leptin and Autoimmune-Diseases

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Topics: Autoimmune Diseases; Bone and Bones; Dyslipidemias; Fatty Liver; Glucose; Humans; Hyperglycemia; Hypertension; Kidney; Leptin; Lipid Metabolism; Lipodystrophy; Quality of Life; Recombinant Proteins; Reproduction; Syndrome

In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Autoimmune Diseases; Diabetes Mellitus; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Infertility; Inflammation; Leptin; Male; Neoplasms; Nutritional Physiological Phenomena; Obesity

Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity.

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Communicable Diseases; Humans; Immunity, Innate; Leptin; Obesity

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly

Topics: Adipose Tissue; Autoimmune Diseases; Diabetes Mellitus, Type 2; Humans; Infections; Leptin; Obesity; Receptors, Leptin

Leptin is an adipocyte-derived hormone product of the obese (ob) gene. Leptin plays an important regulatory role as an immunomodulatory factor in the maintenance and homeostasis of immune functions. Indeed, the role of leptin as an immunomodulator in inflammatory and immune responses has attracted increasing attention in recent years. Leptin mostly affects responses through the immunomodulation of monocytes, dendritic cells, neutrophils, NK cells, and dendritic cells in addition to modulating T and B cell development and functions. Leptin is also an important inflammatory regulator, wherein higher expression influences the secretion rates of IL-6, C-reactive proteins, and TNF-α. Moreover, leptin is highly involved in processes related to human metabolism, inflammatory reactions, cellular development, and diseases, including hematopoiesis. Owing to its diverse immunerelated functions, leptin has been explored as a potential target for therapeutic development in the treatment of autoimmune diseases.

Topics: Adipocytes; Autoimmune Diseases; Dendritic Cells; Hematopoiesis; Homeostasis; Humans; Immune System; Immunologic Factors; Inflammation; Inflammation Mediators; Killer Cells, Natural; Leptin; Monocytes; Neutrophils; Signal Transduction

The literature on thyroid autoimmunity has identified many potential factors at play for the initiation and progression of autoimmune thyroid diseases. These factors include genetic susceptibility, environmental factors, some drugs, iodine and selenium, infection, molecular mimics, and immune system defects. The sheer number of feasible factors makes sorting out the necessary agents from the fellow travelers difficult. In addition, many of these factors have the capability to interact-further confusing the picture. Another difficulty in interpreting these data is that most proposed mechanisms are not able to accomplish the triggering event in which the tolerance to self-antigens is actually overcome. In addition, some findings may be describing the conditions present after a disease is diagnosed and may be consequences of the disease rather than a cause. Recent description of the role of adipokines, which include leptin, tumor necrosis factor-alpha, and interleukin-6, in contributing to the inflammatory environment of the thyroid, along with the presence of thyroid Toll-like receptors for pathogen-associated patterns have the potential to deliver that necessary adjuvant signal to break tolerance, seen as necessary in animal autoimmune models. An additional factor, vitamin D. To describe the many factors at play in thyroid autoimmunity and how they interact.. Thyroid autoimmunity is the result of an interplay of factors, with adipokines produced by WAT and vitamin D providing immune modulating signals external to the thyroid, while thyrocyte innate responses to environmental conditions provide the necessary adjuvant signal. Shaping the response to be reactive to particular self-antigens and likelihood of a response are due to genetics and molecular mimics.

Topics: Autoimmune Diseases; Humans; Leptin; Thyroid Diseases; Thyroid Gland; Vitamin D

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Communicable Diseases; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Leptin; Malnutrition

Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.

Topics: Adipocytes; Appetite; Arthritis, Rheumatoid; Autoimmune Diseases; Disease Progression; Energy Metabolism; Hematopoietic Stem Cells; Humans; Hypothalamus; Leptin; Lupus Erythematosus, Systemic; Molecular Targeted Therapy; Receptors, Leptin; Signal Transduction; Weight Loss

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Astrocytes; Autoimmune Diseases; CD8-Positive T-Lymphocytes; Complement Factor D; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Immune System; Inflammation; Interleukin-17; Leptin; Mesenchymal Stem Cells; Mice; Microglia; Multiple Sclerosis; Nicotinamide Phosphoribosyltransferase; Obesity; Oligodendroglia; Prevalence; Resistin; Risk; Th1 Cells; Th2 Cells

The past twenty years of research on leptin has provided crucial information on the link between metabolic state and immune system function. Adipocytes influence not only the endocrine system but also the immune response, through several cytokine-like mediators known as adipokines, which include leptin. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, diabetes, or degenerative disease including autoimmunity and cancer. In this review, we provide an overview of recent advances on the role of leptin in the pathogenesis of several autoimmune disorders that may be of particular relevance in the modulation of the autoimmune attack through metabolic-based therapeutic approaches.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Humans; Leptin; Obesity

The role of leptin in regulation of energy homeostasis is well established, yet both the diagnostic as well as the therapeutic relevance of leptin in diet-induced obesity remains unresolved. Nevertheless, in the last few years, the substantial impact of leptin substitution in selected forms of monogenic obesity has advanced our knowledge about the neuroendocrine network of body weight regulation. Moreover, leptin seems to play a crucial role in intestinal nutrient reabsorption, regulation of blood pressure, fertility, inflammation and autoimmune diseases. A better understanding of these processes could possibly provide novel diagnostic and therapeutic options in the future.

