on the coordination and interpretation of signals such as those given by insulin and leptin indicating sufficient long-term energy stores as well as short-term, meal-related signals such as those given by cholecystokinin (CCK). Within the last 30 years, our knowledge of short-term signals has increased dramatically. Throughout the cephalo-caudal axis of the gastrointestinal system, discrete enteroendocrine cells respond to both mechanical and chemical stimulation. Meal-associated hormone release is dependent on the concentration and composition of the nutrients ingested. Released signals are transmitted neurally through vagal afferents or humorally as circulating ligands for specific receptor populations in the periphery and central nervous system. These signals are interpreted by the CNS and manifested as a behavioral modification of feeding. This review will present past and recent literature in support of gut hormones and their roles as mediators of satiety. Evidence from pharmacologic and physiologic studies involving both humans and rodents will be presented, along with a short section outlining the knowledge gained through the use of murine knockout models. Last, the contribution of satiety hormones as likely mediators of the effectiveness seen following obesity surgery will be reviewed. Although traditionally thought of as short-term, meal-related signals, enhanced, chronic hormone secretion and signaling resulting from gut reconstruction as seen with gastric bypass surgery most likely contributes to the superior efficacy of surgery as a treatment for obesity.     

Leptin-Induced Sympathetic Nerve Activation: Signaling Mechanisms and Cardiovascular Consequences in Obesity

Obesity increases cardiovascular morbidity and mortality in part by inducing hypertension. One factor linking excess fat mass to cardiovascular diseases may be the sympathetic cardiovascular actions of leptin. Initial studies of leptin showed it regulates appetite and enhances energy expenditure by activating sympathetic nerve activity (SNA) to thermogenic brown adipose tissue. Further study, however, demonstrated leptin also causes sympathetic excitation to the kidney that, in turn, increases arterial pressure. In animal studies, elevating circulating leptin levels increased arterial pressure. Moreover, mice with diet-induced obesity have a preserved arterial pressure response to leptin despite the resistance to the metabolic action of leptin and these mice have elevated baseline arterial pressure. Conversely, severely obese, but leptin-deficient, mice and humans display low sympathetic tone and decreased blood pressure. Together, these findings demonstrate that leptin plays a physiological role in maintaining sympathetic tone and blood pressure, and further suggest that hyperleptinemia may contribute to the elevated blood pressure associated with obesity. Consistent with this selectivity in leptin resistance, mounting evidence suggests that the sympathetic nervous system subserving different tissues is differentially controlled by leptin. For instance, different molecular signaling mechanisms are engaged by the leptin receptor to control the regional sympathetic nerve activity. Understanding the mechanisms by which leptin controls the sympathetic nervous system will provide insight into the cardiovascular complications of obesity.     

Adiposity and cardiovascular disorders: disturbance of the regulatory system consisting of humoral and neuronal signals

Obesity, a major healthcare issue, is associated with significant cardiovascular morbidities, including hypertension and atherosclerosis. Numerous intensive studies conducted this decade have revealed that adipose tissue is a major endocrine organ that secretes a variety of bioactive substances, termed adipocytokines. Adipocytokine secretion profiles are altered as obesity develops, which may increase the risk of obesity-related cardiovascular disorders. For instance, leptin is upregulated in obese subjects and plays important roles in the pathophysiology of obesity-related atherogenesis through multiple mechanisms, such as its proliferative, proinflammatory, prothrombotic, and prooxidant actions. In contrast, adiponectin, which is downregulated in obese subjects, has protective effects against cardiovascular disorders at various atherogenic stages. In addition to these factors secreted by adipose tissue, neuronal circuits involving autonomic nerves are now being recognized as an important metabolic regulatory system and have thus attracted considerable attentions. Alterations in fat accumulation in intraabdominal organs, such as visceral adipose tissue and the liver, send afferent neuronal signals to the brain, leading to modulation of sympathetic tonus and thereby affecting the vasculature. Moreover, these humoral and neuronal signaling pathways communicate with each other, resulting in cooperative metabolic regulation among tissues/organs throughout the body. Further elucidation of these regulatory systems is anticipated to lead to new approaches to devising therapeutic strategies for the metabolic syndrome.     

Leptin and its metabolic interactions: an update

Obesity results from an abnormal accumulation of fat in the white adipose tissue. Recent research utilizing genetic models of obesity in rodents has implicated a major role of leptin as a controller of obesity. Leptin is a 167-amino acid peptide hormone encoded by the obesity gene (ob), which is secreted by adipocytes and plays an important role in regulating food intake, energy expenditure and adiposity. Leptin receptors (OB-R) are expressed in the central nervous system mainly in afferent satiety centres of hypothalamus and in peripheral organs such as adipose tissues, skeletal muscles, pancreatic beta-cells and liver, thus indicating the autocrine and paracrine role of leptin in energy regulation. In human beings, a highly organized circadian pattern of leptin secretion is observed with peak levels in the midnight probably resulting from cumulative hyperinsulinemia of entire day. Leptin has a dual role in weight maintenance. Leptin reflects total body adipose tissue mass whereas in conditions of negative and positive energy balance, the dynamic changes in plasma leptin concentration function as a sensor of energy balance and influence the efferent energy regulation pathways. Many effects of leptin on metabolism are mediated by interaction with Insulin and also by synergistic action with cholecystokinin. Besides physiological roles, leptin may influence pathological conditions like obesity-associated atherosclerosis, oxidative stress and cancers. The purpose of the present review is to summarize the important aspects of the biology, actions, and regulation of leptin and to serve as an update of new information.