Leptin, from fat to inflammation: old questions and new insights

Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.     

Is there NO help for leptin?

Since the initial identification of leptin as the product of the ob gene in 1994, the signaling pathways by which this hormone alters cell physiology have been the subject of extensive investigations. The fact that leptin can induce nitric oxide (NO) production was first demonstrated in studies of the pituitary gland and pancreatic islets. A large number of additional studies further showed that this adipokine stimulates NO synthesis in multiple tissues. This review article discusses the role of leptin in NO production and its pathophysiological consequences. The role of this gaseous messenger in cell physiology depends on the cell type, the concentration of NO and the duration of exposure. It can be either a potent oxidant or a protector of cell integrity against the formation of reactive oxygen species. Leptin plays two opposing roles on arterial pressure. It exerts a hypertensive effect due to sympathetic activation and a vasorelaxant effect due to NO production. This adipokine acts via NO to produce pro-inflammatory factors in cartilage pathology, potentially contributing to an increased risk for osteoarthritis. Another well-documented role of leptin-induced NO, acting either directly or via the hypothalamus, concerns lipid metabolism in muscle and adipose tissue. In adipocytes, the direct and rapid action of leptin is to activate the nitric oxide synthase III, which favors lipolysis. In contrast, in the long-term, leptin reduces lipolysis. However, both in the short-term and in the long-term, glyceroneogenesis and its key enzyme, the cytosolic phosphoenolpyruvatecarboxykinase (PEPCK-C), are down-regulated by the adipokine, thus favoring fatty acid release. Hence, leptin-induced NO production plays a crucial role in fatty acid metabolism in adipose tissue. The resulting effects are to prevent lipid storage and to improve energy expenditure, with possible improvements of the obese state and its associated diseases.     

瘦素与软骨代谢

瘦素最初发现是在白色脂肪组织产生并且与脂肪组织量有强相关性的激素物质。它最初发现于1994年,并且在中枢神经系统起到限制食物摄入,刺激能量消耗的作用。目前发现在几乎所有的组织内都有瘦素受体的表达,而且在细胞层面瘦素参与各种各样的生物学功能,包括免疫反应、炎性疾病以及心血管、呼吸系统的病理生理过程。目前大量研究表明,瘦素在软骨代谢也发挥了重要作用,现综述如下。     

The role of leptin in innate and adaptive immune responses

Leptin is produced primarily by adipocytes and functions in a feedback loop regulating body weight. Leptin deficiency results in severe obesity and a variety of endocrine abnormalities in animals and humans. Several studies indicated that leptin plays an important role in immune responses. It exerts protective anti-inflammatory effects in models of acute inflammation and during activation of innate immune responses. In contrast, leptin stimulates T lymphocyte responses, thus having rather a proinflammatory role in experimental models of autoimmune diseases. Clinical studies have so far yielded inconsistent results, suggesting a rather complex role for leptin in immune-mediated inflammatory conditions in humans.     

The role of transforming growth factor-beta in atherosclerosis

Transforming growth factor-β (TGF-β) plays a pivotal role in a range of biological processes, including the control of cellular proliferation and differentiation, regulation of tissue repair and extracellular matrix accumulation, and modulation of the immune and inflammatory responses. The role of TGF-β in the pathogenesis of atherosclerosis, which is widely perceived as a form of chronic inflammation, has been the subject of debate for a number of years. A pro-atherogenic role was suspected because of its ability to promote fibrosis and to inhibit endothelial regeneration. However, several recent studies have shown that TGF-β limits atherosclerosis by modulating a number of processes, including the accumulation of lipids in the vessel wall and the inflammatory response. This review will discuss the role of TGF-β in atherosclerosis along with the molecular mechanisms underlying its action during the pathogenesis of the disease.     

Leptin, a neuroendocrine mediator of immune responses, inflammation, and sickness behaviors

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Effective immune responses are coordinated by interactions among the nervous, endocrine, and immune systems. Mounting immune, inflammatory, and sickness responses requires substantial energetic investments, and as such, an organism may need to balance energy allocation to these processes with the energetic demands of other competing physiological systems. The metabolic hormone leptin appears to be mediating trade-offs between the immune system and other physiological systems through its actions on immune cells and the brain. Here we review the evidence in both mammalian and non-mammalian vertebrates that suggests leptin is involved in regulating immune responses, inflammation, and sickness behaviors. Leptin has also been implicated in the regulation of seasonal immune responses, including sickness; however, the precise physiological mechanisms remain unclear. Thus, we discuss recent data in support of leptin as a mediator of seasonal sickness responses and provide a theoretical model that outlines how seasonal cues, leptin, and proinflammatory cytokines may interact to coordinate seasonal immune and sickness responses.     

Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e., canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts.     

Leptin as a physiological mediator of energetic trade-offs in ecoimmunology: implications for disease

Organisms must distribute sufficient energy among different and often competing physiological systems. This task can become challenging, however, as resources are often limiting, resulting in energetic trade-offs. For example, energetically based trade-offs between the reproductive and immune systems are common across taxa, yet the regulatory mechanisms underlying these trade-offs remain unclear. The adipose tissue hormone leptin is an ideal candidate for the modulation of energetic trade-offs between different physiological systems as this hormone serves as a gage of fat reserves and also modulates a range of physiological activities including the reproductive and immune processes. This article presents a review of the evidence for the role of leptin as a modulator of energetic trade-offs with the immune system and suggests its importance in disease ecology. In addition, we provide a case study of the ornate tree lizard (Urosaurus ornatus), testing whether leptin is involved in mediating a well-documented influence of energy state on the trade-off between reproductive activity and immune function. Overall, the combined results suggest that leptin serves as a proximate endocrine signal of available energy to the immune system, and therefore likely to affect susceptibility to diseases.     

Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity

Until the identification of leptin, the first adipokine discovered in 1994, adipose tissue was considered only as an energy storage tissue. However, it is now clear that adipose tissue is an endocrine/paracrine/autocrine organ, which plays a relevant role in physiopathology of several inflammatory diseases. Actually, it is mainly involved not only in the low-grade inflammatory status in obesity but also in other relevant inflammatory conditions and autoimmune disorders. In this review article, we discuss the main biological activities of leptin, adiponectin, lipocalin-2, resistin, and visfatin, as well as their contributions to certain inflammatory conditions.     

Leptin and chronic kidney diseases

Chronic kidney diseases (CKD), a common outcome of various kidney diseases, cause a series of refractory complications, which lead to great economic burdens on patients. The clinical outcomes of CKD depend on various factors, including metabolic disorders. Leptin, a peptide hormone, produced in adipose tissues, plays an important role in regulating food consumption and energy expenditure. Leptin also influences the immune system and hematopoiesis. Increased leptin status is observed in CKD, leptin deficiency attenuates the immune response in nephritis. Conversely, leptin inhibits the development of obesity, which is closely associated glomerular disorder. Now, the precise role of leptin in CKD remains elusive. This review will give an integrated understanding of the potential role of leptin and its interactions with other signal molecules in CKD.     

Molecular mechanisms of leptin and pro-apoptotic signals induced by menadione in HepG2 cells

Apoptosis is a significant physiological function in the cell. P⁵³ is known as tumor suppressor cellular factor, executive caspases are also the most involved pathway for apoptosis. Menadione (VK3) has apoptotic action on many harmful cells, but the molecular role of adipokines is not studied enough in this regard, so the ability of menadione to modify the adipokine (leptin hormone), caspase-3 and P⁵³ signals to induce its apoptotic action on HepG2 cells was studied. The study revealed that menadione has anti-viability and apoptotic effect at sub-G1 phase of HepG2 cell cycle. Its cytotoxic effect is mediated by molecular mechanisms included: inhibiting leptin expression and level, activating caspase-3 pathway and up-regulating the expression of P⁵³. Menadione exerts its apoptotic mechanisms in a concentration and time dependent way through ROS generation. In addition to the known apoptotic pathways, the results indicate that suppressing leptin pathway is a significant mechanism for menadione apoptotic effect which made it as a potential therapeutic vitamin in preventing hepatocyte survival and proliferation.     

Leptin: A new predictor of outcome in the patients undergoing traditional on-pump CABG surgery?

Leptin, a 16 kDa peptide product of the obese gene, is an adipocyte-derived cytokine-like molecule which is structurally related to the IL-6 cytokine family. Through its interaction with its receptor Ob-R, a member of the class I cytokine receptor family which is ubiquitously expressed including endothelium, vascular smooth muscle and myocardium, leptin plays a role in a wide range of biological responses such as control of body weight and energy expenditure, neuroendocrine function, angiogenesis, bone formation, modulating immune responses. More and more studies indicated that leptin may be involved in the acute stress response to severe illness and surgery by way of its interaction with hypothalamic–pituitary–adrenal axis and the inflammatory cytokine system. Systemic inflammatory response (SIR) is one of the common complications after on-pump coronary artery bypass grafting in which the severity of SIR directly correlates with the outcome and prognosis. We based our hypothesis on that leptin may participate in the acute stress-SIR induced by on-pump coronary artery bypass grafting and its levels and secretion patterns might be related to the extent of activation of SIR and might serve as marker of the severity and predict the outcome.     