Topics: Autoimmune Diseases; Blood Pressure; Body Composition; Body Weight; Energy Metabolism; Fertility; Homeostasis; Humans; Inflammation; Intestinal Absorption; Leptin; Obesity

Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder that affects millions of people around the world. Leptin is a satiety hormone produced primarily by adipose tissue and acts both centrally and peripherally. Leptin has been shown to play a major role in regulating metabolism, which increases during IBD progression. Leptin mediates several physiological functions including elevated blood pressure, tumorogenesis, cardiovascular pathologies and enhanced immune response in many autoimmune diseases. Recent development of a leptin mutant antagonist that blocks leptin activity raises great hope and opens up new possibilities for therapy in many autoimmune diseases including IBD. To this end, preliminary data from an ongoing study in our laboratory on pegylated leptin antagonist mutant L39A/D40A/F41A (PEG-MLA) treatment shows an inhibition of chronic colitis in IL-10-/- mice. PEG-MLA effectively attenuates the overall clinical scores, reverses colitis-associated pathogenesis including a decrease in body weight, and decreases systemic leptin level. PEG-MLA induces both central and peripheral leptin deficiency by mediating the cellular immune response. In summary, after blocking leptin activity, the correlative outcome between leptin-mediated cellular immune response, systemic leptin levels, and amount of adipose tissue together may provide new strategies for therapeutic intervention in autoimmune diseases, especially for intestinal inflammation.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Gastrointestinal Tract; Humans; Immunity, Cellular; Inflammatory Bowel Diseases; Leptin; T-Lymphocytes, Regulatory

Regulatory T cells (Treg cells) are crucial in mediating immune homeostasis and promoting the establishment and maintenance of peripheral tolerance. Excess body weight and obesity are typified by 'low-degree' chronic inflammation and are associated with an increased risk of atherosclerosis, diabetes, fatty liver disease, autoimmune diseases and cancer. All these pathological conditions are characterized by chronic inflammation, abnormal cytokine production, elevated acute-phase reactants, and the activation of several inflammatory signaling pathways. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. Leptin represents a link among metabolic disorders and immune tolerance; indeed, leptin can negatively affect the generation and proliferation of Treg cells, key players in this context. Treg cells play also a central role in tumor progression; different reports have proposed that tumor microenvironment can induce the recruitment of Treg cells which can promote tumor tolerance and angiogenesis through expression of suppressive molecules, cytokines and angiogenic factors (i.e. vascular endothelial growth factor, leptin). This work aims to discuss some of the most recent advances on the relationship between angiogenesis, leptin and immune tolerance, focusing on the role of Treg cell function in this context.

Topics: Acute-Phase Proteins; Adipose Tissue; Autoimmune Diseases; Cytokines; Gene Expression Regulation; Humans; Immune Tolerance; Inflammation; Leptin; Neovascularization, Pathologic; Neovascularization, Physiologic; Obesity; Signal Transduction; T-Lymphocytes, Regulatory

Leptin is an adipokine whose proinflammatory properties contribute to the pathogenesis of several autoimmune diseases but also to the development and progression of inflammation in several non-autoimmune inflammatory conditions of the kidney, liver, lung, endometrium, blood vessels and endothelia. Here we review the influences of leptin in those conditions and the pertinent experimental work that has defined some mechanisms of action and/or suggested a therapeutic potential for leptin-based modulation of inflammation in non-autoimmune conditions.

Topics: Adipokines; Animals; Autoimmune Diseases; Humans; Inflammation; Leptin

Recent years have seen several advances in our understanding of the functions of adipose tissue regarding not only the energy storage, but also the regulation of complex metabolic and endocrine functions. In this context, leptin and adiponectin, the two most abundant adipocyte products, represent one of the best example of adipocytokines involved in the control of energy expenditure, lipid and carbohydrate metabolism as well as in the regulation of immune responses. Leptin and adiponectin secretion is counter-regulated in vivo, in relation to degree of adiposity, since plasma leptin concentrations are significantly elevated in obese subjects in proportion to body mass index while adiponectin secretion decreases in relation to the amount of adipose tissue. In this review we focus on the main biological activities of leptin and adiponectin on the lipid and carbohydrate metabolism and on their contribute in regulation of innate and adaptive immune responses.

Topics: Adiponectin; Animals; Autoimmune Diseases; Energy Metabolism; Humans; Immunity; Leptin

The study of how different intracellular metabolic signaling pathways impact the control of self-immune tolerance and how metabolic dysregulation in overweight, obesity, and diabetes is able to alter self-immune tolerance are topics of intensive investigation. Recent evidence suggests that metabolic and autoimmune diseases, both characterized by chronic inflammation and an altered self-immune tolerance, are more common in affluent countries. The reasons for such phenomena are still not completely understood, but the 'metabolic pressure' induced by nutritional overload, typical of more developed countries, seems to play a role. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. We believe that there is a strong relationship among leptin, metabolic state, and immunological self-tolerance. We hypothesize that the leptin-induced metabolic pressure sets the basis for an exaggerated immuno-inflammatory response to altered self or non-self, leading to chronic inflammation, metabolic dysregulation, and autoimmunity in subjects with risk factors (i.e. genetic predisposition, environment, sex, infectious agents, etc). Capitalizing on our joint effort and trans-disciplinary expertise in metabolism, self-tolerance, and autoimmune diseases, this review highlights key questions on the basic mechanisms governing immune tolerance in the context of metabolic and autoimmune disease susceptibility.

Topics: Adipose Tissue; Animals; Autoimmune Diseases; Body Weight; Diabetes Mellitus; Energy Metabolism; Humans; Immune Tolerance; Inflammation; Leptin; Self Tolerance; Signal Transduction; T-Lymphocytes

For decades, obesity has been considered to be the result of the complex interaction between genes and the environment and its pathogenesis is still unresolved. The discovery of hormones and neural mediators responsible for the control of food intake and metabolism at the hypothalamic level has provided fundamental insights into the complicated pathways that control food intake. However, the molecular basis for the association between obesity and low-degree chronic inflammation is still unknown. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones, has suggested that nutritional status, through leptin secretion, can control immune self-tolerance modulating Treg suppressive function and responsiveness. Furthermore, recent experimental evidence has shown the presence of an abundant adipose tissue-resident Treg population responsible for the control of metabolic parameters and glucose homeostasis. Better knowledge of the intricate network of interactions among leptin-related energy regulation, Treg activities and obesity could lead to valuable strategies for therapeutic intervention in obesity and obesity-associated insulin resistance.

Topics: Autoimmune Diseases; Basic Helix-Loop-Helix Transcription Factors; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Receptor, Melanocortin, Type 4; Repressor Proteins; T-Lymphocytes, Regulatory

Over the last few years, a series of molecules known to play a function in metabolism has also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production (i.e., genetic leptin deficiency, anorexia nervosa, malnutrition) are associated with increased susceptibility to infections. Conversely, immune-mediated disorders such as autoimmune disorders are associated with increased secretion of leptin and production of proinflammatory, pathogenic cytokines. Leptin could represent the "missing link" among immune response, metabolic function, and nutritional status. Indeed, more recently, leptin-deficient mice have been shown to be resistant to a series of experimentally induced autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Finally, leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signaling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3(+)CD4(+) T cells. These data suggest that leptin can be considered as a link among immune tolerance, metabolic state, and autoimmunity and that strategies aimed at interfering with the leptin axis could represent innovative, therapeutic tools for autoimmune disorders.

Topics: Animals; Autoimmune Diseases; Brain; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Homeostasis; Humans; Immunity; Inflammation; Leptin; Metabolism; Multiple Sclerosis; Obesity; T-Lymphocytes, Regulatory

Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-beta). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.

Topics: Animals; Autoantigens; Autoimmune Diseases; Cytokines; Diabetes Mellitus; Electroporation; Genetic Therapy; Humans; Leptin; Mice; Mice, Inbred NOD; Vaccines, DNA

Leptin, a protein hormone produced by the adipocytes, has long been recognized to regulate metabolism, neuroendorine and other physiological functions. Early findings of increased leptin production during infection and inflammation and dysregulated immune response in leptin signaling-deficient mice provide strong evidence for the involvement of leptin in the immune responses. Recent data have established the regulatory function for leptin in immunity similar to the function of a pro-inflammatory cytokine, while gene-targeting studies also demonstrated an essential role of leptin in regulating hematopoiesis and lymphopoiesis. Moreover, there has been increasing evidence that leptin is involved in the pathogenesis of various autoimmune diseases. This review discusses recent advances in understanding the role of leptin in immunity and leptin-signaling pathways involved in modulating immune homeostasis and autoimmune pathogenesis.

Topics: Animals; Autoimmune Diseases; Hematopoiesis; Humans; Immunity; Leptin; Mice; Signal Transduction

It has recently become apparent that several molecules involved in the control of metabolism also play an important function in the regulation of immune responses. Among those molecules, the adipocyte-derived cytokine leptin has been shown to significantly influence innate and adaptive immune responses both in normal and in pathological conditions. For example, levels of leptin are typically low in infection and high in autoimmunity, both systemically and at the site of inflammation. Moreover, in addition to its long-known effects on the promotion of T helper 1 immune responses and cell-mediated immunity, leptin has more recently been found capable to constrain proliferation of regulatory T cells. As such, leptin represents not only a link between metabolism and immune responses in general but also a pivotal modulator of the magnitude of selected mechanisms of peripheral immunity in relation to body fat mass. We review here the most recent advances on the role of leptin in the control of immune tolerance and critically discuss how strategies aimed at neutralizing the leptin axis could represent innovative tools for the therapy of autoimmune disorders.

Topics: Adipose Tissue; Animals; Autoimmune Diseases; Humans; Leptin

The pivotal role of leptin in regulating body weight and energy homeostasis is very well established. More recently, leptin also emerged as an important regulator of T-cell-dependent immunity. Reduced leptin levels, as observed during periods of starvation, correlate with an impaired cellular immune response, whereby especially the T(H)1 pro-inflammatory immune response appears to be affected. Physiologically, this could reflect the high energy demand of such processes, which are suppressed in animals or people with nutrient shortage. Several autoimmune diseases are T(H)1 T-cell dependent. In line with a pro-inflammatory role for leptin, animal models of leptin deficiency are markedly resistant to a variety of T-cell dependent autoimmune diseases. Here, we review the role of leptin in immune responses, with emphasis on autoimmune diseases. The design and potential use of leptin antagonists is also discussed.

Topics: Animals; Antibody Formation; Autoimmune Diseases; Humans; Leptin

White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Autoimmune Diseases; Complement Factor D; Cytokines; Hormones, Ectopic; Humans; Inflammation; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Macrophages; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Serine Endopeptidases

Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists.

Topics: Adipocytes; Arteriosclerosis; Autoimmune Diseases; Cardiovascular Diseases; Humans; Immunity, Cellular; Insulin Resistance; Leptin; Receptors, Leptin; Receptors, Mitogen; Signal Transduction

Leptin is a an adipocyte-secreted hormone that regulates weight centrally. However, the leptin receptor is expressed not only in the central nervous system, but also in peripheral tissues, such as haematopoietic and immune systems. Therefore, the physiological role of leptin should not be limited to the regulation of food intake and energy expenditure. Moreover, the leptin receptor bears homology to members of the class I cytokine family, and recent data have demonstrated that leptin is able to modulate the immune response. Thus, the leptin receptor is expressed in human peripheral blood mononuclear cells, mediating the leptin effect on proliferation and activation. In vitro activation and HIV infection in vivo induce the expression of the long isoform of the leptin receptor in mononuclear cells. Also, leptin stimulates the production of proinflammatory cytokines from cultured monocytes and enhances the production of Th1 type cytokines from stimulated lymphocytes. Moreover, leptin has a trophic effect on monocytes, preventing apoptosis induced by serum deprivation. Leptin stimulation activates JAK-STAT, IRS-1-PI3K and MAPK signalling pathways. Leptin also stimulates Tyr-phosphorylation of the RNA-binding protein Sam68 mediating the dissociation from RNA. In this way, leptin signalling could modulate RNA metabolism. These signal transduction pathways provide possible mechanisms whereby leptin may modulate activation of peripheral blood mononuclear cells. Therefore, these data support the hypothesis regarding leptin as a proinflammatory cytokine with a possible role as a link between the nutritional status and the immune response. Moreover, these immunoregulatory functions of leptin could have some relevance in the pathophysiology of obesity.