Alterations in mouse hypothalamic adipokine gene expression and leptin signaling following chronic spinal cord injury and with advanced age

Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro-endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting-induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions.     

Adaptive Immunity Alters Distinct Host Feeding Pathways during Nematode Induced Inflammation,a Novel Mechanism in Parasite Expulsion

Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor α receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFα during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection.     

Cross-talk between estrogen and leptin signaling in the hypothalamus

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.     

Leptin action on nonneuronal cells in the CNS: potential clinical applications

Leptin, an adipocyte-derived cytokine, crosses the blood-brain barrier to act on many regions of the central nervous system (CNS). It participates in the regulation of energy balance, inflammatory processes, immune regulation, synaptic formation, memory condensation, and neurotrophic activities. This review focuses on the newly identified actions of leptin on astrocytes. We first summarize the distribution of leptin receptors in the brain, with a focus on the hypothalamus, where the leptin receptor is known to mediate essential feeding suppression activities, and on the hippocampus, where leptin facilitates memory, reduces neurodegeneration, and plays a dual role in seizures. We will then discuss regulation of the nonneuronal leptin system in obesity. Its relationship with neuronal leptin signaling is illustrated by in vitro assays in primary astrocyte culture and by in vivo studies on mice after pretreatment with a glial metabolic inhibitor or after cell-specific deletion of intracellular signaling leptin receptors. Overall, the glial leptin system shows robust regulation and plays an essential role in obesity. Strategies to manipulate this nonneuronal leptin signaling may have major clinical impact.     

Glycogen synthase kinase 3: a point of convergence for the host inflammatory response

The phosphatidylinositol 3-kinase (PI3K) pathway has been shown to play a central role in regulating the host inflammatory response. Recent studies characterizing the downstream effector molecules within the PI3K pathway have identified that the serine/threonine kinase, glycogen synthase kinase 3 (GSK3), plays a pivotal role in regulating the production of pro- and anti-inflammatory cytokines. In innate immune cells, GSK3 inactivation augments anti-inflammatory cytokine production while concurrently suppressing the production of pro-inflammatory cytokines. The role of GSK3 in T cell biology has also been studied in detail and is involved in regulating multiple downstream signaling processes mediated by the T cell receptor (TCR), the co-stimulatory molecule CD28, and the IL-17 receptor. In vivo studies assessing the therapeutic properties of GSK3 inhibitors have shown that the inactivation of GSK3 can protect the host from immune-mediated pathology and death. This review will highlight the immunological importance GSK3 plays within different signal transduction pathways of the immune system, the cellular mechanisms regulating the activity of GSK3, the role of GSK3 in innate and adaptive immune responses, and the in vivo use of GSK3 inhibitors to treat inflammatory mediated diseases in animals.     

Leptin in immunology

Leptin is an adipokine which conveys information on energy availability. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of leptin in the pathophysiology of immune responses.     

AMP-activated protein kinase: balancing the scales

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that plays a key role in the regulation of energy control. AMPK is activated in response to an increase in the ratio of AMP:ATP within the cell. Activation requires phosphorylation of threonine 172 within the catalytic subunit of AMPK by an upstream kinase. The identity of the upstream kinase in the cascade remained frustratingly elusive for many years, but was recently identified as LKB1, a kinase that is inactivated in a rare hereditary form of cancer called Peutz-Jeghers syndrome. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance within the cell. ATP-consuming, anabolic pathways, such as fatty acid synthesis and protein synthesis are switched-off, whereas ATP-generating, catabolic pathways, such as fatty acid oxidation and glycolysis, are switched-on. More recent studies have indicated, that AMPK plays an important role in the regulation of whole body energy metabolism. The adipocyte-derived hormones, leptin and adiponectin, activate AMPK in peripheral tissues, including skeletal muscle and liver, increasing energy expenditure. In the hypothalamus, AMPK is inhibited by leptin and insulin, hormones which suppress feeding, whilst ghrelin, a hormone that increases food intake, activates AMPK. Furthermore, direct pharmacological activation of AMPK in the hypothalamus by 5-aminoimidazole-4-carboxamide ribose increases food intake in rats, demonstrating that AMPK plays a direct role in the regulation of feeding. Taken together these findings indicate that AMPK has a pivotal role in regulating pathways that control both energy expenditure and energy intake.