Topics: Adipocytes; Apoptosis; Autoimmune Diseases; Cells, Cultured; Cytokines; Humans; Janus Kinase 1; Leptin; Leukocytes, Mononuclear; Lymphocyte Activation; MAP Kinase Signaling System; Nutritional Status; Obesity; Phosphatidylinositol 3-Kinases; Protein Isoforms; Protein-Tyrosine Kinases; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Th1 Cells

Current understanding of the role of leptin has expanded from its narrow association with obesity to a variety of effects on different biological processes including immune function. More specifically, leptin links nutritional status and energy balance to regulation of pro-inflammatory T-helper 1 immune responses. This has prompted several studies of targeted intervention with leptin antagonists in rodents to suppress onset and/or progression of chronic inflammation and autoimmunity. This review presents current preclinical evidence and potential applications for leptin-based immune approaches aimed at improving therapy for chronic and autoimmune conditions.

Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Leptin; Nutritional Status; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; T-Lymphocytes

We investigated the role of adipokines in patients with systemic autoimmune diseases who received glucocorticoid therapy.. Fifty-two patients with systemic autoimmune diseases who had started glucocorticoid therapy were prospectively enrolled. One hundred forty healthy persons were also studied as controls. Serum levels of 3 adipokines [resistin, leptin, and high molecular weight (HMW)-adiponectin] were measured with enzyme-linked immunosorbent assay kits before and at weekly intervals for 4 weeks during glucocorticoid therapy. The effects of lipopolysaccharide and dexamethasone on adipokine expression in human peripheral blood mononuclear cells (PBMCs) were also examined.. The serum resistin level was significantly higher in patients than in controls before glucocorticoid therapy, and it decreased after glucocorticoid therapy. Consistent with these results, dexamethasone inhibited lipopolysaccharide-induced upregulation of resistin expression in PBMCs in vitro. Serum leptin and HMW-adiponectin levels were lower in the patients than in the controls at baseline, and both adipokine levels were increased after glucocorticoid therapy. There was a significant correlation between serum resistin and high-sensitivity C-reactive protein. However, there was no association between serum adipokines and intima-media thickness.. Resistin may be associated with the inflammatory process but not atherosclerosis in patients with systemic autoimmune diseases.

Topics: Adipokines; Adiponectin; Autoimmune Diseases; Biomarkers; Cells, Cultured; Dexamethasone; Drug Antagonism; Female; Glucocorticoids; Humans; Inflammation; Leptin; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Middle Aged; Molecular Weight; Prospective Studies; Resistin; Up-Regulation

We examined serum leptin levels in a controlled feeding and alcohol ingestion study to elucidate potential mechanisms by which alcohol may affect cancer and immunologically related health risks. A total of 53 healthy, nonsmoking postmenopausal women completed a random-order, three-period crossover design study in which each woman received zero (0 g of alcohol), one (15 g of alcohol), or two (30 g alcohol) drinks per day. After accounting for differences in body mass index, women who consumed 15 or 30 g of alcohol per day had 7.3% (95% confidence interval [CI] = 3.0% to 15.1%) and 8.9% (95% CI = 1.6% to 16.7%) higher serum leptin levels, respectively (P(trend) =.018), than women who consumed 0 g of alcohol per day. Younger women (i.e., 49-54 years) demonstrated a statistically significantly larger association of alcohol consumption level with the increase in serum leptin levels than older women (i.e., 55-79 years) (24.4%, 95% CI = 9.3% to 42.0% versus 3.7%, 95% CI = -4.1% to 12.1% increase in serum leptin levels for 30 g of alcohol per day relative to 0 g of alcohol per day for the lowest age quartile compared with the three highest age quartiles combined; P =.022). These results indicate that moderate alcohol consumption (15-30 g of alcohol per day) increases serum leptin levels in postmenopausal women and may predispose moderate drinkers to the morbidities associated with chronic elevations of this hormone including cancer.

Topics: Age Factors; Aged; Alcohol Drinking; Autoimmune Diseases; Cross-Over Studies; Female; Humans; Insulin; Leptin; Middle Aged; Neoplasms; Postmenopause; Risk Factors

The purpose of our study was tomeasure the level of leptin and biologically active leptin (bioLEP) in children with type 1 diabetes, depending on the duration of diabetes and its degree of metabolic control.. The study included 94 children (58 boys and 36 girls). In a group of children with diabetes, 40 patients were newly diagnosed with type 1 diabetes, 40 children who have diabetes for more than a year (20 with good metabolic control and 20 with poor metabolic control). The control group consisted of 14 healthy children. The serum level of leptin and bioLEP was measured using a sandwich enzyme-linked immunosorbent assay. To our knowledge, this is the first study to describe bioLEP levels among diabetic children with different forms of disease control.. Lower levels of leptin were found in children with diabetes compared to healthy children. Furthermore, we found a statistically higher concentration of leptin in the group of children with newly diagnosed diabetes compared to children from the diabetic group with poor metabolic control and lower than healthy children (11.19 vs. 7.84 and 20.94 ng/mL). Moreover, children in the metabolically well-controlled group had statistically lower levels of this hormone (5.11 ng/mL) than healthy children. Leptin concentrations differed significantly between underweight, overweight, and obese children.. In our study, the level of bioLEP differed significantly between children in the newly diagnosed diabetes group and children in the long-term, poorly controlled diabetes group and healthy controls. Despite many studies published in recent years, many aspects of leptin secretion, action, and mechanisms of its influence on carbohydrate and fat metabolism are still to be clarified. In our opinion, studies evaluating the status of bioLEP in diabetes can also contribute to a better understanding of the mechanisms regulating metabolism.

Topics: Autoimmune Diseases; Child; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Lipid Metabolism; Male; Pediatric Obesity

Leptin has been found to be involved in the development and progression of many autoimmune diseases. As an organ-specific autoimmune disease, the pathogenesis of Hashimoto's thyroiditis has not been fully elucidated. It has been reported that serum leptin level is increased in Hashimoto's thyroiditis, but other studies have not shown any difference. We replicated a mouse model of experimental autoimmune thyroiditis (EAT) with a high-iodine diet and found that injection of the leptin receptor antagonist Allo-aca reduced thyroid follicle destruction and inflammatory cell infiltration in EAT mice, and thyroxine and thyroid autoimmune antibody levels. Further investigation revealed that Allo-aca promotes the differentiation of Treg cells and inhibits the differentiation of Th17 cells. We believe that Allo-aca can alter the differentiation of Treg/Th17 cells by inhibiting the leptin signaling pathway, thereby alleviating thyroid injury in EAT mice. Interfering with the leptin signaling pathway may be a novel new approach to treat treating and ameliorating Hashimoto's thyroiditis.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Hashimoto Disease; Leptin; Mice; Receptors, Leptin; T-Lymphocytes, Regulatory; Th17 Cells; Thyroiditis, Autoimmune

Lipodystrophy syndromes are rare complex multisystem disorders caused by generalized or partial lack of adipose tissue. Adipose tissue dysfunction in lipodystrophy is associated with leptin deficiency. Lipodystrophy leads to severe metabolic problems. These abnormalities include, but are not limited to, insulin-resistant diabetes, severe hypertriglyceridemia, and lipid accumulation in ectopic organs such as the liver, and are associated with end-organ complications. Metabolic abnormalities can be present at the time of diagnosis or may develop over time as the disease progresses. In addition to metabolic abnormalities, subtype-specific presentations due to underlying molecular etiology in genetic forms and autoimmunity in acquired forms contribute to severe morbidity in lipodystrophy.

Topics: Autoimmune Diseases; Diabetes Mellitus; Heart Diseases; Humans; Hypertriglyceridemia; Insulin Resistance; Kidney Diseases; Leptin; Lipid Metabolism; Lipodystrophy; Liver; Metabolic Syndrome; Neuromuscular Diseases; Non-alcoholic Fatty Liver Disease; Pancreatitis; Syndrome

Topics: Animals; Autoimmune Diseases; Humans; Leptin; Rheumatic Diseases

Acquired generalized lipodystrophy (AGL) is associated with leptin deficiency as a result of adipose tissue loss and hypertriglyceridemia, insulin resistance, and hepatic steatosis. It may coexist with other autoimmune diseases such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic active hepatitis. Metreleptin therapy has been shown to improve metabolic abnormalities in lipodystrophy, but the effect on AGL patients with active autoimmune disease is unknown.. We report 3 cases of pediatric patients with AGL and distinct active autoimmune diseases who were treated with metreleptin over a period of 4-6 years. Case 1 is a 9-year-old girl with active juvenile dermatomyositis, who was successfully treated with leptin with no worsening of her dermatomoysitis. Case 2 is a 16-year-old female with Graves' disease, who could discontinue all her antidiabetic medication completely with improved triglyceride levels. Case 3 is an 11-year-old boy with active autoimmune hepatitis and chronic urticaria, whose hyperphagia has resolved and his liver enzymes and hepatosplenomegaly have improved.. Metreleptin therapy is of considerable clinical benefit to reduce insulin resistance and hypertriglyceridemia and did not appear to alter the clinical course of autoimmune disease nor clinical efficacy of immunosuppressive treatments. Our observations suggest that risk or presence of autoimmune disease should not lead to withholding of metreleptin treatment from patients with AGL, but should prompt close clinical follow up in light of cautionary preclinical data.

Topics: Adolescent; Autoimmune Diseases; Child; Compassionate Use Trials; Dermatomyositis; Female; Graves Disease; Hepatitis, Autoimmune; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Leptin; Lipodystrophy; Male; Severity of Illness Index; Treatment Outcome; Urticaria

Pemphigus is an autoimmune blistering disease mediated by autoantibodies directed against keratinocyte adhesion molecules. Leptin, an adipocyte-derived hormone, plays a role in immune responses and promotes autoimmunity.. This study was conducted to determine whether serum leptin levels are altered in pemphigus patients and whether there is any correlation between leptin levels and the severity of disease.. This study included 47 newly diagnosed patients with pemphigus and 43 age- and sex-matched healthy controls. Clinical characteristics and pemphigus area and activity score (PAAS) were assessed. Serum leptin levels (ng/mL) were measured by a commercial enzyme-linked immunosorbent assay (ELISA).. Patients did not differ significantly in serum leptin levels from healthy controls (median (range): 10.8 (0.1-110) ng/mL versus 12 (0.5-69.9) ng/mL and P = 0.53). There was no significant association between serum leptin concentrations and severity of disease measured by PAAS (r s = 0.06, P = 0.70).. The results suggest that pemphigus does not have a direct influence on serum leptin levels and the pathogenesis of pemphigus seems to be not dependent on the connection with adipose tissue.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Pemphigus; Severity of Illness Index; Young Adult

The relationship between metabolic abnormalities of trace elements and insulin resistance has been established. Recent studies have revealed that insulin resistance is associated with autoimmune responses. The purpose of this study was to examine the correlation between zinc or copper metabolism and insulin resistance in patients with primary biliary cirrhosis (PBC). Sixteen patients with PBC were divided into two groups: early and advanced stage disease. The overall value of the homeostasis model assessment of insulin resistance (HOMA-IR) in patients with advanced stage PBC was significantly higher than that in patients with early stage PBC, although the mean value in advanced stage PBC was significantly lower than that in hepatitis C virus (HCV)-related liver cirrhosis. There was an inverse correlation between serum zinc concentrations and HOMA-IR values in patients with PBC, while we found no correlation between serum copper levels and HOMA-IR values. HOMA-IR values were inversely associated with peripheral platelet counts, indicating the relationship between insulin resistance and hepatic fibrosis. These results suggest that zinc deficiency plays important roles of insulin resistance and subsequent hepatic fibrosis in patients with PBC, although insulin resistance in advanced stage PBC was significantly milder than that in HCV-related liver cirrhosis.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Biomarkers; Copper; Deuteroporphyrins; Disease Progression; Female; Hepatitis C, Chronic; Homeostasis; Humans; Imines; Insulin Resistance; Japan; Leptin; Liver; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Mitochondria, Liver; Platelet Count; Zinc

Serum leptin and adiponectin determinations have been proposed as markers for distinguishing pancreatic cancer and chronic pancreatitis from autoimmune pancreatitis; however, no studies exist in patients with autoimmune pancreatitis and in those with intraductal papillary mucinous tumors of the pancreas. The aim of this paper was to evaluate the circulating concentrations of receptor for advanced glycation end products (RAGE), leptin and adiponectin in patients with chronic pancreatic diseases.. Seventy-five consecutive patients with chronic pancreatic diseases (47 males, 28 females; mean age 67.0 +/- 13.2 years; range 37-97 years) were studied: six (8.0%) had autoimmune pancreatitis, 23 (30.7%) had chronic pancreatitis, 34 (45.3%) had pancreatic cancer and the remaining 12 (16.0%) had intraductal papillary mutinous tumors of the pancreas. Leptin, adiponectin and RAGE were determined in serum using commercially available kits. The leptin concentrations were normalized to the lower and upper reference limits because of the different gender reference ranges.. Normalized leptin concentrations were significantly lower in chronic pancreatitis patients (0.53 +/- 1.28; p = 0.008) and in those with pancreatic cancer (0.12 +/- 0.33; p < 0.001) compared to the overall population (0.58 +/- 1.23), whereas autoimmune pancreatitis patients had significantly higher concentrations of this protein (2.18 +/- 2.56; p = 0.004) compared to the overall population. RAGE and adiponectin concentrations were similar among the four groups of patients studied. Among the clinical variables considered, only pain was significantly related to leptin concentrations (patients with pain 0.18 +/- 0.54, patients without pain 1.07 +/- 1.64; p = 0.001).. Serum leptin seems to be a good serum marker for differentiating autoimmune pancreatitis patients from those with chronic pancreatitis and pancreatic cancer.

Topics: Adiponectin; Aged; Aged, 80 and over; Autoimmune Diseases; Biomarkers; Diagnosis, Differential; Female; Humans; Leptin; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis, Chronic; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Adipose tissue produces a wide range of proteins that may influence the immune system. In this study, we assessed the serum levels of leptin, adiponectin, and ghrelin, in association with the measurements of body composition, in 15 female patients with various autoimmune diseases (systemic lupus erythematosus, primary Sjögren's syndrome, sarcoidosis, mixed connective tissue disease, vasculitis, CREST syndrome, and polymyositis) and in 15 healthy female controls. There were no statistically significant differences between the patients and controls with regard to serum leptin, serum ghrelin, global fat mass, adiposity, and fat mass in the android or gynoid regions, whereas serum adiponectin levels were higher in patients than controls (16.3 ± 1.6 μg/mL versus 9.7 ± 0.6 μg/mL; P = .01). As adiponectin is known to exhibit potent anti-inflammatory properties, a high adiponectinemia in patients with systemic autoimmune disease may mitigate the inflammatory response. However, the precise consequences of these elevated serum adiponectin levels on the metabolic syndrome development and atherosclerotic cardiovascular risk in this patient population still needs to be determined.

Topics: Adiponectin; Adipose Tissue; Autoimmune Diseases; Body Mass Index; Female; Ghrelin; Humans; Insulin; Leptin

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoimmune Diseases; Humans; Leptin; T-Lymphocytes, Regulatory; Vasculitis

To study serum levels of leptin and ghrelin in ANCA-associated vasculitis (AAV).. Thirty-seven patients with AAV (21 patients with active AAV at initial presentation and during follow-up, 16 patients with AAV in long-term remission) and 21 matched healthy controls were included. Serum levels of leptin and ghrelin were measured at 0, 6 and 12 months by radioimmunoassay. Disease activity was gauged by Birmingham Vasculitis Activity Score (BVAS), CRP and circulating endothelial cells (CECs).. Leptin levels were significantly lower in patients than in healthy controls (9.1 +/- 6.1 vs 22.3 +/- 22.4 ng/ml; P < 0.05). The difference persisted when corrected for BMI. Leptin levels increased significantly after 6 (27.8 +/- 21.9 ng/ml; P < 0.001) and 12 months (24.6 +/- 21.0 ng/ml; P < 0.001). Ghrelin levels were significantly elevated in patients compared with controls (402.6 +/- 112.9 vs 294.8 +/- 70.9 pmol/l; P < 0.005) and declined to normal values at 12 months (306.4 +/- 36.2 pmol/l). There was a significant positive correlation between ghrelin levels and disease activity, whereas leptin levels were negatively correlated with disease activity (CRP, BVAS and CECs). Accordingly, correlations between the ghrelin/leptin ratio and markers of disease activity reached the highest level of significance (all P < 0.001).. Active AAV is characterized by decreased serum leptin and increased serum ghrelin, both of which return to normal with successful therapy. The role of leptin and ghrelin during the pathogenesis of AAV and the effects of these peptides on endothelial cells warrant further study.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Autoimmune Diseases; Biomarkers; Body Mass Index; Female; Follow-Up Studies; Ghrelin; Humans; Leptin; Male; Middle Aged; Severity of Illness Index; Vasculitis

Concanavalin A-induced hepatotoxicity was compared in lipodystrophic aP2-nSREBP-1c transgenic mice (LD mice) lacking adipose tissue, obese leptin-deficient ob/ob mice, and lean wild-type (WT) mice. Serum leptin and adiponectin were low in LD mice, whereas ob/ob mice had undetectable leptin, but high adiponectin. Protection from hepatotoxicity was observed in ob/ob, but not in LD mice, despite low cytokine levels and reduced T cell activation and hepatic natural killer T cells in both groups. Administration of adiponectin protected LD mice from hepatotoxicity without altering cytokine levels. In contrast, administration of leptin heightened disease susceptibility by restoring cytokine production. Neutralization of TNF alpha protected LD mice from liver damage. Increased in vivo susceptibility to the hepatotoxic effect of TNF alpha was observed in LD mice. In vitro, adiponectin protected primary hepatocytes from TNF alpha-induced death, whereas leptin had no protective effect. In conclusion, although leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation, adiponectin protects hepatocytes from TNF alpha-induced death.

Topics: Adiponectin; Animals; Apoptosis; Autoimmune Diseases; CCAAT-Enhancer-Binding Proteins; Concanavalin A; Cytokines; DNA-Binding Proteins; Hepatitis; In Situ Nick-End Labeling; Intercellular Signaling Peptides and Proteins; Killer Cells, Natural; Leptin; Lipodystrophy; Lymphocyte Activation; Mice; Mice, Obese; Mice, Transgenic; Obesity; Sterol Regulatory Element Binding Protein 1; T-Lymphocytes; Transcription Factors; Tumor Necrosis Factor-alpha

Leptin is an adipose tissue-derived hormone that signals nutritional status to the hypothalamus. Recent evidence indicates that leptin modifies proinflammatory immune responses and may provide a key link between nutritional deficiency and immune dysfunction. To study the influence of leptin deficiency on immune-mediated renal disease, susceptibility to accelerated nephrotoxic nephritis was examined in leptin-deficient C57BL/6-ob/ob mice and C57BL/6 wild-type controls. The model was induced with sheep anti-mouse glomerular basement membrane antibody injected to mice preimmunized against sheep IgG, and mice were sacrificed 8 days after induction of disease. The leptin-deficient ob/ob mice were strongly protected from glomerular crescent formation, macrophage infiltration, glomerular thrombosis, and albuminuria in this model. Our findings suggest that leptin is required for the induction and maintenance of immune-mediated glomerulonephritis, and that blockade of the leptin axis might provide an attractive therapeutic possibility in human autoimmune disease.

Topics: Animals; Antibody Formation; Autoimmune Diseases; Disease Susceptibility; Fluorescent Antibody Technique; Globulins; Immunoglobulin G; Kidney Glomerulus; Leptin; Male; Mice; Nephritis

The purpose of this study was to evaluate serum leptin levels in idiopathic thrombocytopenic purpura (ITP), in order to determine the influence of leptin on the pathogenesis of ITP.. Forty-six untreated patients with chronic ITP were compared with 40 healthy people of similar age, sex and body mass index (BMI). Serum leptin levels (ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA).. We found that the mean serum leptin levels in patients with ITP (22.11 +/- 15.84 ng/mL) were significantly (P < 0.001) higher than that in healthy control volunteers (5.44 +/- 4.84 ng/mL). Furthermore, serum leptin levels in patients with ITP were inversely related (r = -0.86, P < 0.001) to the platelet counts and positively related to the platelet-associated IgG (PAIgG) levels (r = 0.7, P < 0.001). The levels of PAIgG and platelet counts were significantly different between leptin-positive (level greater than mean +/- 2 SD control value) and leptin-negative patients.. These findings suggest that leptin might play an important role in the pathogenesis of ITP.

Topics: Adult; Antigens, Human Platelet; Autoantibodies; Autoimmune Diseases; Blood Platelets; Female; Humans; Immunoglobulin G; Leptin; Male; Middle Aged; Platelet Count; Purpura, Thrombocytopenic, Idiopathic

The proband, a 9-year-old Hispanic female, presented with hair loss, strabismus, and weight gain. On magnetic resonance imaging (MRI) she was found to have severe primary hypothyroidism and a large pituitary mass. In addition, acanthosis nigricans, obesity, and hyperinsulinism were observed. Findings were similar in three of four siblings. Thyroid peroxidase antibodies were detected in the father and three of four siblings. Although all family members were obese, and hyperinsulinemia with high proinsulin and C-peptide was found in all except one sibling, only the mother and one child had overt type 2 diabetes mellitus. Because of the unusual association of autoimmune thyroid disease, insulin resistance and obesity rather than insulin deficiency, we searched for possible genetic abnormalities. The HLA haplotypes did not cosegregate with autoimmune thyroid disease or insulin resistance. Mutational analysis of known obesity genes was done. Leptin was not deficient, and sequencing of the proband's DNA showed no mutations in the perixisome proliferator activated receptor (PPAR)-gamma, PPAR-gamma(2), PPAR-alpha or melanocortin 4 receptor genes. Maternally inherited diabetes and deafness was ruled out since no mutations were found in mitochondria DNA. Insulin receptor antibodies were not detected. In conclusion, the remarkably high incidence of childhood autoimmune hypothyroidism, pituitary enlargement, insulin resistance and obesity in this family is not linked to known HLA types or known gene defects.

Topics: Autoimmune Diseases; Child; Female; Hormones; Humans; Hypothyroidism; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Male; Obesity; Pedigree; Pituitary Diseases

Leptin has a the potent effect on T cell mediated intestinal autoimmunity and may have a role in the development of such diseases.

Topics: Animals; Autoimmune Diseases; Colitis; Humans; Immunity, Mucosal; Leptin; Mice; T-Lymphocytes

A recent study reports that the interleukin-2 deficient (IL-2(-/-)) mouse model of autoimmune and inflammatory bowel disease (IBD) with elevated pro-inflammatory cytokine production has elevated leptin concentrations during food deprivation. The objective of this study was to examine whether increased tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, contributes to the abnormally elevated leptin in IL-2(-/-) mice.. Eight week old, IL-2(-/-) and wild-type control (IL-2(+/+)), male mice were fed regular laboratory mouse food for two weeks. At the end of the study, blood was collected in the fed state, IL-2(-/-) and IL-2(+/+) mice were injected with either anti-TNF-alpha monoclonal antibody or normal saline, and blood was collected in the starved state.. The IL-2(-/-) mice consumed less food and lost weight. Administration of anti-TNF-alpha antibody markedly reduced serum leptin concentrations in IL-2(-/-) and control mice after food deprivation. Serum leptin in the IL-2(-/-) mice not receiving anti-TNF-alpha antibody increased significantly in the starved state. Serum concentrations of TNF-alpha were higher in IL-2(-/-) mice compared to controls in both the fed and starved state.. These results suggest that elevated TNF-alpha may be one mechanism for the sustained elevated leptin observed in IL-2(-/-) mice during food deprivation.

Topics: Animals; Antibodies, Monoclonal; Apolipoproteins; Autoimmune Diseases; Disease Models, Animal; Food Deprivation; Inflammatory Bowel Diseases; Interleukin-2; Leptin; Male; Mice; Mice, Inbred C57BL; Random Allocation; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha

The neuroendocrine and immune systems are linked through a complex bi-directional network, in which hormones modify immune function, and the immune system, through the action of cytokines, affects neuroendocrine responses involved in the maintenance of body homeostasis. The adipocyte-derived, peptide hormone leptin is a pleiotropic molecule belonging to the helical cytokine family. On pp. 182-187, Matarese et al. suggest the possibility of new leptin-based therapeutic strategies for the treatment of both infection and autoimmune disease.

Topics: Animals; Antibodies, Anti-Idiotypic; Autoimmune Diseases; Female; Leptin; Male; Mice; Neutralization Tests; Nutritional Status; Rats

The immune responses to many infections have long been known to share features with autoimmune responses. In particular, both types of response are typified by the enhanced reactivity of T helper 1 cells - with high levels of interleukin-2, interferon gamma and tumor necrosis factor alpha - and are accompanied often by organ-specific and/or systemic damage and the production of IgG. Paradoxically, the geographical distributions of incidence of infectious diseases and autoimmunity are complementary, rather than coincident. In less-developed societies, an epidemiological association between susceptibility to infection and malnutrition has been observed, whereas in affluent countries, an increased incidence of autoimmune diseases has been described. We suggest that these observations can be explained partly by taking into consideration the immune effects of the adipocyte-derived hormone leptin, which has been shown recently to act as a link between nutritional status and the immune response.

Topics: Adipose Tissue; Animals; Autoimmune Diseases; Autoimmunity; Disease Susceptibility; Female; Humans; Infections; Inflammation; Leptin; Male; Mice; Models, Immunological; Nutritional Status; Rats

Topics: Apoptosis; Autoimmune Diseases; Humans; Immunity, Cellular; Immunologic Memory; Leptin; Lymphocyte Count; Magnesium Deficiency; Nutrition Disorders; T-Lymphocytes; Thymus Gland

Leptin is an adipose tissue hormone whose plasma levels reflect energy stores. Although pathological thyroid function is related to changes in energy expenditure and body composition, its possible influence on leptin levels remains to be determined. The objective of the study was to provide new data on the relationship between plasma leptin levels and thyroid function. Sixteen patients with primary autoimmune hypothyroidism, and seventeen patients with primary autoimmune hyperthyroidism were prospectively studied from the time of clinical diagnosis and then every 6-8 weeks until thyroid function was completely restored (plasma tri-iodothyronine, free thyroxine and TSH within normal ranges). Fasting immunoreactive plasma leptin levels and body composition (bioelectrical impedance) were assessed at every visit. Plasma leptin levels were correlated with percentage body fat, as previously described, both at the time of diagnosis (r=0.60, P<0.001) and after normalisation of thyroid function (r=0.63, P< 0.001). There was no correlation between serum leptin and thyroid hormone levels at any time during the study. Plasma leptin levels as well as percentage body fat (BF) did not change significantly from the beginning until the end of the study, either in the hypothyroid (leptin: 14.54+/-2.61 vs 16.92+/-2.61 ng/ml, BF: 25.25+/-2.47 vs 25.90+/-3.22%) or in the hyperthyroid (leptin: 10.69+/-1.81 vs 12.36+/-2.19 ng/ml, BF: 22.01+/-2.31 vs 25.39+/-1.13%) group of patients. In conclusion, these results suggest that thyroid function per se is not a major determinant of plasma leptin levels.

Topics: Aged; Autoimmune Diseases; Body Mass Index; Female; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Male; Proteins; Regression Analysis; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine